FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Concheiro, M Jones, HE Johnson, RE Choo, R Huestis, MA AF Concheiro, M. Jones, H. E. Johnson, R. E. Choo, R. Huestis, M. A. TI Buprenorphine sublingual tablet pharmacokinetics in plasma, oral fluid and sweat during treatment of opioid-dependent pregnant SO THERAPEUTIC DRUG MONITORING LA English DT Meeting Abstract CT 12th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology CY OCT 02-06, 2011 CL Stuttgart, GERMANY DE buprenorphine; norbuprenorphine; oral fluid; plasma; sweat C1 [Concheiro, M.] Univ Santiago de Compostela, Inst Ciencias Forenses, Santiago De Compostela, Spain. [Jones, H. E.; Johnson, R. E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Choo, R.] Univ Pittsburgh, Dept Biol, Pittsburgh, PA USA. [Huestis, M. A.] Natl Inst Drug Abuse, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD AUG PY 2011 VL 33 IS 4 BP 492 EP 493 PG 2 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 792PY UT WOS:000292761500107 ER PT J AU Ellenstein, A Kranick, SM Hallett, M AF Ellenstein, Aviva Kranick, Sarah M. Hallett, Mark TI An Update on Psychogenic Movement Disorders SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Movement disorder; Psychogenic; Motor conversion; Somatoform disorder; Dissociative disorder; Functional disorder; Medically unexplained; Hysterical; Neurologic symptom; Diagnostic technique ID COGNITIVE-BEHAVIORAL THERAPY; MOTOR CONVERSION DISORDER; CLINICAL-TRIAL; DSM-V; PARALYSIS; PHENOMENOLOGY; SYMPTOMS; RECOVERY; STRESS; CORTEX AB Psychogenic movement disorders (PMD) and other conversion disorders (CD) with apparent neurologic signs (neurologic CD) plague patients and perplex physicians. Due to a lack of objective evidence of underlying brain lesions, CD were largely abandoned by neurologists and remained poorly understood psychiatric diagnoses throughout most of the 20th century. Modern neuroscience now supports increasingly comprehensive biological models for these complex disorders, definitively establishing their place in both neurology and psychiatry. Although it is often clinically useful to distinguish a movement disorder as either "organic" or "psychogenic," this dichotomy is difficult to defend scientifically. Here we describe the neuroimaging and neurophysiologic evidence for dysfunctional neural networks in PMD, explain the diagnostic potential of clinical neurophysiologic testing, discuss the promising if increasingly complex role of neuropsychiatric genetics, and review current treatment strategies. C1 [Ellenstein, Aviva; Kranick, Sarah M.; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Ellenstein, A (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 7D42,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM ellensteina@ninds.nih.gov; mattes1@ninds.nih.gov; hallettm@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002667-23] NR 50 TC 11 Z9 12 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD AUG PY 2011 VL 11 IS 4 BP 396 EP 403 DI 10.1007/s11910-011-0205-z PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 788RU UT WOS:000292462900006 PM 21559795 ER PT J AU Domanski, M Pocock, S Bernaud, C Borer, J Geller, N Revkin, J Zannad, F AF Domanski, Michael Pocock, Stuart Bernaud, Corine Borer, Jeffrey Geller, Nancy Revkin, James Zannad, Faiez TI Surrogate endpoints in randomized cardiovascular clinical trials SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Review DE randomized clinical trials; surrogate endpoints AB Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints. C1 [Domanski, Michael; Geller, Nancy] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Pocock, Stuart] London Sch Hyg & Trop Med, Med Stat Unit, London WC1, England. [Bernaud, Corine] AstraZeneca, Zaventem, Belgium. [Borer, Jeffrey] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Revkin, James] Pfizer, New York, NY USA. [Zannad, Faiez] Hop Jeanne Darc, FESC CIC INSERM CHU, F-54200 Toul, France. RP Domanski, M (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM domanskimj@mail.nih.gov NR 10 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0767-3981 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD AUG PY 2011 VL 25 IS 4 BP 411 EP 413 DI 10.1111/j.1472-8206.2010.00865.x PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 788NM UT WOS:000292451700001 PM 20698890 ER PT J AU Mabley, J Gordon, S Pacher, P AF Mabley, Jon Gordon, Sevelanne Pacher, Pal TI Nicotine Exerts an Anti-inflammatory Effect in a Murine Model of Acute Lung Injury SO INFLAMMATION LA English DT Article DE inflammation; nicotine; acetylcholine; lung; chemokine ID ACETYLCHOLINE-RECEPTOR ALPHA-7; RESPIRATORY-DISTRESS-SYNDROME; KAPPA-B; IN-VIVO; IMPROVES SURVIVAL; INFLAMMATION; ACTIVATION; PATHWAY; MICE; STIMULATION AB Activation of the cholinergic anti-inflammatory pathway through direct activation of nicotinic acetylcholine receptors on immune cells can inhibit pro-inflammatory chemokine and cytokine release and thereby protect in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against acute lung inflammation. Mice challenged with intratracheal lipopolysaccharide (LPS, 50 mu g) were treated with nicotine (0.2 or 0.4 mg/kg, sc). After 24 h, bronchoalveolar lavage fluid (BALF) was obtained to measure leukocyte infiltration, lung edema, and pro-inflammatory chemokine (MIP-1 alpha, MIP-2, and eotaxin) and cytokine (IL-1, IL-6, and TNF-alpha) levels. Nicotine treatment reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by decreased BALF inflammatory cells, myeloperoxidase, and protein. Nicotine also downregulated lung production of pro-inflammatory chemokines and cytokines. These data support the proposal that activation of the cholinergic anti-inflammatory pathway may represent a useful addition to the therapy of acute respiratory distress syndrome. C1 [Mabley, Jon; Gordon, Sevelanne] Univ Brighton, Sch Pharm & Biomol Sci, Brighton BN2 4GJ, E Sussex, England. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Mabley, J (reprint author), Univ Brighton, Sch Pharm & Biomol Sci, Cockcroft Bldg,Lewes Rd, Brighton BN2 4GJ, E Sussex, England. EM j.g.Mabley@brighton.ac.uk RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z01 AA000375-02, Z01 AA000375-03, Z99 AA999999, ZIA AA000375-04, ZIA AA000375-06] NR 41 TC 23 Z9 24 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 J9 INFLAMMATION JI Inflammation PD AUG PY 2011 VL 34 IS 4 BP 231 EP 237 DI 10.1007/s10753-010-9228-x PG 7 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 788LR UT WOS:000292446900002 PM 20625922 ER PT J AU Furu, K Karlstad, O Skurtveit, S Haberg, SE Nafstad, P London, SJ Nystad, W AF Furu, Kari Karlstad, Oystein Skurtveit, Svetlana Haberg, Siri E. Nafstad, Per London, Stephanie J. Nystad, Wenche TI High validity of mother-reported use of antiasthmatics among children: a comparison with a population-based prescription database SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Asthma; Children; Mother-reported; Pharmacoepidemiology; Prescription database; Validity ID ASTHMA SYMPTOMS; MEDICATION USE; QUESTIONNAIRE; DEFINITIONS; INFORMATION; AGREEMENT; RECALL; COHORT; ISAAC AB Objectives: To examine the validity of (1) maternal questionnaire report of children's use of antiasthmatics using a prescription database as the reference standard and (2) dispensed antiasthmatics as a measure of asthma using maternal report of children's asthma as the reference standard. Study Design and Setting: A total of 3,394 children in the Norwegian Mother and Child Cohort Study aged 7 years were linked to the Norwegian Prescription Database. Maternal report of both children's use of antiasthmatics during the preceding year and the presence of asthma was compared with data on dispensed antiasthmatics. Results: A total of 2,056 mothers responded and reported use of antiasthmatics during the previous year in 125 of 147 children who had been dispensed antiasthmatics (sensitivity 85.0%). Of the 1,909 children with no dispensed antiasthmatics, 1,848 had no maternal report of antiasthmatic use (specificity 96.8%). Mothers reported current asthma in 133 (6.5% of 2,056) children, including in 122(5.9%) reported as verified by a doctor. Of these 122, 98 had been dispensed antiasthmatics during the preceding year (sensitivity 80.3%). Only 12% of the children without reported asthma were dispensed antiasthmatics. Conclusion: Mother-reported use of antiasthmatics during the previous year among 7-year-old children is highly valid. Dispensed antiasthmatics would be a useful proxy for the presence of current asthma when disease data are not available. C) 2011 Elsevier Inc. All rights reserved. C1 [Furu, Kari; Karlstad, Oystein; Skurtveit, Svetlana; Haberg, Siri E.; Nafstad, Per; Nystad, Wenche] Norwegian Inst Publ Hlth, Div Epidemiol, N-0403 Oslo, Norway. [Furu, Kari] Univ Tromso, Dept Pharm, Tromso, Norway. [Nafstad, Per] Univ Oslo, Inst Hlth & Soc, Oslo, Norway. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Furu, K (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, POB 4404, N-0403 Oslo, Norway. EM kari.furu@fhi.no OI London, Stephanie/0000-0003-4911-5290; Karlstad, Oystein/0000-0003-1204-787X FU Norwegian Ministry of Health, National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS) [ES-044008]; NIH/National Institute of Neurological Disorders and Stroke [UO1 NS 047537-01]; Norwegian Research Council (NRC) [151918/S10, 175314]; NIEHS, NIH, Department of Health and Human Services FX The MoBa is supported by the Norwegian Ministry of Health, National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS) (contract no. ES-044008), NIH/National Institute of Neurological Disorders and Stroke (grant no. UO1 NS 047537-01), and the Norwegian Research Council (NRC)/Functional genomics (FUGE) (grant no. 151918/S10). Dr London is supported by the Intramural Research Program, NIEHS, NIH, Department of Health and Human Services. Ph D student Karlstad is supported by the NRC (grant no. 175314). NR 22 TC 24 Z9 24 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 2011 VL 64 IS 8 BP 878 EP 884 DI 10.1016/j.jclinepi.2010.10.014 PG 7 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 787YU UT WOS:000292413400009 PM 21232920 ER PT J AU Berry, SH Elliott, MN Suttorp, M Bogart, LM Stoto, MA Eggers, P Nyberg, L Clemens, JQ AF Berry, Sandra H. Elliott, Marc N. Suttorp, Marika Bogart, Laura M. Stoto, Michael A. Eggers, Paul Nyberg, Leroy Clemens, J. Quentin TI Prevalence of Symptoms of Bladder Pain Syndrome/Interstitial Cystitis Among Adult Females in the United States SO JOURNAL OF UROLOGY LA English DT Article DE cystitis, interstitial; cross-sectional studies; prevalence; urinary bladder ID MANAGED CARE POPULATION; INTERSTITIAL CYSTITIS; NONRESPONSE RATES; WOMEN; BIAS AB Purpose: Bladder pain syndrome/interstitial cystitis is a poorly understood condition that can cause serious disability. We provide the first population based symptom prevalence estimate to our knowledge among United States adult females. Materials and Methods: We developed and validated 2 case definitions to identify bladder pain syndrome/interstitial cystitis symptoms. Beginning in August 2007 we telephoned United States households, seeking adult women with bladder symptoms or a bladder pain syndrome/interstitial cystitis diagnosis. Second stage screening identified those subjects who met case definition criteria. Each completed a 60-minute interview on the severity and impact of bladder symptoms, health care seeking and demographics. Data collection ended in April 2009. Using population and nonresponse weights we calculated prevalence estimates based on definitions spanning a range of sensitivity and specificity. We used United States Census counts to estimate the number of affected women in 2006. The random sample included 146,231 households, of which 131,691 included an adult female. Of these households 32,474 reported an adult female with bladder symptoms or diagnosis, of which 12,752 completed the questionnaire. Results: Based on the high sensitivity definition 6.53% (95% CI 6.28, 6.79) of women met symptom criteria. Based on the high specificity definition 2.70% (95% CI 2.53, 2.86) of women met the criteria. These percentages translated into 3.3 to 7.9 million United States women 18 years old or older with bladder pain syndrome/ interstitial cystitis symptoms. Symptom severity and impact were comparable to those of adult women with established diagnoses. However, only 9.7% of the women reported being assigned a bladder pain syndrome/interstitial cystitis diagnosis. Conclusions: Bladder pain syndrome/interstitial cystitis symptoms are widespread among United States women and associated with considerable disability. These results suggest bladder pain syndrome/interstitial cystitis may be underdiagnosed. C1 [Berry, Sandra H.; Elliott, Marc N.; Suttorp, Marika; Bogart, Laura M.] RAND Corp, Santa Monica, CA 90407 USA. [Bogart, Laura M.] Childrens Hosp, Boston, MA 02115 USA. [Stoto, Michael A.] Georgetown Univ, Washington, DC USA. [Eggers, Paul; Nyberg, Leroy] NIDDK, Bethesda, MD USA. [Clemens, J. Quentin] Univ Michigan, Ann Arbor, MI 48109 USA. [Clemens, J. Quentin] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Berry, SH (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90407 USA. EM berry@rand.org FU National Institute of Diabetes and Digestive and Kidney Disorders [U01DK070234-01] FX Supported by Cooperative Agreement U01DK070234-01 from the National Institute of Diabetes and Digestive and Kidney Disorders. National Institute of Diabetes and Digestive and Kidney Disorders staff participated in study design and analysis. Research protocol approved by the Human Subjects Protection Committee (FWA00003425). The authors vouch for the accuracy and completeness of the reported findings. NR 14 TC 115 Z9 118 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2011 VL 186 IS 2 BP 540 EP 544 DI 10.1016/j.juro.2011.03.132 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 789VJ UT WOS:000292545100059 PM 21683389 ER PT J AU Markland, AD Richter, HE Fwu, CW Eggers, P Kusek, JW AF Markland, Alayne D. Richter, Holly E. Fwu, Chyng-Wen Eggers, Paul Kusek, John W. TI Prevalence and Trends of Urinary Incontinence in Adults in the United States, 2001 to 2008 SO JOURNAL OF UROLOGY LA English DT Article DE urinary incontinence; risk factors; epidemiology; female; male ID NUTRITION EXAMINATION SURVEY; TRACT SYMPTOMS; RISK-FACTORS; NATIONAL-HEALTH; OBESE WOMEN; WEIGHT-LOSS; POPULATION; PREDICTORS; SURGERY; COHORT AB Purpose: We estimate trends in the prevalence of urinary incontinence in the adult population of the United States from 2001 through 2008 before and after adjusting for other potential associated factors. Materials and Methods: We analyzed data on 17,850 adults 20 years old or older who participated in the 2001 to 2008 cycles of the National Health and Nutrition Examination Survey. Any urinary incontinence was defined as a positive response to questions on urine leakage during physical activity, before reaching the toilet and during nonphysical activity. During this period changes in demographic and clinical factors associated with urinary incontinence included age, race/ethnicity, obesity, diabetes and chronic medical conditions (prostate disease in men). Age standardized prevalence estimates and prevalence ORs of urinary incontinence trends were determined using adjusted multivariate models with appropriate sampling weights. Results: The age standardized prevalence of urinary incontinence in the combined surveys was 51.1% in women and 13.9% in men. Prevalence in women increased from 49.5% in 2001 to 2002, to 53.4% in 2007 to 2008 (P(trend) = 0.01) and in men from 11.5% to 15.1%, respectively (P(trend) = 0.01). In women increased prevalence was partially explained by differences in age, race/ethnicity, obesity, diabetes and select chronic diseases across the survey periods. After adjustment the prevalence OR for 2007 to 2008 vs 2001 to 2002 decreased from 1.22 (95% CI 1.03-1.45) to 1.16 (95% CI 0.99-1.37). In men adjustment for potentially associated factors did not explain the increasing prevalence of urinary incontinence. Conclusions: The age standardized prevalence of urinary incontinence increased in men and women from 2001 through 2008. Decreasing obesity and diabetes may lessen the burden of urinary incontinence, especially in women. C1 [Richter, Holly E.] Univ Alabama, Dept Obstet & Gynecol, Div Womans Pelv Med & Reconstruct Surg, Birmingham, AL 35249 USA. [Markland, Alayne D.] Univ Alabama, Dept Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL 35249 USA. [Markland, Alayne D.] Univ Alabama, Dept Med, Div Gerontol Geriatr & Palliat Care, Birmingham, AL 35249 USA. [Fwu, Chyng-Wen] Social & Sci Syst Inc, Silver Spring, MD USA. [Eggers, Paul; Kusek, John W.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Richter, HE (reprint author), Univ Alabama, Dept Obstet & Gynecol, Div Womans Pelv Med & Reconstruct Surg, Birmingham, AL 35249 USA. EM hrichter@uabmc.edu FU NIDDK NIH HHS [K24 DK068389] NR 29 TC 59 Z9 63 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2011 VL 186 IS 2 BP 589 EP 593 DI 10.1016/j.juro.2011.03.114 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 789VJ UT WOS:000292545100080 PM 21684555 ER PT J AU Nager, CW Sirls, L Litman, HJ Richter, H Nygaard, I Chai, T Kraus, S Zyczynski, H Kenton, K Huang, LY Kusek, J Lemack, G AF Nager, Charles W. Sirls, Larry Litman, Heather J. Richter, Holly Nygaard, Ingrid Chai, Toby Kraus, Stephen Zyczynski, Halina Kenton, Kim Huang, Liyuan Kusek, John Lemack, Gary CA Urinary Incontinence Treatment Net TI Baseline Urodynamic Predictors of Treatment Failure 1 Year After Mid Urethral Sling Surgery SO JOURNAL OF UROLOGY LA English DT Article DE urinary incontinence; stress; urodynamics; surgical procedures; operative ID FREE VAGINAL TAPE; STRESS URINARY-INCONTINENCE; INTRINSIC SPHINCTER DEFICIENCY; TRANSOBTURATOR TAPE; MIDURETHRAL SLINGS; RANDOMIZED-TRIAL; PRESSURE-FLOW; WOMEN AB Purpose: We determined whether baseline urodynamic study variables predict failure after mid urethral sling surgery. Materials and Methods: Preoperative urodynamic study variables and postoperative continence status were analyzed in women participating in a randomized trial comparing retropubic to transobturator mid urethral sling. Objective failure was defined by positive standardized stress test, 15 ml or greater on 24-hour pad test, or re-treatment for stress urinary incontinence. Subjective failure criteria were self-reported stress symptoms, leakage on 3-day diary or re-treatment for stress urinary incontinence. Logistic regression was used to assess associations between covariates and failure controlling for treatment group and clinical variables. Receiver operator curves were constructed for relationships between objective failure and measures of urethral function. Results: Objective continence outcomes were available at 12 months for 565 of 597 (95%) women. Treatment failed in 260 women (245 by subjective criteria, 124 by objective criteria). No urodynamic variable was significantly associated with subjective failure on multivariate analysis. Valsalva leak point pressure, maximum urethral closure pressure and urodynamic stress incontinence were the only urodynamic variables consistently associated with objective failure on multivariate analysis. No specific cut point was determined for predicting failure for Valsalva leak point pressure or maximum urethral closure pressure by ROC. The lowest quartile (Valsalva leak point pressure less than 86 cm H(2)O, maximum urethral closure pressure less than 45 cm H(2)O) conferred an almost 2-fold increased odds of objective failure regardless of sling route (OR 2.23, 1.20-4.14 for Valsalva leak point pressure and OR 1.88, 1.04-3.41 for maximum urethral closure pressure). Conclusions: Women with a Valsalva leak point pressure or maximum urethral closure pressure in the lowest quartile are nearly 2-fold more likely to experience stress urinary incontinence 1 year after transobturator or retropubic mid urethral sling. C1 [Nager, Charles W.] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92103 USA. [Sirls, Larry] William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. [Litman, Heather J.; Huang, Liyuan] New England Res Inst, Watertown, MA 02172 USA. [Richter, Holly] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Nygaard, Ingrid] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Chai, Toby] Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. [Kusek, John] NIDDKD, NIH, Bethesda, MD 20892 USA. [Kraus, Stephen] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Lemack, Gary] Univ Texas SW, Dept Urol, Dallas, TX USA. [Zyczynski, Halina] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Kenton, Kim] Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Maywood, IL 60153 USA. RP Nager, CW (reprint author), 9350 Campus Point Dr,Suite 2A,Mailcode 0974, La Jolla, CA 92037 USA. EM cnager@ucsd.edu OI Wadie, Bassem/0000-0002-6977-6849 FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases FX The Urinary Incontinence Treatment Network was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (see Appendix). NR 25 TC 48 Z9 49 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2011 VL 186 IS 2 BP 597 EP 603 DI 10.1016/j.juro.2011.03.105 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 789VJ UT WOS:000292545100082 PM 21683412 ER PT J AU Denton, PW Othieno, F Martinez-Torres, F Zou, W Krisko, JF Fleming, E Zein, S Powell, DA Wahl, A Kwak, YT Welch, BD Kay, MS Payne, DA Gallay, P Appella, E Estes, JD Lu, M Garcia, JV AF Denton, Paul W. Othieno, Florence Martinez-Torres, Francisco Zou, Wei Krisko, John F. Fleming, Elisa Zein, Sima Powell, Daniel A. Wahl, Angela Kwak, Youn Tae Welch, Brett D. Kay, Michael S. Payne, Deborah A. Gallay, Philippe Appella, Ettore Estes, Jacob D. Lu, Min Garcia, J. Victor TI One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; PHASE-III TRIAL; SHIV TRANSMISSION; IMMUNE-RESPONSES; REFERENCE VALUES; DOUBLE-BLIND; PREVENTION; INHIBITOR AB Recent iPrEx clinical trial results provided evidence that systemic preexposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) can partially prevent rectal HIV transmission in humans. Similarly, we have previously demonstrated that systemic administration of the same FTC-TDF combination efficiently prevented rectal transmission in humanized bone marrow/liver/thymus (BLT) mice. The CAPRISA 004 trial recently demonstrated that topical application of the tenofovir could partially prevent vaginal HIV-1 transmission in humans. To further validate the usefulness of the BLT mouse model for testing HIV prevention strategies, we evaluated the topical administration of tenofovir as used in CAPRISA 004 to prevent vaginal HIV transmission in BLT mice. Our results demonstrate that vaginally administered 1% tenofovir significantly reduced HIV transmission in BLT mice (P = 0.002). Together with the results obtained after systemic antiretroviral PrEP, these topical inhibitor data serve to validate the use of humanized BLT mice to evaluate both systemic and topical inhibitors of HIV transmission. Based on these observations, we tested six additional microbicide candidates for their ability to prevent vaginal HIV transmission: a C-peptide fusion inhibitor (C52L), a membrane-disrupting amphipathic peptide inhibitor (C5A), a trimeric D-peptide fusion inhibitor (PIE12-Trimer), a combination of reverse transcriptase inhibitors (FTC-TDF), a thioester zinc finger inhibitor (TC247), and a small-molecule Rac inhibitor (NSC23766). No protection was seen with the Rac inhibitor NSC23766. The thioester compound TC247 offered partial protection. Significant protection was afforded by FTC-TDF, and complete protection was offered by three different peptide inhibitors tested. Our results demonstrate that these effective topical inhibitors have excellent potential to prevent vaginal HIV transmission in humans. C1 [Denton, Paul W.; Martinez-Torres, Francisco; Zou, Wei; Krisko, John F.; Wahl, Angela; Garcia, J. Victor] Univ N Carolina, Ctr AIDS Res, Dept Internal Med, Div Infect Dis, Chapel Hill, NC 27510 USA. [Othieno, Florence; Fleming, Elisa; Zein, Sima; Powell, Daniel A.; Kwak, Youn Tae] Univ Texas SW Med Ctr Dallas, Div Infect Dis, Dallas, TX 75390 USA. [Welch, Brett D.; Kay, Michael S.] Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA. [Payne, Deborah A.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Gallay, Philippe] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Appella, Ettore] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Estes, Jacob D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Lu, Min] Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA. RP Garcia, JV (reprint author), Univ N Carolina, Sch Med, UNC Ctr AIDS Res, Div Infect Dis, Genet Med Bldg 2044, Chapel Hill, NC 27599 USA. EM victor_garcia@med.unc.edu OI Denton, Paul/0000-0003-2458-8147 FU National Institutes of Health [AI073146, AI071940, AI082637, AI078791, AI079782, AI68591, AI076168, 5T32AI005284]; National Cancer Institute, National Institutes of Health [HHSN266200400088C]; UNC Center for AIDS Research [P30 AI50410]; American Foundation for AIDS Research (amfAR) [107752-44-RFRL] FX This work was supported in part with federal funds from National Institutes of Health grants AI073146 (J.V.G.), AI071940 (J.V.G.), AI082637 (J.V.G.), AI078791 (P.G.), AI079782 (P.G.), AI68591 (M.L.), AI076168 (M.S.K.), and 5T32AI005284 (J.F.K.), the National Cancer Institute, National Institutes of Health, under contract HHSN266200400088C (J.D.E.), and the UNC Center for AIDS Research Grant P30 AI50410. This work was supported in part by fellowship number 107752-44-RFRL from the American Foundation for AIDS Research (amfAR) (P.W.D.). NR 57 TC 83 Z9 84 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2011 VL 85 IS 15 BP 7582 EP 7593 DI 10.1128/JVI.00537-11 PG 12 WC Virology SC Virology GA 788LV UT WOS:000292447300012 PM 21593172 ER PT J AU Rockx, B Brining, D Kramer, J Callison, J Ebihara, H Mansfield, K Feldmann, H AF Rockx, Barry Brining, Douglas Kramer, Joshua Callison, Julie Ebihara, Hideki Mansfield, Keith Feldmann, Heinz TI Clinical Outcome of Henipavirus Infection in Hamsters Is Determined by the Route and Dose of Infection SO JOURNAL OF VIROLOGY LA English DT Article ID HENDRA VIRUS-INFECTION; RESPIRATORY SYNDROME CORONAVIRUS; TO-PERSON TRANSMISSION; NIPAH VIRUS; RISK-FACTORS; FATAL ENCEPHALITIS; DISTRESS-SYNDROME; MOUSE MODEL; OUTBREAK; PARAMYXOVIRUS AB Nipah virus (NiV) and Hendra virus (HeV) are emerging zoonotic viruses and the causative agents of severe respiratory disease and encephalitis in humans. Little is known about the mechanisms that govern the development of respiratory and neurological disease. Using a hamster model of lethal NiV and HeV infection, we describe the role of the route and dose of infection on the clinical outcome and determine virus tropism and host responses following infection. Infection of hamster with a high dose of NiV or HeV resulted in acute respiratory distress. NiV initially replicated in the upper respiratory tract epithelium, whereas HeV initiated infection primarily in the interstitium. In contrast, infection with a low dose of NiV or HeV resulted in the development of neurological signs and more systemic spread of the virus through involvement of the endothelium. The development of neurological signs coincided with disruption of the blood-brain barrier (BBB) and expression of tumor necrosis alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta). In addition, interferon-inducible protein 10 (IP-10) was identified as playing an important role in NiV and HeV pathogenesis. These studies reveal novel information on the development and progression of NiV and HeV clinical disease, provide a mechanism for the differences in transmission observed between NiV and HeV outbreaks, and identify specific cytokines and chemokines that serve as important targets for treatment. C1 [Rockx, Barry] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Rockx, Barry] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Rockx, Barry; Callison, Julie; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Brining, Douglas] NIAID, Div Intramural Res, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Kramer, Joshua; Mansfield, Keith] Harvard Univ, Sch Med, Southborough, MA 01772 USA. RP Rockx, B (reprint author), Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. EM barry.rockx@utmb.edu FU Division of Intramural Research (DIR), NIAID, NIH FX This study was financially supported by the Division of Intramural Research (DIR), NIAID, NIH. NR 38 TC 50 Z9 50 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2011 VL 85 IS 15 BP 7658 EP 7671 DI 10.1128/JVI.00473-11 PG 14 WC Virology SC Virology GA 788LV UT WOS:000292447300019 PM 21593160 ER PT J AU McLellan, JS Yang, YP Graham, BS Kwong, PD AF McLellan, Jason S. Yang, Yongping Graham, Barney S. Kwong, Peter D. TI Structure of Respiratory Syncytial Virus Fusion Glycoprotein in the Postfusion Conformation Reveals Preservation of Neutralizing Epitopes SO JOURNAL OF VIROLOGY LA English DT Article ID F-PROTEIN; MONOCLONAL-ANTIBODIES; MEMBRANE-FUSION; ELECTRON-MICROSCOPY; CRYSTAL-STRUCTURE; HIV-1 GP41; VACCINE; DISEASE; HEMAGGLUTININ; INFECTION AB Respiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies, such as 101F, palivizumab, and motavizumab, target two major antigenic sites on the RSV F glycoprotein. The structures of these sites as peptide complexes with motavizumab and 101F have been previously determined, but a structure for the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here, we present the 2.8-angstrom crystal structure of the trimeric RSV F ectodomain in its postfusion conformation. The structure revealed that the 101F and motavizumab epitopes are present in the postfusion state and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the postfusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and motavizumab can bind to multiple conformations of the fusion glycoprotein and can neutralize late in the entry process. The structural preservation of neutralizing epitopes in the postfusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen. C1 [McLellan, Jason S.; Yang, Yongping; Graham, Barney S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP McLellan, JS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Rm 2613B, Bethesda, MD 20892 USA. EM mclellanja@mail.nih.gov RI McLellan, Jason/A-6874-2010 FU National Institute of Allergy and Infectious Diseases; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX Support for this work was provided by the Intramural Research Program (National Institute of Allergy and Infectious Diseases). Use of sector 22 (SER-CAT) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. NR 47 TC 127 Z9 133 U1 24 U2 38 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2011 VL 85 IS 15 BP 7788 EP 7796 DI 10.1128/JVI.00555-11 PG 9 WC Virology SC Virology GA 788LV UT WOS:000292447300030 PM 21613394 ER PT J AU Parks, CG DeRoo, LA Miller, DB McCanlies, EC Cawthon, RM Sandler, DP AF Parks, C. G. DeRoo, L. A. Miller, D. B. McCanlies, E. C. Cawthon, R. M. Sandler, D. P. TI Employment and work schedule are related to telomere length in women SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; LIFE-STYLE; CIGARETTE-SMOKING; PERCEIVED STRESS; HEALTH BEHAVIORS; LONG WORKHOURS; OVERTIME WORK; MORTALITY; ASSOCIATION; RECOVERY AB Objectives To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status. Methods This cross-sectional analysis of 608 women aged 35-74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones. oResults Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of -329 bp (95% CI -110 to -548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of -472 bp, 95% CI -786 to -158 for 20+ vs 1-5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels. Conclusions Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL. C1 [Parks, C. G.; DeRoo, L. A.; Sandler, D. P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27599 USA. [Miller, D. B.] NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. [McCanlies, E. C.] NIOSH, Biostat & Epidemiol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. [Cawthon, R. M.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, NIH, A3-05,POB 12233, Res Triangle Pk, NC 27599 USA. EM parks1@mail.nih.gov RI Miller, Diane/O-2927-2013; OI Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences [Z01 ES044005]; Department of Defense [BC045286] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044005), and by Department of Defense Breast Cancer Research Concept Award (BC045286). NR 39 TC 19 Z9 19 U1 1 U2 13 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 2011 VL 68 IS 8 BP 582 EP 589 DI 10.1136/oem.2010.063214 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 788MT UT WOS:000292449800006 PM 21540175 ER PT J AU Xu, Y Deng, Z O'hUigin, C Wang, D Gao, S Zeng, J Yang, B Jin, S Zou, H AF Xu, Y. Deng, Z. O'hUigin, C. Wang, D. Gao, S. Zeng, J. Yang, B. Jin, S. Zou, H. TI Characterization and polymorphic analysis of 4.5 kb genomic full-length HLA-C in the Chinese Han population SO TISSUE ANTIGENS LA English DT Article DE evolution; genomic full-length; high-fidelity polymerase chain reaction amplification; human leukocyte antigen C; single-nucleotide polymorphisms ID MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; MESSENGER-RNA; MARROW-TRANSPLANTATION; SURFACE EXPRESSION; UNRELATED DONOR; ALPHA-3 DOMAIN; HEAVY-CHAIN; RECOGNITION; BINDING AB This study used long-range polymerase chain reaction to sequence 4.5 or 4.3 kb of genomic DNA covering human leukocyte antigen C (HLA-C) and its flanks in 45 Chinese Han subjects to better characterize variation in the gene in a single population. Sequences of 35 HLA-C alleles were obtained from the population, including major alleles of 13 lineages of HLA-C. Four novel alleles, C*03:04:01:02, C*04:01:01:03, C*08:22, and C*17:01:01:02, were identified, and complete full-length sequences of 18 HLA-C alleles were obtained for the first time. All sequences herein reported also represent extensions through the promoter region and the 3'-untranslated region. Fourteen 5'-nucleotide sequences and 14 3'-nucleotide sequences were detected outside the coding region. In total, 316 single-nucleotide polymorphisms unequally distributed in HLA-C subregions were observed. In addition to exons 2 and 3, nucleotide variability was found to be particularly high in exon 5, which encodes the transmembrane region. The differentiation of the C*07 and C*17 lineages in this region accounts for the high variability. The congruence of phylogeny across most regions of the gene suggests that gene conversion or recombination has not markedly influenced divergence between lineages in the evolution of HLA-C. C1 [Xu, Y.; Deng, Z.; Wang, D.; Gao, S.; Zeng, J.; Yang, B.; Jin, S.; Zou, H.] Shenzhen Blood Ctr, Immunogenet Lab, Shenzhen 518035, Guangdong, Peoples R China. [O'hUigin, C.] NCI, Genet Core Canc & Inflammat Program, SAIC Frederick, Frederick, MD 21702 USA. RP Deng, Z (reprint author), Shenzhen Blood Ctr, Immunogenet Lab, Shenzhen 518035, Guangdong, Peoples R China. EM zhihui_deng@yahoo.com.cn; ohuiginc@mail.nih.gov FU Guangdong Science and Technology Department [2008B030301277]; Guangdong Natural Science Fund [9451803501004124]; National Cancer Institute, National Institutes of Health, Frederick, MD, USA; [HHSN261200800001E] FX Sample preparation, sequencing analysis, and all experimental work were conducted at the Shenzhen Blood Center, Shenzhen, Guangdong, China, which was supported by the Research Fund of Guangdong Science and Technology Department (Project No. 2008B030301277) and the Guangdong Natural Science Fund (Project No. 9451803501004124). Additional phylogenetic analysis was conducted by Dr CO, who was supported by the National Cancer Institute, National Institutes of Health, Frederick, MD, USA, with federal funds under HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 41 TC 5 Z9 6 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 AUG PY 2011 VL 78 IS 2 BP 102 EP 114 DI 10.1111/j.1399-0039.2011.01710.x PG 13 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 788NC UT WOS:000292450700005 PM 21658009 ER PT J AU Li, L Ding, YY Wu, ZY Rotheram-Borus, MJ Guo, S AF Li, Li Ding, Ying Ying Wu, Zunyou Rotheram-Borus, Mary Jane Guo, Sam CA NIMH Collaborative HIV STD TI Normative Beliefs and Sexual Risk in China SO AIDS AND BEHAVIOR LA English DT Article DE China; Normative beliefs; Sexually transmitted infection; Gender roles ID HIV PREVENTION INTERVENTIONS; TRANSMITTED-DISEASES; SERVICE PROVIDERS; EXTRAMARITAL SEX; HIDDEN EPIDEMIC; MARKET VENDORS; EASTERN CHINA; SOCIAL NORMS; CONDOM USE; AT-RISK AB We examined normative beliefs about multiple sexual partners and social status in China and their association with risky sexual behaviors and sexually transmitted infections (STIs). Self-reported and biological markers of sexual risk were examined among 3,716 market vendors from a city in eastern China. Men who were older or with less education believed having multiple sexual partners was linked to higher social status. Adjusting for demographic characteristics, normative beliefs were significantly associated with having multiple sexual partners, while having multiple sexual partners was significantly associated with STIs. Normative beliefs regarding sexual behaviors may play an important role in individual risk behaviors. Future HIV/STI interventions must address community beliefs about the positive meaning of sexual risks, particularly among men with traditional beliefs about gender roles. C1 [Li, Li; Ding, Ying Ying; Rotheram-Borus, Mary Jane; Guo, Sam] Univ Calif Los Angeles, Ctr Community Hlth, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Wu, Zunyou] China CDC, Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. [Wu, Zunyou] NIMH, NIMH Collaborat HIV STD Prevent Trial Grp, Bethesda, MD 20892 USA. RP Li, L (reprint author), Univ Calif Los Angeles, Ctr Community Hlth, Semel Inst Neurosci & Human Behav, 10920 Wilshire Blvd,Suite 350, Los Angeles, CA 90024 USA. EM lililili@ucla.edu FU NIAID NIH HHS [AI067854]; NIMH NIH HHS [U10 MH061513, P30 MH058107] NR 56 TC 4 Z9 4 U1 2 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD AUG PY 2011 VL 15 IS 6 BP 1251 EP 1258 DI 10.1007/s10461-010-9835-4 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 785YF UT WOS:000292268400018 PM 20960047 ER PT J AU Napoli, N Pedone, C Pozzilli, P Lauretani, F Bandinelli, S Ferrucci, L Incalzi, RA AF Napoli, Nicola Pedone, Claudio Pozzilli, Paolo Lauretani, Fulvio Bandinelli, Stefania Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Effect of ghrelin on bone mass density: The In Chianti study SO BONE LA English DT Article DE Ghrelin; Bone mass; pQCT; Aged, 65 years and older; Cross-sectional studies ID SYMPATHETIC-NERVOUS-SYSTEM; MINERAL DENSITY; POSTMENOPAUSAL WOMEN; SERUM LEPTIN; FAT MASS; PLASMA GHRELIN; BODY-MASS; ADIPONECTIN; OBESITY; TURNOVER AB Introduction: Ghrelin is a stomach secreted hormone, believed to play an important role in energy balance and in food intake. Experimental studies have shown a positive effect of ghrelin on bone metabolism, but both in vivo and clinical findings have been contradictory. We aimed to investigate the effect of ghrelin on volumetric BMD in a large cohort of elderly subjects. Methods: We have studied 401 women (mean age 75.1 years, range 65-94) and 306 men (mean age 73.9 years, range 65-94) from the InChianti study, which included measurements of BMD using quantitative CT of the tibia and of body composition using bio impedancemetry. Serum ghrelin was measured using ELISA. We excluded participants with diabetes, hyperthyroidism, using hormone replacement or glucocorticoid therapy. We evaluated the correlation of ghrelin with total, trabecular, and cortical BMD using Pearson's coefficient, and linear regression models to estimate the association between ghrelin and BMD controlling for potential confounders. Results: In women, after correction for potential confounders, ghrelin was associated with trabecular BMD (beta = 7.08, P < 0.02), but not with total or cortical BMD. In men, adjusted multivariable models showed a nearly significant association between serum ghrelin and trabecular BMD (beta = 4.99, P = 0.069) and no association with either cortical or total BMD. Conclusions: Serum ghrelin is positively correlated with trabecular BMD in a cohort of elderly healthy Italian women. The fact that trabecular is more metabolically active than cortical bone and the larger number of females might explain this selective association. (C) 2011 Elsevier Inc. All rights reserved. C1 [Pedone, Claudio; Incalzi, Raffaele Antonelli] Univ Campus Biomed Roma, Ctr Salute Anziano, Area Geriatria, I-00128 Rome, Italy. [Napoli, Nicola; Pozzilli, Paolo] Univ Campus Biomed Roma, Div Endocrinol & Diabet, I-00128 Rome, Italy. [Napoli, Nicola] Washington Univ, Div Bone & Mineral Dis, St Louis, MO USA. [Lauretani, Fulvio] Univ Hosp Pamm, Geriatr Rehabil Dept, Geriatr Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Pamm, Geriatr Rehabil Dept, Lab Movement Anal, Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Incalzi, Raffaele Antonelli] Fdn San Raffaele, Cittadella Della Carita, Taranto, Italy. RP Pedone, C (reprint author), Univ Campus Biomed Roma, Ctr Salute Anziano, Area Geriatria, Via Alvaro del Portillo 21, I-00128 Rome, Italy. EM c.pedone@unicampus.it RI Antonelli Incalzi, Raffaele/G-3978-2012; Lauretani, Fulvio/K-5115-2016; OI Antonelli Incalzi, Raffaele/0000-0003-2100-2075; Napoli, Nicola/0000-0002-3091-8205; Pedone, Claudio/0000-0003-1847-9032; Lauretani, Fulvio/0000-0002-5287-9972; Pozzilli, Paolo/0000-0001-5090-636X FU Intramural NIH HHS [ZIA AG001050-09] NR 37 TC 17 Z9 17 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD AUG PY 2011 VL 49 IS 2 BP 257 EP 263 DI 10.1016/j.bone.2011.03.772 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 787EC UT WOS:000292358400013 PM 21501701 ER PT J AU Goor, RM Neall, LF Hoffman, D Sherry, ST AF Goor, Robert M. Neall, Lisa Forman Hoffman, Douglas Sherry, Stephen T. TI A Mathematical Approach to the Analysis of Multiplex DNA Profiles SO BULLETIN OF MATHEMATICAL BIOLOGY LA English DT Article DE DNA; STR; Multiplex; Electrophoresis; Cubic spline; Inner product; Norm; Gaussian; OSIRIS; Forensics; Profile; Biomedical ID CAPILLARY-ELECTROPHORESIS AB Multiplex DNA profiles are used extensively for biomedical and forensic purposes. However, while DNA profile data generation is automated, human analysis of those data is not, and the need for speed combined with accuracy demands a computer-automated approach to sample interpretation and quality assessment. In this paper, we describe an integrated mathematical approach to modeling the data and extracting the relevant information, while rejecting noise and sample artifacts. We conclude with examples showing the effectiveness of our algorithms. C1 [Goor, Robert M.; Neall, Lisa Forman; Hoffman, Douglas; Sherry, Stephen T.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Goor, RM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM goorrob@mail.nih.gov FU NIH, National Library of Medicine FX We wish to thank Masato Kimura for many valuable discussions. We also wish to thank John Spouge for his help with the mathematical modeling of the electrophoresis process. This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 12 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0092-8240 J9 B MATH BIOL JI Bull. Math. Biol. PD AUG PY 2011 VL 73 IS 8 BP 1909 EP 1931 DI 10.1007/s11538-010-9598-0 PG 23 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 784MB UT WOS:000292160300010 PM 21103945 ER PT J AU Sales, JD Lara, FA Amadeu, TP Fulco, TD Nery, JAD Sampaio, EP Pinheiro, RO Sarno, EN AF de Souza Sales, J. Lara, F. A. Amadeu, T. P. de Oliveira Fulco, T. da Costa Nery, J. A. Sampaio, E. P. Pinheiro, R. O. Sarno, E. N. TI The role of indoleamine 2, 3-dioxygenase in lepromatous leprosy immunosuppression SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE IDO; IFN-gamma; lepromatous leprosy; monocytes; Mycobacterium leprae ID NECROSIS-FACTOR-ALPHA; ERYTHEMA-NODOSUM LEPROSUM; REACTIVE T-CELLS; INTERFERON-GAMMA; DENDRITIC CELLS; 2,3-DIOXYGENASE ACTIVITY; TRYPTOPHAN CATABOLISM; INTRADERMAL INJECTION; CYTOKINE PRODUCTION; SKIN-LESIONS AB To elucidate further the possible role of the tryptophan, rate-limiting enzyme indoleamine 2, 3-dioxygenase (IDO) in leprosy, the distribution of IDO-positive cells and IDO activity in the skin biopsies and sera of these patients representing the entire spectrum of the disease were studied. An increased number of macrophages/dendritic cells (DC-lineage IDO(+) cells were found in lepromatous (LL) compared to tuberculoid (BT) and reversal reaction (RR) patients. IDO-positive cells showing CD68 and CD86 surface markers predominated in LL lesions, while higher levels of IDO activity were observed in the sera of LL versus BT patients. Tests revealed an increased IDO message in Mycobacterium leprae-stimulated peripheral blood mononuclear cells (PBMC) by real-time polymerase chain reaction (PCR) and increased IDO expression in M. leprae-stimulated CD14(+) cells of both healthy controls (HC) and LL patients, as evaluated via flow cytometry. Increased M. leprae-induced IDO-protein synthesis was also confirmed by Western blot. Based on our in vitro studies, it was confirmed that M. leprae up-regulated IDO expression and activity in HC and LL monocytes. Interferon (IFN)-gamma synergized with M. leprae in promoting IDO expression and activity in monocytes. IDO expression induced by both IFN-gamma and M. leprae was abrogated by 1-methyltryptophan (1-MT). Our data suggest that M. leprae chronic infection activates the suppressive molecule IDO which, in turn, contributes to the specific immunosuppression observed in LL leprosy. C1 [de Souza Sales, J.; Amadeu, T. P.; de Oliveira Fulco, T.; da Costa Nery, J. A.; Sampaio, E. P.; Pinheiro, R. O.; Sarno, E. N.] Fiocruz MS, Oswaldo Cruz Fdn, Leprosy Lab, BR-21040900 Rio De Janeiro, Brazil. [Lara, F. A.] Fiocruz MS, Cellular Microbiol Lab, Leprosy Lab, BR-21040900 Rio De Janeiro, Brazil. [Sampaio, E. P.] NIH, Lab Clin Infect Dis, Ctr Clin, Bethesda, MD 20892 USA. RP Sarno, EN (reprint author), Fiocruz MS, Oswaldo Cruz Fdn, Leprosy Lab, Av Brasil 4365, BR-21040900 Rio De Janeiro, Brazil. EM euzenir@ioc.fiocruz.br RI Amadeu, Thais/C-2152-2013; Lara, Flavio/L-1861-2013 FU National Institutes of Health FX We would especially like to thank Helen Ferreira for her excellent technical assistance, Dr Paulo Redner, Dr Daniel Serra de Carvalho, Ariane Leite de Oliveira, and Danielle Fonseca de Moura for their insightful discussion of the manuscript and Judy Grevan for editing the text. This study was partially supported by National Institutes of Health. NR 59 TC 14 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD AUG PY 2011 VL 165 IS 2 BP 251 EP 263 DI 10.1111/j.1365-2249.2011.04412.x PG 13 WC Immunology SC Immunology GA 786WI UT WOS:000292338200013 ER PT J AU Wang, F Niu, G Chen, XY Cao, F AF Wang, Fu Niu, Gang Chen, Xiaoyuan Cao, Feng TI Molecular imaging of microRNAs SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Review DE MicroRNA; Molecular imaging; Reporter gene ID GENE-EXPRESSION; IN-VIVO; LIVING CELLS; POSTTRANSCRIPTIONAL REGULATION; TRANSGENE EXPRESSION; ENDOGENOUS MICRORNA; RNA DETECTION; CANCER; IDENTIFICATION; BIOGENESIS AB MicroRNAs (miRNAs) are a novel class of small noncoding RNAs that regulate gene expression by targeting mRNAs for either cleavage or translational repression. They have been shown to play important roles in a broad range of biological processes including development, cellular differentiation, proliferation and apoptosis. Conventional detection methods, such as northern blot, real-time PCR or microarray, have been used to assess miRNA expression. However, these techniques require the fixation or lysis of cells, and thus cannot be used to study the dynamic function of miRNAs in living cells. Recent remarkable advances in molecular imaging techniques have provided the capability of noninvasive repeated quantitative imaging of tumour or stem cells in living animals. The current brief discussion focuses on the reporter and fluorescent beacon imaging approaches to visualize miRNA expression in living subjects. C1 [Wang, Fu; Cao, Feng] Fourth Mil Med Univ, Dept Cardiol, Xijing Hosp, Xian 710032, Peoples R China. [Wang, Fu] Xidian Univ, Life Sci Res Ctr, Sch Life Sci & Technol, Xian 710071, Peoples R China. [Niu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Cao, F (reprint author), Fourth Mil Med Univ, Dept Cardiol, Xijing Hosp, Xian 710032, Peoples R China. EM shawn.chen@nih.gov; wind8828@gmail.com RI Life, MC/M-9554-2013; OI Wang, Fu/0000-0001-9222-0833 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; National Basic Research and Development Program of China (973) [2006CB705700, 2011CB707702]; National Natural Science Foundation of China [81090272, 81090274, 81000632, 30900334, 30970845]; Fundamental Research Funds for the Central Universities [JY10000910002] FX This work was supported in part by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, the National Basic Research and Development Program of China (973) under grant nos. 2006CB705700 and 2011CB707702, the National Natural Science Foundation of China under grant nos. 81090272, 81090274, 81000632, 30900334 and 30970845, and the Fundamental Research Funds for the Central Universities under grant no. JY10000910002. NR 54 TC 24 Z9 25 U1 6 U2 44 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD AUG PY 2011 VL 38 IS 8 BP 1572 EP 1579 DI 10.1007/s00259-011-1786-0 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 785ZV UT WOS:000292272700019 PM 21448701 ER PT J AU Hoffer, BJ AF Hoffer, Barry J. TI Commentary on chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Merja H. Voutilainen et al. SO EXPERIMENTAL NEUROLOGY LA English DT Editorial Material ID MIDBRAIN DOPAMINERGIC-NEURONS; NERVE GROWTH-FACTOR; NEUROTROPHIC FACTOR GDNF; IN-VIVO; INDUCED DEGENERATION; LIGAND FAMILY; GENE-TRANSFER; LESION MODEL; BRAIN; 6-HYDROXYDOPAMINE C1 NIDA, Intramural Res Program, Bethesda, MD USA. RP Hoffer, BJ (reprint author), NIDA, Intramural Res Program, Bethesda, MD USA. EM bhoffer@intra.nida.nih.gov FU NINDS NIH HHS [R01 NS070825] NR 69 TC 1 Z9 2 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2011 VL 230 IS 2 BP 162 EP 166 DI 10.1016/j.expneurol.2011.04.015 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 783CF UT WOS:000292058400002 PM 21554875 ER PT J AU Chou, JY Mansfield, BC AF Chou, Janice Y. Mansfield, Brian C. TI Recombinant AAV-directed gene therapy for type I glycogen storage diseases SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE AAV; endoplasmic reticulum; gene therapy; glucose homeostasis; glucose-6-phosphatase; glucose-6-phosphate transporter; glycogen storage disease; hepatic gene delivery ID ADENOASSOCIATED VIRUS VECTORS; NONHUMAN PRIMATE LIVER; HIGHLY EFFICIENT TRANSDUCTION; COLONY-STIMULATING FACTOR; RATE-LIMITING STEP; T-CELL RESPONSES; GLUCOSE-6-PHOSPHATE TRANSPORTER; VIRAL VECTORS; IMMUNE-RESPONSES; CANINE MODEL AB Introduction: Glycogen storage disease (GSD) type Ia and Ib are disorders of impaired glucose homeostasis affecting the liver and kidney. GSD-Ib also affects neutrophils. Current dietary therapies cannot prevent long-term complications. In animal studies, recombinant adeno-associated virus (rAAV) vector-mediated gene therapy can correct or minimize multiple aspects of the disorders, offering hope for human gene therapy. Areas covered: A summary of recent progress in rAAV-mediated gene therapy for GSD-I; strategies to improve rAAV-mediated gene delivery, transduction efficiency and immune avoidance; and vector refinements that improve expression. Expert opinion: rAAV-mediated gene delivery to the liver can restore glucose homeostasis in preclinical models of GSD-I, but some long-term complications of the liver and kidney remain. Gene therapy for GSD-Ib is less advanced than for GSD-Ia and only transient correction of myeloid dysfunction has been achieved. A question remains as to whether a single rAAV vector can meet the expression efficiency and tropism required to treat all aspects of GSD-I, or if a multi-pronged approach is needed. An understanding of the strengths and weaknesses of rAAV vectors in the context of strategies to achieve efficient transduction of the liver, kidney and hematopoietic stem cells is required for treating GSD-I. C1 [Chou, Janice Y.; Mansfield, Brian C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Mansfield, Brian C.] Correlog Syst Inc, Germantown, MD 20876 USA. RP Chou, JY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bldg 10,Room 9D42, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov OI Mansfield, Brian/0000-0002-8533-2789 FU Eunice Kennedy Shriver National Institute Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute Institute of Child Health and Human Development, National Institutes of Health. NR 109 TC 7 Z9 9 U1 0 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD AUG PY 2011 VL 11 IS 8 BP 1011 EP 1024 DI 10.1517/14712598.2011.578067 PG 14 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 785CG UT WOS:000292204400004 PM 21504389 ER PT J AU Freedman, ND Murray, LJ Kamangar, F Abnet, CC Cook, MB Nyren, O Ye, WM Wu, AH Bernstein, L Brown, LM Ward, MH Pandeya, N Green, AC Casson, AG Giffen, C Risch, HA Gammon, MD Chow, WH Vaughan, TL Corley, DA Whiteman, DC AF Freedman, Neal D. Murray, Liam J. Kamangar, Farin Abnet, Christian C. Cook, Michael B. Nyren, Olof Ye, Weimin Wu, Anna H. Bernstein, Leslie Brown, Linda M. Ward, Mary H. Pandeya, Nirmala Green, Adele C. Casson, Alan G. Giffen, Carol Risch, Harvey A. Gammon, Marilie D. Chow, Wong-Ho Vaughan, Thomas L. Corley, Douglas A. Whiteman, David C. TI Alcohol intake and risk of oesophageal adenocarcinoma: a pooled analysis from the BEACON Consortium SO GUT LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GASTRIC CARDIA CARCINOMAS; ESOPHAGOGASTRIC JUNCTION; CANCER INCIDENCE; UNITED-STATES; TOBACCO; SMOKING; OBESITY; METAANALYSIS; CONSUMPTION AB Background and aims Alcohol intake is a strong and well established risk factor for oesophageal squamous cell carcinoma (OSCC), but the association with oesophageal adenocarcinoma (OA) or adjacent tumours of the oesophagogastric junction (OGJA), remains unclear. Therefore, the association of alcohol intake with OSCC, OA, and OGJA was determined in nine case-control studies and two cohort studies of the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium (BEACON). Materials and methods Information was collected on alcohol intake, age, sex, education, body mass index, gastro-oesophageal reflux, and tobacco smoking from each study. Along with 10 854 controls, 1821 OA, and 1837 OGJA, seven studies also collected OSCC cases (n=1016). Study specific ORs and 95% CIs were calculated from multivariate adjusted logistic regression models for alcohol intake in categories compared to non-drinkers. Summary risk estimates were obtained by random effects models. Results No increase was observed in the risk of OA or OGJA for increasing levels of any of the alcohol intake measures examined. ORs for the highest frequency category (>= 7 drinks per day) were 0.97 (95% CI 0.68 to 1.36) for OA and 0.77 (95% CI=0.54 to 1.10) for OGJA. Suggestive findings linked moderate intake (eg, 0.5 to <1 drink per day) to decreased risk of OA (OR 0.63, 95% CI 0.41 to 0.99) and OGJA (OR 0.78, 95% CI 0.62 to 0.99). In contrast, alcohol intake was strongly associated with increased risk of OSCC (OR for >= 7 drinks per day 9.62, 95% CI 4.26 to 21.71). Conclusions In contrast to OSCC, higher alcohol consumption was not associated with increased risk of either OA or OGJA. The apparent inverse association observed with moderate alcohol intake should be evaluated in future prospective studies. C1 [Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS,Nutr Epidemiol Branch, Rockville, MD 20852 USA. [Murray, Liam J.] Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Nyren, Olof; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Wu, Anna H.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Brown, Linda M.] RTI Int, Rockville, MD USA. [Pandeya, Nirmala; Green, Adele C.; Whiteman, David C.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Giffen, Carol] Informat Management Serv Inc, Bethesda, MD USA. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Corley, Douglas A.] Northern Calif, Div Res, Oakland, CA USA. [Corley, Douglas A.] Northern Calif, Oakland Med Ctr, Oakland, CA USA. RP Freedman, ND (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS,Nutr Epidemiol Branch, 6120 Executive Blvd,EPS 320,MSC 7232, Rockville, MD 20852 USA. EM freedmanne@mail.nih.gov RI Cook, Michael/A-5641-2009; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Whiteman, David/P-2728-2014; Green, Adele/P-2736-2014; Pandeya, Nirmala/F-8054-2010 OI Cook, Michael/0000-0002-0533-7302; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Whiteman, David/0000-0003-2563-9559; Green, Adele/0000-0002-2753-4841; Pandeya, Nirmala/0000-0003-1462-4968 FU National Institutes of Health [R01 DK063616, R21DKO77742]; California Tobacco Related Research Program [3RT-0122, 10RT-0251]; National Cancer Institute [CA59636]; Nova Scotia Health Research Foundation [N419]; Ireland-Northern Ireland Co-operation Research Project; Northern Ireland Research & Development Office; Health Research Board, Ireland; Queensland Cancer Fund; National Health and Medical Research Council (NHMRC) of Australia [199600]; [R01-CA30022]; [R37-CA41530]; [U01-CA57949]; [U01-CA57983]; [U01-CA57923]; [R01 CA57947-03] FX This work was supported in part by the Intramural Program of the National Institutes of Health. The Population Health Study was funded by the Intramural Program of the National Institutes of Health. The Larynx, Oesophagus, and Oral Cavity (LEO) Study was funded by grants R01-CA30022 and R37-CA41530 (both awarded to TLV, David Thomas, Scott Davis, Bonnie Worthington Roberts, Ruth Little, and Mary Rogers). The US Multi-Center Study was funded by grants U01-CA57949 (awarded to TLV), U01-CA57983 (awarded to MDG), and U01-CA57923 (awarded to HAR). The Swedish Esophageal Cancer Study was funded by grant number R01 CA57947-03 (awarded to ON and Hans-Olov Adami). The Los Angeles County Multi-ethnic Case-control Study was funded by grants 3RT-0122 ('Smoking and Risk of Proximal vs Distal Gastric Cancer', awarded to AHW) and 10RT-0251 ('Smoking, microsatellite instability & gastric cancers', awarded to AHW) from the California Tobacco Related Research Program and grant CA59636 (awarded to LB) from the National Cancer Institute. The Nebraska Health Study was funded by the Intramural Program of the National Institutes of Health. The Nova Scotia Barrett Oesophagus Study was supported by the Nova Scotia Health Research Foundation ('Molecular mechanisms and lifestyle risk factor interactions in the pathogenesis of human esophageal adenocarcinoma', N419, awarded to AGC). The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study was funded by an Ireland-Northern Ireland Co-operation Research Project Grant sponsored by the Northern Ireland Research & Development Office, and the Health Research Board, Ireland (All-Ireland case-control study of Oesophageal Adenocarcinoma and Barrett's Oesophagus, awarded to LJM and Harry Comber). The Australian Cancer Study was supported by the Queensland Cancer Fund and the National Health and Medical Research Council (NHMRC) of Australia (Program no. 199600, awarded to DCW, ACG, Nicholas K Hayward, Peter G Parsons, David M Purdie, and Penelope M Webb). NIH-AARP was funded by the Intramural Program of the National Institutes of Health. Reported analyses with the Kaiser-Permanente Multiphasic Health check-up Study were funded by NIH grant number R01 DK063616 (Epidemiology and Incidence of Barrett's Oesophagus, Kaiser Permanente, awarded to DAC) and NIH grant R21DK077742 (Barrett's Oesophagus: Risk Factors in Women, awarded to DAC and Nicholas J Shaheen). NR 31 TC 44 Z9 44 U1 0 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD AUG PY 2011 VL 60 IS 8 BP 1029 EP 1037 DI 10.1136/gut.2010.233866 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 786OQ UT WOS:000292318200004 PM 21406386 ER PT J AU Chen, X Oppenheim, JJ AF Chen, Xin Oppenheim, Joost J. TI The phenotypic and functional consequences of tumour necrosis factor receptor type 2 expression on CD4(+) FoxP3(+) regulatory T cells SO IMMUNOLOGY LA English DT Review DE CD4(+) FoxP3(+) regulatory T cells; CD4(+) FoxP3(-) effector T cells; immunological phenotype; immunosuppression; tumour necrosis factor receptor 2 ID TNF-ALPHA THERAPY; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; PERIPHERAL-BLOOD; DENDRITIC CELLS; INDUCTION; SUPPRESSION; TOLERANCE; MECHANISM; P75 AB Cytokine receptors expressed by CD4(+) FoxP3(+) regulatory T cells (Treg cells) not only serve as a phenotypic marker for the identification of this important population of immunosuppressive cells, they also promote the function of Treg cells. CD25, the alpha-chain of interleukin-2 receptor, is a prototype of such a receptor, which enables Treg cells to be activated by interleukin-2. We and others have found that tumour necrosis factor receptor type 2 (TNFR2) is another important cytokine receptor preferentially expressed by Treg cells with important phenotypic and functional roles. TNFR2 is preferentially expressed by highly functional human and mouse Treg cells, and mediates the activating effect of TNF on Treg cells. We review here the studies of the regulation of expression of TNFR2 on functional Treg cells as well as on CD4(+) FoxP3(-) effector T cells (Teff cells). We document the critical role of this receptor in the activation, proliferative expansion and survival of Treg cells. The contribution of TNFR2 expression on Treg and Teff cells to the beneficial and detrimental effects of anti-TNF treatment in autoimmune disorders will also be discussed. C1 [Chen, Xin] NCI, BSP, SAIC Frederick Inc, Lab Mol Immunoregulat,Canc Inflammat Program,Ctr, Frederick, MD 21702 USA. RP Chen, X (reprint author), NCI, BSP, SAIC Frederick Inc, Lab Mol Immunoregulat,Canc Inflammat Program,Ctr, POB B,Bldg 560,Rm 31-19, Frederick, MD 21702 USA. EM chenxin@mail.nih.gov; oppenhej@mail.nih.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 53 TC 23 Z9 26 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 2011 VL 133 IS 4 BP 426 EP 433 DI 10.1111/j.1365-2567.2011.03460.x PG 8 WC Immunology SC Immunology GA 786TZ UT WOS:000292332100004 PM 21631498 ER PT J AU Tooley, PW Browning, M Leighty, RM AF Tooley, Paul W. Browning, Marsha Leighty, Robert M. TI Infectivity and Sporulation of Phytophthora ramorum on Northern Red Oak and Chestnut Oak SO JOURNAL OF PHYTOPATHOLOGY LA English DT Article DE ramorum blight; chlamydospore; epidemiology ID FOREST; SUSCEPTIBILITY; CALIFORNIA; DEATH; RHODODENDRON; PATHOGEN; INOCULUM AB We evaluated the effect of moisture period on foliar disease development by Phytophthora ramorum on 2- to 3-year-old northern red oak (Quercus rubra) and chestnut oak (Q. prinus). We also determined the propensity of P. ramorum to form sporangia and chlamydospores on these two host species. Leaves were dip-inoculated with ca. 5000 sporangia/ml of P. ramorum isolate Pr-6 and incubated at 100% relative humidity in dew chambers in darkness for up to 6 days. Several plants were removed each day to a greenhouse, and foliar infection was evaluated on day 7. Sporangia were collected over a 7-day period from diseased foliage in a mist tent. A significant relationship between moisture period and disease incidence was found for both tree species. Chestnut oak exhibited significantly greater disease incidence and severity compared with northern red oak. However, sporulation levels were larger in northern red oak over the 7-day period of sporangia collection, and northern red oak also produced significantly greater numbers of sporangia per square centimetre of lesion area compared with chestnut oak. Chlamydospore production in diseased leaves sampled 1 month following moist incubation was also significantly greater for northern red oak compared with chestnut oak. Knowledge of P. ramorum sporulation capacity in relation to disease incidence and severity on Eastern US oak species will help determine the potential for epidemic development should the pathogen become established in this region. C1 [Tooley, Paul W.; Browning, Marsha] USDA ARS, Foreign Dis Weed Sci Res Unit, Ft Detrick, MD 21702 USA. [Leighty, Robert M.] NCI, Data Management Serv, Frederick, MD 21702 USA. RP Tooley, PW (reprint author), USDA ARS, Foreign Dis Weed Sci Res Unit, 1301 Ditto Ave, Ft Detrick, MD 21702 USA. EM paul.tooley@ars.usda.gov NR 26 TC 1 Z9 1 U1 1 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0931-1785 J9 J PHYTOPATHOL JI J. Phytopathol. PD AUG PY 2011 VL 159 IS 7-8 BP 516 EP 521 DI 10.1111/j.1439-0434.2011.01797.x PG 6 WC Plant Sciences SC Plant Sciences GA 786XG UT WOS:000292340600008 ER PT J AU Zhang, F Niu, G Lu, GM Chen, XY AF Zhang, Fan Niu, Gang Lu, Guangming Chen, Xiaoyuan TI Preclinical Lymphatic Imaging SO MOLECULAR IMAGING AND BIOLOGY LA English DT Review DE Lymphatic imaging; Lymphangiography; Contrast agent; Molecular imaging ID POSITRON-EMISSION-TOMOGRAPHY; INTERSTITIAL MR-LYMPHOGRAPHY; MAGNETIC RESONANCE LYMPHANGIOGRAPHY; SUPERPARAMAGNETIC IRON-OXIDE; SOLID LIPID NANOPARTICLES; PROMOTES TUMOR-METASTASIS; REPORTER GENE-EXPRESSION; DUAL-MODALITY PET/CT; CELL LUNG-CANCER; GROWTH FACTOR-C AB Noninvasive in vivo imaging of lymphatic vessels and lymphatic nodes is expected to fulfill the purpose of analyzing lymphatic vessels and their function, understanding molecular mechanisms of lymphangiogenesis and lymphatic spread of tumors, and utilizing lymphatic molecular markers as a prognostic or diagnostic indicator. In this review, we provide a comprehensive summary of in vivo imaging modalities for detecting lymphatic vessels, lymphatic drainage, and lymphatic nodes, which include conventional lymphatic imaging techniques such as dyes and radionuclide scintigraphy as well as novel techniques for lymphatic imaging such as optical imaging, computed tomography, magnetic resonance imaging, ultrasound, positron emission tomography using lymphatic biomarkers, photoacoustic imaging, and combinations of multiple modalities. The field of lymphatic imaging is ever evolving, and technological advances, combined with the development of new contrast agents, continue to improve the research of lymphatic vascular system in health and disease states as well as to improve the accuracy of diagnosis in the relevant diseases. C1 [Zhang, Fan; Niu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Zhang, Fan; Lu, Guangming] Nanjing Univ, Coll Med, Sch Clin, Nanjing Jinling Hosp,Dept Radiol, Nanjing 210002, Peoples R China. [Niu, Gang] Ctr Clin, Imaging Sci Training Program, Bethesda, MD 20892 USA. RP Niu, G (reprint author), NIBIB, LOMIN, NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM niug@mail.nih.gov; shawn.chen@nih.gov RI liang, xue/F-9088-2011 FU National Natural Science Foundation of China (NSFC) [30930028]; 973 grants, China [CB705707]; Radiology and Imaging Sciences Department, NIH Clinical Center; NIBIB, NIH FX F. Zhang and G. Lu are supported by the National Natural Science Foundation of China (NSFC grant No. 30930028) and 973 grants (2006, CB705707, China). G. Niu 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. This research was supported by the Intramural Research Program of the NIBIB, NIH. We acknowledge Dr. Henry S. Eden for critically reading this manuscript. NR 164 TC 19 Z9 20 U1 2 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD AUG PY 2011 VL 13 IS 4 BP 599 EP 612 DI 10.1007/s11307-010-0421-y PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 786LN UT WOS:000292310000001 PM 20862613 ER PT J AU Zhang, F Xie, J Liu, G He, YL Lu, GM Chen, XY AF Zhang, Fan Xie, Jin Liu, Gang He, Yulong Lu, Guangming Chen, Xiaoyuan TI In Vivo MRI Tracking of Cell Invasion and Migration in a Rat Glioma Model SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Superparamagnetic iron oxide (SPIO) nanoparticles; Cell trafficking; Glioma; Magnetic resonance imaging (MRI); Tumor invasion and migration ID MESENCHYMAL STEM-CELLS; BRAIN; TRAFFICKING; MICE; MECHANISMS; EMISSION; SURVIVAL; PROTEIN; CANCER; TUMORS AB Malignant brain tumors are characterized by extensive infiltration into the normal brain tissue. Tumor migration is a complicated process which results from the interplay of a number of mechanisms, and the extent to which anatomic structure determined the migration pattern has not been extensively addressed. In the present study, we labeled C6 glioma cells with iron oxide nanoparticles and monitored the fate of the cells in vivo with magnetic resonance imaging (MRI). C6 glioma cells were labeled with ferumoxide-poly-l-lysine complexes and their migration in the brains of rats tracked by T2-weighted MRI. The same amount of iron-laden cells were implanted into the caudate nucleus (CN) and at the vicinity of anterior commissure (AC), respectively, and MRI was performed during the course of 20-day monitoring period to track tumor growth and migration. A clear tendency of tumor migration along the white matter fiber tracts was observed in the AC group, which is consistent with the previous reports; by contrast, tumor expanded to but remained confined within the boundary of right hemisphere in the CN group. We successfully demonstrated the ability of MRI to investigate the impact of anatomical structure on the glioma migration pathway in vivo. C1 [Zhang, Fan; Lu, Guangming] Nanjing Univ, Coll Med, Sch Clin, Nanjing Jinling Hosp,Dept Radiol, Nanjing 210002, Peoples R China. [Zhang, Fan; Xie, Jin; Liu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [He, Yulong] Nanjing Univ, Sch Med, Model Anim Res Ctr, Nanjing 210061, Peoples R China. RP Lu, GM (reprint author), Nanjing Univ, Coll Med, Sch Clin, Nanjing Jinling Hosp,Dept Radiol, Nanjing 210002, Peoples R China. EM cjr.luguangming@vip.163.com; shawn.chen@nih.gov RI liang, xue/F-9088-2011; Xie, Jin/E-8193-2010; OI Liu, Gang/0000-0002-9475-5134; HE, YULONG/0000-0002-0099-3749 FU 973 grants, China [CB705707]; National Natural Science Foundation, China [30930028]; NIBIB, NIH FX F Zhang, Y He, and G Lu are partially supported by 973 grants (2006, CB705707, China) and National Natural Science Foundation (30930028, China). F Zhang, J Xie, G Liu, and X Chen are supported by the Intramural Research Program (IRP) at NIBIB, NIH. NR 23 TC 14 Z9 16 U1 0 U2 10 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 AUG PY 2011 VL 13 IS 4 BP 695 EP 701 DI 10.1007/s11307-010-0401-2 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 786LN UT WOS:000292310000010 PM 20717735 ER PT J AU Smith, MA Maris, JM Lock, R Kolb, EA Gorlick, R Keir, ST Carol, H Morton, CL Reynolds, CP Kang, MH Houghton, PJ AF Smith, Malcolm A. Maris, John M. Lock, Richard Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Carol, Hernan Morton, Christopher L. Reynolds, C. Patrick Kang, Min H. Houghton, Peter J. TI Initial Testing (Stage 1) of the Polyamine Analog PG11047 by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; preclinical testing; polyamine ID TARGETING ORNITHINE-DECARBOXYLASE; POSTRADIOTHERAPY CHEMOTHERAPY; GLIOBLASTOMA-MULTIFORME; SLEEPING SICKNESS; CANCER CELLS; NEUROBLASTOMA; INHIBITOR; TRIAL; MYCN; DFMO AB Background. PG11047 is a novel conformationally restricted analog of the natural polyamine, spermine that lowers cellular endogenous polyamine levels and competitively inhibits natural polyamine functions leading to cancer cell growth inhibition. The activity of PG11047 was evaluated against the PPTP's in vitro and in vivo panels. Procedures. PG11047 was evaluated against the PPTP in vitro panel using 96 hr exposure at concentrations ranging from 10nM to 100 mu M. It was tested against the PPTP in vivo panels at a dose of 100 mg/kg administered by the intraperitoneal route weekly for 6 weeks. Results. In vitro PG11047 demonstrated a concentration-response pattern consistent with cytostatic activity. The median EC(50) for PG11047 was 71 nM. Cell lines of the Ewing sarcoma panel had a lower median EC(50) value compared to the remaining cell lines in the panel, while cell lines of the neuroblastoma panel had a higher median EC(50) value. In vivo PG11047 induced significant differences in EFS distribution compared to control in 5 of 32 (15.6%) of the evaluable solid tumor xenografts and in 0 of 7 (0%) of the evaluable ALL xenografts. The single case of tumor regression occurred in an ependymoma xenograft. Conclusions. Further pediatric development of PG11047 will require better defining a target population and identifying combinations for which there is a tumor-selective cytotoxic effect. The regression observed for an ependymoma xenograft and the exquisite sensitivity of some Ewing sarcoma cell lines to the antiproliferative effects of PG11047 provide leads for further preclinical investigations. Pediatr Blood Cancer 2011; 56: 268-274. (C) 2011 Wiley-Liss, Inc. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 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. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Morton, Christopher L.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, Room 7025,6130 Execut Blvd, Bethesda, MD 20892 USA. EM smithm@ctep.nci.nih.gov RI Houghton, Peter/E-3265-2011; 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] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 26 TC 4 Z9 4 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 AUG PY 2011 VL 57 IS 2 BP 268 EP 274 DI 10.1002/pbc.22797 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 786JE UT WOS:000292301400016 PM 21360650 ER PT J AU Rochowski, A Sun, CX Glogauer, M Alter, BP AF Rochowski, Andrzej Sun, Chunxiang Glogauer, Michael Alter, Blanche P. TI Neutrophil Functions in Patients With Inherited Bone Marrow Failure Syndromes SO PEDIATRIC BLOOD & CANCER LA English DT Article DE inherited bone marrow failure; neutrophil; respiratory burst ID SHWACHMAN-DIAMOND-SYNDROME; FANCONI-ANEMIA; DYSKERATOSIS-CONGENITA; FAMILY-MEMBERS; DEFECT; CHEMOTAXIS; LEUKOCYTES; RELEASE; CANCER AB Background. The inherited bone marrow failure syndromes (IBMFS) include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome (SDS). Previous studies reported decreased neutrophil chemotaxis in patients with SDS; there are no reports of neutrophil function in other IBMFS. In this study we examined neutrophil respiratory burst function in IBMFS patients. Procedure. Samples from 43 IBMFS patients and 61 healthy family members were collected, shipped, and analyzed within 24 hr. We also studied samples from 12 healthy control persons immediately after collection. Neutrophils were stimulated with phorbol 12-myristate acetate (PMA) and N-formyl-methyonyl-leucyl-phenylalanine (fMLP), and respiratory burst analyzed by reduction of dihydro-rhodamine and cytochromec. Results. There was no significant difference in the degree of fMLP or PMA-driven respiratory burst activity between each of the IBMFS subgroups and their respective family members. There was also no difference in respiratory burst activity between any IBMFS, pooled group of all healthy family members and healthy controls. Conclusions. Neutrophil respiratory burst activity from IBMFS patients does not differ from that of healthy family members and controls. Pediatr Blood Cancer. 2011; 57: 306-309. (C) 2010Wiley-Liss, Inc. C1 [Rochowski, Andrzej; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20852 USA. [Rochowski, Andrzej] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Sun, Chunxiang; Glogauer, Michael] Univ Toronto, Fac Dent, Canadian Inst Hlth Res Grp Matrix Dynam, Toronto, ON, Canada. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S,Room 7020, Bethesda, MD 20852 USA. EM alterb@mail.nih.gov OI Glogauer, Michael/0000-0002-6248-5977 FU NIH; National Cancer Institute FX Grant sponsor: NIH; Grant sponsor: National Cancer Institute. NR 21 TC 2 Z9 2 U1 0 U2 4 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 AUG PY 2011 VL 57 IS 2 BP 306 EP 309 DI 10.1002/pbc.22885 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 786JE UT WOS:000292301400023 PM 21671367 ER PT J AU Ehler, M Galanis, J AF Ehler, Martin Galanis, Jennifer TI Frame theory in directional statistics SO STATISTICS & PROBABILITY LETTERS LA English DT Article DE Frames; Directional statistics; Bingham test; Granular rods ID BI-FRAMES; TIGHT FRAMES; DISTRIBUTIONS; EXPANSIONS; ERASURES; MIXTURE; ORDER; SHAPE AB Distinguishing between uniform and non-uniform sample distributions is a common problem in directional data analysis; however for many tests, non-uniform distributions exist that fail uniformity rejection. To predict these distributions, we merge directional statistics with frame theory and find that probabilistic tight frames yield non-uniform distributions that minimize directional potentials, leading to failure of uniformity rejection for the Bingham test. Finally, we apply our results to model patterns found in granular rod experiments. (C) 2011 Elsevier B.V. All rights reserved. C1 [Ehler, Martin; Galanis, Jennifer] NICHHD, NIH, Sect Med Biophys, Bethesda, MD 20892 USA. [Ehler, Martin] Univ Maryland, Dept Math, Norbert Wiener Ctr, College Pk, MD 20742 USA. [Galanis, Jennifer] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Galanis, Jennifer] Hebrew Univ Jerusalem, Fritz Haber Ctr, IL-91904 Jerusalem, Israel. RP Ehler, M (reprint author), NICHHD, NIH, Sect Med Biophys, Bethesda, MD 20892 USA. EM ehlermar@mail.nih.gov; galanis@fh.huji.ac.il FU National Institute of Child Health and Human Development, National Institutes of Health; Minerva Foundation, Munich, Germany; NIH/DFG [EH 405/1-1/575910] FX The authors are supported, in part, by intramural research funds from the National Institute of Child Health and Human Development, National Institutes of Health. The Fritz Haber research center is supported by the Minerva Foundation, Munich, Germany. In addition, ME is supported by the NIH/DFG Research Career Transition Awards Program (EH 405/1-1/575910). NR 36 TC 10 Z9 10 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD AUG PY 2011 VL 81 IS 8 BP 1046 EP 1051 DI 10.1016/j.spl.2011.02.027 PG 6 WC Statistics & Probability SC Mathematics GA 785MI UT WOS:000292232700020 ER PT J AU Uthus, E Begaye, A Ross, S Zeng, HW AF Uthus, Eric Begaye, Adrienne Ross, Sharon Zeng, Huawei TI The von Hippel-Lindau (VHL) Tumor-suppressor Gene is Down-regulated by Selenium Deficiency in Caco-2 Cells and Rat Colon Mucosa SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE Tumor-suppressor; DNA methylation; Selenium; Se-methylselenocysteine; Caco-2 cells; Von Hippel-Lindau; Rat; DNA methylation array ID ABERRANT CRYPT FORMATION; DNA METHYLATION; DIETARY SELENIUM; GLUTATHIONE-PEROXIDASE; HISTONE DEACETYLASE; FISHER-344 RATS; SERUM SELENIUM; CANCER; METABOLISM; RISK AB To test the hypothesis that selenium affects DNA methylation and hence gene regulation, we employed a methylation array (Panomics) in the human colonic epithelial Caco-2 cell model. The array profiles DNA methylation from promoter regions of 82 human genes. After conditioning cells to repeatedly reduced concentrations of fetal bovine serum, a serum-free culture was established. Se-methylselenocysteine (SeMSC) was added at 0 (deficient Se) or 250 (control Se) nM to cells maintained in DMEM. After 7 days, cells were collected and stored at -80A degrees C until analysis; experiments were replicated three times. Glutathione peroxidase activity was significantly decreased in cells grown in low SeMSC. Cells grown in 250 nM SeMSC had maximal GPx activity. Genomic DNA from cells grown in the low-SeMSC media and media containing 250 nM SeMSC was incubated with methylation-binding protein followed by isolation of methylated DNA. The methylated DNA was labeled with biotin and hybridized to the methylation array. Thus, genes with promoter methylation will produce a higher chemiluminescence signal than those genes with no promoter methylation. Of the genes profiled, the von Hippel-Lindau (VHL) gene was most different as indicated by quantification following chemiluminescence detection demonstrating that the promoter region of VHL was hypermethylated in cells from the low-SeMSC media. To determine whether promoter methylation affected transcription, we isolated RNA from replicate samples and performed real-time RT PCR. VHL (mRNA) was down-regulated (fold change significantly < 1) in cells grown in low SeMSC compared to cells grown in 250 nM SeMSC (control; fold change = 1). We also show that (mRNA) Vhl expression is significantly reduced in mucosa from rats fed a diet deficient in Se. Our results suggest that low Se status affects DNA promoter region methylation and that this can result in down-regulation of the tumor suppressor gene VHL. C1 [Uthus, Eric; Zeng, Huawei] ARS, USDA, Human Nutr Res Ctr, Grand Forks, ND 58202 USA. [Begaye, Adrienne] Univ Arizona, Tucson, AZ USA. [Ross, Sharon] NCI, NIH, Nutr Sci Res Grp, Rockville, MD 20892 USA. RP Uthus, E (reprint author), ARS, USDA, Human Nutr Res Ctr, POB 9034, Grand Forks, ND 58202 USA. EM eric.uthus@ars.usda.gov NR 38 TC 7 Z9 7 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0163-4984 J9 BIOL TRACE ELEM RES JI Biol. Trace Elem. Res. PD AUG PY 2011 VL 142 IS 2 BP 223 EP 231 DI 10.1007/s12011-010-8764-4 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 778WY UT WOS:000291741300012 PM 20632125 ER PT J AU Decrausaz, L Domingos-Pereira, S Duc, M Bobst, M Romero, P Schiller, JT Jichlinski, P Nardelli-Haefliger, D AF Decrausaz, Loane Domingos-Pereira, Sonia Duc, Melanie Bobst, Martine Romero, Pedro Schiller, John T. Jichlinski, Patrice Nardelli-Haefliger, Denise TI Parenteral is more efficient than mucosal immunization to induce regression of human papillomavirus-associated genital tumors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; cervical cancer; genital tumor model; therapeutic vaccination; mucosal vaccination ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSMITTED VIRAL-INFECTION; REGULATORY T-CELLS; INTRAEPITHELIAL NEOPLASIA; CPG OLIGODEOXYNUCLEOTIDES; INTRANASAL IMMUNIZATION; PROTECTIVE IMMUNITY; INTERFERON-GAMMA; LYMPH-NODES; MICE AB Cervical cancer is a public health concern as it represents the second cause of cancer death in women worldwide. High-risk human papillomaviruses (HPV) are the etiologic agents, and HPV E6 and/or E7 oncogene-specific therapeutic vaccines are under development to treat HPV-related lesions in women. Whether the use of mucosal routes of immunization may be preferable for inducing cell-mediated immune responses able to eradicate genital tumors is still debated because of the uniqueness of the female genital mucosa (GM) and the limited experimentation. Here, we compared the protective activity resulting from immunization of mice via intranasal (i.n.), intravaginal (IVAG) or subcutaneous (s.c.) routes with an adjuvanted HPV type 16 E7 polypeptide vaccine. Our data show that s.c. and i.n. immunizations elicited similar frequencies and avidity of TetE7(+) CD8(+) and E7-specific Interferon-gamma-secreting cells in the GM, whereas slightly lower immune responses were induced by IVAG immunization. In a novel orthotopic murine model, both s.c. and i.n. immunizations allowed for complete long-term protection against genital E7-expressing tumor challenge. However, only s.c. immunization induced complete regression of already established genital tumors. This suggests that the higher E7-specific systemic response observed after s.c. immunization may contribute to the regression of growing genital tumors, whereas local immune responses may be sufficient to impede genital challenges. Thus, our data show that for an efficiently adjuvanted protein-based vaccine, parenteral vaccination route is superior to mucosal vaccination route for inducing regression of established genital tumors in a murine model of HPV-associated genital cancer. C1 [Nardelli-Haefliger, Denise] CHU Vaudois, Dept Urol, IMUL, CH-1011 Lausanne, Switzerland. [Decrausaz, Loane; Domingos-Pereira, Sonia; Duc, Melanie; Bobst, Martine; Jichlinski, Patrice; Nardelli-Haefliger, Denise] Univ Lausanne, Lausanne, Switzerland. [Romero, Pedro] Ludwig Inst Canc Res, Div Clin Oncoimmunol, Lausanne, Switzerland. [Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Nardelli-Haefliger, D (reprint author), CHU Vaudois, Dept Urol, IMUL, Bugnon 48, CH-1011 Lausanne, Switzerland. EM dnardell@hospvd.ch OI nardelli-haefliger, denise/0000-0003-1812-9905 FU Swiss National Science Foundation [310000-112406]; Oncosuisse [02304-082008]; Fondation Mercier; Fondation Emma Muschamp FX Grant sponsor: Swiss National Science Foundation; Grant number: 310000-112406; Grant sponsor: Oncosuisse; Grant number: 02304-082008; Grant sponsor: Fondation Mercier, Fondation Emma Muschamp NR 50 TC 18 Z9 18 U1 1 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 AUG 1 PY 2011 VL 129 IS 3 BP 762 EP 772 DI 10.1002/ijc.25973 PG 11 WC Oncology SC Oncology GA 777HH UT WOS:000291606000025 PM 21384340 ER PT J AU Ellis, JR Heinrich, B Mautner, VF Kluwe, L AF Ellis, James R., Jr. Heinrich, Bianca Mautner, Victor-F. Kluwe, Lan TI Effects of Splicing Mutations on NF2-Transcripts: Transcript Analysis and Information Theoretic Predictions SO GENES CHROMOSOMES & CANCER LA English DT Article ID GERM-LINE MUTATIONS; NEUROFIBROMATOSIS 2; NF2 GENE; SITE MUTATIONS; SEQUENCES; IDENTIFICATION; SEVERITY; DISEASE; EXON AB This study examined the effects of 22 putative splicing mutations in the NF2 gene by means of transcript analysis and information theory based prediction. Fourteen mutations were within the dinucleotide acceptor and donor regions, often referred to as (AG/GT) sequences. Six were outside these dinucleotide regions but within the more broadly defined splicing regions used in the information theory based model. Two others were in introns and outside the broadly defined regions. Transcript analysis revealed exon skipping or activation of one or more cryptic splicing sites for 17 mutations. No alterations were found for the two intronic mutations and for three mutations in the broadly defined splicing regions. Concordance and partial concordance between the calculated predictions and the results of transcript analysis were found for 14 and 6 mutations, respectively. For two mutations, the predicted alteration was not found in the transcripts. Our results demonstrate that the effects of splicing mutations in NF2 are often complex and that information theory based analysis is helpful in elucidating the consequences of these mutations. (C) 2011 Wiley-Liss, Inc. C1 [Ellis, James R., Jr.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Heinrich, Bianca] Univ Med Ctr Hamburg Eppendorf, Dept Neurosurg, Hamburg, Germany. [Mautner, Victor-F.; Kluwe, Lan] Univ Med Ctr Hamburg Eppendorf, Dept Oral & Maxillofacial Surg, Hamburg, Germany. RP Ellis, JR (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jrellis@helix.nih.gov FU NIH; German Cancer Foundation [108793] FX Supported by: NIH Intramural Research Program; German Cancer Foundation, Grant number: 108793 NR 22 TC 3 Z9 3 U1 0 U2 0 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 AUG PY 2011 VL 50 IS 8 BP 571 EP 584 DI 10.1002/gcc.20876 PG 14 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 777BP UT WOS:000291588500001 PM 21563229 ER PT J AU Venere, M Fine, HA Dirks, PB Rich, JN AF Venere, Monica Fine, Howard A. Dirks, Peter B. Rich, Jeremy N. TI Cancer Stem Cells in Gliomas: Identifying and Understanding the Apex Cell in Cancer's Hierarchy SO GLIA LA English DT Article DE glioma; cancer stem cell; therapy resistance ID TUMOR-INITIATING CELLS; ACUTE MYELOID-LEUKEMIA; HUMAN GLIOBLASTOMA; SIDE POPULATION; GROWTH-FACTOR; HEMATOPOIETIC STEM; PERIVASCULAR NICHE; PANCREATIC-CANCER; GENE-EXPRESSION; POSITIVE CELLS AB Neuro-oncology research has rediscovered a complexity of nervous system cancers through the incorporation of cellular heterogeneity into tumor models with cellular subsets displaying stem-cell characteristics. Self-renewing cancer stem cells (CSCs) can propagate tumors and yield nontumorigenic tumor bulk cells that display a more differentiated phenotype. The ability to prospectively isolate and interrogate CSCs is defining molecular mechanisms responsible for the tumor maintenance and growth. The clinical relevance of CSCs has been supported by their resistance to cytotoxic therapies and their promotion of tumor angiogenesis. Although the field of CSC biology is relatively young, continued elucidation of the features of these cells holds promise for the development of novel patient therapies. (C) 2011 Wiley-Liss, Inc. C1 [Venere, Monica; Rich, Jeremy N.] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44118 USA. [Fine, Howard A.] Natl Inst Neurol Disorders & Stroke, Neurooncol Branch, NCI, NIH, Bethesda, MD USA. [Dirks, Peter B.] Hosp Sick Children, Div Neurosurg, Dev & Stem Cell Biol Program, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada. RP Venere, M (reprint author), Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, NE30,9500 Euclid Ave, Cleveland, OH 44118 USA. EM venerem@ccf.org; richj@ccf.org FU National Brain Tumor Society; Goldhirsh Foundation; NIH [NS054276, CA129958, CA116659, CA154130]; National Research Service [NS058042]; Damon Runyon Cancer Research Foundation; American Brain Tumor Association; Canadian Cancer Society Research Institute; Canadian Institutes for Health Research; Ontario Institute for Cancer Research; Terry Fox Foundation; Hospital for Sick Children Foundation; Jessica's Footprint Foundation; National Cancer Institute; National Institutes of Neurological Disorders, and Stroke/National Institutes of Health FX Grant sponsor: National Brain Tumor Society, Goldhirsh Foundation; Grant sponsor: NIH; Grant numbers: NS054276, CA129958, CA116659, CA154130; Grant sponsor: National Research Service Awards; Grant number: NS058042; Grant sponsors: Damon Runyon Cancer Research Foundation, American Brain Tumor Association Basic Research Fellowship, Canadian Cancer Society Research Institute, the Canadian Institutes for Health Research, the Ontario Institute for Cancer Research, the Terry Fox Foundation, the Hospital for Sick Children Foundation, Jessica's Footprint Foundation, National Cancer Institute, National Institutes of Neurological Disorders, and Stroke/National Institutes of Health. NR 70 TC 69 Z9 72 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD AUG PY 2011 VL 59 IS 8 SI SI BP 1148 EP 1154 DI 10.1002/glia.21185 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 777CN UT WOS:000291591800003 PM 21547954 ER PT J AU Fitzgerald, ML Lupica, CR Pickel, VM AF Fitzgerald, Megan L. Lupica, Carl R. Pickel, Virginia M. TI Decreased Parvalbumin Immunoreactivity in the Cortex and Striatum of Mice Lacking the CB1 Receptor SO SYNAPSE LA English DT Article DE CB1 knockout; caudate putamen; primary motor cortex; medial prefrontal cortex ID CALCIUM-BINDING PROTEIN; CANNABINOID RECEPTORS; RAT NEOSTRIATUM; CONTAINING INTERNEURONS; GABAERGIC INTERNEURONS; CORTICAL INTERNEURONS; POSTNATAL-DEVELOPMENT; SOMATOSENSORY CORTEX; BASAL GANGLIA; GABA RELEASE AB Cortical and striatal regions of the brain contain high levels of the cannabinoid-1 (CB1) receptor, the central neuronal mediator of activity-dependent synaptic plasticity evoked by endocannabinoids. The expression levels of parvalbumin, a calcium-binding protein found in fast-spiking interneurons of both regions, may be controlled in part by synaptic activity during critical periods of development. However, there is currently no evidence that CB1 receptor expression affects parvalbumin levels in either cortical or striatal interneurons. To assess this possibility, we examined parvalbumin immunoreactivity in the dorsolateral striatum, primary motor cortex (M1), and prefrontal cortex (PFC) of CB1 knockout and wild-type C57/BL6 mice. Quantitative densitometry showed a significant decrease in parvalbumin immunoreactivity within individual neurons in each of these regions of CB1 knockout mice relative to controls. A significantly lower density (number of cells per unit area) of parvalbumin-labeled neurons was observed in the striatum, but not the cortical regions of CB1 knockout mice. These findings suggest that CB1 receptor deletion may elicit a compensatory mechanism for network homeostasis affecting parvalbumin-containing cortical and striatal interneurons. Synapse 65:827-831, 2011. Published 2011 Wiley-Liss, Inc.(dagger) C1 [Fitzgerald, Megan L.; Pickel, Virginia M.] Cornell Univ, Div Neurobiol, Dept Neurol & Neurosci, Weill Med Coll, New York, NY 10065 USA. [Lupica, Carl R.] Natl Inst Drug Abuse, Electrophysiol Res Sect, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Pickel, VM (reprint author), Weill Cornell Med Coll, Div Neurobiol, 407 E 61st St, New York, NY 10065 USA. EM vpickel@med.cornell.edu FU National Institutes of Health [1P01 HL096571, MH40342, DA04600, T32 DA 7274]; National Institute on Drug Abuse FX Contract grant sponsor: National Institutes of Health; Contract grant numbers: 1P01 HL096571, MH40342, DA04600, T32 DA 7274; Contract grant sponsor: National Institute on Drug Abuse Intramural Research Program NR 41 TC 13 Z9 13 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD AUG PY 2011 VL 65 IS 8 BP 827 EP 831 DI 10.1002/syn.20911 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 777FO UT WOS:000291601500015 PM 21445945 ER PT J AU Malinovsky, Y Rinott, Y AF Malinovsky, Yaakov Rinott, Yosef TI Best invariant and minimax estimation of quantiles in finite populations SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Monotone transformations; Sampling and estimation strategies; Behavioral and randomized estimators; Loss functions; Median; Simple random sample ID RANDOMIZATION; STATISTICS AB The theoretical literature on quantile and distribution function estimation in infinite populations is very rich, and invariance plays an important role in these studies. This is not the case for the commonly occurring problem of estimation of quantiles in finite populations. The latter is more complicated and interesting because an optimal strategy consists not only of an estimator, but also of a sampling design, and the estimator may depend on the design and on the labels of sampled individuals, whereas in iid sampling, design issues and labels do not exist. We study the estimation of finite population quantiles, with emphasis on estimators that are invariant under the group of monotone transformations of the data, and suitable invariant loss functions. Invariance under the finite group of permutation of the sample is also considered. We discuss nonrandomized and randomized estimators, best invariant and minimax estimators, and sampling strategies relative to different classes. Invariant loss functions and estimators in finite population sampling have a nonparametric flavor, and various natural combinatorial questions and tools arise as a result. Published by Elsevier B.V. C1 [Malinovsky, Yaakov] NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Rinott, Yosef] Hebrew Univ Jerusalem, IL-91905 Jerusalem, Israel. [Rinott, Yosef] LUISS, Rome, Italy. RP Malinovsky, Y (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM yaakov.malinovsky@nih.gov; rinott@mscc.huji.ac.il FU Israel Science Foundation [473/04]; National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Gil Kalai for several enlightening discussions of this work, and three reviewers for many useful comments. This research was supported in part by Grant no. 473/04 from the Israel Science Foundation. The first author also supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 29 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD AUG PY 2011 VL 141 IS 8 BP 2633 EP 2644 DI 10.1016/j.jspi.2011.02.016 PG 12 WC Statistics & Probability SC Mathematics GA 770DO UT WOS:000291067400012 PM 21643478 ER PT J AU Di Costanzo, A Festa, L Roscigno, G Vivo, M Pollice, A Morasso, M La Mantia, G Calabro, V AF Di Costanzo, Antonella Festa, Luisa Roscigno, Giuseppina Vivo, Maria Pollice, Alessandra Morasso, Maria La Mantia, Girolama Calabro, Viola TI A Dominant Mutation Etiologic for Human Tricho-Dento-Osseous Syndrome Impairs the Ability of DLX3 to Downregulate Delta Np63 alpha SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID HUMAN PRIMARY KERATINOCYTES; HOMEODOMAIN PROTEIN DLX3; HOMEOBOX GENE DLX3; ECTODERMAL DYSPLASIAS; P53 HOMOLOG; IN-VITRO; P63; DIFFERENTIATION; PHOSPHORYLATION; EXPRESSION AB The homeodomain transcription factors play crucial roles in many developmental processes ranging from organization of the body plan to differentiation of individual tissues. The homeodomain protein Distal-less-3 (DLX3) has an essential role in epidermal stratification and development of ectodermal appendages, placenta and bones. A four-nucleotide deletion in the human DLX3 gene is etiologic for the human hereditary tricho-dento-osseous (TDO) ectodermal dysplasia, a dominant syndrome characterized by abnormalities in hair, nails, teeth, and bones. We have previously demonstrated that DLX3 gene expression induces degradation of Delta Np63 alpha, a specific product of the TP63 gene, a master regulator of multi-layered epithelia. Here we show that the DLX3(TDO) mutant protein is unable to promote Delta Np63 alpha protein degradation and impairs the expression of cell cycle regulatory proteins and skin differentiation markers. However, we found that in cell expressing equal amounts of mutant and wild-type DLX3, Delta Np63 alpha protein level is efficiently regulated implying that genetic heterozygosity at the DLX3 locus protects TDO patients from developing severe p63-associated skin defects. J. Cell. Physiol. 226: 2189-2197, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Di Costanzo, Antonella; Festa, Luisa; Roscigno, Giuseppina; Vivo, Maria; Pollice, Alessandra; La Mantia, Girolama; Calabro, Viola] Univ Naples Federico 2, Dept Struct & Mol Biol, Naples, Italy. [Morasso, Maria] NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD USA. RP Calabro, V (reprint author), Univ Naples Federico 2, Dipartimento Biol Strutturale & Funz, Viale Cinzia, I-80126 Naples, Italy. EM vcalabro@unina.it FU Associazione Italiana per la Ricerca sul Cancro (AIRC) FX Contract grant sponsor: Associazione Italiana per la Ricerca sul Cancro (AIRC). NR 37 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 2011 VL 226 IS 8 BP 2189 EP 2197 DI 10.1002/jcp.22553 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 762ZJ UT WOS:000290520900025 PM 21520071 ER PT J AU Nemes, E Lugli, E Bertoncelli, L Nasi, M Pinti, M Manzini, S Prati, F Manzini, L Del Giovane, C D'Amico, R Cossarizza, A Mussini, C AF Nemes, Elisa Lugli, Enrico Bertoncelli, Linda Nasi, Milena Pinti, Marcello Manzini, Serena Prati, Francesca Manzini, Lisa Del Giovane, Cinzia D'Amico, Roberto Cossarizza, Andrea Mussini, Cristina TI CD4(+) T-cell differentiation, regulatory T cells and gag-specific T lymphocytes are unaffected by CD4-guided treatment interruption and therapy resumption SO AIDS LA English DT Article DE CD4-guided treatment interruptions; chronic HIV infection; gag-specific response; regulatory T cells; T-cell activation; T-cell differentiation; T-cell polyfunctionality ID HIV-INFECTED PATIENTS; HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SCHEDULED TREATMENT INTERRUPTIONS; MONITORED TREATMENT INTERRUPTION; CD40 LIGAND DYSREGULATION; CD4+COUNT-GUIDED INTERRUPTION; HIV-1-INFECTED PATIENTS; IMMUNE ACTIVATION; RNA LEVELS AB Objectives: Despite limiting exposure to antiretroviral drugs, structured treatment interruptions can influence multiple aspects of T-cell immunity, particularly those regarding CD4(+) T lymphocytes. We evaluated the impact of CD4-guided treatment interruption (CD4-GTI) and treatment resumption on regulatory T cells (Tregs), T-lymphocyte activation, differentiation and polyfunctional gag-specific response. Methods: Patients were analyzed just prior to treatment interruption, at 2 and 6 months after treatment interruption, just prior to treatment resumption and at 2 and 6 months after treatment resumption. Thawed peripheral blood mononuclear cells were stained immediately for phenotype analysis or stimulated with HIV-gag peptides and analyzed by polychromatic flow cytometry. Results: Treatment interruption resulted in a CD4(+) cell count decrease and plasma viral load (pVL) increase, but did not preclude a good immune reconstitution and a complete suppression of pVL after treatment resumption. Treatment interruption did not influence CD4(+) T-cell differentiation and Treg subsets. During treatment interruption, gag-specific CD4(+) T cells were not lost, although the frequency of HIV-specific CD8(+) cells increased. Most gag-specific CD4(+) T cells were potentially cytotoxic (CD107a(+)) and were not influenced by pVL or by HAART. Most helper (CD154(+)) gag-specific CD4(+) T lymphocytes did not produce interferon-g or interleukin-2. Conclusion: CD4-GTI did not cause depletion of memory cells, Tregs or HIV-specific CD4(+) cells and, on the contrary, could induce HIV-specific responses. If guided by CD4(+) T-cell count, treatment interruption does not provoke irreversible immune damages. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Cossarizza, Andrea] Univ Modena & Reggio Emilia, Dept Biomed Sci, Chair Immunol, I-41125 Modena, Italy. [Prati, Francesca; Manzini, Lisa; Mussini, Cristina] Univ Modena & Reggio Emilia, Infect Dis Clin, Azienda Osped, Univ Policlin Modena, I-41125 Modena, Italy. [Del Giovane, Cinzia; D'Amico, Roberto] Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, I-41125 Modena, Italy. [Lugli, Enrico] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Cossarizza, A (reprint author), Univ Modena & Reggio Emilia, Dept Biomed Sci, Chair Immunol, Via Campi 287, I-41125 Modena, Italy. EM andrea.cossarizza@unimore.it RI D'Amico, Roberto/I-8106-2014; Pinti, Marcello/C-9351-2015; Nasi, Milena/J-4425-2016; OI D'Amico, Roberto/0000-0002-3211-6687; Pinti, Marcello/0000-0001-9118-1262; Nasi, Milena/0000-0003-3079-8001; Cossarizza, Andrea/0000-0002-5381-1558 FU Istituto Superiore di Sanita (Rome, Italy); VI Programma Nazionale di Ricerca sull'AIDS [40G.62, 40G.43] FX The authors thank all the patients who participated in this study. This study has been sponsored by the Istituto Superiore di Sanita (Rome, Italy), VI Programma Nazionale di Ricerca sull'AIDS, grants No. 40G.62 to A.C. and 40G.43 to C.M. The authors acknowledge Partec GmbH (Germany) and Space srl (Milan, Italy) for their continuous support. NR 52 TC 10 Z9 10 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2011 VL 25 IS 12 BP 1443 EP 1453 DI 10.1097/QAD.0b013e328347b5e2 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 791BW UT WOS:000292636300001 PM 21505295 ER PT J AU Kiser, JJ Rutstein, RM Samson, P Graham, B Aldrovandi, G Mofenson, LM Smith, E Schnittman, S Fenton, T Brundage, RC Fletcher, CV AF Kiser, Jennifer J. Rutstein, Richard M. Samson, Pearl Graham, Bobbie Aldrovandi, Grace Mofenson, Lynne M. Smith, Elizabeth Schnittman, Steven Fenton, Terry Brundage, Richard C. Fletcher, Courtney V. TI Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents SO AIDS LA English DT Article DE atazanavir; children; HIV; pediatrics; pharmacokinetics; protease inhibitor ID LOPINAVIR/RITONAVIR; COMBINATION; LAMIVUDINE; TENOFOVIR; RITONAVIR AB Objective: To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV (ATV/r) in children aged 91 days to 21 years. Design: A phase I/II, open-label, multicenter study of once-daily ATV and ATV/r as part of combination antiretroviral treatment in HIV-infected treatment-experienced and treatment-naive children. Setting: Sites in the United States and South Africa. Participants: One hundred and ninety-five children enrolled; 172 had evaluable ATV pharmacokinetics on day 7. Intervention: Children were entered in age, dose, and formulation (powder or capsule) cohorts. Intensive pharmacokinetic sampling occurred 7 days after starting ATV. ATV doses were increased or decreased if the 24-h area under the concentration time curves (AUC(0-24hr)) were less than 30 or more than 90 mu g x h/ml, respectively. Main outcomes: Cohorts satisfied protocol-defined pharmacokinetic criteria if the median ATV AUC(0-24hr) was 60 mu g x h/ml or less, and AUC(0-24hr) and ATV concentrations 24-h postdose (C(24)) were more than 30 mu g x h/ml and at least 60 ng/ml, respectively, in at least 80% of the children, with no individual AUC(0-24hr) less than 15 mu g x h/ml. Results: Unboosted ATV capsules satisfied pharmacokinetic criteria at a dose of 520 mg/m(2) for those aged more than 2 to 13 years or less and 620 mg/m(2) for those aged more than 13 to 21 years or less. ATV/r capsules satisfied criteria at a dose of 205 mg/m(2) for those aged more than 2 to 21 years or less. ATV/r powder satisfied criteria at a dose of 310 mg/m(2) for those aged more than 2 to 13 years or less, but pharmacokinetics in those aged 2 years or less were highly variable. Conclusion: Body surface area-determined doses of ATV capsules and of ATV/r powder and capsules provide ATV exposures in children of more than 2 years that approximate concentrations in adults receiving ATV/r. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Fletcher, Courtney V.] Univ Nebraska Med Ctr, Coll Pharm, Omaha, NE 68198 USA. [Kiser, Jennifer J.] Univ Colorado Denver, Aurora, CO USA. [Rutstein, Richard M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Samson, Pearl; Fenton, Terry] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Graham, Bobbie] Frontier Sci Technol Res Fdn, Amherst, NY USA. [Aldrovandi, Grace] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Mofenson, Lynne M.] NICHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Smith, Elizabeth] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Schnittman, Steven] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Brundage, Richard C.] Univ Minnesota, Minneapolis, MN USA. RP Fletcher, CV (reprint author), Univ Nebraska Med Ctr, Coll Pharm, 986000 Nebraska Med Ctr, Omaha, NE 68198 USA. EM cfletcher@unmc.edu OI Mofenson, Lynne/0000-0002-2818-9808 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]; Bristol Myers Squibb; 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) [U01 AI068616]; IMPAACT Group; NICHD [N01-DK-9-001/HHSN267200800001C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (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 study was also supported by Bristol Myers Squibb. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 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 NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). NR 14 TC 12 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2011 VL 25 IS 12 BP 1489 EP 1496 DI 10.1097/QAD.0b013e328348fc41 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 791BW UT WOS:000292636300006 PM 21610486 ER PT J AU Braithwaite, RS Nucifora, KA Yiannoutsos, CT Musick, B Kimaiyo, S Diero, L Bacon, MC Wools-Kaloustian, K AF Braithwaite, R. Scott Nucifora, Kimberly A. Yiannoutsos, Constantin T. Musick, Beverly Kimaiyo, Sylvester Diero, Lameck Bacon, Melanie C. Wools-Kaloustian, Kara TI Alternative antiretroviral monitoring strategies for HIV-infected patients in east Africa: opportunities to save more lives? SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article ID RESOURCE-LIMITED SETTINGS; VIRAL LOAD; COST-EFFECTIVENESS; THERAPY; ADHERENCE; OUTCOMES; PROGRAMS; MODEL AB Background: Updated World Health Organization guidelines have amplified debate about how resource constraints should impact monitoring strategies for HIV-infected persons on combination antiretroviral therapy (cART). We estimated the incremental benefit and cost effectiveness of alternative monitoring strategies for east Africans with known HIV infection. Methods: Using a validated HIV computer simulation based on resource-limited data (USAID and AMPATH) and circumstances (east Africa), we compared alternative monitoring strategies for HIV-infected persons newly started on cART. We evaluated clinical, immunologic and virologic monitoring strategies, including combinations and conditional logic (e. g., only perform virologic testing if immunologic testing is positive). We calculated incremental cost-effectiveness ratios (ICER) in units of cost per quality-adjusted life year (QALY), using a societal perspective and a lifetime horizon. Costs were measured in 2008 US dollars, and costs and benefits were discounted at 3%. We compared the ICER of monitoring strategies with those of other resource-constrained decisions, in particular earlier cART initiation (at CD4 counts of 350 cells/mm(3) rather than 200 cells/mm3). Results: Monitoring strategies employing routine CD4 testing without virologic testing never maximized health benefits, regardless of budget or societal willingness to pay for additional health benefits. Monitoring strategies employing virologic testing conditional upon particular CD4 results delivered the most benefit at willingness-to-pay levels similar to the cost of earlier cART initiation (approximately $2600/QALY). Monitoring strategies employing routine virologic testing alone only maximized health benefits at willingness-to-pay levels (> $4400/QALY) that greatly exceeded the ICER of earlier cART initiation. Conclusions: CD4 testing alone never maximized health benefits regardless of resource limitations. Programmes routinely performing virologic testing but deferring cART initiation may increase health benefits by reallocating monitoring resources towards earlier cART initiation. C1 [Braithwaite, R. Scott; Nucifora, Kimberly A.] NYU, Sch Med, Dept Med, Sect Value & Comparat Effectiveness, New York, NY 10012 USA. [Yiannoutsos, Constantin T.; Musick, Beverly] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN USA. [Kimaiyo, Sylvester; Diero, Lameck] Moi Univ, Sch Med, Dept Med, Eldoret, Kenya. [Bacon, Melanie C.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Wools-Kaloustian, Kara] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. RP Braithwaite, RS (reprint author), NYU, Sch Med, Dept Med, Sect Value & Comparat Effectiveness, New York, NY 10012 USA. EM scott.braithwaite@nyumc.org FU National Institute of Allergy and Infectious Disease [UO1AI069911-01]; US National Institutes of Health; US NIH FX This work is supported by National Institute of Allergy and Infectious Disease Award UO1AI069911-01 (IeDEA East Africa), US National Institutes of Health. MCB is employed by the US NIH, which provided funding for this study through a grant. The study sponsor had no role in the study design, interpretation of data, the writing of the paper, or the decision to submit the paper for publication. NR 29 TC 24 Z9 24 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUL 30 PY 2011 VL 14 AR 38 DI 10.1186/1758-2652-14-38 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GN UT WOS:000296353600001 PM 21801434 ER PT J AU Smith, B Lyakhov, I Loomis, K Needle, D Baxa, U Yavlovich, A Capala, J Blumenthal, R Puri, A AF Smith, Brandon Lyakhov, Ilya Loomis, Kristin Needle, Danielle Baxa, Ulrich Yavlovich, Amichai Capala, Jacek Blumenthal, Robert Puri, Anu TI Hyperthermia-triggered intracellular delivery of anticancer agent to HER2(+) cells by HER2-specific affibody (ZHER2-GS-Cys)-conjugated thermosensitive liposomes (HER2(+) affisomes) SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Drug delivery; Triggerable liposomes; Targeting; Affibody; Hyperthermia ID DRUG-DELIVERY; HER2-POSITIVE TUMORS; SENSITIVE LIPOSOME; DOXORUBICIN; MOLECULES; RECOMBINANT; THERAPY; CANCER; MODEL AB We previously reported the formulation and physical properties of HER2 (human epidermal growth factor receptor 2)-specific affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2(+) affisomes). Here we examined localized delivery potential of these affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. We modified ZHER2:342-Cys by introducing a glycine-serine spacer before the C-terminus cysteine (called ZHER2-GS-Cys) to achieve accessibility to cell surface expressed HER2. This modification did not affect HER2-specific binding and ZHER2-GS-Cys retained its ability to conjugate to the liposomes containing dipalmitoyl phosphatidyl choline: DSPE-PEG2000-Malemide, 96:04 mole ratios (HER2(+) affisomes). HER2(+) affisomes were either (i) fluorescently labeled with rhodamine-PE and calcein or (ii) loaded with an anticancer drug doxorubicin (DOX). Fluorescently labeled HER2(+) affisomes showed at least 10-fold increase in binding to HER2(+) cells (SK-BR-3) when compared to HER2(-) cells ( MDA-MB-468) at 37 degrees C. A competition experiment using free ZHER2-GS-Cys blocked HER2(+) affisome-SK-BR-3 cell associations. Imaging with confocal microscopy showed that HER2(+) affisomes accumulated in the cytosol of SK-BR-3 cells at 37 degrees C Hyperthermia-induced intracellular release experiments showed that the treatment of HER2(+) affisome/SK-BR-3 cell complexes with a 45 degrees C (+/- 1 degrees C) pre-equilibrated buffer resulted in cytosolic delivery of calcein. Substantial calcein release was observed within 20 mm at 45 degrees C, with no effect on cell viability under these conditions. Similarly, DOX-loaded HER2(+) affisomes showed at least 2- to 3-fold higher accumulation of DOX in SK-BR-3 cells as compared to control liposomes. DOX-mediated cytotoxicity was more pronounced in SK-BR-3 cells especially at lower doses of HER2(+) affisomes. Brief exposure of liposome-cell complexes at 45 degrees C prior to the onset of incubations for cell killing assays resulted in enhanced cytotoxicity for affisomes and control liposomes. However, Doxil (a commercially available liposome formulation) showed significantly lower toxicity under identical conditions. Therefore, our data demonstrate that HER2(+) affisomes encompass both targeting and triggering potential and hence may prove to be viable nanodrug delivery carriers for breast cancer treatment. Published by Elsevier B.V. C1 [Puri, Anu] NCI, Membrane Struct & Funct Sect, CCRNP, NIH, Frederick, MD 21701 USA. [Lyakhov, Ilya; Capala, Jacek] NCI, Radiat Oncol Branch, CCR, Bethesda, MD 20892 USA. [Baxa, Ulrich] SAIC Frederick, Electron Microscopy Lab, ATP, Frederick, MD USA. RP Puri, A (reprint author), NCI, Membrane Struct & Funct Sect, CCRNP, NIH, Bldg 469,Room 216A,POB B,Miller Dr, Frederick, MD 21701 USA. EM puria@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261 200 800 001E] FX This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261 200 800 001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 28 TC 37 Z9 41 U1 0 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 30 PY 2011 VL 153 IS 2 BP 187 EP 194 DI 10.1016/j.jconrel.2011.04.005 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 799UZ UT WOS:000293312900012 PM 21501640 ER PT J AU Polley, MYC AF Polley, Mei-Yin C. TI Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient accrual and late-onset toxicities SO STATISTICS IN MEDICINE LA English DT Article DE phase I clinical trials; Time-to-Event Continual Reassessment Method; dose finding; late-onset toxicity; adaptive design; Bayesian inference ID CLINICAL-TRIALS; DOSE-ESCALATION; TITE-CRM; DESIGNS; IMPROVEMENTS AB The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3+3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE-CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Polley, Mei-Yin C.] NCI, Biometr Res Branch, Rockville, MD 20852 USA. RP Polley, MYC (reprint author), Execut Plaza N,Room 8124,6130 Execut Blvd, Rockville, MD 20852 USA. EM polleymc@mail.nih.gov FU UCSF FX This work was supported by the UCSF Resource Allocation Program (RAP) REAC grant. The author is grateful to Professors Kathleen Lamborn and Michael Prados at UCSF, who served as the author's mentors on this grant award. The author also wishes to thank the editor, two referees, Professor Ken Cheung at Columbia University, and members of the Biostatistics and Computational Biology Core at the UCSF Cancer Center whose helpful comments and suggestions led to an improved paper. NR 32 TC 7 Z9 7 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2011 VL 30 IS 17 BP 2130 EP 2143 DI 10.1002/sim.4255 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 792JK UT WOS:000292739500009 PM 21590790 ER PT J AU Blair, KS Geraci, M Otero, M Majestic, C Odenheimer, S Jacobs, M Blair, RJR Pine, DS AF Blair, Karina S. Geraci, Manilla Otero, Marcela Majestic, Catherine Odenheimer, Stephanie Jacobs, Madeline Blair, R. J. R. Pine, Daniel S. TI Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Social phobia; fMRI; Self-referentiality; Medial prefrontal cortex; Amygdala ID CORTICAL MIDLINE STRUCTURES; ANTERIOR CINGULATE CORTEX; ANXIETY-DISORDER; AMYGDALA ACTIVATION; FACES; BRAIN; FMRI; CRITICISM; EMOTION; METAANALYSIS AB Generalized social phobia (GSP) involves the fear of being negatively evaluated. Previous work suggests that self-referentiality, mediated by the medial prefrontal cortex (MFPC), plays an important role in the disorder. However, it is not clear whether this anomalous MPFC response to self-related information in patients with GSP concerns an increased representation of their own or others' opinions. In this article, we examine whether GSP is associated with increased response to own (1st person) or other individuals' (2nd person) opinions relative to healthy individuals. Unmedicated individuals with GSP (n = 15) and age-. IQ-, and gender-matched comparison individuals (n = 15) read 1st (e.g., I'm ugly), and 2nd (e.g., You're ugly) person viewpoint comments during functional magnetic resonance imaging. We observed significant group-by-viewpoint interactions within the ventral MPFC. Whereas the healthy comparison individuals showed significantly increased (or less decreased) BOLD responses to 1st relative to 2nd person viewpoints, the patients showed significantly increased responses to 2nd relative to 1st person viewpoints. The reduced BOLD responses to 1st person viewpoint comments shown by the patients correlated significantly with severity of social anxiety symptom severity. These results underscore the importance of dysfunctional self-referential processing and MPFC in GSP. We believe that these data reflect a reorganization of self-referential reasoning in the disorder with a self-concept perhaps atypically related to the view of others. Published by Elsevier Ireland Ltd. C1 [Blair, Karina S.; Geraci, Manilla; Otero, Marcela; Majestic, Catherine; Odenheimer, Stephanie; Jacobs, Madeline; Blair, R. J. R.; Pine, Daniel S.] NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Blair, KS (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov FU NIH, National Institute of Mental Health FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health. The authors have no conflicts of interest or financial disclosures to report. NR 60 TC 34 Z9 34 U1 17 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2011 VL 193 IS 1 BP 38 EP 45 DI 10.1016/j.pscychresns.2010.12.016 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 788US UT WOS:000292470500005 PM 21601433 ER PT J AU Takikita, M Xie, R Chung, JY Cho, H Ylaya, K Hong, SM Moskaluk, CA Hewitt, SM AF Takikita, Mikiko Xie, Ran Chung, Joon-Yong Cho, Hanbyoul Ylaya, Kris Hong, Seung-Mo Moskaluk, Christopher A. Hewitt, Stephen M. TI Membranous expression of Her3 is associated with a decreased survival in head and neck squamous cell carcinoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; FACTOR RECEPTOR EGFR; BREAST-CANCER; CORRESPONDING METASTASES; FAMILY-MEMBERS; OVARIAN-CANCER; PRIMARY TUMORS; C-ERBB-2 GENE; THERAPY AB Background: Head and neck squamous cell carcinoma (HNSCC) still remains a lethal malignancy benefiting from the identification of the new target for early detection and/or development of new therapeutic regimens based on a better understanding of the biological mechanism for treatment. The overexpression of Her2 and Her3 receptors have been identified in various solid tumors, but its prognostic relevance in HNSCC remains controversial. Methods: Three hundred eighty-seven primary HNSCCs, 20 matching metasis and 17 recurrent HNSCCs were arrayed into tissue microarrays. The relationships between Her2 and Her3 protein expression and clinicopathological parameters/survival of HNSCC patients were analyzed with immunohistochemistry. Results: Her3 is detected as either a cytoplasmic or a membranous dominant expression pattern whereas Her2 expression showed uniform membranous form. In primary tumor tissues, high membranous Her2 expression level was found in 104 (26.9%) cases while positive membranous and cytoplasmic Her3 expression was observed in 34 (8.8%) and 300 (77.5%) samples, respectively. Membranous Her2 expression was significantly associated with histological grade (P = 0.021), as grade 2 tumors showed the highest positive expression. Membranous Her3 overexpression was significantly prevalent in metastatic tissues compared to primary tumors (P = 0.003). Survival analysis indicates that membranous Her3 expression is significantly associated with worse overall survival (P = 0.027) and is an independent prognostic factor in multivariate analysis (hazard ratio, 1.51; 95% confidence interval, 1.01-2.23; P = 0.040). Conclusions: These results suggest that membranous Her3 expression is strongly associated with poor prognosis of patients with HNSCC and is a potential candidate molecule for targeted therapy. C1 [Takikita, Mikiko; Xie, Ran; Cho, Hanbyoul; Ylaya, Kris; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Appl Mol Pathol Lab, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Hong, Seung-Mo] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Moskaluk, Christopher A.] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA 22908 USA. RP Hewitt, SM (reprint author), NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hong, Seung-Mo/0000-0002-8888-6007; Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU NIH, National Cancer Institute, Center for Cancer Research; University of Virginia School of Medicine FX Collection of the material and TMA construction was supported by The University of Virginia School of Medicine through fellowship support of Seung-Mo Hong who collected cases and provided the design for the TMA construction. Special thanks to Ms. Angela Miller of the Biorepository and Tissue Research Facility of The University of Virginia for construction of the TMAs used in this study. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 47 TC 25 Z9 25 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 29 PY 2011 VL 9 AR 126 DI 10.1186/1479-5876-9-126 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 813AE UT WOS:000294337000001 PM 21801427 ER PT J AU Xiao, XD Feng, Y Zhu, ZY Dimitrov, DS AF Xiao, Xiaodong Feng, Yang Zhu, Zhongyu Dimitrov, Dimiter S. TI Identification of a putative Crimean-Congo hemorrhagic fever virus entry factor SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE CCHFV; Gn; Gc; Nucleolin; Receptor; Receptor-binding domain ID SURFACE-EXPRESSED NUCLEOLIN; CELL-SURFACE; TARGET-CELLS; PROTEIN; RECEPTOR; PSEUDOPEPTIDE; GLYCOPROTEINS; LOCALIZATION; HANTAVIRUSES; REPLICATION AB Entry of enveloped viruses into cells is initiated by binding of their envelope glycoproteins (Envs) to cell surface-associated receptors. The Crimean-Congo hemorrhagic fever virus (CCHFV) has two Envs, Gn and Gc, with poorly understood role in binding to susceptible cells. We expressed codon optimized Gn and Gc, and identified independently folded soluble Env fragments, one of which (Gc residues 180-300) bound CCHFV susceptible cells supposedly by interacting with a putative receptor. This receptor binding domain (RBD) was used to identify its interacting partner by coimmunoprecipitation and mass spectrometry. Thus we identified the human cell surface nucleolin as a putative CCHFV entry factor. Nucleolin was expressed on all susceptible cells tested but not on the surface of cells resistant to CCHFV infection. Further studies are needed to explore the nucleolin function as a plausible CCHFV receptor and the molecular mechanisms of the Gc-nucleolin interactions. The identification of the CCHFV RBD and its binding partner could provide novel targets for therapy and tools for prevention as well as more complete understanding of the mechanisms of CCHFV entry and pathogenesis. Published by Elsevier Inc. C1 [Xiao, Xiaodong; Feng, Yang; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimitrdi@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; NIAID FX We thank Robert Doms and Christopher Broder for providing reagents and for helpful discussions, and the members of our group for help. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and the NIAID Biodefense Intramural Program (to D.S.D.). NR 30 TC 28 Z9 28 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 29 PY 2011 VL 411 IS 2 BP 253 EP 258 DI 10.1016/j.bbrc.2011.06.109 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 806LS UT WOS:000293809900005 PM 21723257 ER PT J AU Niu, G Chen, XY AF Niu, Gang Chen, Xiaoyuan TI Size Effect in Molecular Imaging of Vascular Endothelial Growth Factor SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID CANCER AB Visualizing and quantifying vascular endothelial growth factor (VEGF) levels are crucial factors in understanding the tumor environment and monitoring antiangiogenic treatment. The small peptidic probes described by Fedorova et al. in this issue appear to be superior to antibodies in reflecting the dynamics of VEGF as they facilitate image quantification. C1 [Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-02] NR 8 TC 2 Z9 2 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUL 29 PY 2011 VL 18 IS 7 BP 819 EP 820 DI 10.1016/j.chembiol.2011.07.002 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809VQ UT WOS:000294085200002 PM 21802000 ER PT J AU Lu, Y Zha, XM Kim, EY Schachtele, S Dailey, ME Hall, DD Strack, S Green, SH Hoffman, DA Hell, JW AF Lu, Yuan Zha, Xiang-ming Kim, Eun Young Schachtele, Scott Dailey, Michael E. Hall, Duane D. Strack, Stefan Green, Steven H. Hoffman, Dax A. Hell, Johannes W. TI A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LONG-TERM POTENTIATION; NMDA RECEPTOR ACTIVATION; AMPA RECEPTORS; POSTSYNAPTIC DENSITIES; HIPPOCAMPAL-NEURONS; NERVOUS-SYSTEM; DEPENDENT PLASTICITY; PKA PHOSPHORYLATION; SYNAPTIC PLASTICITY; SCAFFOLD PROTEIN AB The A kinase anchor protein AKAP150 recruits the cAMP-dependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development. C1 [Lu, Yuan; Hall, Duane D.; Strack, Stefan; Hell, Johannes W.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Pharmacol, Iowa City, IA 52242 USA. [Zha, Xiang-ming; Schachtele, Scott; Dailey, Michael E.; Green, Steven H.] Univ Iowa, Coll Liberal Arts & Sci, Dept Biol, Iowa City, IA 52242 USA. [Lu, Yuan] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Zha, Xiang-ming] Univ S Alabama, Coll Med, Dept Cell Biol & Neurosci, Mobile, AL 36688 USA. [Kim, Eun Young; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. [Hell, Johannes W.] Univ Calif Davis, Sch Med, Dept Pharmacol, Davis, CA 95615 USA. RP Lu, Y (reprint author), Magnuson Clin Ctr, Bldg 10,7D38,10 Ctr Dr, Bethesda, MD 20892 USA. EM luyuan@mail.nih.gov; jwhell@ucdavis.edu RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU National Institutes of Health [DA015916, GM032875, NS043254, NS056244, NS057714, DC002961, NS035563, NS017502]; American Heart Association [0655764Z]; University of South Alabama; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported, in whole or in part, by Grants DA015916, GM032875 (to G. S. M.), NS043254, NS056244, NS057714 (to S. S.), DC002961 (to S. H. G.), and NS035563, NS017502 (to J. W. H.) from the National Institutes of Health. This work was also supported by Grant 0655764Z (to M. E. D.) from the American Heart Association, startup funds from the University of South Alabama (to X. M. Z.), and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 74 TC 14 Z9 14 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2011 VL 286 IS 30 BP 26496 EP 26506 DI 10.1074/jbc.M111.254912 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796UK UT WOS:000293078200028 PM 21652711 ER PT J AU Meruvu, S Hugendubler, L Mueller, E AF Meruvu, Sunitha Hugendubler, Lynne Mueller, Elisabetta TI Regulation of Adipocyte Differentiation by the Zinc Finger Protein ZNF638 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING NUCLEAR-PROTEIN; TRANSCRIPTIONAL CONTROL; DOMAIN; ZFP423; FAMILY; MOTIF AB Zinc finger proteins constitute the largest family of transcription regulators in eukaryotes. These factors are involved in diverse processes in many tissues, including development and differentiation. We report here the characterization of the zinc finger protein ZNF638 as a novel regulator of adipogenesis. ZNF638 is induced early during adipocyte differentiation. Ectopic expression of ZNF638 increases adipogenesis in vitro, whereas its knockdown inhibits differentiation and decreases the expression of adipocyte-specific genes. ZNF638 physically interacts and transcriptionally cooperates with CCAAT/enhancer-binding protein (C/EBP) beta and C/EBP delta. This interaction leads to the expression of peroxisome proliferator-activated receptor gamma, which is the key regulator of adipocyte differentiation. In summary, ZNF638 is a novel and early regulator of adipogenesis that works as a transcription cofactor of C/EBPs. C1 [Meruvu, Sunitha; Hugendubler, Lynne; Mueller, Elisabetta] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mueller, E (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Rm 8D12B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM elisabettam@niddk.nih.gov FU National Institutes of Health NIDDK FX This work was supported in whole by the National Institutes of Health NIDDK Intramural Research Program. NR 14 TC 20 Z9 25 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2011 VL 286 IS 30 BP 26516 EP 26523 DI 10.1074/jbc.M110.212506 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796UK UT WOS:000293078200030 PM 21602272 ER PT J AU Dong, SY Wang, Y Cassidy-Amstutz, C Lu, G Bigler, R Jezyk, MR Li, CH Hall, TMT Wang, ZF AF Dong, Shuyun Wang, Yang Cassidy-Amstutz, Caleb Lu, Gang Bigler, Rebecca Jezyk, Mark R. Li, Chunhua Hall, Traci M. Tanaka Wang, Zefeng TI Specific and Modular Binding Code for Cytosine Recognition in Pumilio/FBF (PUF) RNA-binding Domains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID YEAST 3-HYBRID SYSTEM; PROTEIN INTERACTIONS; MYOTONIC-DYSTROPHY; HOMOLOGY DOMAIN; ELEGANS; DISEASE; SMART; MODES; CELLS; VEGF AB Pumilio/fem-3 mRNA-binding factor (PUF) proteins possess a recognition code for bases A, U, and G, allowing designed RNA sequence specificity of their modular Pumilio (PUM) repeats. However, recognition side chains in a PUM repeat for cytosine are unknown. Here we report identification of a cytosine-recognition code by screening random amino acid combinations at conserved RNA recognition positions using a yeast three-hybrid system. This C-recognition code is specific and modular as specificity can be transferred to different positions in the RNA recognition sequence. A crystal structure of a modified PUF domain reveals specific contacts between an arginine side chain and the cytosine base. We applied the C-recognition code to design PUF domains that recognize targets with multiple cytosines and to generate engineered splicing factors that modulate alternative splicing. Finally, we identified a divergent yeast PUF protein, Nop9p, that may recognize natural target RNAs with cytosine. This work deepens our understanding of natural PUF protein target recognition and expands the ability to engineer PUF domains to recognize any RNA sequence. C1 [Dong, Shuyun; Wang, Yang; Bigler, Rebecca; Wang, Zefeng] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Cassidy-Amstutz, Caleb; Lu, Gang; Jezyk, Mark R.; Hall, Traci M. Tanaka] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Cassidy-Amstutz, Caleb] N Carolina State Univ, Program Bioinformat, Raleigh, NC 27695 USA. [Li, Chunhua] Beijing Univ Technol, Coll Life Sci & Bioengn, Beijing 100124, Peoples R China. RP Wang, ZF (reprint author), Univ N Carolina, Dept Pharmacol, CB 7365, Chapel Hill, NC 27599 USA. EM zefeng@med.unc.edu OI Wang, Zefeng/0000-0002-6605-3637; Dong, Shuyun/0000-0003-2988-6864; Bigler, Rebecca/0000-0002-0075-6188 FU National Institute of Environmental Health Sciences; Beckman Foundation; Kimmel Sidney Scholar; United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported, in whole or in part, by a grant from the Intramural Research Program of the National Institute of Environmental Health Sciences (to T. M. T. H.) and by a grant from the Beckman Foundation and the Kimmel Sidney Scholar award (to Z.W.).; We thank Dr. Marvin Wickens (University of Wisconsin) for providing the plasmids and yeast strains for the Y3H assay. We thank Dr. Rajarshi Chudhury for suggestions and help in protein purification, Dr. Chen Qiu for help with RNA binding assays, and Dr. Lars Pedersen and the staff at the SER-CAT beamline for help with X-ray data collection. Data were collected at SER-CAT 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found on-line. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 34 TC 50 Z9 50 U1 1 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2011 VL 286 IS 30 BP 26732 EP 26742 DI 10.1074/jbc.M111.244889 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796UK UT WOS:000293078200050 PM 21653694 ER PT J AU Madsen, DH Ingvarsen, S Jurgensen, HJ Melander, MC Kjoller, L Moyer, A Honore, C Madsen, CA Garred, P Burgdorf, S Bugge, TH Behrendt, N Engelholm, LH AF Madsen, Daniel H. Ingvarsen, Signe Jurgensen, Henrik J. Melander, Maria C. Kjoller, Lars Moyer, Amanda Honore, Christian Madsen, Charlotte A. Garred, Peter Burgdorf, Sven Bugge, Thomas H. Behrendt, Niels Engelholm, Lars H. TI The Non-phagocytic Route of Collagen Uptake A DISTINCT DEGRADATION PATHWAY SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMINOGEN-ACTIVATOR RECEPTOR; MACROPHAGE MANNOSE RECEPTOR; TUMOR-CELL LINES; UROKINASE RECEPTOR; HUMAN-FIBROBLASTS; MONOCLONAL-ANTIBODIES; ENDOTHELIAL-CELLS; TRANSMEMBRANE GLYCOPROTEIN; BINDING-PROPERTIES; LECTIN RECEPTOR AB The degradation of collagens, the most abundant proteins of the extracellular matrix, is involved in numerous physiological and pathological conditions including cancer invasion. An important turnover pathway involves cellular internalization and degradation of large, soluble collagen fragments, generated by initial cleavage of the insoluble collagen fibers. We have previously observed that in primary mouse fibroblasts, this endocytosis of collagen fragments is dependent on the receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180. Others have identified additional mechanisms of collagen uptake, with different associated receptors, in other cell types. These receptors include beta 1-integrins, being responsible for collagen phagocytosis, and the mannose receptor. We have now utilized a newly developed monoclonal antibody against uPARAP/Endo180, which down-regulates the receptor protein level on treated cells, to examine the role of uPARAP/Endo180 as a mediator of collagen internalization by a wide range of cultured cell types. With the exception of macrophages, all cells that proved capable of efficient collagen internalization were of mesenchymal origin and all of these utilized uPARAP/Endo180 for their collagen uptake process. Macrophages internalized collagen in a process mediated by the mannose receptor, a protein belonging to the same protein family as uPARAP/Endo180. beta 1-Integrins were found not to be involved in the endocytosis of soluble collagen, irrespectively of whether this was mediated by uPARAP/Endo180 or the mannose receptor. This further distinguishes these pathways from the phagocytic uptake of particulate collagen. C1 [Madsen, Daniel H.; Ingvarsen, Signe; Jurgensen, Henrik J.; Melander, Maria C.; Kjoller, Lars; Madsen, Charlotte A.; Behrendt, Niels; Engelholm, Lars H.] Rigshosp, Finsen Lab BRIC, DK-2200 Copenhagen, Denmark. [Honore, Christian; Garred, Peter] Rigshosp, Dept Clin Immunol, Mol Med Lab, DK-2200 Copenhagen, Denmark. [Ingvarsen, Signe] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark. [Moyer, Amanda; Bugge, Thomas H.] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Burgdorf, Sven] Univ Bonn, Life & Med Sci LIMES Inst, D-53115 Bonn, Germany. RP Engelholm, LH (reprint author), Copenhagen Bioctr, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. EM lhe@finsenlab.dk OI Madsen, Daniel Hargboel/0000-0002-3183-6201; Engelholm, Lars/0000-0002-6616-1232 FU National Institutes of Health NIDCR; Danish Cancer Society; Danish Medical Research Council; Danish Cancer Research Foundation; Lundbeck Foundation; Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer); European Community [201279]; "Grosserer Alfred Nielsen og Hustrus" foundation; Copenhagen University Hospital; University of Copenhagen, Faculty of Science FX This work was supported, in whole or in part, by the National Institutes of Health NIDCR Intramural Research Program (to A. M. and T. H. B.), the Danish Cancer Society, the Danish Medical Research Council, the Danish Cancer Research Foundation, the Lundbeck Foundation, the Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer), European Community's Seventh Framework Programme FP7/2007-2011 Grant 201279 (to N. B.), grants from the Lundbeck Foundation and the "Grosserer Alfred Nielsen og Hustrus" foundation (to L. H. E.), the Copenhagen University Hospital (to D. H. M. and H. J. J.), and the University of Copenhagen, Faculty of Science (to S. I.). NR 81 TC 45 Z9 45 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2011 VL 286 IS 30 BP 26996 EP 27010 DI 10.1074/jbc.M110.208033 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796UK UT WOS:000293078200073 PM 21652704 ER PT J AU van Hees, VT Renstrom, F Wright, A Gradmark, A Catt, M Chen, KY Lof, M Bluck, L Pomeroy, J Wareham, NJ Ekelund, U Brage, S Franks, PW AF van Hees, Vincent T. Renstrom, Frida Wright, Antony Gradmark, Anna Catt, Michael Chen, Kong Y. Lof, Marie Bluck, Les Pomeroy, Jeremy Wareham, Nicholas J. Ekelund, Ulf Brage, Soren Franks, Paul W. TI Estimation of Daily Energy Expenditure in Pregnant and Non-Pregnant Women Using a Wrist-Worn Tri-Axial Accelerometer SO PLOS ONE LA English DT Article ID DOUBLY-LABELED-WATER; PHYSICAL-ACTIVITY; VALIDATION; ADULTS AB Background: Few studies have compared the validity of objective measures of physical activity energy expenditure (PAEE) in pregnant and non-pregnant women. PAEE is commonly estimated with accelerometers attached to the hip or waist, but little is known about the validity and participant acceptability of wrist attachment. The objectives of the current study were to assess the validity of a simple summary measure derived from a wrist-worn accelerometer (GENEA, Unilever Discover, UK) to estimate PAEE in pregnant and non-pregnant women, and to evaluate participant acceptability. Methods: Non-pregnant (N = 73) and pregnant (N = 35) Swedish women (aged 20-35 yrs) wore the accelerometer on their wrist for 10 days during which total energy expenditure (TEE) was assessed using doubly-labelled water. PAEE was calculated as 0.96TEE-REE. British participants (N = 99; aged 22-65 yrs) wore accelerometers on their non-dominant wrist and hip for seven days and were asked to score the acceptability of monitor placement (scored 1 [least] through 10 [most] acceptable). Results: There was no significant correlation between body weight and PAEE. In non-pregnant women, acceleration explained 24% of the variation in PAEE, which decreased to 19% in leave-one-out cross-validation. In pregnant women, acceleration explained 11% of the variation in PAEE, which was not significant in leave-one-out cross-validation. Median (IQR) acceptability of wrist and hip placement was 9(8-10) and 9(7-10), respectively; there was a within-individual difference of 0.47 (p < .001). Conclusions: A simple summary measure derived from a wrist-worn tri-axial accelerometer adds significantly to the prediction of energy expenditure in non-pregnant women and is scored acceptable by participants. C1 [van Hees, Vincent T.; Wareham, Nicholas J.; Ekelund, Ulf; Brage, Soren] Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. [Renstrom, Frida; Gradmark, Anna; Franks, Paul W.] Umea Univ Hosp, Genet Epidemiol & Clin Res Grp, Med Sect, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. [Renstrom, Frida; Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Wright, Antony; Bluck, Les] Med Res Council Human Nutr Res, Cambridge, England. [Catt, Michael] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Chen, Kong Y.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. [Lof, Marie] Linkoping Univ, Dept Clin & Expt Med, Div Nutr, Linkoping, Sweden. [Pomeroy, Jeremy] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP van Hees, VT (reprint author), Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. EM vincent.vanhees@mrc-epid.cam.ac.uk RI Brage, Soren/C-6415-2013; OI Brage, Soren/0000-0002-1265-7355; Franks, Paul/0000-0002-0520-7604; Chen, Kong/0000-0002-0306-1904 FU LifeGene (Torsten and Ragnar Soderbergs Foundation); Fredrik and Ingrid Thurings Foundation; Umea University; Vasterbottens regional health authority FX This work was supported by Grants from LifeGene (Torsten and Ragnar Soderbergs Foundation), Fredrik and Ingrid Thurings Foundation, Umea University Young Investigator's Award, and the Vasterbottens regional health authority (all grants to PWF). LifeGene is a charity, by which no commercial interests are involved (https://www.lifegene.se/In-english/). GENEA monitors in the Swedish study were loaned pro gratis from Unilever Discover Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 45 Z9 45 U1 1 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 JUL 29 PY 2011 VL 6 IS 7 AR e22922 DI 10.1371/journal.pone.0022922 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799KV UT WOS:000293286500052 PM 21829556 ER PT J AU Janssen, MJ Yasuda, RP Vicini, S AF Janssen, Megan J. Yasuda, Robert P. Vicini, Stefano TI GABA(A) receptor beta 3 subunit expression regulates tonic current in developing striatopallidal medium spiny neurons SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE GABA; tonic inhibition; striatum; patch-clamp; Cre-lox genetics ID CHILDHOOD ABSENCE EPILEPSY; A RECEPTOR; BETA(3) SUBUNIT; ELECTROPHYSIOLOGICAL PROPERTIES; GABAERGIC INTERNEURONS; GENE-EXPRESSION; MICE LACKING; NETWORK; MODULATION; ACTIVATION AB The striatum is a key structure for movement control, but the mechanisms that dictate the output of distinct subpopulations of medium spiny projection neurons (MSNs), striatonigral projecting and dopamine D1 receptor-(D1+) or striatopallidal projecting and dopamine D2 receptor-(D2+) expressing neurons, remains poorly understood. GABA-mediated tonic inhibition largely controls neuronal excitability and action potential firing rates, and we previously suggested with pharmacological analysis that the GABA(A) receptor beta 3 subunit plays a large role in the basal tonic current seen in D2+ MSNs from young mice (Ade et al., 2008; Janssen et al., 2009). In this study, we demonstrated the essential role of the beta 3 GABA(A) receptor subunit in mediating MSN tonic currents using conditional beta 3 subunit knock-out(beta 3f/f(Drd2)) mice. Cre-lox genetics were used to generate mice where Cre recombinase was expressed under the D2 receptor (Drd2) promoter. We show that while the wild-type MSN tonic current pattern demonstrates a high degree of variability, tonic current patterns from beta 3f/f(Drd2) mice are narrow, suggesting that the beta 3 subunit is essential to striatal MSN GABA-mediated tonic current. Our data also suggest that a distinct population of synaptic receptors upregulate due to beta 3 subunit removal. Further, deletion of this subunit significantly decreases the D2+ MSN excitability. These results offer insight for target mechanisms in Parkinson's disease, where symptoms arise due to the imbalance in striatal D1+ and D2+ MSN excitability and output. C1 [Janssen, Megan J.; Yasuda, Robert P.; Vicini, Stefano] Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, Washington, DC USA. [Vicini, Stefano] Georgetown Univ, Sch Med, Interdisciplinary Program Neurosci, Washington, DC USA. RP Janssen, MJ (reprint author), NICHD, Mol Neurobiol Sect, NIH, Bldg 35,Room 2C-1001,35 Lincoln Dr, Bethesda, MD 20892 USA. EM megan.janssen-schroeder@nih.gov FU NIH [MH64797] FX We thank Dr. David Lovinger at the National Institute on Alcoholism and Alcohol Abuse for providing the BAC-D2-EGFP mice, Dr. Nicole Calakos from Duke University for the Drd1a-tdTomato mice, and Dr. Baoji Xu at Georgetown University for providing the Drd2-Cre mice. The authors also appreciate the technical assistance of Patrick Forcelli and Patrick Hussman from Georgetown University. Supported by: NIH grant MH64797. NR 45 TC 13 Z9 13 U1 0 U2 3 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD JUL 28 PY 2011 VL 5 AR 15 DI 10.3389/fncel.2011.00015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 886ZY UT WOS:000299895900001 PM 21847370 ER PT J AU Song, G Hsu, CH Riemer, C Zhang, Y Kim, HL Hoffmann, F Zhang, LX Hardison, RC Green, ED Miller, W AF Song, Giltae Hsu, Chih-Hao Riemer, Cathy Zhang, Yu Kim, Hie Lim Hoffmann, Federico Zhang, Louxin Hardison, Ross C. Green, Eric D. Miller, Webb CA NISC Comparative Sequencing TI Conversion events in gene clusters SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; TOBACCO-SPECIFIC CARCINOGEN; HUMAN CYP2A13 GENE; GLOBIN GENES; FUNCTIONAL-CHARACTERIZATION; METABOLIC-ACTIVATION; SEQUENCE ALIGNMENTS; LUNG ADENOCARCINOMA; GAMMA-GLOBIN; EVOLUTION AB Background: Gene clusters containing multiple similar genomic regions in close proximity are of great interest for biomedical studies because of their associations with inherited diseases. However, such regions are difficult to analyze due to their structural complexity and their complicated evolutionary histories, reflecting a variety of large-scale mutational events. In particular, conversion events can mislead inferences about the relationships among these regions, as traced by traditional methods such as construction of phylogenetic trees or multi-species alignments. Results: To correct the distorted information generated by such methods, we have developed an automated pipeline called CHAP (Cluster History Analysis Package) for detecting conversion events. We used this pipeline to analyze the conversion events that affected two well-studied gene clusters (alpha-globin and beta-globin) and three gene clusters for which comparative sequence data were generated from seven primate species: CCL (chemokine ligand), IFN (interferon), and CYP2abf (part of cytochrome P450 family 2). CHAP is freely available at http://www.bx.psu.edu/miller_lab. Conclusions: These studies reveal the value of characterizing conversion events in the context of studying gene clusters in complex genomes. C1 [Song, Giltae; Riemer, Cathy; Zhang, Yu; Kim, Hie Lim; Hardison, Ross C.; Miller, Webb] Penn State Univ, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. [Hsu, Chih-Hao] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Hoffmann, Federico] Mississippi State Univ, Dept Biochem & Mol Biol, Mississippi State, MS 39760 USA. [Zhang, Louxin] Natl Univ Singapore, Dept Math, Singapore 117543, Singapore. [Green, Eric D.] NHGRI, NISC, NIH, Bethesda, MD 20892 USA. [Green, Eric D.; NISC Comparative Sequencing] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Song, G (reprint author), Penn State Univ, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. EM gsong@bx.psu.edu RI Zhang, Louxin /M-4865-2016; Kim, Hie Lim/E-7393-2017; OI Zhang, Louxin /0000-0003-0260-824X; Kim, Hie Lim/0000-0003-3080-9524; Song, Giltae/0000-0001-8796-4678 FU National Human Genome Research Institute [HG02238]; National Institute of Diabetes, Digestive and Kidney Diseases [DK065806] FX This work was supported by grant HG02238 to WM from the National Human Genome Research Institute and grant DK065806 to RCH from the National Institute of Diabetes, Digestive and Kidney Diseases. NR 54 TC 7 Z9 7 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD JUL 28 PY 2011 VL 11 AR 226 DI 10.1186/1471-2148-11-226 PG 18 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 811DV UT WOS:000294183300001 PM 21798034 ER PT J AU Kotowski, SJ Hopf, FW Seif, T Bonci, A von Zastrow, M AF Kotowski, Sarah J. Hopf, F. Woodward Seif, Taban Bonci, Antonello von Zastrow, Mark TI Endocytosis Promotes Rapid Dopaminergic Signaling SO NEURON LA English DT Article ID AGONIST-INDUCED DESENSITIZATION; D1A RECEPTOR RESPONSIVENESS; PROTEIN-COUPLED RECEPTORS; STRIATAL NEURONS; D-1 RECEPTOR; PLASMA-MEMBRANE; SYNAPTIC-TRANSMISSION; RECYCLING SIGNAL; PRIMARY CULTURES; IN-VIVO AB D(1) dopamine receptors are primary mediators of dopaminergic signaling in the CNS. These receptors internalize rapidly following agonist-induced activation, but the functional significance of this process is unknown. We investigated D(1) receptor endocytosis and signaling in HEK293 cells and cultured striatal neurons using real-time fluorescence imaging and cAMP biosensor technology. Agonist-induced activation of D(1) receptors promoted endocytosis of receptors with a time course overlapping that of acute cAMP accumulation. Inhibiting receptor endocytosis blunted acute D(1) receptor-mediated signaling in both dissociated cells and striatal slice preparations. Although endocytic inhibition markedly attenuated acute cAMP accumulation, inhibiting the subsequent recycling of receptors had no effect. Further, D(1) receptors localized in close proximity to endomembrane-associated trimeric G protein and adenylyl cyclase immediately after endocytosis. Together, these results suggest a previously unanticipated role of endocytosis, and the early endocytic pathway, in supporting rapid dopaminergic neurotransmission. C1 [Kotowski, Sarah J.; von Zastrow, Mark] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94158 USA. [Kotowski, Sarah J.; von Zastrow, Mark] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Kotowski, Sarah J.] Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94143 USA. [Hopf, F. Woodward; Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Hopf, F. Woodward; Seif, Taban; Bonci, Antonello] Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. [Bonci, Antonello] NIDA, Baltimore, MD 21224 USA. RP von Zastrow, M (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94158 USA. EM mark.vonzastrow@ucsf.edu FU National Institutes of Health [DA-010711, DA-010154, MH-24468, AAA-015358]; State of California for medical research on alcohol and substance abuse through the University of California, San Francisco FX We thank Dr. Martin Lohse (University of Wurzburg, Germany) for providing the Epac1 cAMPs construct and Dr. Tomas Kirchhausen (Harvard Medical School) for providing dynasore, used in initial experiments and instructions for its effective use. Data for this study were collected at the Nikon Imaging Center (NIC) at the University of California, San Francisco. We are grateful to Dr. Kurt Thorn, Director of the NIC, for valuable instruction and advice. We also thank Drs. Guillermo Yudowski and Kit Wong for advice and assistance and Dr. Jin Tomshine for useful discussion. This work was supported by grants from the National Institutes of Health (DA-010711 and DA-010154 to M.Z., MH-24468 to S.J.K., AAA-015358 to F.W.H.) and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B.). NR 60 TC 51 Z9 52 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 28 PY 2011 VL 71 IS 2 BP 278 EP 290 DI 10.1016/j.neuron.2011.05.036 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 801JF UT WOS:000293433900012 PM 21791287 ER PT J AU Kumar, J Schuck, P Mayer, ML AF Kumar, Janesh Schuck, Peter Mayer, Mark L. TI Structure and Assembly Mechanism for Heteromeric Kainate Receptors SO NEURON LA English DT Article ID N-TERMINAL DOMAIN; GLUTAMATE-RECEPTOR; NMDA RECEPTORS; LIGAND-BINDING; AMPA RECEPTORS; ENDOPLASMIC-RETICULUM; PROTEIN INTERACTIONS; SYNAPSE FORMATION; CRYSTAL-STRUCTURE; EPHB RECEPTORS AB Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5-7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of K(d) 11 nM, 32,000-fold lower than the K(d) for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors. C1 [Kumar, Janesh; Mayer, Mark L.] NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. [Schuck, Peter] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, DHHS, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov RI Mayer, Mark/H-5500-2013; OI Schuck, Peter/0000-0002-8859-6966 FU National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Science [Y1-GM-1104]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; NICHD; NIBIB, NIH, DHHS FX We thank Carla Glasser and Andrea Balbo for technical assistance and Drs. Peter Kwong and Yongping Yang for advice with suspension cell cultures. Nucleic acid sequencing was performed by the NINDS DNA sequencing facility. Synchrotron diffraction data was collected at the GM/CA CAT 23 ID-B beamline. GM/CA CAT has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. This work was supported by the intramural research programs of NICHD and NIBIB, NIH, DHHS (M.L.M. and P.S.). NR 62 TC 60 Z9 63 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 28 PY 2011 VL 71 IS 2 BP 319 EP 331 DI 10.1016/j.neuron.2011.05.038 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 801JF UT WOS:000293433900015 PM 21791290 ER PT J AU Keele, BF Estes, JD AF Keele, Brandon F. Estes, Jacob D. TI Barriers to mucosal transmission of immunodeficiency viruses SO BLOOD LA English DT Review ID SIV VAGINAL TRANSMISSION; INTESTINAL MUCUS BARRIER; FEMALE RHESUS-MACAQUES; INTRAVAGINAL INOCULATION; HIV-1 INFECTION; HETEROSEXUAL TRANSMISSION; SEXUAL TRANSMISSION; GENITAL-TRACT; MALE CIRCUMCISION; DENDRITIC CELLS AB Lentiviruses such as HIV have a daunting challenge in gaining access to a new host predominantly through the penile, rectal, or vaginal/cervical mucosal tissue after sexual exposure. Multiple mechanisms have evolved to help prevent such infections, including anatomical barriers, innate inhibitors, and adaptive immune responses. For lentiviruses, it appears that in naive or even conventionally vaccinated hosts, typical adaptive immune responses are generally too little and too late to prevent infection. Nevertheless, a combination of anatomical barriers and innate immune responses may limit transmission, especially in patients without predisposing conditions such as mucosal lesions or preexisting sexually transmitted infections. Furthermore, when infection does occur, most often the primary viremia of the acute infection can be traced back genetically to a single founder virus. Unfortunately, even a single virion can establish an infection that will ultimately lead to the demise of the host. This review seeks to describe the biology of and barriers to establishment of systemic, disseminated productive infection with HIV after sexual exposure and to discuss the possible mechanisms leading to infection by a single viral variant. Understanding the initial events of infection, before systemic spread, could provide insights into strategies for reducing acquisition or ameliorating clinical outcome. (Blood. 2011;118(4):839-846) C1 [Keele, Brandon F.; Estes, Jacob D.] NCI, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21702 USA. RP Keele, BF (reprint author), NCI, AIDS & Canc Virus Program, SAIC Frederick, 1050 Boyles St, Frederick, MD 21702 USA. EM keelebf@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN266200400088C] FX This work was supported with federal funds from the National Cancer Institute, National Institutes of Health under contract HHSN266200400088C. This work represents the opinions of the authors and not necessarily the National Institutes of Health or the Department of Health and Human Services. NR 72 TC 41 Z9 41 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 28 PY 2011 VL 118 IS 4 BP 839 EP 846 DI 10.1182/blood-2010-12-325860 PG 8 WC Hematology SC Hematology GA 798PC UT WOS:000293221700009 PM 21555745 ER PT J AU Brenchley, JM Paiardini, M AF Brenchley, Jason M. Paiardini, Mirko TI Immunodeficiency lentiviral infections in natural and non-natural hosts SO BLOOD LA English DT Review ID CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; HUMORAL IMMUNE-RESPONSES; ACUTE SIV INFECTION; SOOTY MANGABEYS; HIV-1 INFECTION; VIRUS-REPLICATION; RHESUS MACAQUES; GASTROINTESTINAL-TRACT; DISEASE PROGRESSION AB The host immune system is profoundly affected during the acute phase of progressive immunodeficiency lentiviral infections. Studies of these alterations have been quite restricted in humans because of the limited availability of samples from acutely HIV-infected persons. Therefore, numerous studies have turned attention to nonhuman primate models. Specifically, SIV-infected rhesus macaques (RMs) have been informative for understanding the pathogenesis of HIV infection in humans. Indeed, advantages of the nonhuman primate model include the ability to study the very early events after infection and the ability to retrieve copious amounts of tissues. In addition, nonhuman primates allow for comparative studies between non-natural and natural hosts for SIV, in which SIV infection results in progression, or not, to AIDS, respectively. Although SIV infection of RM is the best model for HIV infection, the immunologic and/or virologic phenomena in SIV-infected RM do not always reflect those seen in HIV-infected humans. Here virologic and immunologic aspects of acute HIV infection of humans and SIV infection of Asian and African nonhuman primates are discussed and compared in relation to how these aspects relate to disease progression. (Blood. 2011;118(4):847-854) C1 [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Paiardini, Mirko] Emory Univ, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike,Bldg 4,Rm 301, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov; mirko.paiardini@emory.edu FU National Institutes of Health [R01 AI084836]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported in part by the National Institutes of Health (grant R01 AI084836; M.P.) and the intramural National Institute of Allergy and Infectious Diseases, National Institutes of Health program. NR 100 TC 23 Z9 23 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 28 PY 2011 VL 118 IS 4 BP 847 EP 854 DI 10.1182/blood-2010-12-325936 PG 8 WC Hematology SC Hematology GA 798PC UT WOS:000293221700010 PM 21505193 ER PT J AU Machado, RF Barst, RJ Yovetich, NA Hassell, KL Kato, GJ Gordeuk, VR Gibbs, JSR Little, JA Schraufnagel, DE Krishnamurti, L Girgis, RE Morris, CR Rosenzweig, EB Badesch, DB Lanzkron, S Onyekwere, O Castro, OL Sachdev, V Waclawiw, MA Woolson, R Goldsmith, JC Gladwin, MT AF Machado, Roberto F. Barst, Robyn J. Yovetich, Nancy A. Hassell, Kathryn L. Kato, Gregory J. Gordeuk, Victor R. Gibbs, J. Simon R. Little, Jane A. Schraufnagel, Dean E. Krishnamurti, Lakshmanan Girgis, Reda E. Morris, Claudia R. Rosenzweig, Erika B. Badesch, David B. Lanzkron, Sophie Onyekwere, Onyinye Castro, Oswaldo L. Sachdev, Vandana Waclawiw, Myron A. Woolson, Rob Goldsmith, Jonathan C. Gladwin, Mark T. CA Walk-PhaSST Investigators Patients TI Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity SO BLOOD LA English DT Article ID NITRIC-OXIDE SYNTHASE; PULMONARY ARTERIAL-HYPERTENSION; SYSTOLIC HEART-FAILURE; PHARMACOLOGICAL INHIBITION; THERMAL HYPERALGESIA; INFLAMMATORY PAIN; GENETIC KNOCKOUT; INOS-DEFICIENT; MICE; HEMOLYSIS AB In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV >= 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P =.022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P =.029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [ 95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531. (Blood. 2011;118(4):855-864) C1 [Gladwin, Mark T.] Univ Pittsburgh, UPMC Montefiore Hosp, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Machado, Roberto F.; Schraufnagel, Dean E.] Univ Illinois, Chicago, IL USA. [Barst, Robyn J.; Rosenzweig, Erika B.] Columbia Univ, New York, NY USA. [Yovetich, Nancy A.; Woolson, Rob] Rho Inc, Chapel Hill, NC USA. [Hassell, Kathryn L.; Badesch, David B.] Univ Colorado, Denver, CO 80202 USA. [Kato, Gregory J.; Sachdev, Vandana] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Gordeuk, Victor R.; Onyekwere, Onyinye; Castro, Oswaldo L.] Howard Univ, Washington, DC 20059 USA. [Gibbs, J. Simon R.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Little, Jane A.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Girgis, Reda E.; Lanzkron, Sophie] Johns Hopkins Univ, Baltimore, MD USA. [Morris, Claudia R.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Waclawiw, Myron A.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, UPMC Montefiore Hosp, Div Pulm Allergy & Crit Care Med, NW628,3459 5th Ave, Pittsburgh, PA 15213 USA. EM gladwinmt@upmc.edu RI Krishnamurti, Lakshmanan/F-7637-2011; Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Schraufnagel, Dean/0000-0003-0063-7223 FU NIH [UL1 RR024131]; NIHR Biomedical Research Centre; NHLBI, NIH, Department of Health and Human Services [HHSN268200617182C] FX This work was supported in part by an NIH Clinical and Translational Science Award (UL1 RR024131 to C.R.M.) and a NIHR Biomedical Research Centre grant (to J.S.R.G.). Study drug and placebo were donated by Pfizer Inc (New York, NY). This project was funded with federal funds from the NHLBI, NIH, Department of Health and Human Services, under contract HHSN268200617182C. NR 37 TC 73 Z9 74 U1 3 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 28 PY 2011 VL 118 IS 4 BP 855 EP 864 DI 10.1182/blood-2010-09-306167 PG 10 WC Hematology SC Hematology GA 798PC UT WOS:000293221700011 PM 21527519 ER PT J AU Yang, SC Liu, F Wang, QJ Rosenberg, SA Morgan, RA AF Yang, Shicheng Liu, Fang Wang, Qiong J. Rosenberg, Steven A. Morgan, Richard A. TI The Shedding of CD62L (L-Selectin) Regulates the Acquisition of Lytic Activity in Human Tumor Reactive T Lymphocytes SO PLOS ONE LA English DT Article ID CENTRAL MEMORY; CELL SUBSETS; SECRETORY LYSOSOMES; EFFECTOR FUNCTION; GENE-EXPRESSION; CD8+T CELLS; RECEPTOR; ADHESION; ANTIGEN; IDENTIFICATION AB CD62L/L-selectin is a marker found on naive T cells and further distinguishes central memory (Tcm, CD62L+) from effector memory (Tem, CD62L-) T cells. The regulation of CD62L plays a pivotal role in controlling the traffic of T lymphocytes to and from peripheral lymph nodes. CD62L is shed from the cell membrane following T cell activation, however, the physiological significance of this event remains to be elucidated. In this study, we utilized in vitro generated anti-tumor antigen T cells and melanoma lines as a model to evaluate the dynamics of CD62L shedding and expression of CD107a as a marker of lytic activity. Upon encounter, with matched tumor lines, antigen reactive T cells rapidly lose CD62L expression and this was associated with the acquisition of CD107a. By CD62L ELISA, we confirmed that this transition was mediated by the shedding of CD62L when T cells encountered specific tumor antigen. The introduction of a shedding resistant mutant of CD62L into the tumor antigen-reactive T cell line JKF6 impaired CD107a acquisition following antigen recognition and this was correlated with decreased lytic activity as measured by (51)Cr release assays. The linkage of the shedding of CD62L from the surface of anti-tumor T cells and acquisition of lytic activity, suggests a new function for CD62L in T cell effector functions and anti-tumor activity. C1 [Yang, Shicheng; Liu, Fang; Wang, Qiong J.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Yang, SC (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU Center for Cancer Research, National Cancer Institute; National Institutes of Health, Bethesda, Maryland, United States of America FX This work was supported by Intramural Research Program of the Center for Cancer Research, National Cancer Institute, and the National Institutes of Health, Bethesda, Maryland, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 32 Z9 33 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2011 VL 6 IS 7 AR e22560 DI 10.1371/journal.pone.0022560 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799KC UT WOS:000293284600018 PM 21829468 ER PT J AU Li, FY Chaigne-Delalande, B Kanellopoulou, C Davis, JC Matthews, HF Douek, DC Cohen, JI Uzel, G Su, HC Lenardo, MJ AF Li, Feng-Yen Chaigne-Delalande, Benjamin Kanellopoulou, Chrysi Davis, Jeremiah C. Matthews, Helen F. Douek, Daniel C. Cohen, Jeffrey I. Uzel, Gulbu Su, Helen C. Lenardo, Michael J. TI Second messenger role for Mg2+ revealed by human T-cell immunodeficiency SO NATURE LA English DT Article ID X-CHROMOSOME INACTIVATION; HIV-INFECTION; ACQUIRED-IMMUNODEFICIENCY; LYMPHOCYTE-PROLIFERATION; MAGNESIUM HOMEOSTASIS; EMBRYONIC-DEVELOPMENT; SIGNAL-TRANSDUCTION; PERIPHERAL-BLOOD; ACTIVATION; CALCIUM AB The magnesium ion, Mg2+, is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca2+ does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg2+ influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg2+ influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase C gamma 1 and a markedly impaired Ca2+ influx in T cells but not B cells. These observations reveal a role for Mg2+ as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics. C1 [Li, Feng-Yen; Chaigne-Delalande, Benjamin; Kanellopoulou, Chrysi; Matthews, Helen F.; Lenardo, Michael J.] NIAID, Mol Dev Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, Bethesda, MD 20892 USA. [Li, Feng-Yen] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA. [Davis, Jeremiah C.; Su, Helen C.] NIAID, Human Immunol Dis Unit, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Cohen, Jeffrey I.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Li, FY (reprint author), NIAID, Mol Dev Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, Bethesda, MD 20892 USA. EM lenardo@nih.gov RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health FX We thank L. Zheng, A. Weiss, R. Germain, R. Siegel, F. Wolf and P. Schwartzberg for critically reading the manuscript; F. Wolf for advice on magnesium assessments; L. Zheng, C. Lowell and A. Weiss for advice on experiments and data; H. Jing for making HVS lines from patient cells; P. Chen for assistance with plasmid DNA preparation; N. Sandler for flow cytometry assistance; A. Snow and H. Jing for assistance with genomic DNA library preparation for Solexa sequencing; J. Almenara and Illumina staff for Solexa assistance; D. Killilea for assistance with MS-ICP data interpretation; and A. Irani for referring the patients. F.-Y.L. is in the Medical Scientist Training Program at the University of California-San Francisco and thanks K. Shannon and J. Toutolmin for support and encouragement. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. NR 51 TC 152 Z9 157 U1 4 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 28 PY 2011 VL 475 IS 7357 BP 471 EP U63 DI 10.1038/nature10246 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797ZA UT WOS:000293167900034 PM 21796205 ER PT J AU Peterson, KE Cinelli, MA Morrell, AE Mehta, A Dexheimer, TS Agama, K Antony, S Pommier, Y Cushman, M AF Peterson, Katherine E. Cinelli, Maris A. Morrell, Andrew E. Mehta, Akhil Dexheimer, Thomas S. Agama, Keli Antony, Smitha Pommier, Yves Cushman, Mark TI Alcohol-, Diol-, and Carbohydrate-Substituted Indenoisoquinolines as Topoisomerase I Inhibitors: Investigating the Relationships Involving Stereochemistry, Hydrogen Bonding, and Biological Activity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PLANT ANTITUMOR AGENTS; DNA CLEAVAGE; REBECCAMYCIN ANALOGS; NITRATED INDENOISOQUINOLINES; MJ-III-65 NSC-706744; ANTICANCER AGENTS; CAMPTOTHECIN; BINDING; INDOLOCARBAZOLE; DERIVATIVES AB The DNA-relaxing enzyme topoisomerase I (Top 1) can be inhibited by heterocyclic compounds such as indolocarbazoles and indenoisoquinolines. Carbohydrate and hydroxyl-containing side chains are essential for the biological activity of indolocarbazoles. The current study investigated how similar functionalities could be "translated" to the indenoisoquinoline system and how stereochemistry and hydrogen bonding affect biological activity. Herein is described the preparation and assay of indenoisoquinolines substituted with short-chain alcohols, diols, and carbohydrates. Several compounds (including those derived from sugars) display potent Top1 poisoning and antiproliferative activities. The Top1 poisoning activity of diol-substituted indenoisoquinolines is dependent upon stereochemistry. Although the effect is striking, molecular modeling and docking studies do not indicate any reason for the difference in activity due to similar calculated interactions between the ligand and Top1-DNA complex and ambiguity about the binding mode. A stereo chemical dependence was also observed for carbohydrate-derived indenoisoquinolines. Although similar trends were observed in other classes of Top1 inhibitors, the exact nature of this effect has yet to be elucidated. C1 [Peterson, Katherine E.; Cinelli, Maris A.; Morrell, Andrew E.; Mehta, Akhil; Cushman, Mark] Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. [Peterson, Katherine E.; Cinelli, Maris A.; Morrell, Andrew E.; Mehta, Akhil; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Dexheimer, Thomas S.; Agama, Keli; Antony, Smitha; 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@pharmacy.purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566]; Purdue University; Purdue Research Foundation [203202]; DCTD, National Cancer Institute [NO1-CO-56000]; NIH, National Cancer Institute, Center for Cancer Research FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grant UO1 CA89566, by the Frederick N. Andrews Fellowship sponsored by Purdue University (K.E.P.), and by a Purdue Research Foundation Grant (no. 203202, MAC.). In vitro cytotoxicity testing was conducted through the Developmental Therapeutics Program, DCTD, National Cancer Institute, under contract NO1-CO-56000. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. MAC. thanks Dr. Karl Wood, Evgeny Kiselev, and Dr. Xiangshu Xiao (Oregon Health and Science University) for valuable discussions. NR 68 TC 23 Z9 24 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2011 VL 54 IS 14 BP 4937 EP 4953 DI 10.1021/jm101338z PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 794JO UT WOS:000292892300001 PM 21710981 ER PT J AU Goldsborough, AS Handley, MD Dulcey, AE Pluchino, KM Kannan, P Brimacombe, KR Hall, MD Griffiths, G Gottesman, MM AF Goldsborough, Andrew S. Handley, Misty D. Dulcey, Andres E. Pluchino, Kristen M. Kannan, Pavitra Brimacombe, Kyle R. Hall, Matthew D. Griffiths, Gary Gottesman, Michael M. TI Collateral Sensitivity of Multidrug-Resistant Cells to the Orphan Drug Tiopronin SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID P-GLYCOPROTEIN; LINES; CANCER; TOXICITY; NEOCARZINOSTATIN; TRANSPORTERS; EXPRESSION; COLCHICINE; INHIBITORS; TUBULIN AB A major challenge in the treatment of cancer is multidrug resistance (MDR) that develops during chemotherapy. Here we demonstrate that tiopronin (1), a thiol-substituted N-propanoylglycine derivative, was selectively toxic to a series of cell lines expressing the drug efflux pump P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1). Treatment of MDR cells with 1 led to instability of the ABCB1 mRNA and consequently a reduction in P-gp protein, despite functional assays demonstrating that tiopronin does not interact with P-gp. Long-term exposure of P-gp-expressing cells to 1 sensitized them to doxorubicin and paclitaxel, both P-gp substrates. Treatment of MRP1-overexpressing cells with tiopronin led to a significant reduction in MRP1 protein. Synthesis and screening of analogues of tiopronin demonstrated that the thiol functional group was essential for collateral sensitivity while substitution of the amino acid backbone altered but did not destroy specificity, pointing to future development of targeted analogues. C1 [Goldsborough, Andrew S.; Handley, Misty D.; Pluchino, Kristen M.; Brimacombe, Kyle R.; Hall, Matthew D.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Dulcey, Andres E.; Griffiths, Gary] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA. [Kannan, Pavitra] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM gottesmm@mail.nih.gov OI Kannan, Pavitra/0000-0002-9170-6062 FU National Institutes of Health; National Cancer Institute; National Heart, Lung, and Blood Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and National Heart, Lung, and Blood Institute. We thank George Leiman for editorial assistance. We thank King-Leung Fung for the gift of LLC-PK1 cells. NR 38 TC 18 Z9 20 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2011 VL 54 IS 14 BP 4987 EP 4997 DI 10.1021/jm2001663 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 794JO UT WOS:000292892300005 PM 21657271 ER PT J AU Romagnoli, R Baraldi, PG Brancale, A Ricci, A Hamel, E Bortolozzi, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Brancale, Andrea Ricci, Antonio Hamel, Ernest Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro TI Convergent Synthesis and Biological Evaluation of 2-Amino-4-(3 ',4 ',5 '-trimethoxyphenyl)-5-aryl Thiazoles as Microtubule Targeting Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COMBRETASTATIN A-4 ANALOGS; LUNG-CANCER CELLS; MITOTIC CATASTROPHE; MEDICINAL CHEMISTRY; ANTITUMOR-ACTIVITY; TUBULIN; APOPTOSIS; COLCHICINE; PHOSPHATE; POTENT AB Combretastatin A-4, a potent tubulin polymerization inhibitor, caused us to synthesize a novel series of 2-amino-4-(3',4',5'-trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the phenyl at the 5-position of the thiazole skeleton on biological activities. An ethoxy group at the para-position produced the most active compound in the series, with IC(50) values of 0.03-0.9 nM against five of seven cancer cell lines. The most active compounds retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addition to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Brancale, Andrea; Ricci, Antonio] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Pediat, Lab Oncoematol, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; giampietro.viola1@unipd.it RI Viola, Giampietro/I-4095-2012; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; OI Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Intramural NIH HHS [Z99 CA999999] NR 59 TC 45 Z9 47 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 JUL 28 PY 2011 VL 54 IS 14 BP 5144 EP 5153 DI 10.1021/jm200392p PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 794JO UT WOS:000292892300017 PM 21663319 ER PT J AU Mueller, S Yang, XD Sottero, TL Gragg, A Prasad, G Polley, MY Weiss, WA Matthay, KK Davidoff, AM DuBois, SG Haas-Kogan, DA AF Mueller, Sabine Yang, Xiaodong Sottero, Theo L. Gragg, Ashley Prasad, Gautam Polley, Mei-Yin Weiss, William A. Matthay, Katherine K. Davidoff, Andrew M. DuBois, Steven G. Haas-Kogan, Daphne A. TI Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: Efficacy and underlying mechanisms SO CANCER LETTERS LA English DT Article DE Metastatic neuroblastoma; Radiation; Vorinostat; DNA repair ID HISTONE DEACETYLASE INHIBITOR; IN-VITRO; CELLS; EXPRESSION; RADIOSENSITIVITY; ACETYLATION; COMBINATION; PROGRESSION; GLIOMAS AB Histone deacetylase (HDAC) inhibitors can radiosensitize cancer cells. Radiation is critical in high-risk neuroblastoma treatment, and combinations of HDAC inhibitor vorinostat and radiation are proposed for neuroblastoma trials. Therefore, we investigated radiosensitizing effects of vorinostat in neuroblastoma. Treatment of neuroblastoma cell lines decreased cell viability and resulted in additive effects with radiation. In a murine metastatic neuroblastoma in vivo model vorinostat and radiation combinations decreased tumor volumes compared to single modality. DNA repair enzyme Ku-86 was reduced in several neuroblastoma cells treated with vorinostat. Thus, vorinostat potentiates anti-neoplastic effects of radiation in neuroblastoma possibly due to down-regulation of DNA repair enzyme Ku-86. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Mueller, Sabine; Weiss, William A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yang, Xiaodong; Sottero, Theo L.; Gragg, Ashley; Prasad, Gautam; Haas-Kogan, Daphne A.] Univ Calif San Francisco, Dept Radiat Oncol, Helen Diller Family Canc Res Ctr, San Francisco, CA 94158 USA. [Polley, Mei-Yin] NCI, Biometr Res Branch, Rockville, MD 20852 USA. [Mueller, Sabine; Weiss, William A.; Haas-Kogan, Daphne A.] Univ San Francisco, Dept Neurosurg, San Francisco, CA 94117 USA. [Davidoff, Andrew M.] St Jude Childrens Hosp, Dept Surg, Memphis, TN 38105 USA. RP Mueller, S (reprint author), Univ Calif San Francisco, Dept Neurol, 505 Parnassus Ave,M688,Box 0106, San Francisco, CA 94143 USA. EM muellers@neuropeds.ucsf.edu OI Weiss, William/0000-0003-2230-9132 FU NIH [PO1 NS-42927-27A2, PO1 CA81403]; NIH Brain Tumor SPORE [P50 CA097257]; NIH/NCRR/OD UCSF-CTSI [KL2 RR024130, NIH-R01CA133091]; Nancy and Stephen Grand Philanthropic Fund; V Foundation; Dougherty Foundation; Thrasher Foundation; Alex's Lemonade Stand Foundation; Campini Foundation FX This research was supported in part by NIH-PO1 NS-42927-27A2 (DHK), PO1 CA81403 (KKM), NIH Brain Tumor SPORE Grant P50 CA097257 (DHK, MYP, WAW), NIH/NCRR/OD UCSF-CTSI Grant No. KL2 RR024130 (SGD), NIH-R01CA133091 (WAW), The Nancy and Stephen Grand Philanthropic Fund (DAH-K), The V Foundation (DHK, KKM, WAW), Dougherty Foundation (KKM), Thrasher Foundation (WAW, KKM, DHK), Alex's Lemonade Stand Foundation (KKM), Campini Foundation (SM, KKM, SGD). NR 21 TC 27 Z9 30 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 28 PY 2011 VL 306 IS 2 BP 223 EP 229 DI 10.1016/j.canlet.2011.03.010 PG 7 WC Oncology SC Oncology GA 771VE UT WOS:000291188000012 PM 21497989 ER PT J AU Keppler-Noreuil, KM Blumhorst, C Sapp, JC Brinckman, D Johnston, J Nopoulos, PC Biesecker, LG AF Keppler-Noreuil, Kim M. Blumhorst, Catherine Sapp, Julie C. Brinckman, Danielle Johnston, Jennifer Nopoulos, Peggy C. Biesecker, Leslie G. TI Brain tissue- and region-specific abnormalities on volumetric MRI scans in 21 patients with Bardet-Biedl syndrome (BBS) SO BMC MEDICAL GENETICS LA English DT Article ID HUMAN OBESITY SYNDROME; SYNDROME GENE; NULL MICE; CHILDREN; IDENTIFICATION; MUTATIONS; PHENOTYPE; PROTEINS; MOUSE; ADOLESCENTS AB Background: Bardet-Biedl syndrome (BBS) is a heterogeneous human disorder inherited in an autosomal recessive pattern, and characterized by the primary findings of obesity, polydactyly, hypogonadism, and learning and behavioural problems. BBS mouse models have a neuroanatomical phenotype consisting of third and lateral ventriculomegaly, thinning of the cerebral cortex, and reduction in the size of the corpus striatum and hippocampus. These abnormalities raise the question of whether humans with BBS have a characteristic morphologic brain phenotype. Further, although behavioral, developmental, neurological and motor defects have been noted in patients with BBS, to date, there are limited reports of brain findings in BBS. The present study represents the largest systematic evaluation for the presence of structural brain malformations and/or progressive changes, which may contribute to these functional problems. Methods: A case-control study of 21 patients, most aged 13-35 years, except for 2 patients aged 4 and 8 years, who were diagnosed with BBS by clinical criteria and genetic analysis of known BBS genes, and were evaluated by qualitative and volumetric brain MRI scans. Healthy controls were matched 3:1 by age, sex and race. Statistical analysis was performed using SAS language with SAS STAT procedures. Results: All 21 patients with BBS were found to have statistically significant region-and tissue-specific patterns of brain abnormalities. There was 1) normal intracranial volume; 2) reduced white matter in all regions of the brain, but most in the occipital region; 3) preserved gray matter volume, with increased cerebral cortex volume in only the occipital lobe; 4) reduced gray matter in the subcortical regions of the brain, including the caudate, putamen and thalamus, but not in the cerebellum; and 5) increased cerebrospinal fluid volume. Conclusions: There are distinct and characteristic abnormalities in tissue-and region-specific volumes of the brain in patients with BBS, which parallel the findings, described in BBS mutant mouse models. Some of these brain abnormalities may be progressive and associated with the reported neurological and behavioral problems. Further future correlation of these MRI scan findings with detailed neurologic and neuropsychological exams together with genotype data will provide better understanding of the pathophysiology of BBS. C1 [Keppler-Noreuil, Kim M.] Univ Iowa, Dept Pediat, Div Med Genet, Childrens Hosp, Iowa City, IA 52242 USA. [Blumhorst, Catherine; Sapp, Julie C.; Brinckman, Danielle; Johnston, Jennifer; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Nopoulos, Peggy C.] Univ Iowa, Childrens Hosp, Dept Psychiat, Iowa City, IA 52242 USA. RP Keppler-Noreuil, KM (reprint author), Univ Iowa, Dept Pediat, Div Med Genet, Childrens Hosp, Iowa City, IA 52242 USA. EM kim-keppler@uiowa.edu FU National Human Genome Research Institute, NIH FX The authors thank the patients and their families, who so generously gave of their time and without whom this study would not be possible. The authors also would like to thank Dr. Nick Petronas for his contribution in the initial planning of selection and acquisition of the MRI scanners at the NIH. The opinions expressed here are those of the authors and do not necessarily reflect the opinions of the institutions to which they are affiliated. This study was supported by funds from the Intramural Research Programs of the National Human Genome Research Institute, NIH. NR 58 TC 12 Z9 12 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUL 27 PY 2011 VL 12 AR 101 DI 10.1186/1471-2350-12-101 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 814EJ UT WOS:000294429300001 PM 21794117 ER PT J AU Hunsberger, JG Machado-Vieira, R Austin, DR Zarate, C Chuang, DM Chen, G Reed, JC Manji, HK AF Hunsberger, Joshua G. Machado-Vieira, Rodrigo Austin, Daniel R. Zarate, Carlos Chuang, De-Maw Chen, Guang Reed, John C. Manji, Husseini K. TI Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience SO BRAIN RESEARCH LA English DT Article DE Bax inhibitor 1; Affective resiliency; Endoplasmic reticulum; Calcium homeostasis; ER stress ID ENDOPLASMIC-RETICULUM STRESS; SUBGENUAL PREFRONTAL CORTEX; BIPOLAR AFFECTIVE-DISORDER; SINGLE T-LYMPHOCYTES; INTRACELLULAR CALCIUM; ANTIDEPRESSANT ACTION; DEPRESSED-PATIENTS; CATECHOLAMINE DEPLETION; MAJOR DEPRESSION; CA2+ INFLUX AB The endoplasmic reticulum (ER) is a critical site for intracellular calcium storage as well as protein synthesis, folding, and trafficking. Disruption of these processes is gaining support for contributing to heritable vulnerability of certain diseases. Here, we investigated Bax inhibitor 1 (BI-1), an anti-apoptotic protein that primarily resides in the ER and associates with B-cell lymphoma 2 (Bcl-2) and Bcl-XL, as an affective resiliency factor through its modulation of calcium homeostasis. We found that trans genic (TG) mice with BI-1 reinforced expression, via the neuronal specific enolase promoter, showed protection against the learned helplessness (LH) paradigm, an animal model to test stress coping. TG mice were also protected against anhedonia following both serotonin and catecholamine depletion as measured in two different models, the female urine sniffing test and the saccharine preference test. In addition, we used primary mouse cortical cultures to explore the ability of BI-1 to influence calcium homeostasis under basal conditions and also following challenge with thapsigargin (THPS), an inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) that disrupts calcium homeostasis. TG neurons showed decreased basal cytosolic calcium levels and decreased Ca(2+) cytosolic accumulation following challenge with THPS as compared to WT neuronal cultures. Together, these data suggest that BI-1, through its actions on calcium homeostasis, may confer affective resiliency in multiple animal models of depression and anhedonia. Published by Elsevier B.V. C1 [Hunsberger, Joshua G.; Machado-Vieira, Rodrigo; Austin, Daniel R.; Zarate, Carlos; Chuang, De-Maw; Chen, Guang; Manji, Husseini K.] NIMH, NIH, Bethesda, MD 20892 USA. [Reed, John C.] Sanford Burnham Med Res Inst, La Jolla, CA USA. RP Hunsberger, JG (reprint author), NIMH, NIH, MSC 1363,10 Ctr Dr, Bethesda, MD 20892 USA. EM hunsbergerj@mail.nih.gov; machadovieirar@gmail.com; adaniel@mail.nih.gov; zaratec@mail.nih.gov; chuang@mail.nih.gov; guangchen@mail.nih.gov; jreed@sanfordburnham.org; hmanji@its.jnj.com RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Chen, Guang/A-2570-2017 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; FU NIMH; NIH [AG-015393] FX This work was funded by the NIMH Intramural Program and by NIH grant AG-015393. We thank Danielle Warrinllal and Wenji Xu for technical assistance with mouse breeding and genotyping. We would like to thank Emily Fessler and Peter Leeds for editorial suggestions. We would like to thank S Brian Andrews for use of his facility to perform the calcium experiments. NR 61 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 27 PY 2011 VL 1403 BP 19 EP 27 DI 10.1016/j.brainres.2011.05.067 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 797UY UT WOS:000293156800003 PM 21718971 ER PT J AU Chaudhry, C Scimemi, A Kumar, J AF Chaudhry, Charu Scimemi, Annalisa Kumar, Janesh TI Building and Breaking Interfaces: How a Receptor Takes Shape SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material C1 [Chaudhry, Charu] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Scimemi, Annalisa] NINDS, Synapt Physiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Chaudhry, C (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, 35 Convent Dr,3B1006, Bethesda, MD 20892 USA. RI Scimemi, Annalisa/O-5396-2014 OI Scimemi, Annalisa/0000-0003-4975-093X FU Intramural NIH HHS [Z99 HD999999] NR 9 TC 0 Z9 0 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 27 PY 2011 VL 31 IS 30 BP 10749 EP 10751 DI 10.1523/JNEUROSCI.2312-11.2011 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 798AG UT WOS:000293171900001 PM 21795526 ER PT J AU Tricoire, L Pelkey, KA Erkkila, BE Jeffries, BW Yuan, XQ McBain, CJ AF Tricoire, Ludovic Pelkey, Kenneth A. Erkkila, Brian E. Jeffries, Brian W. Yuan, Xiaoqing McBain, Chris J. TI A Blueprint for the Spatiotemporal Origins of Mouse Hippocampal Interneuron Diversity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CAUDAL GANGLIONIC EMINENCE; NITRIC-OXIDE SYNTHASE; FATE MAPPING REVEALS; AXO-AXONIC CELLS; RAT HIPPOCAMPUS; CORTICAL INTERNEURONS; GABAERGIC INTERNEURONS; CA1 AREA; PYRAMIDAL CELLS; ADULT-RAT AB Although vastly outnumbered, inhibitory interneurons critically pace and synchronize excitatory principal cell populations to coordinate cortical information processing. Precision in this control relies upon a remarkable diversity of interneurons primarily determined during embryogenesis by genetic restriction of neuronal potential at the progenitor stage. Like their neocortical counterparts, hippocampal interneurons arise from medial and caudal ganglionic eminence (MGE and CGE) precursors. However, while studies of the early specification of neocortical interneurons are rapidly advancing, similar lineage analyses of hippocampal interneurons have lagged. A "hippocampocentric" investigation is necessary as several hippocampal interneuron subtypes remain poorly represented in the neocortical literature. Thus, we investigated the spatiotemporal origins of hippocampal interneurons using transgenic mice that specifically report MGE- and CGE-derived interneurons either constitutively or inducibly. We found that hippocampal interneurons are produced in two neurogenic waves between E9-E12 and E12-E16 from MGE and CGE, respectively, and invade the hippocampus by E14. In the mature hippocampus, CGE-derived interneurons primarily localize to superficial layers in strata lacunosum moleculare and deep radiatum, while MGE-derived interneurons readily populate all layers with preference for strata pyramidale and oriens. Combined molecular, anatomical, and electrophysiological interrogation of MGE/CGE-derived interneurons revealed that MGE produces parvalbumin-, somatostatin-, and nitric oxide synthase-expressing interneurons including fast-spiking basket, bistratified, axo-axonic, orienslacunosum moleculare, neurogliaform, and ivy cells. In contrast, CGE-derived interneurons contain cholecystokinin, calretinin, vasoactive intestinal peptide, and reelin including non-fast-spiking basket, Schaffer collateral-associated, mossy fiber-associated, trilaminar, and additional neurogliaform cells. Our findings provide a basic blueprint of the developmental origins of hippocampal interneuron diversity. C1 [Tricoire, Ludovic; Pelkey, Kenneth A.; Erkkila, Brian E.; Jeffries, Brian W.; Yuan, Xiaoqing; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP Pelkey, KA (reprint author), Porter Neurosci Res Ctr, 35 Lincoln Dr,MSC 3715, Bethesda, MD 20892 USA. EM pelkeyk2@mail.nih.gov FU National Institute of Child Health and Human Development (NICHD) FX This work was supported by a National Institute of Child Health and Human Development (NICHD) intramural award (C.J.M.). L.T. is a NIH Visiting Fellow and a NIH/CNRS European Career Transition Award Fellow. Daniel Abebe provided expert technical assistance. Microscopy imaging was performed at the Microscopy and Imaging Core (NICHD-NIH) with the assistance of Dr. Vincent Schram and at the imaging facility of the IFR83 (Paris, France) with the assistance of Susanne Bolt and Richard Schwartzmann. We thank Dr. Gordin V. Ohning for supplying us with the CCK antibody, Dr. Gabor Szabo for providing the GAD65-GFP mouse line, Dr. Stuart Anderson for providing the Nkx2-1Cre driver line, and Dr. Gord Fishell for providing the Olig2CreER and Mash1CreER driver lines as well as the RCE reporter line. NR 130 TC 101 Z9 103 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 27 PY 2011 VL 31 IS 30 BP 10948 EP 10970 DI 10.1523/JNEUROSCI.0323-11.2011 PG 23 WC Neurosciences SC Neurosciences & Neurology GA 798AG UT WOS:000293171900020 PM 21795545 ER PT J AU Hyde, TM Lipska, BK Ali, T Mathew, SV Law, AJ Metitiri, OE Straub, RE Ye, TZ Colantuoni, C Herman, MM Bigelow, LB Weinberger, DR Kleinman, JE AF Hyde, Thomas M. Lipska, Barbara K. Ali, Towhid Mathew, Shiny V. Law, Amanda J. Metitiri, Ochuko E. Straub, Richard E. Ye, Tianzhang Colantuoni, Carlo Herman, Mary M. Bigelow, Llewellyn B. Weinberger, Daniel R. Kleinman, Joel E. TI Expression of GABA Signaling Molecules KCC2, NKCC1, and GAD1 in Cortical Development and Schizophrenia SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; K-CL COTRANSPORTER; POSTMORTEM HUMAN BRAIN; GENE-EXPRESSION; RAT-BRAIN; CHLORIDE TRANSPORTERS; NERVOUS-SYSTEM; MESSENGER-RNAS; NEURONS; HIPPOCAMPUS AB GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia. C1 [Hyde, Thomas M.; Lipska, Barbara K.; Ali, Towhid; Mathew, Shiny V.; Law, Amanda J.; Metitiri, Ochuko E.; Straub, Richard E.; Ye, Tianzhang; Colantuoni, Carlo; Herman, Mary M.; Bigelow, Llewellyn B.; Weinberger, Daniel R.; Kleinman, Joel E.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,IRP,NIH, Bethesda, MD 20892 USA. [Hyde, Thomas M.; Colantuoni, Carlo] Johns Hopkins Univ Med Campus, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Colantuoni, Carlo] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP Hyde, TM (reprint author), NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,IRP,NIH, Room 4N306,Bldg 10, Bethesda, MD 20892 USA. EM hydet@mail.nih.gov RI Law, Amanda/G-6372-2012; Lipska, Barbara/E-4569-2017; OI Law, Amanda/0000-0002-2574-1564 FU Intramural NIH HHS [Z01 MH002399-18, ZIA MH002399-23] NR 53 TC 103 Z9 106 U1 2 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 27 PY 2011 VL 31 IS 30 BP 11088 EP 11095 DI 10.1523/JNEUROSCI.1234-11.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 798AG UT WOS:000293171900032 PM 21795557 ER PT J AU Cea, M Soncini, D Fruscione, F Raffaghello, L Garuti, A Emionite, L Moran, E Magnone, M Zoppoli, G Reverberi, D Caffa, I Salis, A Cagnetta, A Bergamaschi, M Casciaro, S Pierri, I Damonte, G Ansaldi, F Gobbi, M Pistoia, V Ballestrero, A Patrone, F Bruzzone, S Nencioni, A AF Cea, Michele Soncini, Debora Fruscione, Floriana Raffaghello, Lizzia Garuti, Anna Emionite, Laura Moran, Eva Magnone, Mirko Zoppoli, Gabriele Reverberi, Daniele Caffa, Irene Salis, Annalisa Cagnetta, Antonia Bergamaschi, Micaela Casciaro, Salvatore Pierri, Ivana Damonte, Gianluca Ansaldi, Filippo Gobbi, Marco Pistoia, Vito Ballestrero, Alberto Patrone, Franco Bruzzone, Santina Nencioni, Alessio TI Synergistic Interactions between HDAC and Sirtuin Inhibitors in Human Leukemia Cells SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; HEMATOLOGIC MALIGNANCIES; BIOSYNTHESIS INHIBITOR; ANTITUMOR-ACTIVITY; MELANOMA-CELLS; APOPTOSIS; P53 AB Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD(+)-independent HDACs are an established therapeutic target, the relevance of NAD(+)-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+)-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527) and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction wasmonitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+) levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+)-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited. C1 [Cea, Michele; Soncini, Debora; Garuti, Anna; Moran, Eva; Zoppoli, Gabriele; Caffa, Irene; Casciaro, Salvatore; Ballestrero, Alberto; Patrone, Franco; Nencioni, Alessio] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Cea, Michele; Cagnetta, Antonia] Harvard Univ, Sch Med, Jerome Lipper Multiple Myeloma Ctr, Dana Farber Canc Inst,Boston Novartis Inst BioMed, Cambridge, MA 02138 USA. [Fruscione, Floriana] ABC, Genoa, Italy. [Raffaghello, Lizzia; Pistoia, Vito] IRCCS G Gaslini, Lab Oncol, Genoa, Italy. [Emionite, Laura] Natl Canc Inst, Anim Facil, Genoa, Italy. [Magnone, Mirko; Salis, Annalisa; Damonte, Gianluca; Bruzzone, Santina] Univ Genoa, Biochem Sect, Dept Expt Med, Genoa, Italy. [Reverberi, Daniele] Natl Canc Inst, Med Oncol Div C, Genoa, Italy. [Cagnetta, Antonia; Bergamaschi, Micaela; Pierri, Ivana; Gobbi, Marco] San Martino Hosp, Dept Hematol & Oncol, Genoa, Italy. [Ansaldi, Filippo] Univ Genoa, Dept Hlth Sci, Genoa, Italy. RP Cea, M (reprint author), Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. EM A.Nencioni@gmx.net RI Bruzzone, Santina/A-4264-2015; Zoppoli, Gabriele/B-6935-2016; Caffa, Irene/J-9835-2016; OI Bruzzone, Santina/0000-0003-2034-3716; Zoppoli, Gabriele/0000-0003-3890-5588; Caffa, Irene/0000-0003-1111-9915; Raffaghello, Lizzia/0000-0003-2357-0607 FU Associazione Italiana per la Ricerca sul Cancro (AIRC); Associazione Italiana contro le Leucemie-Linfomi e Mieloma; University of Genoa FX This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, AN and LR), the Associazione Italiana contro le Leucemie-Linfomi e Mieloma, and by the University of Genoa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 30 Z9 32 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2011 VL 6 IS 7 AR e22739 DI 10.1371/journal.pone.0022739 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799JJ UT WOS:000293282700069 PM 21818379 ER PT J AU Johnson, C Drgon, T Walther, D Uhl, GR AF Johnson, Catherine Drgon, Tomas Walther, Donna Uhl, George R. TI Genomic Regions Identified by Overlapping Clusters of Nominally-Positive SNPs from Genome-Wide Studies of Alcohol and Illegal Substance Dependence SO PLOS ONE LA English DT Article ID ADDICTION MOLECULAR-GENETICS; SAMPLE-SIZE CALCULATIONS; NICOTINE DEPENDENCE; POLYSUBSTANCE ABUSERS; MACULAR DEGENERATION; VULNERABILITY LOCI; SMOKING-CESSATION; ASSOCIATION; GENES; INDIVIDUALS AB Declaring "replication" from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication is unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally-significant association in each of several independent samples. This approach provides one "nontemplate" approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 M SNP GWA results for dependence on: a) alcohol (including many individuals with dependence on other addictive substances) and b) at least one illegal substance (including many individuals dependent on alcohol). This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally-significant SNPs from samples of the same racial/ethnic background identify the same sets of chromosomal regions. It identifies several genes that are also reported in other independent alcohol-dependence GWA datasets. There is more modest confidence in: a) identification of individual chromosomal regions and genes that are not also identified by data from other independent samples, b) the more modest overlap between results from samples of different racial/ethnic backgrounds and c) the extent to which any gene not identified herein is excluded, since the power of each of these individual samples is modest. Nevertheless, the strong overlap identified among the samples with similar racial/ethnic backgrounds supports contributions to individual differences in vulnerability to addictions that come from newer allelic variants that are common in subsets of current humans. C1 [Johnson, Catherine; Drgon, Tomas; Walther, Donna; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Johnson, C (reprint author), Natl Inst Drug Abuse, Mol Neurobiol Branch, NIH, Intramural Res Program, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU NCI NIH HHS [P01 CA089392]; NHGRI NIH HHS [U01 HG004422, U01 HG004446]; NIAAA NIH HHS [U10 AA008401]; NIDA NIH HHS [R01 DA013423] NR 40 TC 22 Z9 22 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2011 VL 6 IS 7 AR e19210 DI 10.1371/journal.pone.0019210 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799JJ UT WOS:000293282700002 PM 21818250 ER PT J AU Price, DP Nagarajan, V Churbanov, A Houde, P Milligan, B Drake, LL Gustafson, JE Hansen, IA AF Price, David P. Nagarajan, Vijayaraj Churbanov, Alexander Houde, Peter Milligan, Brook Drake, Lisa L. Gustafson, John E. Hansen, Immo A. TI The Fat Body Transcriptomes of the Yellow Fever Mosquito Aedes aegypti, Pre- and Post- Blood Meal SO PLOS ONE LA English DT Article ID PROTEIN GENE-EXPRESSION; AMINO-ACID-SEQUENCES; DROSOPHILA-MELANOGASTER; CATHEPSIN-B; SIGNALING CASCADE; IMMUNITY; CDNA; RNA; CARBOXYPEPTIDASE; ANNOTATION AB Background: The fat body is the main organ of intermediary metabolism in insects and the principal source of hemolymph proteins. As part of our ongoing efforts to understand mosquito fat body physiology and to identify novel targets for insect control, we have conducted a transcriptome analysis of the fat body of Aedes aegypti before and in response to blood feeding. Results: We created two fat body non-normalized EST libraries, one from mosquito fat bodies non-blood fed (NBF) and another from mosquitoes 24 hrs post-blood meal (PBM). 454 pyrosequencing of the non-normalized libraries resulted in 204,578 useable reads from the NBF sample and 323,474 useable reads from the PBM sample. Alignment of reads to the existing reference Ae. aegypti transcript libraries for analysis of differential expression between NBF and PBM samples revealed 116,912 and 115,051 matches, respectively. De novo assembly of the reads from the NBF sample resulted in 15,456 contigs, and assembly of the reads from the PBM sample resulted in 15,010 contigs. Collectively, 123 novel transcripts were identified within these contigs. Prominently expressed transcripts in the NBF fat body library were represented by transcripts encoding ribosomal proteins. Thirty-five point four percent of all reads in the PBM library were represented by transcripts that encode yolk proteins. The most highly expressed were transcripts encoding members of the cathepsin b, vitellogenin, vitellogenic carboxypeptidase, and vitelline membrane protein families. Conclusion: The two fat body transcriptomes were considerably different from each other in terms of transcript expression in terms of abundances of transcripts and genes expressed. They reflect the physiological shift of the pre-feeding fat body from a resting state to vitellogenic gene expression after feeding. C1 [Price, David P.; Gustafson, John E.; Hansen, Immo A.] New Mexico State Univ, Program Mol Biol, Las Cruces, NM 88003 USA. [Churbanov, Alexander; Houde, Peter; Milligan, Brook; Drake, Lisa L.; Gustafson, John E.; Hansen, Immo A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Hansen, Immo A.] New Mexico State Univ, Inst Appl Biosci, Las Cruces, NM 88003 USA. [Churbanov, Alexander; Houde, Peter; Milligan, Brook] New Mexico State Univ, Roadrunner Sequencing Lab, Las Cruces, NM 88003 USA. [Nagarajan, Vijayaraj] NIAID, BCBB, OCICB, OSMO,OD,NIH, Bethesda, MD 20892 USA. RP Price, DP (reprint author), New Mexico State Univ, Program Mol Biol, Las Cruces, NM 88003 USA. EM immoh@nmsu.edu FU NIH/NIGMS [1SC2GM092300-01]; NSF [DBI-0821806] FX NIH/NIGMS 1SC2GM092300-01 (IAH). NSF DBI-0821806 (PH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 30 Z9 30 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2011 VL 6 IS 7 AR e22573 DI 10.1371/journal.pone.0022573 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799JJ UT WOS:000293282700042 PM 21818341 ER PT J AU Sanford, T Chung, PH Reinish, A Valera, V Srinivasan, R Linehan, WM Bratslavsky, G AF Sanford, Thomas Chung, Paul H. Reinish, Ariel Valera, Vladimir Srinivasan, Ramaprasad Linehan, W. Marston Bratslavsky, Gennady TI Molecular Sub-Classification of Renal Epithelial Tumors Using Meta-Analysis of Gene Expression Microarrays SO PLOS ONE LA English DT Article ID DNA COPY NUMBER; CELL CARCINOMA; MET PROTOONCOGENE; MUTATIONS; CANCER; NEOPLASMS; KIDNEY; ONCOCYTOMA; SIGNATURES; MARKER AB Purpose: To evaluate the accuracy of the sub-classification of renal cortical neoplasms using molecular signatures. Experimental Design: A search of publicly available databases was performed to identify microarray datasets with multiple histologic sub-types of renal cortical neoplasms. Meta-analytic techniques were utilized to identify differentially expressed genes for each histologic subtype. The lists of genes obtained from the meta-analysis were used to create predictive signatures through the use of a pair-based method. These signatures were organized into an algorithm to sub-classify renal neoplasms. The use of these signatures according to our algorithm was validated on several independent datasets. Results: We identified three Gene Expression Omnibus datasets that fit our criteria to develop a training set. All of the datasets in our study utilized the Affymetrix platform. The final training dataset included 149 samples represented by the four most common histologic subtypes of renal cortical neoplasms: 69 clear cell, 41 papillary, 16 chromophobe, and 23 oncocytomas. When validation of our signatures was performed on external datasets, we were able to correctly classify 68 of the 72 samples (94%). The correct classification by subtype was 19/20 (95%) for clear cell, 14/14 (100%) for papillary, 17/19 (89%) for chromophobe, 18/19 (95%) for oncocytomas. Conclusions: Through the use of meta-analytic techniques, we were able to create an algorithm that sub-classified renal neoplasms on a molecular level with 94% accuracy across multiple independent datasets. This algorithm may aid in selecting molecular therapies and may improve the accuracy of subtyping of renal cortical tumors. C1 [Sanford, Thomas; Chung, Paul H.; Reinish, Ariel; Valera, Vladimir; Srinivasan, Ramaprasad; Linehan, W. Marston; Bratslavsky, Gennady] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Bratslavsky, Gennady] SUNY Syracuse, Upstate Med Univ, Dept Urol, Syracuse, NY USA. RP Sanford, T (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. EM bratslag@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; United States Federal government [1. Z01 BC011028-01, 2. Z01 BC011038-01, 3. Z01 BC011043-01, 10. Z01 BC 011023] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The study was supported by grants from the United States Federal government: 1. Z01 BC011028-01 Molecular Genetics RCC; 2. Z01 BC011038-01 Mol Ther: VHL and FH; and 3. Z01 BC011043-01 Mol Ther: MET and BHD 10. Z01 BC 011023 Fellowship Training. The U.S. Federal government had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 6 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 JUL 27 PY 2011 VL 6 IS 7 AR e21260 DI 10.1371/journal.pone.0021260 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 799JJ UT WOS:000293282700006 PM 21818257 ER PT J AU Volkow, ND McLellan, TA AF Volkow, Nora D. McLellan, Thomas A. TI Reducing Opioid Abuse and Diversion Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID PAIN C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. [McLellan, Thomas A.] Univ Penn, Sch Med, Penn Ctr Subst Abuse Solut, Philadelphia, PA 19104 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, Bethesda, MD USA. EM nvolkow@nida.nih.gov NR 3 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 27 PY 2011 VL 306 IS 4 BP 382 EP 383 DI 10.1001/jama.2011.1043 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 797KL UT WOS:000293125800019 ER PT J AU Giuliano, AE Hawes, D Ballman, KV Whitworth, PW Blumencranz, PW Reintgen, DS Morrow, M Leitch, AM Hunt, KK McCall, LM Abati, A Cote, R AF Giuliano, Armando E. Hawes, Debra Ballman, Karla V. Whitworth, Pat W. Blumencranz, Peter W. Reintgen, Douglas S. Morrow, Monica Leitch, A. Marilyn Hunt, Kelly K. McCall, Linda M. Abati, Andrea Cote, Richard TI Association of Occult Metastases in Sentinel Lymph Nodes and Bone Marrow With Survival Among Women With Early-Stage Invasive Breast Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CIRCULATING TUMOR-CELLS; PROGNOSTIC-SIGNIFICANCE; CLINICAL-TRIAL; MICROMETASTASES; DISSECTION; CARCINOMA AB Context Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. Objective To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. Design, Setting, and Patients From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. Interventions All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylineosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. Main Outcome Measures Overall survival (primary end point) and disease-free survival (a secondary end point). Results Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P=.64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P=.64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P=.04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P=.70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P=.15) was statistically significant on multivariable analysis. Conclusion Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. C1 [Giuliano, Armando E.] St Johns Hlth Ctr, John Wayne Canc Inst, Div Surg Oncol, Santa Monica, CA USA. [Hawes, Debra] Univ So Calif, Dept Pathol, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Ballman, Karla V.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Whitworth, Pat W.] Nashville Breast Ctr, Nashville, TN USA. [Blumencranz, Peter W.] Morton Plant Hosp, Clearwater, FL USA. [Reintgen, Douglas S.] Lakeland Reg Canc Ctr, Lakeland, FL USA. [Morrow, Monica] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Leitch, A. Marilyn] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Hunt, Kelly K.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [McCall, Linda M.] Amer Coll Surg Oncol Grp, Durham, NC USA. [Abati, Andrea] NCI, Cytopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Cote, Richard] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. RP Giuliano, AE (reprint author), Cedars Sinai Med Ctr, 310 N San Vicente Blvd,3rd Floor, Los Angeles, CA 90048 USA. EM armando.giuliano@cshs.org OI Ballman, Karla/0000-0002-4492-0357 FU NIH [NCI R01 CA 85840]; US Department of Defense; California Breast Cancer Research; Whittier Foundation; V-Force; American College of Surgeons Oncology Group [NCI U10 CA076001] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Giuliano reported that he has received support from ACOSOG for travel to ACOSOG meetings. Dr Hawes reported receiving grant support from the NIH and travel support from ACOSOG and has personal and institutional grants pending from the NIH, the US Department of Defense, California Breast Cancer Research, Whittier Foundation, and V-Force. Dr Ballman reported institutional support from the National Institute of Cancer and other support from AstraZeneca, Lilly, and Novartis. Dr Whitworth reported travel support from ACOSOG. Dr Blumencranz reported institutional support from Morton Plant Hospital, serving on the Florida Society of General Surgeons board of directors; and institutional payment for lectures from Hologic. Dr Morrow reported grant support from ACOSOG. Dr Leitch reported travel support from ACOSOG and institutional support from ACOSOG for capitation payments for patients enrolled in a study.; This study was supported by funds from the National Institutes of Health, under the grants entitled "Bone Marrow and Sentinel Node Micrometastases in Breast Cancer" (NCI R01 CA 85840; R. Cote, principal investigator) and American College of Surgeons Oncology Group (NCI U10 CA076001). NR 24 TC 105 Z9 106 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 27 PY 2011 VL 306 IS 4 BP 385 EP 393 DI 10.1001/jama.2011.1034 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 797KL UT WOS:000293125800024 PM 21791687 ER PT J AU Nee, R Hurst, FP Dharnidharka, VR Jindal, RM Agodoa, LY Abbott, KC AF Nee, Robert Hurst, Frank P. Dharnidharka, Vikas R. Jindal, Rahul M. Agodoa, Lawrence Y. Abbott, Kevin C. TI Racial Variation in the Development of Posttransplant Lymphoproliferative Disorders After Renal Transplantation SO TRANSPLANTATION LA English DT Article DE United States Renal Data System; Renal transplantation; Cancer ID PEDIATRIC KIDNEY-TRANSPLANTATION; BARR-VIRUS INFECTION; NON-HODGKIN-LYMPHOMA; UNITED-STATES; RISK-FACTORS; COLLABORATIVE TRANSPLANT; MODERN IMMUNOSUPPRESSION; ALLOGRAFT RECIPIENTS; GRAFT-SURVIVAL; DISEASE AB Background. We previously reported that posttransplant lymphoproliferative disorders (PTLD) occurred more frequently in non-African American (AF) kidney transplant recipients. An in-depth analysis of racial differences in the development of PTLD has not been reported. Methods. We assessed Medicare claims for PTLD in a retrospective cohort of 53,719 patients who underwent transplantation from January 2000 to September 2006 and followed up through December 2007. Results. There were 719 (1.3%) patients with claims for PTLD. Non-AF recipient race (including all races analyzed separately, adjusted hazard ratio [AHR] 1.38, 95% confidence interval [CI] 1.13-1.68), recipient Epstein-Barr virus (EBV) immunoglobulin G (IgG) seronegative status (AHR 1.88, 95% CI 1.53-2.34), and de novo sirolimus (AHR 1.22, 95% CI 1.03-1.45) were associated with an increased risk of PTLD. Furthermore, de novo sirolimus showed a significant interaction with EBV IgG; among EBV IgG-negative recipients, sirolimus use was significant (P=0.003), but among EBV IgG-positive recipients, it was not significant (P=0.18). EBV IgG-seronegative status was significant in all races except for AFs, and racial differences were a significant effect modifier for EBV IgG status and risk of PTLD. Mortality subsequent to PTLD did not differ by race. Conclusions. AF kidney transplant recipients were at lower risk for PTLD, irrespective of the recipient EBV IgG serostatus. On the contrary, recipient EBV IgG-seronegative status was associated with a higher risk of PTLD in the non-AF population. De novo sirolimus therapy was associated with increased risk of PTLD in EBV IgG-negative recipients, regardless of race. C1 [Nee, Robert] Walter Reed Army Med Ctr, Dept Nephrol, Serv Nephrol, Washington, DC 20307 USA. [Nee, Robert; Hurst, Frank P.; Abbott, Kevin C.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Dharnidharka, Vikas R.] Univ Florida, Coll Med, Div Pediat Nephrol, Gainesville, FL USA. [Dharnidharka, Vikas R.] Shands Childrens Hosp, Gainesville, FL USA. [Jindal, Rahul M.] Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. [Agodoa, Lawrence Y.] NIDDK, NIH, Bethesda, MD USA. RP Nee, R (reprint author), Walter Reed Army Med Ctr, Dept Nephrol, Serv Nephrol, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM robert.nee@us.army.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 24 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 27 PY 2011 VL 92 IS 2 BP 190 EP 195 DI 10.1097/TP.0b013e3182200e8a PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 791AU UT WOS:000292633000016 PM 21577180 ER PT J AU McCaffery, JM Jablonski, KA Franks, PW Dagogo-Jack, S Wing, RR Knowler, WC Delahanty, L Dabelea, D Hamman, R Shuldiner, AR Florez, JC AF McCaffery, Jeanne M. Jablonski, Kathleen A. Franks, Paul W. Dagogo-Jack, Sam Wing, Rena R. Knowler, William C. Delahanty, Linda Dabelea, Dana Hamman, Richard Shuldiner, Alan R. Florez, Jose C. CA Diabet Prevention Program Res Grp TI TCF7L2 Polymorphism, Weight Loss and Proinsulin: Insulin Ratio in the Diabetes Prevention Program SO PLOS ONE LA English DT Article ID VARIANTS; GENE; POPULATION; SECRETION; ASSOCIATION; CONVERSION; EVOLUTION; GLUCOSE; RISK AB Aims: TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses. Methods: We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults. Results: We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P, 0.001), higher baseline proinsulin: insulin ratio (p<0.0001) and increased proinsulin: insulin ratio over a median of 2.5 years of follow-up (P = 0.003). Effects were comparable across treatment arms. Conclusions: The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin: insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production. C1 [McCaffery, Jeanne M.; Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [McCaffery, Jeanne M.; Wing, Rena R.] Miriam Hosp, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. [McCaffery, Jeanne M.; Wing, Rena R.] Brown Med Sch, Providence, RI USA. [Franks, Paul W.] Lund Univ, Dept Genet & Mol Epidemiol, Malmo, Sweden. [Dagogo-Jack, Sam] Univ Tennessee, Coll Med, Div Endocrinol Diabet & Metab, Memphis, TN USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Delahanty, Linda; Dabelea, Dana] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Hamman, Richard] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Metab, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP McCaffery, JM (reprint author), George Washington Univ, Ctr Biostat, Rockville, MD USA. EM dppmail@bsc.gwu.edu RI de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health, the National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; American Diabetes Association; McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Bristol-Myers Squibb and Parke-Davis provided medication; LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co. and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 22 TC 13 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 26 PY 2011 VL 6 IS 7 AR e21518 DI 10.1371/journal.pone.0021518 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798BE UT WOS:000293175100004 PM 21814547 ER PT J AU Kato, H van Ingen, H Zhou, BR Feng, HQ Bustin, M Kay, LE Bai, YW AF Kato, Hidenori van Ingen, Hugo Zhou, Bing-Rui Feng, Hanqiao Bustin, Michael Kay, Lewis E. Bai, Yawen TI Architecture of the high mobility group nucleosomal protein 2-nucleosome complex as revealed by methyl-based NMR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLECULAR-WEIGHT PROTEINS; HMGN PROTEINS; CHROMOSOMAL-PROTEIN; CORE PARTICLE; HISTONE H1; CHROMATIN; BINDING; ENHANCEMENT; DOCKING; HMG-17 AB Chromatin structure and function are regulated by numerous proteins through specific binding to nucleosomes. The structural basis of many of these interactions is unknown, as in the case of the high mobility group nucleosomal (HMGN) protein family that regulates various chromatin functions, including transcription. Here, we report the architecture of the HMGN2-nucleosome complex determined by a combination of methyl-transverse relaxation optimized nuclear magnetic resonance spectroscopy (methyl-TROSY) and mutational analysis. We found that HMGN2 binds to both the acidic patch in the H2A-H2B dimer and to nucleosomal DNA near the entry/exit point, "stapling" the histone core and the DNA. These results provide insight into how HMGNs regulate chromatin structure through interfering with the binding of linker histone H1 to the nucleosome as well as a structural basis of how phosphorylation induces dissociation of HMGNs from chromatin during mitosis. Importantly, our approach is generally applicable to the study of nucleosome-binding interactions in chromatin. C1 [Kato, Hidenori; Zhou, Bing-Rui; Feng, Hanqiao; Bai, Yawen] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [van Ingen, Hugo; Kay, Lewis E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [van Ingen, Hugo; Kay, Lewis E.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [van Ingen, Hugo; Kay, Lewis E.] Univ Toronto, Dept Chem, Toronto, ON M5S 1A8, Canada. [Bustin, Michael] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov RI Zhou, Bing-Rui/D-4766-2009; van Ingen, Hugo/Q-2883-2016; Bustin, Michael/G-6155-2015 OI van Ingen, Hugo/0000-0002-0808-3811; FU National Cancer Institute; National Sciences and Engineering Research Council of Canada; Canadian Institutes of Health Research; JSPS; Niels Stensen Foundation; Dutch Science Foundation FX We thank Drs. C. Wu, K. Luger, and T. Richmond for plasmids of histones and DNA, C. Klee, C. Wu, and M. Lichten for comments on the manuscript, and A. Bonvin and Y. Postnikov for helpful discussions. This work was supported by the intramural research program of National Cancer Institute (to Y.B.) and grants from the National Sciences and Engineering Research Council of Canada (to L.E.K.) and Canadian Institutes of Health Research (to L.E.K.). L.E.K. holds a Canada Research Chair in Biochemistry. H.K. acknowledges a JSPS fellowship and H.v.I. received support from the Niels Stensen Foundation as well as a Veni-fellowship from the Dutch Science Foundation. NR 41 TC 65 Z9 66 U1 1 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2011 VL 108 IS 30 BP 12283 EP 12288 DI 10.1073/pnas.1105848108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797LS UT WOS:000293129900024 PM 21730181 ER PT J AU Kortum, RL Sommers, CL Alexander, CP Pinski, JM Li, WM Grinberg, A Lee, J Love, PE Samelson, LE AF Kortum, Robert L. Sommers, Connie L. Alexander, Clayton P. Pinski, John M. Li, Wenmei Grinberg, Alex Lee, Jan Love, Paul E. Samelson, Lawrence E. TI Targeted Sos1 deletion reveals its critical role in early T-cell development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Son of Sevenless; beta-selection; conditional knockout; Cre; lymphocyte signaling ID DISTINCT SIGNALING PATHWAYS; NUCLEOTIDE EXCHANGE FACTOR; NEGATIVE SELECTION; THYMOCYTE DEVELOPMENT; ANTIGEN RECEPTOR; TRANSGENIC MICE; RAS ACTIVATION; TYROSINE KINASES; THYMIC SELECTION; PRE-TCR AB Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre-T-cell receptor (pre-TCR)-but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR-stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development. C1 [Kortum, Robert L.; Sommers, Connie L.; Alexander, Clayton P.; Pinski, John M.; Li, Wenmei; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Grinberg, Alex; Lee, Jan; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM samelson@helix.nih.gov FU Center for Cancer Research, National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institute of General Medical Sciences, National Institutes of Health FX We thank Pamela Schwartzberg, Jennifer Cannons, Lakshmi Balagopalan, and B. J. Fowlkes for helpful discussions throughout the project and for thoughtful reading of the manuscript. We thank Lionel Feigenbaum for the production of founder Sos1 mice from the ES cells we generated. We also thank Barbara Taylor for expert assistance with sorting. RasGRP1-/- mice were a generous gift from James Stone. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. R.L.K. received additional support from a Pharmacology Research Associate (PRAT) Fellowship, National Institute of General Medical Sciences, National Institutes of Health. NR 53 TC 27 Z9 28 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2011 VL 108 IS 30 BP 12407 EP 12412 DI 10.1073/pnas.1104295108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797LS UT WOS:000293129900045 PM 21746917 ER PT J AU Parkhitko, A Myachina, F Morrison, TA Hindi, KM Auricchio, N Karbowniczek, M Wu, JJ Finkel, T Kwiatkowski, DJ Yu, JJ Henske, EP AF Parkhitko, Andrey Myachina, Faina Morrison, Tasha A. Hindi, Khadijah M. Auricchio, Neil Karbowniczek, Magdalena Wu, J. Julia Finkel, Toren Kwiatkowski, David J. Yu, Jane J. Henske, Elizabeth Petri TI Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE metabolism; cell survival; therapy; chloroquine ID TUMOR-SUPPRESSOR; MTOR PATHWAY; CELL-GROWTH; CANCER; TSC2; GENE; ACTIVATION; MODEL; P62; ANGIOMYOLIPOMA AB Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome characterized by benign tumors in multiple organs, including the brain and kidney. TSC-associated tumors exhibit hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), a direct inhibitor of autophagy. Autophagy can either promote or inhibit tumorigenesis, depending on the cellular context. The role of autophagy in the pathogenesis and treatment of the multisystem manifestations of TSC is unknown. We found that the combination of mTORC1 and autophagy inhibition was more effective than either treatment alone in inhibiting the survival of tuberin (TSC2)-null cells, growth of TSC2-null xenograft tumors, and development of spontaneous renal tumors in Tsc2(+/-) mice. Down-regulation of Atg5 induced extensive central necrosis in TSC2-null xenograft tumors, and loss of one allele of Beclin1 almost completely blocked macroscopic renal tumor formation in Tsc2(+/-) mice. Surprisingly, given the finding that lowering autophagy blocks TSC tumorigenesis, genetic down-regulation of p62/sequestosome 1 (SQSTM1), the autophagy substrate that accumulates in TSC tumors as a consequence of low autophagy levels, strongly inhibited the growth of TSC2-null xenograft tumors. These data demonstrate that autophagy is a critical component of TSC tumorigenesis, suggest that mTORC1 inhibitors may have autophagy-dependent prosurvival effects in TSC, and reveal two distinct therapeutic targets for TSC: autophagy and the autophagy target p62/SQSTM1. C1 [Parkhitko, Andrey; Myachina, Faina; Morrison, Tasha A.; Hindi, Khadijah M.; Yu, Jane J.; Henske, Elizabeth Petri] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Parkhitko, Andrey; Myachina, Faina; Morrison, Tasha A.; Hindi, Khadijah M.; Auricchio, Neil; Kwiatkowski, David J.; Yu, Jane J.; Henske, Elizabeth Petri] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Parkhitko, Andrey] Russian State Med Univ, Dept Mol Biol, Moscow 117997, Russia. [Auricchio, Neil; Kwiatkowski, David J.] Brigham & Womens Hosp, Dept Med, Div Translat Med, Boston, MA 02115 USA. [Karbowniczek, Magdalena] Texas Tech Univ, Sch Pharm, Hlth Sci Ctr, Abilene, TX 79601 USA. [Wu, J. Julia; Finkel, Toren] NHLBI, Bethesda, MD 20892 USA. RP Yu, JJ (reprint author), Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. EM jyu13@partners.org; ehenske@partners.org FU LAM Foundation; Adler Foundation; LAM Treatment Alliance; National Institute of Diabetes and Digestive and Kidney Diseases [DK51052]; National Heart, Lung, and Blood Institute [HL098216]; National Cancer Institute [P01 CA120964] FX We thank Beth Levine for providing the Beclin1+/- mice, Mustafa Sahin for providing the p62/SQSTM1 shRNA, Craig Thompson and Julian Lum for providing the Atg5 shRNA, and Michael Jarnik for performing TEM. This work was supported by the LAM Foundation, the Adler Foundation, the LAM Treatment Alliance, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK51052 (to E.P.H.), National Heart, Lung, and Blood Institute Grant HL098216 (to J.J.Y.), and National Cancer Institute Grant P01 CA120964 (to D.J.K.). This research was conducted in partial fulfillment of A.P.'s doctoral degree requirements at the Department of Molecular Biology, Russian State Medical University, under the supervision of Dr. Olga Favorova. NR 50 TC 94 Z9 98 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2011 VL 108 IS 30 BP 12455 EP 12460 DI 10.1073/pnas.1104361108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797LS UT WOS:000293129900053 PM 21746920 ER PT J AU Middleton, LE Manini, TM Simonsick, EM Harris, TB Barnes, DE Tylavsky, F Brach, JS Everhart, JE Yaffe, K AF Middleton, Laura E. Manini, Todd M. Simonsick, Eleanor M. Harris, Tamara B. Barnes, Deborah E. Tylavsky, Frances Brach, Jennifer S. Everhart, James E. Yaffe, Kristine TI Activity Energy Expenditure and Incident Cognitive Impairment in Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY QUESTIONNAIRES; ALZHEIMERS-DISEASE; EXERCISE; DEMENTIA; DECLINE; HEALTH; RISK; WOMEN; VARIABILITY; POPULATION AB Background: Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on self-reports of physical activity, which only moderately correlate with objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment. Methods: We calculated AEE as 90% of total energy expenditure (assessed during 2 weeks using doubly labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean age, 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998-1999). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination. Cognitive impairment was defined as a decline of at least 1.0 SD (9 points) between baseline and follow-up evaluations. Results: After adjustment for baseline Modified Mini-Mental State Examination scores, demographics, fatfree mass, sleep duration, self-reported health, and diabetes mellitus, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (odds ratio, 0.09; 95% confidence interval, 0.01-0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (P=.05 for trend over tertiles). Conclusions: These findings indicate that greater AEE may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined. C1 [Middleton, Laura E.] Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Heart & Stroke Fdn Ctr Stroke Recovery, Toronto, ON M4N 3M5, Canada. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Barnes, Deborah E.; Yaffe, Kristine] San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA USA. [Barnes, Deborah E.; Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tylavsky, Frances] Univ Tennessee, Dept Biostat & Epidemiol, Memphis, TN USA. [Brach, Jennifer S.] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. [Everhart, James E.] NIDDK, Epidemiol & Data Syst Program, Bethesda, MD USA. RP Middleton, LE (reprint author), Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Heart & Stroke Fdn Ctr Stroke Recovery, 2075 Bayview Ave,A421, Toronto, ON M4N 3M5, Canada. EM Middleton_l@hotmail.com RI Middleton, Laura/C-6024-2009 OI Middleton, Laura/0000-0001-8624-3123 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, K01-AG-024069, AG 031155]; National Institutes of Health, National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases; Canadian Institute of Health Research fellowship; National Institute on Aging Claude D. Pepper Center [P30AG028740]; Alzheimer's Association [IIRG-06-27306]; American Federation of Aging Research Paul Beeson Career Development Award [K23 AG026766-01] FX This work was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Middleton is supported by a Canadian Institute of Health Research fellowship; Dr Manini is supported by grant P30AG028740 from the National Institute on Aging Claude D. Pepper Center; Dr Barnes was supported in part by grant K01-AG-024069 from the National Institute on Aging and grant IIRG-06-27306 from the Alzheimer's Association; Dr Brach is supported in part by a National Institutes on Aging and American Federation of Aging Research Paul Beeson Career Development Award (K23 AG026766-01); and Dr Yaffe is supported in part by NIA grant AG 031155 and an Independent Investigator Award from the Alzheimer's Association. NR 44 TC 58 Z9 61 U1 2 U2 21 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 JUL 25 PY 2011 VL 171 IS 14 BP 1251 EP 1257 DI 10.1001/archinternmed.2011.277 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 796WN UT WOS:000293084300007 PM 21771893 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Pseudodisease, the Next Great Epidemic in Coronary Atherosclerosis? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID SCREENING-TESTS; NEUROBLASTOMA C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 10 TC 11 Z9 11 U1 0 U2 0 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 JUL 25 PY 2011 VL 171 IS 14 BP 1268 EP 1269 DI 10.1001/archinternmed.2011.205 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 796WN UT WOS:000293084300010 PM 21606092 ER PT J AU Legros, M Magori, K Morrison, AC Xu, CG Scott, TW Lloyd, AL Gould, F AF Legros, Mathieu Magori, Krisztian Morrison, Amy C. Xu, Chonggang Scott, Thomas W. Lloyd, Alun L. Gould, Fred TI Evaluation of Location-Specific Predictions by a Detailed Simulation Model of Aedes aegypti Populations SO PLOS ONE LA English DT Article ID YELLOW-FEVER MOSQUITO; LIFE TABLE MODEL; DENGUE VIRUS; PUERTO-RICO; PERU; DYNAMICS; DIPTERA; VALIDATION; CULICIDAE; IQUITOS AB Background: Skeeter Buster is a stochastic, spatially explicit simulation model of Aedes aegypti populations, designed to predict the outcome of vector population control methods. In this study, we apply the model to two specific locations, the cities of Iquitos, Peru, and Buenos Aires, Argentina. These two sites differ in the amount of field data that is available for location-specific customization. By comparing output from Skeeter Buster to field observations in these two cases we evaluate population dynamics predictions by Skeeter Buster with varying degrees of customization. Methodology/Principal Findings: Skeeter Buster was customized to the Iquitos location by simulating the layout of houses and the associated distribution of water-holding containers, based on extensive surveys of Ae. aegypti populations and larval habitats that have been conducted in Iquitos for over 10 years. The model is calibrated by adjusting the food input into various types of containers to match their observed pupal productivity in the field. We contrast the output of this customized model to the data collected from the natural population, comparing pupal numbers and spatial distribution of pupae in the population. Our results show that Skeeter Buster replicates specific population dynamics and spatial structure of Ae. aegypti in Iquitos. We then show how Skeeter Buster can be customized for Buenos Aires, where we only had Ae. aegypti abundance data that was averaged across all locations. In the Argentina case Skeeter Buster provides a satisfactory simulation of temporal population dynamics across seasons. Conclusions: This model can provide a faithful description of Ae. aegypti populations, through a process of location-specific customization that is contingent on the amount of data available from field collections. We discuss limitations presented by some specific components of the model such as the description of food dynamics and challenges that these limitations bring to model evaluation. C1 [Legros, Mathieu; Xu, Chonggang; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Legros, Mathieu; Morrison, Amy C.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Magori, Krisztian] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Scott, Thomas W.; Lloyd, Alun L.; Gould, Fred] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. RP Legros, M (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM mlegros@ncsu.edu RI Legros, Mathieu/E-6767-2011; xu, chonggang/B-1256-2012; Lloyd, Alun/H-4944-2012; OI Legros, Mathieu/0000-0003-3807-8594; Xu, Chonggang/0000-0002-0937-5744 FU NIH [R01-AI54954-0IA2]; Foundation for the National Institutes of Health (NIH), through the Grand Challenges in Global Health initiative; Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work is funded by an NIH grant R01-AI54954-0IA2 and a grant to the Regents of the University of California, from the Foundation for the National Institutes of Health (NIH), through the Grand Challenges in Global Health initiative to FG. Funding support also came from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, 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 52 TC 12 Z9 12 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 25 PY 2011 VL 6 IS 7 AR e22701 DI 10.1371/journal.pone.0022701 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 798AP UT WOS:000293172900069 PM 21799936 ER PT J AU Hernandez, L Paredes, D Rada, P AF Hernandez, Luis Paredes, Daniel Rada, Pedro TI Feeding behavior as seen through the prism of brain microdialysis SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Dopamine; Serotonin; Acetylcholine; Norepinephrine; Glutamate; Ingestive behavior ID D-ASPARTIC ACID; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; ACCUMBENS DOPAMINE RELEASE; MEDIAL PREFRONTAL CORTEX; VENTRAL TEGMENTAL AREA; OBESE ZUCKER RATS; INCREASES EXTRACELLULAR SEROTONIN; BASOLATERAL AMYGDALAR NUCLEI; IN-VIVO MICRODIALYSIS; LATERAL HYPOTHALAMUS AB The knowledge of feeding behavior mechanisms gained through brain microdialysis is reviewed. Most of the chemical changes so far reported concern to the limbic system in rodents. A picture showing increases and decreases of extracellular neurotransmitters correlating to different aspects of feeding behavior is gradually emerging. Depending on the region, the same neurotransmitter may signal opposite aspects of feeding. Dopamine (DA) in the nucleus accumbens (NAC) correlates with food reward, stimulus saliency, and goal directed hyperlocomotion but in the ventromedial hypothalamus DA correlates with satiety and hypolocomotion. The findings accumulated in the last 25 years suggest that the control of a particular function relies on the interaction of several neurotransmitters rather than on a single neurotransmitter. The poor sensitivity of most analytical techniques hinders time and spatial resolution of microdialysis. Therefore, neurochemical correlates of short lasting behaviors are hard to figure out. As new and more sensitive analytical techniques are applied, new neurochemical correlates of feeding show up. Sometimes the proper analytical techniques are simply not available. As a consequence, critical signals such as neuropeptides are not yet completely placed in the puzzle. Despite such limitations, brain microdialysis has yielded a great deal of knowledge on the neurochemical basis of feeding. (C) 2011 Elsevier Inc. All rights reserved. C1 [Hernandez, Luis; Rada, Pedro] Univ Los Andes, Lab Behav Physiol, Sch Med, Merida 5101A, Venezuela. [Paredes, Daniel] Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rada, P (reprint author), Univ Los Andes, Lab Behav Physiol, Sch Med, Merida 5101A, Venezuela. EM radap@ula.ve RI Paredes , Daniel/L-6610-2013 NR 157 TC 3 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUL 25 PY 2011 VL 104 IS 1 SI SI BP 47 EP 56 DI 10.1016/j.physbeh.2011.04.031 PG 10 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 789AQ UT WOS:000292486100008 PM 21549733 ER PT J AU Tobian, AAR Quinn, TC Gray, RH AF Tobian, Aaron A. R. Quinn, Thomas C. Gray, Ronald H. TI Male circumcision for prevention of oncogenic HPV infection SO LANCET LA English DT Letter C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Tobian, Aaron A. R.; Gray, Ronald H.] Johns Hopkins Univ, Sch Med, Dept Epidemiol, Baltimore, MD 21287 USA. [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Intramural NIH HHS [ZIA AI000361-28]; NICHD NIH HHS [R24 HD042854] NR 6 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 23 PY 2011 VL 378 IS 9788 BP 314 EP 315 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 803XL UT WOS:000293615800019 PM 21784258 ER PT J AU Kim, S Bolton, EE Bryant, SH AF Kim, Sunghwan Bolton, Evan E. Bryant, Stephen H. TI PubChem3D: Biologically relevant 3-D similarity SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID HIGH-THROUGHPUT; COMBINATORIAL CHEMISTRY; ACTIVITY-CLIFFS; SHAPE; INFORMATION; MOLECULES; ASSAYS AB Background: The use of 3-D similarity techniques in the analysis of biological data and virtual screening is pervasive, but what is a biologically meaningful 3-D similarity value? Can one find statistically significant separation between "active/active" and "active/inactive" spaces? These questions are explored using 734,486 biologically tested chemical structures, 1,389 biological assay data sets, and six different 3-D similarity types utilized by PubChem analysis tools. Results: The similarity value distributions of 269.7 billion unique conformer pairs from 734,486 biologically tested compounds (all-against-all) from PubChem were utilized to help work towards an answer to the question: what is a biologically meaningful 3-D similarity score? The average and standard deviation for the six similarity measures STST-opt, CTST-opt, ComboT(ST-opt), STCT-opt, CTCT-opt, and ComboT(CT-opt) were 0.54 +/- 0.10, 0.07 +/- 0.05, 0.62 +/- 0.13, 0.41 +/- 0.11, 0.18 +/- 0.06, and 0.59 +/- 0.14, respectively. Considering that this random distribution of biologically tested compounds was constructed using a single theoretical conformer per compound (the "default" conformer provided by PubChem), further study may be necessary using multiple diverse conformers per compound; however, given the breadth of the compound set, the single conformer per compound results may still apply to the case of multi-conformer per compound 3-D similarity value distributions. As such, this work is a critical step, covering a very wide corpus of chemical structures and biological assays, creating a statistical framework to build upon. The second part of this study explored the question of whether it was possible to realize a statistically meaningful 3-D similarity value separation between reputed biological assay "inactives" and "actives". Using the terminology of noninactive-noninactive (NN) pairs and the noninactive-inactive (NI) pairs to represent comparison of the "active/active" and "active/inactive" spaces, respectively, each of the 1,389 biological assays was examined by their 3-D similarity score differences between the NN and NI pairs and analyzed across all assays and by assay category types. While a consistent trend of separation was observed, this result was not statistically unambiguous after considering the respective standard deviations. While not all "actives" in a biological assay are amenable to this type of analysis, e. g., due to different mechanisms of action or binding configurations, the ambiguous separation may also be due to employing a single conformer per compound in this study. With that said, there were a subset of biological assays where a clear separation between the NN and NI pairs found. In addition, use of combo Tanimoto (ComboT) alone, independent of superposition optimization type, appears to be the most efficient 3-D score type in identifying these cases. Conclusion: This study provides a statistical guideline for analyzing biological assay data in terms of 3-D similarity and PubChem structure-activity analysis tools. When using a single conformer per compound, a relatively small number of assays appear to be able to separate "active/active" space from "active/inactive" space. C1 [Kim, Sunghwan; Bolton, Evan E.; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, US Dept HHS, Bethesda, MD 20894 USA. RP Bolton, EE (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, US Dept HHS, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU National Library of Medicine, National Institutes of Health, U. S. Department of Health and Human Services FX We are grateful to the NCBI Systems staff, especially Ron Patterson, Charlie Cook, and Don Preuss, whose efforts helped make the PubChem3D project possible. This research was supported (in part) by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, U. S. Department of Health and Human Services. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). NR 40 TC 16 Z9 16 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD JUL 22 PY 2011 VL 3 AR 26 DI 10.1186/1758-2946-3-26 PG 22 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 891OZ UT WOS:000300227800001 PM 21781288 ER PT J AU Alonso, WJ Nascimento, FC Acuna-Soto, R Schuck-Paim, C Miller, MA AF Alonso, Wladimir J. Nascimento, Francielle C. Acuna-Soto, Rodolfo Schuck-Paim, Cynthia Miller, Mark A. TI The 1918 influenza pandemic in Florianopolis: A subtropical city in Brazil SO VACCINE LA English DT Article DE 1918; Pandemic; Tropics; Influenza ID MORTALITY AB Few studies have addressed the impact and dynamics of the 1918-1919 influenza pandemic in tropical and sub-tropical areas. To help cover this gap, we analyzed all death certificates issued from October 1913 to June 1921 in Florianopolis (Brazil), a subtropical state capital with a population of 41,298 inhabitants in 1920. In November and December 1918 (spring) there were a total of 70 and 14 deaths due to influenza and pneumonia, respectively, in contrast to a mean annual mortality attributed to-these causes of 8.1 deaths, usually concentrated between January and August (summer to winter). We also determined the mortality burden due to the pandemic through the analysis of excess mortality during the pandemic period against the baseline mortality in the same months from other years. We obtained a total of 127 deaths (0.33% of the total population), nearly twice the number of deaths documented by death certificates from this period. No other influenza pandemic waves were detected in earlier or subsequent months. Our results confirm the observed patterns of age-shift in mortality in pandemic scenarios, with young adults as the most affected age-group. The pandemic in Florianopolis was further characterized by some specific outcomes: (1) there was a discrete peak in mortality due to renal causes in the initial phase of the pandemic; (2) pandemic influenza did not affect the number of reported bronchitis and bronchiolitis deaths (unusually high in the year preceding the pandemic); and (3) the mortality burden was proportionally lower in Florianopolis than in large urban centers such as Sao Paulo and Rio de Janeiro. We suggest that this latter outcome was the result of an effective and prompt network of voluntary solidarity assistance (as endorsed by contemporaneous documents), which was probably more difficult to implement in larger metropolis. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Alonso, Wladimir J.] NIH, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. [Alonso, Wladimir J.; Nascimento, Francielle C.; Schuck-Paim, Cynthia] Origem Sci, Florianopolis, SC, Brazil. [Nascimento, Francielle C.; Acuna-Soto, Rodolfo] Univ Nacl Autonoma Mexico, Sch Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico. RP Alonso, WJ (reprint author), NIH, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, Bldg 16,Stone House,MSC 6705, Bethesda, MD 20892 USA. EM alonsow@mail.nih.gov FU Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services FX We are grateful to the members of the Municipal Historic Archive "Professor Oswaldo Rodrigues Cabral" and to the members of the Cemetery ltacorubi for kindly granting us in situ access to the death certificates, and for being so helpful in assisting us during this process. To contribute to the preservation of this historic heritage, we provided the digitalized files with the death certificates to the Archive. Access to historic documents for this research were also granted at "Arquivo Publico de Santa Catarina", "Hospital da Caridade","Biblioteca Poblica Estadual" and "Center for Research Libraries" (www.crl.edu/brazil). We also thank Vikash Parekh for his comments on the manuscript. This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health. Funding for this project comes from the Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services. NR 23 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 22 PY 2011 VL 29 SU 2 BP B16 EP B20 DI 10.1016/j.vaccine.2011.02.047 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 802ZW UT WOS:000293550500004 PM 21757098 ER PT J AU Andreasen, V Simonsen, L AF Andreasen, Viggo Simonsen, Lone TI The perils of using annual all-cause mortality data to estimate pandemic influenza burden SO VACCINE LA English DT Article DE Pandemic influenza; Mortality; Modeling; Global burden ID UNITED-STATES; WAVE; VACCINATION; COPENHAGEN; DENMARK; DEATHS AB Measuring the burden of historic pandemics is not straightforward and often must be based on suboptimal mortality data. For example, the critical 1918 pandemic global burden estimate was based on excess in annual all-cause mortality - calculated as the difference between deaths during 1918-1920 and the surrounding 3-year periods. One intriguing result was a similar to 40-fold between-country variation in pandemic mortality burden: similar to 0.2% of Danes died, compared to similar to 8% of populations in some Indian provinces (Murray et al., 2006 [16]). Using the same methodology and data source we explore the robustness of this methodology for different age-groups. For infants the country estimates varied 100-fold, from 15 to 1500 excess deaths/10,000 population, while for adults >= 45 years estimates ranged from -70 to 170/10,000 population. In contrast, estimates for children, 1-14 years, and adults aged 15-44 years, were far more stable. We next used detailed mortality data from Copenhagen to compare such estimates to the more precise estimates obtained from monthly mortality time series data and respiratory deaths. We found that the all-cause annual method substantially underestimated due to an unexplained depression in all-cause mortality in Denmark in 1918 and deaths caused by other epidemic diseases during the baseline periods. We conclude that country estimates for infants and older adults were highly variable by the Murray method due to substantial variability in annual all-cause mortality. A more precise 1918 pandemic burden estimate would be gotten from either focusing analysis on persons age 1-44 who suffered 95% of all pandemic deaths and had a substantial rise over their baseline mortality level, or if possible focus analysis on annual respiratory deaths. For less severe pandemics, including the ongoing 2009 H1N1 pandemic, the use of all-cause mortality data requires careful consideration of excess deaths in defined pandemic periods and a focus on age groups known to be at risk. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Andreasen, Viggo] Roskilde Univ, Dept Sci, Roskilde, Denmark. [Andreasen, Viggo; Simonsen, Lone] NIH, Fogarty Int Ctr, Bethesda, MD USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC 20052 USA. RP Andreasen, V (reprint author), Roskilde Univ, Dept Sci, Roskilde, Denmark. EM viggo@ruc.dk OI Simonsen, Lone/0000-0003-1535-8526 FU Danish Medical Research Council [271-07-0555]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This research was supported in part by a grant 271-07-0555 from the Danish Medical Research Council and by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 23 TC 6 Z9 6 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 22 PY 2011 VL 29 SU 2 BP B49 EP B55 DI 10.1016/j.vaccine.2011.03.061 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 802ZW UT WOS:000293550500010 PM 21757104 ER PT J AU Chowell, G Viboud, C Simonsen, L Miller, MA Hurtado, J Soto, G Vargas, R Guzman, MA Ulloa, M Munayco, CV AF Chowell, G. Viboud, C. Simonsen, L. Miller, M. A. Hurtado, J. Soto, G. Vargas, R. Guzman, M. A. Ulloa, M. Munayco, C. V. TI The 1918-1920 influenza pandemic in Peru SO VACCINE LA English DT Article DE 1918 influenza pandemic; Peru; Lima; Iquitos; Transmissibility; Age-specific mortality ID SPANISH INFLUENZA; MORTALITY IMPACT; WAVE; TRANSMISSIBILITY; PATTERNS; ILLNESS; EUROPE; NUMBER; CITY; AGE AB Background: Increasing our knowledge of past influenza pandemic patterns in different regions of the world is crucial to guide preparedness plans against future influenza pandemics. Here, we undertook extensive archival collection efforts from three representative cities of Peru Lima in the central coast, Iquitos in the northeastern Amazon region, Ica in the southern coast to characterize the temporal, age and geographic patterns of the 1918-1920 influenza pandemic in this country. Materials and methods: We analyzed historical documents describing the 1918-1920 influenza pandemic in Peru and retrieved individual mortality records from local provincial archives for quantitative analysis. We applied seasonal excess mortality models to daily and monthly respiratory mortality rates for 1917-1920 and quantified transmissibility estimates based on the daily growth rate in respiratory deaths. Results: A total of 52,739 individual mortality records were inspected from local provincial archives. We found evidence for an initial mild pandemic wave during July-September 1918 in Lima, identified a synchronized severe pandemic wave of respiratory mortality in all three locations during November 1918-February 1919, and a severe pandemic wave during January 1920-March 1920 in Lima and July-October 1920 in Ica. There was no recrudescent pandemic wave in 1920 in Iquitos. Remarkably, Lima experienced the brunt of the 1918-1920 excess mortality impact during the 1920 recrudescent wave, with all age groups experiencing an increase in all cause excess mortality from 1918-1919 to 1920. Middle age groups experienced the highest excess mortality impact, relative to baseline levels, in the 1918-1919 and 1920 pandemic waves. Cumulative excess mortality rates for the 1918-1920 pandemic period were higher in Iquitos (2.9%) than Lima (1.6%). The mean reproduction number for Lima was estimated in the range 1.3-1.5. Conclusions: We identified synchronized pandemic waves of intense excess respiratory mortality during November 1918-February 1919 in Lima, Iquitos, Ica, followed by asynchronous recrudescent waves in 1920. Cumulative data from quantitative studies of the 1918 influenza pandemic in Latin American settings have confirmed the high mortality impact associated with this pandemic. Further historical studies in lesser studied regions of Latin America, Africa, and Asia are warranted for a full understanding of the global impact of the 1918 pandemic virus. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Chowell, G.; Miller, M. A.] Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, G.; Viboud, C.; Simonsen, L.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, L.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. [Hurtado, J.; Soto, G.; Ulloa, M.; Munayco, C. V.] Peru Minist Salud, Direcc Gen Epidemiol, Lima, Peru. [Vargas, R.] Hosp Belen, Direcc Reg Salud, La Libertad, Peru. [Guzman, M. A.] Univ Nacl Amazonia Peruana, Iquitos, Peru. RP Chowell, G (reprint author), Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Munayco, Cesar/G-9990-2013; Chowell, Gerardo/F-5038-2012; OI Munayco, Cesar/0000-0001-7872-8913; Chowell, Gerardo/0000-0003-2194-2251; Simonsen, Lone/0000-0003-1535-8526 FU Intramural NIH HHS [Z99 TW999999] NR 34 TC 17 Z9 17 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 22 PY 2011 VL 29 SU 2 BP B21 EP B26 DI 10.1016/j.vaccine.2011.02.048 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 802ZW UT WOS:000293550500005 PM 21757099 ER PT J AU Saglanmak, N Andreasen, V Simonsen, L Molbak, K Miller, MA Viboud, C AF Saglanmak, Neslihan Andreasen, Viggo Simonsen, Lone Molbak, Kare Miller, Mark A. Viboud, Cecile TI Gradual changes in the age distribution of excess deaths in the years following the 1918 influenza pandemic in Copenhagen: Using epidemiological evidence to detect antigenic drift SO VACCINE LA English DT Article DE 1918 Influenza pandemic; Excess mortality; Age shift; Antigenic drift; Copenhagen ID MORTALITY; VACCINATION; IMPACT; WAVE AB Background: The 1918 influenza pandemic was associated with an unusual age pattern of mortality, with most deaths occurring among young adults. Few studies have addressed changes in the age distribution for influenza-related mortality in the pre-pandemic and post-pandemic period, which has implications for pandemic preparedness. In the present paper, we analyse the age patterns of influenza-related excess mortality in the decades before and after the 1918 pandemic, using detailed historic surveillance data from Copenhagen. Methods: Weekly age-specific rates of respiratory mortality and influenza-like-illnesses were compiled for 1904-1937. Seasonal excess rates of morbidity and mortality attributable to influenza were calculated using a seasonal regression approach. To characterize the age patterns of influenza-related deaths in individual seasons, we used two rate ratio (RR) measures representing ratios of excess mortality rates between age groups and influenza seasons. Results: Individuals aged 15-64 years experienced sharply elevated excess respiratory mortality rates in the 1918-1919 and 1919-1920 pandemic periods, compared to pre-pandemic seasons (RR for excess mortality in the fall of 1918 = 67 relative to inter-pandemic seasons). Of all excess respiratory deaths occurring during 1918-1919,84% were reported in individuals 15-64 years. By contrast, seniors over 65 years of age experienced no measurable excess mortality during 1918-1919 and moderate excess mortality in the recrudescent pandemic wave of 1919-1920. The first post-pandemic season associated with high excess mortality rates in individuals over 65 years was 1928-1929, with 73% of excess deaths occurring among seniors. We estimate that the age patterns of influenza-related mortality returned to pre-pandemic levels after 1925, based on trends in the rate ratio of excess respiratory mortality in people under and over 65 years. Conclusions: The unusual elevation of excess respiratory mortality rates in young and middle-aged adults was confined to the first three years of A/H1N1 virus circulation 1918-1920; the rapid return to "epidemic" mortality pattern in this age group was probably due to high attack rates and build-up of immunity. In contrast, seniors were completely spared from pandemic mortality during 1918-1919, likely due to childhood exposure to an A/H1-like influenza virus. The rise in excess mortality rates in seniors in the recrudescent pandemic wave of 1919-1920 may suggest the emergence of an early influenza A/H1N1 drift variant. Subsequent drift events may have been associated with the particularly severe 1928-1929 epidemic in Denmark and elsewhere. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Saglanmak, Neslihan; Andreasen, Viggo] Roskilde Univ Ctr, DK-4000 Roskilde, Denmark. [Saglanmak, Neslihan; Andreasen, Viggo; Simonsen, Lone; Miller, Mark A.; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Washington, DC USA. [Molbak, Kare] Statens Serum Inst, Copenhagen, Denmark. RP Saglanmak, N (reprint author), Roskilde Univ Ctr, IMFUFA NSM Bygning 27,Univ Vej 1,Postboks 260, DK-4000 Roskilde, Denmark. EM neslihan@ruc.dk OI Molbak, Kare/0000-0002-3100-4990; Simonsen, Lone/0000-0003-1535-8526 FU Fogarty International Center, National Institutes of Health; Office of Global Health Affairs' International Influenza Unit, Office of the Secretary, Department of Health and Human Services; Danish Council for Independent Research-Medical Sciences; Science & Technology Directorate, Department of Homeland Security FX This work was conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiological and evolutionary patterns (http://www.origem.info/misms/index.php). This effort is supported in part by Fogarty International Center, National Institutes of Health and the Office of Global Health Affairs' International Influenza Unit, Office of the Secretary, Department of Health and Human Services. NS was partly sponsored by The Danish Council for Independent Research-Medical Sciences. LS and VA acknowledge support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security. The authors would like to thank the four anonymous reviewers for their time in reviewing the manuscript. NR 27 TC 16 Z9 17 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 22 PY 2011 VL 29 SU 2 BP B42 EP B48 DI 10.1016/j.vaccine.2011.02.065 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 802ZW UT WOS:000293550500009 PM 21757103 ER PT J AU Simonsen, L Viboud, C Chowell, G Andreasen, V Olson, DR Parekh, V Molbak, K Miller, MA AF Simonsen, Lone Viboud, Cecile Chowell, Gerardo Andreasen, Viggo Olson, Donald R. Parekh, Vikash Molbak, Kare Miller, Mark A. TI The need for interdisciplinary studies of historic pandemics SO VACCINE LA English DT Editorial Material ID EXTRACORPOREAL MEMBRANE-OXYGENATION; INFLUENZA MORTALITY; H1N1 INFLUENZA; WAVE C1 [Simonsen, Lone] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Andreasen, Viggo] Roskilde Univ Ctr, Roskilde, Denmark. [Olson, Donald R.] Int Soc Dis Surveillance, Brighton, MA 02135 USA. [Molbak, Kare] Statens Serum Inst, Copenhagen, Denmark. RP Simonsen, L (reprint author), NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM lone@gwu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Molbak, Kare/0000-0002-3100-4990; Simonsen, Lone/0000-0003-1535-8526 NR 32 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 22 PY 2011 VL 29 SU 2 BP B1 EP B5 DI 10.1016/j.vaccine.2011.03.094 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 802ZW UT WOS:000293550500001 PM 21757096 ER PT J AU Hall, JA Grainger, JR Spencer, SP Belkaid, Y AF Hall, Jason A. Grainger, John R. Spencer, Sean P. Belkaid, Yasmine TI The Role of Retinoic Acid in Tolerance and Immunity SO IMMUNITY LA English DT Review ID REGULATORY T-CELLS; CD103(+) DENDRITIC CELLS; VITAMIN-A-DEFICIENCY; INFLAMMATORY-BOWEL-DISEASE; LAMINA-PROPRIA; IN-VIVO; SMALL-INTESTINE; X-RECEPTOR; TH17 CELLS; FUNCTIONAL SPECIALIZATION AB Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology. C1 [Hall, Jason A.; Grainger, John R.; Spencer, Sean P.; Belkaid, Yasmine] NIAID, Mucosal Immun Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Hall, Jason A.; Spencer, Sean P.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. RP Hall, JA (reprint author), NIAID, Mucosal Immun Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM halljas@niaid.nih.gov; ybelkaid@mail.nih.gov OI Grainger, John/0000-0002-4052-5923 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Office of Dietary Supplements FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Office of Dietary Supplements. We thank E. Wohlfert and T. Hand for helpful discussions and critical reading of the manuscript. NR 129 TC 203 Z9 207 U1 2 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 22 PY 2011 VL 35 IS 1 BP 13 EP 22 DI 10.1016/j.immuni.2011.07.002 PG 10 WC Immunology SC Immunology GA 797EM UT WOS:000293107300006 PM 21777796 ER PT J AU Checkley, MA Luttge, BG Freed, EO AF Checkley, Mary Ann Luttge, Benjamin G. Freed, Eric O. TI HIV-1 Envelope Glycoprotein Biosynthesis, Trafficking, and Incorporation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE HIV-1; retrovirus; envelope glycoprotein; assembly; trafficking ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP41 CYTOPLASMIC TAIL; TYPE-1 TRANSMEMBRANE PROTEIN; PRENYLATED RAB ACCEPTOR; CELL-CELL FUSION; C-TERMINAL TAIL; CHOLESTEROL-BINDING COMPOUND; POLARIZED EPITHELIAL-CELLS; MEMBRANE-SPANNING DOMAIN; AMINO-ACID SUBSTITUTIONS AB The HIV-1 envelope (Env) glycoproteins play an essential role in the virus replication cycle by mediating the fusion between viral and cellular membranes during the entry process. The Env glycoproteins are synthesized as a polyprotein precursor (gp160) that is cleaved by cellular proteases to the mature surface glycoprotein gp120 and the transmembrane glycoprotein gp41. During virus assembly, the gp120/gp41 complex is incorporated as heterotrimeric spikes into the lipid bilayer of nascent virions. These gp120/gp41 complexes then initiate the infection process by binding receptor and coreceptor on the surface of target cells. Much is currently known about the HIV-1 Env glycoprotein trafficking pathway and the structure of gp120 and the extracellular domain of gp41. However, the mechanism by which the Env glycoprotein complex is incorporated into virus particles remains incompletely understood. Genetic data support a major role for the cytoplasmic tail of gp41 and the matrix domain of Gag in Env glycoprotein incorporation. Still to be defined are the identities of host cell factors that may promote Env incorporation and the role of specific membrane microdomains in this process. Here, we review our current understanding of HIV-1 Env glycoprotein trafficking and incorporation into virions. Published by Elsevier Ltd. C1 [Checkley, Mary Ann; Luttge, Benjamin G.; Freed, Eric O.] NCI Frederick, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI Frederick, Virus Cell Interact Sect, HIV Drug Resistance Program, Bldg 535,Room 108,1050 Boyles St, Frederick, MD 21702 USA. EM efreed@nih.gov FU National Institutes of Health; National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program FX We thank P. D. Kwong, S. Subramaniam, A. Ono, J. D. Steckbeck, R. Montelaro, C. K. Leonard, and T. J. Gregory for permission to reproduce or adapt published figures. We are grateful to M. Johnson and members of the Freed laboratory for helpful discussions. Research in our laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and by the Intramural AIDS Targeted Antiviral Program. NR 307 TC 137 Z9 139 U1 5 U2 44 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 22 PY 2011 VL 410 IS 4 SI SI BP 582 EP 608 DI 10.1016/j.jmb.2011.04.042 PN 1 PG 27 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 804SJ UT WOS:000293674000009 PM 21762802 ER PT J AU Goicochea, NL Datta, SAK Ayaluru, M Kao, C Rein, A Dragnea, B AF Goicochea, Nancy L. Datta, Siddhartha A. K. Ayaluru, Murali Kao, Cheng Rein, Alan Dragnea, Bogdan TI Structure and Stoichiometry of Template-Directed Recombinant HIV-1 Gag Particles SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV Gag; nanoparticle; templated virus assembly; liquid crystal; electron microscopy ID IMMUNODEFICIENCY-VIRUS TYPE-1; ASSEMBLY IN-VITRO; NUCLEOCAPSID PROTEIN; ELECTRON CRYOTOMOGRAPHY; 3-DIMENSIONAL STRUCTURE; GOLD NANOPARTICLES; MATRIX PROTEIN; CAPSIDS; DOMAIN; CORE AB Size polydispersity of immature human immunodeficiency virus type 1 (HIV-1) particles represents a challenge for traditional methods of biological ultrastructural analysis. An in vitro model for immature HIV-1 particles constructed from recombinant Gag proteins lacking residues 16-99 and the p6 domain assembled around spherical nanoparticles functionalized with DNA. This template-directed assembly approach led to a significant reduction in size polydispersity and revealed previously unknown structural features of immature-like HIV-1 particles. Electron microscopy and image reconstruction of these particles suggest that the Gag shell formed from different protein regions that are connected by a "scar"-an extended defect connecting the edges of two continuous, regularly packed protein layers. Thus, instead of a holey protein array, the experimental model presented here appears to consist of a continuous array of similar to 5000 proteins enveloping the core, in which regular regions are separated by extended areas of disorder. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Datta, Siddhartha A. K.; Rein, Alan] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Goicochea, Nancy L.; Dragnea, Bogdan] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA. [Ayaluru, Murali; Kao, Cheng] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM reina@mail.nih.gov; dragnea@indiana.edu RI Murali, Ayaluru/G-3401-2014; OI Murali, Ayaluru/0000-0001-6406-6840; Datta, Siddhartha/0000-0002-4098-7490 FU National Science Foundation [0832651, 0708590]; National Institutes of Health [GM081029]; NIH, National Cancer Institute, Center for Cancer Research FX We gratefully acknowledge support from the National Science Foundation (grants 0832651 and 0708590) and the National Institutes of Health (grant GM081029). This work was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 56 TC 13 Z9 13 U1 0 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 22 PY 2011 VL 410 IS 4 SI SI BP 667 EP 680 DI 10.1016/j.jmb.2011.04.012 PN 1 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 804SJ UT WOS:000293674000014 PM 21762807 ER PT J AU Begum, N Hockman, S Manganiello, VC AF Begum, Najma Hockman, Steven Manganiello, Vincent C. TI Phosphodiesterase 3A (PDE3A) Deletion Suppresses Proliferation of Cultured Murine Vascular Smooth Muscle Cells (VSMCs) via Inhibition of Mitogen-activated Protein Kinase (MAPK) Signaling and Alterations in Critical Cell Cycle Regulatory Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE PHOSPHODIESTERASES; DIFFERENTIAL REGULATION; INSULIN REGULATION; MESANGIAL CELLS; GROWTH-FACTOR; NITRIC-OXIDE; CAMP; EXPRESSION; MIGRATION; ATHEROSCLEROSIS AB Cyclic nucleotide phosphodiesterase 3 (PDE3) is an important regulator of cyclic adenosine monophosphate (cAMP) signaling within the cardiovascular system. In this study, we examined the role of PDE3A and PDE3B isoforms in regulation of growth of cultured vascular smooth muscle cells (VSMCs) and the mechanisms by which they may affect signaling pathways that mediate mitogen-induced VSMC proliferation. Serum-and PDGF-induced DNA synthesis in VSMCs grown from aortas of PDE3A-deficient (3A-KO) mice was markedly less than that in VSMCs from PDE3A wild type (3A-WT) and PDE3B-deficient (3B-KO) mice. The reduced growth response was accompanied by significantly less phosphorylation of extracellular signal-regulated kinase (ERK) in 3A-KO VSMCs, most likely due to a combination of greater site-specific inhibitory phosphorylation of Raf-1(Ser-259) by protein kinase A (PKA) and enhanced dephosphorylation of ERKs due to elevated mitogen-activated protein kinase phosphatase 1 (MKP-1). Furthermore, 3A-KO VSMCs, compared with 3A-WT, exhibited higher basal PKA activity and cAMP response element-binding protein (CREB) phosphorylation, higher levels of p53 and p53 phosphorylation, and elevated p21 protein together with lower levels of Cyclin-D1 and retinoblastoma (Rb) protein and Rb phosphorylation. Adenoviral overexpression of inactive CREB partially restored growth effects of serum in 3A-KO VSMCs. In contrast, exposure of 3A-WT VSMCs to VP16 CREB (active CREB) was associated with inhibition of serum-induced DNA synthesis similar to that in untreated 3A-KO VSMCs. Transfection of 3A-KO VSMCs with p53 siRNA reduced p21 and MKP-1 levels and completely restored growth without affecting amounts of Cyclin-D1 and Rb phosphorylation. We conclude that PDE3A regulates VSMC growth via two complementary pathways, i.e. PKA-catalyzed inhibitory phosphorylation of Raf-1 with resulting inhibition of MAPK signaling and PKA/CREB-mediated induction of p21, leading to G(0)/G(1) cell cycle arrest, as well as by increased accumulation of p53, which induces MKP-1, p21, and WIP1, leading to inhibition of G(1) to S cell cycle progression. C1 [Begum, Najma; Hockman, Steven; Manganiello, Vincent C.] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Begum, N (reprint author), NHLBI, Cardiovasc Pulm Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 5N322,MSC-1076, Bethesda, MD 20892 USA. EM begumn@mail.nih.gov FU National Institutes of Health through NHLBI FX This work was supported, in whole or in part, by the National Institutes of Health through the Intramural Research Program of the NHLBI. NR 53 TC 20 Z9 21 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 22 PY 2011 VL 286 IS 29 BP 26238 EP 26249 DI 10.1074/jbc.M110.214155 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 796SS UT WOS:000293073000081 PM 21632535 ER PT J AU Bailey, JA Ray, B Greig, NH Lahiri, DK AF Bailey, Jason A. Ray, Balmiki Greig, Nigel H. Lahiri, Debomoy K. TI Rivastigmine Lowers A beta and Increases sAPP alpha Levels, Which Parallel Elevated Synaptic Markers and Metabolic Activity in Degenerating Primary Rat Neurons SO PLOS ONE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; CHOLINESTERASE-INHIBITORS; PRESYNAPTIC PROTEINS; HIPPOCAMPAL-NEURONS; GLUCOSE-METABOLISM; PEPTIDE LEVELS; MESSENGER-RNA; CELL-LINES AB Overproduction of amyloid-beta (A beta) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence A beta precursor protein (APP) processing and A beta production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and A beta on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and A beta. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased a-secretase cleaved sAPP alpha and decreased A beta secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the a-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity. C1 [Bailey, Jason A.; Ray, Balmiki; Lahiri, Debomoy K.] Indiana Univ Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN USA. [Greig, Nigel H.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Bailey, JA (reprint author), Indiana Univ Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN USA. EM dlahiri@iupui.edu FU National Institutes of Health [R01-AG18379, R01-AG18884]; National Institute on Aging; Novartis FX This research is supported by National Institutes of Health grants (R01-AG18379 and R01-AG18884) to DKL and the Intramural Research Program of the National Institute on Aging (NHG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; I have read the journal's policy and have the following conflict: Dr. Lahiri is a member of the scientific advisory board of QR Pharma, Inc, Randon, PA. He was previously a receipient of a grant from Novartis. Currently, he and the other co-authors of this study are declaring no financial relationship with Novartis, and this past relationship does not interfere with the PLoS ONE policies on sharing of data and materials. NR 62 TC 47 Z9 47 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 22 PY 2011 VL 6 IS 7 AR e21954 DI 10.1371/journal.pone.0021954 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797BJ UT WOS:000293097300008 PM 21799757 ER PT J AU Devine, MJ Kaganovich, A Ryten, M Mamais, A Trabzuni, D Manzoni, C McGoldrick, P Chan, D Dillman, A Zerle, J Horan, S Taanman, JW Hardy, J Marti-Masso, JF Healey, D Schapira, AH Wolozin, B Bandopadhyay, R Cookson, MR van der Brug, MP Lewis, PA AF Devine, Michael J. Kaganovich, Alice Ryten, Mina Mamais, Adamantios Trabzuni, Daniah Manzoni, Claudia McGoldrick, Philip Chan, Diane Dillman, Allissa Zerle, Julia Horan, Susannah Taanman, Jan-Willem Hardy, John Marti-Masso, Jose-Felix Healey, Daniel Schapira, Anthony H. Wolozin, Benjamin Bandopadhyay, Rina Cookson, Mark R. van der Brug, Marcel P. Lewis, Patrick A. TI Pathogenic LRRK2 Mutations Do Not Alter Gene Expression in Cell Model Systems or Human Brain Tissue SO PLOS ONE LA English DT Article ID PARKINSONS-DISEASE; PHOSPHORYLATION; PROTEINS; HEALTH; 4E-BP AB Point mutations in LRRK2 cause autosomal dominant Parkinson's disease. Despite extensive efforts to determine the mechanism of cell death in patients with LRRK2 mutations, the aetiology of LRRK2 PD is not well understood. To examine possible alterations in gene expression linked to the presence of LRRK2 mutations, we carried out a case versus control analysis of global gene expression in three systems: fibroblasts isolated from LRRK2 mutation carriers and healthy, non-mutation carrying controls; brain tissue from G2019S mutation carriers and controls; and HEK293 inducible LRRK2 wild type and mutant cell lines. No significant alteration in gene expression was found in these systems following correction for multiple testing. These data suggest that any alterations in basal gene expression in fibroblasts or cell lines containing mutations in LRRK2 are likely to be quantitatively small. This work suggests that LRRK2 is unlikely to play a direct role in modulation of gene expression, although it remains possible that this protein can influence mRNA expression under pathogenic cicumstances. C1 [Devine, Michael J.; Ryten, Mina; Mamais, Adamantios; Trabzuni, Daniah; Manzoni, Claudia; Zerle, Julia; Hardy, John; Bandopadhyay, Rina; Lewis, Patrick A.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Kaganovich, Alice; Dillman, Allissa; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mamais, Adamantios; Bandopadhyay, Rina] UCL Inst Neurol, Rita Lila Weston Inst, London, England. [Mamais, Adamantios; Bandopadhyay, Rina] UCL Inst Neurol, Queen Sq Brain Bank, London, England. [McGoldrick, Philip] UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London, England. [Chan, Diane; Wolozin, Benjamin] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. [Horan, Susannah; Taanman, Jan-Willem; Healey, Daniel; Schapira, Anthony H.] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Marti-Masso, Jose-Felix] Hosp Donastia, San Sebastian, Spain. [van der Brug, Marcel P.] Scripps Res Inst, Jupiter, FL USA. RP Devine, MJ (reprint author), UCL Inst Neurol, Dept Mol Neurosci, London, England. EM mvanderb@scripps.edu; p.lewis@ion.ucl.ac.uk RI Hardy, John/C-2451-2009; Taanman, Jan/A-5379-2011; Lewis , Patrick/C-3674-2009; manzoni, claudia/F-4831-2014; Bandopadhyay, Rina /C-7926-2009; Trabzuni, Daniah/C-4034-2012; Marti Masso, Jose Felix/D-8619-2013; OI Taanman, Jan/0000-0002-5476-9785; Trabzuni, Daniah/0000-0003-4826-9570; Marti Masso, Jose Felix/0000-0001-8428-4386; Lewis, Patrick/0000-0003-4537-0489; Devine, Mike/0000-0001-6076-3382 FU Medical Research Council [G0800437]; Parkinson's UK [F-1002]; Brain Research Trust; Michael J. Fox foundation; Wellcome/MRC Parkinson's Disease Consortium; National Institute on Aging FX This work was funded by the Medical Research Council (fellowship G0800437, MJD), Parkinson's UK (fellowship F-1002, PAL), Brain Research Trust and the Michael J. Fox foundation. It was supported in part by the Wellcome/MRC Parkinson's Disease Consortium grant and by the intramural program of the National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 14 Z9 14 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 22 PY 2011 VL 6 IS 7 AR e22489 DI 10.1371/journal.pone.0022489 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797BJ UT WOS:000293097300053 PM 21799870 ER PT J AU Duncan, CJA Sheehy, SH Ewer, KJ Douglas, AD Collins, KA Halstead, FD Elias, SC Lillie, PJ Rausch, K Aebig, J Miura, K Edwards, NJ Poulton, ID Hunt-Cooke, A Porter, DW Thompson, FM Rowland, R Draper, SJ Gilbert, SC Fay, MP Long, CA Zhu, DM Wu, YM Martin, LB Anderson, CF Lawrie, AM Hill, AVS Ellis, RD AF Duncan, Christopher J. A. Sheehy, Susanne H. Ewer, Katie J. Douglas, Alexander D. Collins, Katharine A. Halstead, Fenella D. Elias, Sean C. Lillie, Patrick J. Rausch, Kelly Aebig, Joan Miura, Kazutoyo Edwards, Nick J. Poulton, Ian D. Hunt-Cooke, Angela Porter, David W. Thompson, Fiona M. Rowland, Ros Draper, Simon J. Gilbert, Sarah C. Fay, Michael P. Long, Carole A. Zhu, Daming Wu, Yimin Martin, Laura B. Anderson, Charles F. Lawrie, Alison M. Hill, Adrian V. S. Ellis, Ruth D. TI Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909 SO PLOS ONE LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM MALARIA; POLYMERASE-CHAIN-REACTION; BLOOD-STAGE VACCINE; GROWTH-RATES; INHIBITORY ANTIBODIES; CLINICAL-TRIAL; VIRUS ANKARA; PHASE; VITRO AB Background: Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. Methods: In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. Results: A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = -0.93 [95% CI: -1.0, -0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = -0.93 [95% CI: -0.99, -0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5-9], control group median 9 days [range 7-9]). Conclusions: Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. C1 [Duncan, Christopher J. A.; Sheehy, Susanne H.; Lillie, Patrick J.; Poulton, Ian D.; Hunt-Cooke, Angela; Porter, David W.; Thompson, Fiona M.; Rowland, Ros; Lawrie, Alison M.; Hill, Adrian V. S.] Univ Oxford, Jenner Inst, Ctr Clin Vaccinol & Trop Med, Oxford, England. [Ewer, Katie J.; Douglas, Alexander D.; Collins, Katharine A.; Halstead, Fenella D.; Elias, Sean C.; Edwards, Nick J.; Draper, Simon J.; Gilbert, Sarah C.; Hill, Adrian V. S.] Univ Oxford, Jenner Inst Labs, Oxford, England. [Rausch, Kelly; Aebig, Joan; Miura, Kazutoyo; Fay, Michael P.; Long, Carole A.; Zhu, Daming; Wu, Yimin; Martin, Laura B.; Anderson, Charles F.; Ellis, Ruth D.] NIAID, Bethesda, MD 20892 USA. RP Duncan, CJA (reprint author), Univ Oxford, Jenner Inst, Ctr Clin Vaccinol & Trop Med, Oxford, England. EM christopher.duncan@ndm.ox.ac.uk RI Draper, Simon/F-1758-2011; Duncan, Christopher/A-2018-2012; Douglas, Alexander/E-7040-2012; Martin, Laura/N-1789-2013; Ewer, Katie/B-4328-2011; OI Draper, Simon/0000-0002-9415-1357; Fay, Michael P./0000-0002-8643-9625; Duncan, Christopher/0000-0003-4181-2315; Douglas, Alexander/0000-0002-5410-7562; Martin, Laura/0000-0002-4431-4381; Ewer, Katie/0000-0001-9827-9836; Edwards, Nick/0000-0002-7030-7839; Gilbert, Sarah/0000-0002-6823-9750; Lillie, Patrick/0000-0002-4811-4774; Collins, Katharine/0000-0002-7080-2215 FU National Institute of Allergy and Infectious Disease, National Institutes of Health; UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre; Wellcome Trust [RTEI0, 089455/2/09/2] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and the Wellcome Trust. C.J.A.D. and A. D. D. hold Wellcome Trust Training Fellowships for Clinicians in Basic Sciences (grant numbers RTEI0 and 089455/2/09/2 respectively). A. V. S. H., S. C. G. and S.J.D. are Jenner Institute Investigators. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 41 Z9 41 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 22 PY 2011 VL 6 IS 7 AR e22271 DI 10.1371/journal.pone.0022271 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 797BJ UT WOS:000293097300024 PM 21799809 ER PT J AU Prince, T Neckers, L AF Prince, Thomas Neckers, Len TI A Network of Its Own: The Unique Interactome of the Hsp90 Cochaperone, Sba1/p23 SO MOLECULAR CELL LA English DT Editorial Material ID COMPLEX; CHAPERONE; PROTEIN; P23 AB In this issue of Molecular Cell, Echtenkamp et al. (2011) show that the molecular chaperone Sba1/p23, thought to function primarily as a key modulator of the Hsp90 chaperone complex, also operates in its own sphere of influence outside of its obligations to Hsp90. C1 [Prince, Thomas; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM neckers@nih.gov FU Intramural NIH HHS [Z01 SC010074-12, Z99 CA999999, ZIA SC010074-15, Z01 SC010074-13, ZIA SC010074-14] NR 10 TC 2 Z9 2 U1 4 U2 5 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 JUL 22 PY 2011 VL 43 IS 2 BP 159 EP 160 DI 10.1016/j.molcel.2011.07.005 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 797TG UT WOS:000293152400002 PM 21777805 ER PT J AU Chernova, TA Romanyuk, AV Karpova, TS Shanks, JR Ali, M Moffatt, N Howie, RL O'Dell, A McNally, JG Liebman, SW Chernoff, YO Wilkinson, KD AF Chernova, Tatiana A. Romanyuk, Andrey V. Karpova, Tatiana S. Shanks, John R. Ali, Moiez Moffatt, Nela Howie, Rebecca L. O'Dell, Andrew McNally, James G. Liebman, Susan W. Chernoff, Yury O. Wilkinson, Keith D. TI Prion Induction by the Short-Lived, Stress-Induced Protein Lsb2 Is Regulated by Ubiquitination and Association with the Actin Cytoskeleton SO MOLECULAR CELL LA English DT Article ID SACCHAROMYCES-CEREVISIAE; YEAST PRION; PSI+ PRION; ENDOCYTIC PATHWAY; ARP2/3 COMPLEX; SYSTEM; SUP35; PIN+; AGGREGATION; PROPAGATION AB Yeast prions are self-perpetuating, ON-rich amyloids that control heritable traits and serve as a model for mammalian amyloidoses. De novo prion formation by overproduced prion protein is facilitated by other aggregated ON-rich protein(s) and is influenced by alterations of protein homeostasis. Here we explore the mechanism by which the Las17-binding protein Lsb2 (Pin3) promotes conversion of the translation termination factor Sup35 into its prion form, [PSI(+)]. We show that Lsb2 localizes with some Sup35 aggregates and that Lsb2 is a short-lived protein whose levels are controlled via the ubiquitin-proteasome system and are dramatically increased by stress. Loss of Lsb2 decreases stability of [PSI(+)] after brief heat shock. Mutations interfering with Lsb2 ubiquitination increase prion induction, while a mutation eliminating association of Lsb2 with the actin cytoskeleton blocks its aggregation and prion-inducing ability. These findings directly implicate the UPS and actin cytoskeleton in regulating prions via a stress-inducible QN-rich protein. C1 [Chernova, Tatiana A.; Shanks, John R.; Ali, Moiez; Moffatt, Nela; Wilkinson, Keith D.] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. [Romanyuk, Andrey V.; Howie, Rebecca L.; Chernoff, Yury O.] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Romanyuk, Andrey V.; Howie, Rebecca L.; Chernoff, Yury O.] Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA. [Karpova, Tatiana S.; McNally, James G.] NCI, Ctr Canc Res, Core Fluorescence Imaging Facil, Lab Receptor Biol & Gene Express,NIH, Bethesda, MD 20892 USA. [O'Dell, Andrew; Liebman, Susan W.] Univ Illinois, Dept Biol Sci, Chicago, IL 60607 USA. RP Wilkinson, KD (reprint author), Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. EM genekdw@emory.edu RI Chernoff, Yury/J-2833-2014; OI Chernoff, Yury/0000-0002-8934-9051 FU NIH [GM30308, GM58763, GM56350] FX We thank S. Lindquist, J. Frydman, D. Rotin, M. French, L. Hicke, M. Hochstrasser, and R. Parker for reagents; N. Russel, N. Degtyareva, and Z. Astakhova for helpful discussion; and D. Kiktev and G. Newnam for technical help. This work was supported by the grants GM30308 (K.D.W.), GM58763 (Y.O.C.), and GM56350 (S.W.L.) from NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. NR 44 TC 44 Z9 46 U1 1 U2 6 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 JUL 22 PY 2011 VL 43 IS 2 BP 242 EP 252 DI 10.1016/j.molcel.2011.07.001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 797TG UT WOS:000293152400011 PM 21777813 ER PT J AU Buxton, DB AF Buxton, Denis B. TI Nanotechnology Research Support at the National Heart, Lung, and Blood Institute SO CIRCULATION RESEARCH LA English DT Article ID ABDOMINAL AORTIC-ANEURYSMS; MAGNETIC-RESONANCE; GROWTH; ATHEROSCLEROSIS C1 NHLBI, Basic & Early Translat Res Program, Div Cardiovasc Sci, DCVS, Bethesda, MD 20892 USA. RP Buxton, DB (reprint author), NHLBI, Basic & Early Translat Res Program, Div Cardiovasc Sci, DCVS, Rockledge 2,Room 8216,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM db225a@nih.gov OI Buxton, Denis/0000-0003-3077-6435 NR 27 TC 3 Z9 3 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 22 PY 2011 VL 109 IS 3 BP 250 EP 254 DI 10.1161/RES.0b013e31822a97cd PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 795FG UT WOS:000292958200004 PM 21778434 ER PT J AU Kaiser, J Varmus, H AF Kaiser, Jocelyn Varmus, Harold TI Newsmaker Interview: Harold Varmus - Piloting Cancer Research With a Shrinking Budget SO SCIENCE LA English DT Editorial Material C1 [Varmus, Harold] NIH, Bethesda, MD 20892 USA. [Varmus, Harold] NCI, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 5 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 22 PY 2011 VL 333 IS 6041 BP 397 EP 397 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 795FR UT WOS:000292959600014 ER PT J AU Neunuebel, MR Chen, Y Gaspar, AH Backlund, PS Yergey, A Machner, MP AF Neunuebel, M. Ramona Chen, Yang Gaspar, Andrew H. Backlund, Peter S., Jr. Yergey, Alfred Machner, Matthias P. TI De-AMPylation of the Small GTPase Rab1 by the Pathogen Legionella pneumophila SO SCIENCE LA English DT Article ID EFFECTOR PROTEIN DRRA; ENDOPLASMIC-RETICULUM; VESICULAR TRANSPORT; BINDING; SYSTEM; MUTANTS AB The bacterial pathogen Legionella pneumophila exploits host cell vesicle transport by transiently manipulating the activity of the small guanosine triphosphatase (GTPase) Rab1. The effector protein SidM recruits Rab1 to the Legionella-containing vacuole (LCV), where it activates Rab1 and then AMPylates it by covalently adding adenosine monophosphate (AMP). L. pneumophila GTPase-activating protein LepB inactivates Rab1 before its removal from LCVs. Because LepB cannot bind AMPylated Rab1, the molecular events leading to Rab1 inactivation are unknown. We found that the effector protein SidD from L. pneumophila catalyzed AMP release from Rab1, generating de-AMPylated Rab1 accessible for inactivation by LepB. L. pneumophila mutants lacking SidD were defective for Rab1 removal from LCVs, identifying SidD as the missing link connecting the processes of early Rab1 accumulation and subsequent Rab1 removal during infection. C1 [Neunuebel, M. Ramona; Chen, Yang; Gaspar, Andrew H.; Machner, Matthias P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Backlund, Peter S., Jr.; Yergey, Alfred] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biomed Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. [Chen, Yang] Peking Univ, Ctr Hlth Sci, Beijing 100191, Peoples R China. RP Machner, MP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM machnerm@mail.nih.gov RI Machner, Matthias/G-2758-2015; OI Machner, Matthias/0000-0002-6971-7451 FU NIH FX We thank G. Storz, S. Gottesman, J. Bonifacino, J. Neunuebel, and M. Barzik for critical reading and insightful discussion and R. Isberg and V. Losick for kindly providing reagents. This work was supported by the Intramural Research Program of the NIH. NR 20 TC 105 Z9 110 U1 1 U2 18 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 22 PY 2011 VL 333 IS 6041 BP 453 EP 456 DI 10.1126/science.1207193 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 795FR UT WOS:000292959600046 PM 21680813 ER PT J AU Ascierto, PA Marincola, FM AF Ascierto, Paolo A. Marincola, Francesco M. TI Combination therapy: the next opportunity and challenge of medicine SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID MONOTHERAPY; MELANOMA AB From an historical point of view, combination therapy was the basis for the care of important diseases like infection diseases or cancer. Today the "cocktail drug" of the Highly Active Anti Retroviral Therapy (HAART) has reduced the death for HIV infection changing the outcome of such disease. Moreover, the combination of different strategies changed the course of transplants (both in haematology and surgical transplant). Different diseases with high social impact including cardiovascular, metabolic (obesity, hypercholesterolaemia and diabetes) and autoimmune diseases, have better results with combinations of different drug classes of drugs. After recent successes in the immunotherapy field (Sepuleucel-T, ipilimumab) and the new promising small molecule therapies, cancer should be the next challenge for combination strategies. C1 [Ascierto, Paolo A.] Fdn G Pascale, Med Oncol & Innovat Therapies Unit, Ist Nazl Studio & Cura Tumori, Naples, Italy. [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. RP Ascierto, PA (reprint author), Fdn G Pascale, Med Oncol & Innovat Therapies Unit, Ist Nazl Studio & Cura Tumori, Naples, Italy. EM paolo.ascierto@gmail.com NR 18 TC 16 Z9 17 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 21 PY 2011 VL 9 AR 115 DI 10.1186/1479-5876-9-115 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 808SR UT WOS:000293999200001 PM 21777474 ER PT J AU Aguila, JR Liao, WB Yang, JC Avila, C Hagag, N Senzel, L Ma, YP AF Aguila, Jerell R. Liao, Wenbin Yang, Jianchang Avila, Cecilia Hagag, Nabil Senzel, Lisa Ma, Yupo TI SALL4 is a robust stimulator for the expansion of hematopoietic stem cells SO BLOOD LA English DT Article ID EX-VIVO EXPANSION; EARLY EMBRYONIC-DEVELOPMENT; CORD BLOOD; LEUKEMIC-CELLS; DIFFERENTIATION; PLURIPOTENCY; REGULATOR; MICE AB HSCs are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The lack of donors and current inability to rapidly and efficiently expand HSCs are roadblocks in the development of successful cell therapies. Thus, the challenge of ex vivo human HSC expansion remains a fertile and critically important area of investigation. Here, we show that either SALL4A- or SALL4B-transduced human HSCs obtained from the mobilized peripheral blood are capable of rapid and efficient expansion ex vivo by > 10 000-fold for both CD34(+)/CD38(-) and CD34(+)/CD38(+) cells in the presence of appropriate cytokines. We found that these cells retained hematopoietic precursor cell immunophenotypes and morphology as well as normal in vitro or vivo potential for differentiation. The SALL4-mediated expansion was associated with enhanced stem cell engraftment and long-term repopulation capacity in vivo. Also, we demonstrated that constitutive expression of SALL4 inhibited granulocytic differentiation and permitted expansion of undifferentiated cells in 32D myeloid progenitors. Furthermore, a TAT-SALL4B fusion rapidly expanded CD34(+) cells, and it is thus feasible to translate this study into the clinical setting. Our findings provide a new avenue for investigating mechanisms of stem cell self-renewal and achieving clinically significant expansion of human HSCs. (Blood. 2011;118(3):576-585) C1 [Aguila, Jerell R.; Liao, Wenbin; Hagag, Nabil; Senzel, Lisa; Ma, Yupo] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA. [Yang, Jianchang] NCI, Div Lab Med, Las Vegas, NV USA. [Avila, Cecilia] SUNY Stony Brook, Dept Obstet & Gynecol, Stony Brook, NY 11794 USA. RP Ma, YP (reprint author), SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA. EM yupo.ma@stonybrook.edu RI Liao, Wenbin/A-7146-2012 FU National Institutes of Health [NIH R01HL087948, NIH 7R01HL087948-04] FX This work is supported in part by a grant from the National Institutes of Health (NIH R01HL087948; Y.M.) and an NIH research fellowship for postdoctoral training (NIH 7R01HL087948-04; J.A.). NR 24 TC 46 Z9 50 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 21 PY 2011 VL 118 IS 3 BP 576 EP 585 DI 10.1182/blood-2011-01-333641 PG 10 WC Hematology SC Hematology GA 795IG UT WOS:000292967300018 PM 21602528 ER PT J AU Du, M Butchi, NB Woods, T Peterson, KE AF Du, Min Butchi, Niranjan B. Woods, Tyson Peterson, Karin E. TI Poly-Thymidine Oligonucleotides Mediate Activation of Murine Glial Cells Primarily Through TLR7, Not TLR8 SO PLOS ONE LA English DT Article ID TOLL-LIKE RECEPTOR-7; CEREBROSPINAL-FLUID; IMMUNE-RESPONSES; DENDRITIC CELLS; INNATE IMMUNITY; RECOGNITION; OLIGODEOXYNUCLEOTIDES; AGONISTS; BRAIN; TOLL-LIKE-RECEPTOR-8 AB The functional role of murine TLR8 in the inflammatory response of the central nervous system (CNS) remains unclear. Murine TLR8 does not appear to respond to human TLR7/8 agonists, due to a five amino acid deletion in the ectodomain. However, recent studies have suggested that murine TLR8 may be stimulated by alternate ligands, which include vaccinia virus DNA, phosphothioate oligodeoxynucleotides (ODNs) or the combination of phosphothioate poly-thymidine oligonucleotides (pT-ODNs) with TLR7/8 agonists. In the current study, we analyzed the ability of pT-ODNs to induce activation of murine glial cells in the presence or absence of TLR7/8 agonists. We found that TLR7/8 agonists induced the expression of glial cell activation markers and induced the production of multiple proinflammatory cytokines and chemokines in mixed glial cultures. In contrast, pT-ODNs alone induced only low level expression of two cytokines, CCL2 and CXCL10. The combination of pT-ODNs along with TLR7/8 agonists induced a synergistic response with substantially higher levels of proinflammatory cytokines and chemokines compared to CL075. This enhancement was not due to cellular uptake of the agonist, indicating that the pT-ODN enhancement of cytokine responses was due to effects on an intracellular process. Interestingly, this response was also not due to synergistic stimulation of both TLR7 and TLR8, as the loss of TLR7 abolished the activation of glial cells and cytokine production. Thus, pT-ODNs act in synergy with TLR7/8 agonists to induce strong TLR7-dependent cytokine production in glial cells, suggesting that the combination of pT-ODNs with TLR7 agonists may be a useful mechanism to induce pronounced glial activation in the CNS. C1 [Du, Min; Butchi, Niranjan B.; Woods, Tyson; Peterson, Karin E.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Du, M (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 FU National Institutes of Health; National Center for Research Resources [IP20RR020159] FX This work was supported by the Intramural Research Program of the National Institutes of Health and by National Center for Research Resources Grant IP20RR020159. No additional external funding was received for this funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 6 Z9 6 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2011 VL 6 IS 7 AR e22454 DI 10.1371/journal.pone.0022454 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 795FA UT WOS:000292956800059 PM 21811614 ER PT J AU Gilbert-Sirieix, M Makoukji, J Kimura, S Talbot, M Caillou, B Massaad, C Massaad-Massade, L AF Gilbert-Sirieix, Marie Makoukji, Joelle Kimura, Shioko Talbot, Monique Caillou, Bernard Massaad, Charbel Massaad-Massade, Liliane TI Wnt/beta-Catenin Signaling Pathway Is a Direct Enhancer of Thyroid Transcription Factor-1 in Human Papillary Thyroid Carcinoma Cells SO PLOS ONE LA English DT Article ID BETA-CATENIN; NUCLEAR-LOCALIZATION; MOLECULAR-MECHANISM; CANCER-CELLS; EXPRESSION; GENE; TARGET; LINES; TTF-1; OVEREXPRESSION AB The Wnt/beta-catenin signaling pathway is involved in the normal development of thyroid gland, but its disregulation provokes the appearance of several types of cancers, including papillary thyroid carcinomas (PTC) which are the most common thyroid tumours. The follow-up of PTC patients is based on the monitoring of serum thyroglobulin levels which is regulated by the thyroid transcription factor 1 (TTF-1): a tissue-specific transcription factor essential for the differentiation of the thyroid. We investigated whether the Wnt/beta-catenin pathway might regulate TTF-1 expression in a human PTC model and examined the molecular mechanisms underlying this regulation. Immunofluorescence analysis, real time RT-PCR and Western blot studies revealed that TTF-1 as well as the major Wnt pathway components are co-expressed in TPC-1 cells and human PTC tumours. Knocking-down the Wnt/beta-catenin components by siRNAs inhibited both TTF-1 transcript and protein expression, while mimicking the activation of Wnt signaling by lithium chloride induced TTF-1 gene and protein expression. Functional promoter studies and ChIP analysis showed that the Wnt/beta-catenin pathway exerts its effect by means of the binding of beta-catenin to TCF/LEF transcription factors on the level of an active TCF/LEF response element at [2798, 2792 bp] in TTF-1 promoter. In conclusion, we demonstrated that the Wnt/beta-catenin pathway is a direct and forward driver of the TTF-1 expression. The localization of TCF-4 and TTF-1 in the same area of PTC tissues might be of clinical relevance, and justifies further examination of these factors in the papillary thyroid cancers follow-up. C1 [Gilbert-Sirieix, Marie; Massaad-Massade, Liliane] Inst Gustave Roussy, CNRS, UMR 8203, Villejuif, France. [Makoukji, Joelle; Massaad, Charbel] Univ Paris 05, CNRS, UMR 8194, Paris, France. [Kimura, Shioko] NCI, Lab Metab, Bethesda, MD 20892 USA. [Talbot, Monique; Caillou, Bernard] Inst Gustave Roussy, CNRS, UMR 8200, Villejuif, France. RP Gilbert-Sirieix, M (reprint author), Inst Gustave Roussy, CNRS, UMR 8203, Villejuif, France. EM liliane.massade@igr.fr FU Centre National de la Recherche Scientifique; University Paris 11; Institut Gustave Roussy FX This work was supported by the Centre National de la Recherche Scientifique, by the University Paris 11, and by Institut Gustave Roussy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 9 Z9 10 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2011 VL 6 IS 7 AR e22280 DI 10.1371/journal.pone.0022280 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 795FA UT WOS:000292956800037 PM 21814573 ER PT J AU Vargovic, P Ukropec, J Laukova, M Cleary, S Manz, B Pacak, K Kvetnansky, R AF Vargovic, Peter Ukropec, Jozef Laukova, Marcela Cleary, Susannah Manz, Bernhard Pacak, Karel Kvetnansky, Richard TI Adipocytes as a new source of catecholamine production SO FEBS LETTERS LA English DT Article DE Adipocyte; Endogenous catecholamine; Catecholamine biosynthetic enzyme; Gene expression ID PHENYLETHANOLAMINE-N-METHYLTRANSFERASE; WHITE ADIPOSE-TISSUE; NEURAL CREST; RAT-HEART; EXPRESSION; FAT; STRESS; CELLS; GENE AB Catecholamines are an important regulator of lipolysis in adipose tissue. Here we show that rat adipocytes, isolated from mesenteric adipose tissue, express genes of catecholamine biosynthetic enzymes and produce catecholamines de novo. Administration of tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, in vitro significantly reduced concentration of catecholamines in isolated adipocytes. We hypothesize that the sympathetic innervation of adipose tissues is not the only source of catecholamines, since adipocytes also have the capacity to produce both norepinephrine and epinephrine. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Vargovic, Peter; Laukova, Marcela; Kvetnansky, Richard] Slovak Acad Sci, Inst Expt Endocrinol, Lab Stress Res, SK-83306 Bratislava, Slovakia. [Ukropec, Jozef] Slovak Acad Sci, Inst Expt Endocrinol, Diabet & Metab Res Lab, SK-83306 Bratislava, Slovakia. [Manz, Bernhard] LDN Lab Diagnost Nord, D-48531 Nordhorn, Germany. [Cleary, Susannah; Pacak, Karel] NICHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. RP Vargovic, P (reprint author), Slovak Acad Sci, Inst Expt Endocrinol, Lab Stress Res, Vlarska 3, SK-83306 Bratislava, Slovakia. EM peter.vargovic@gmail.com FU Slovak Research and Development Agency [APVV-0148-06, APVV-0088-10]; VEGA [2/0188/09, 2/0036/11]; [Transmed1-26240120008-ERDF] FX This research was supported by Slovak Research and Development Agency (No. APVV-0148-06 and APVV-0088-10), Transmed1-26240120008-ERDF and VEGA Grants (2/0188/09 and 2/0036/11). NR 27 TC 26 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 21 PY 2011 VL 585 IS 14 BP 2279 EP 2284 DI 10.1016/j.febslet.2011.06.001 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 792TK UT WOS:000292772800024 PM 21689652 ER PT J AU Gurnev, PA Rostovtseva, TK Bezrukov, SM AF Gurnev, Philip A. Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI Tubulin-blocked state of VDAC studied by polymer and ATP partitioning SO FEBS LETTERS LA English DT Article DE Voltage-dependent anion channel; Selectivity; PEG; Mitochondria; Microtubule; Planar lipid bilayer ID DEPENDENT ANION CHANNEL; MITOCHONDRIAL CHANNEL; VOLUME CHANGES; PORE-SIZE; SELECTIVITY; TRANSPORT; DYNAMICS AB Recently reported functional interaction between voltage-dependent anion channel of the outer mitochondrial membrane, VDAC, and dimeric tubulin is observed as a reversible channel blockage. Using partitioning of poly-(ethylene glycol)s of different molecular weights and reversal potential measurements, we probe the size and ion selectivity of the fully open and tubulin-blocked states of VDAC reconstituted into planar lipid bilayers. While the effective radius of the channel decreases by only a factor of 1.34 +/- 0.15, the selectivity reverses from initially anionic to cationic. Directly measuring ATP partitioning we demonstrate that these changes prohibit ATP from entering the channel in its tubulin-blocked state. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Gurnev, Philip A.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Rostovtseva, TK (reprint author), NICHD, NIH, 9000 Rockville Pike,Bldg 9,Rm 1E-106, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX Authors thank Kely Sheldon for VDAC purification. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 25 TC 25 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 21 PY 2011 VL 585 IS 14 BP 2363 EP 2366 DI 10.1016/j.febslet.2011.06.008 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 792TK UT WOS:000292772800038 PM 21722638 ER PT J AU Stuber, GD Sparta, DR Stamatakis, AM van Leeuwen, WA Hardjoprajitno, JE Cho, S Tye, KM Kempadoo, KA Zhang, F Deisseroth, K Bonci, A AF Stuber, Garret D. Sparta, Dennis R. Stamatakis, Alice M. van Leeuwen, Wieke A. Hardjoprajitno, Juanita E. Cho, Saemi Tye, Kay M. Kempadoo, Kimberly A. Zhang, Feng Deisseroth, Karl Bonci, Antonello TI Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking SO NATURE LA English DT Article ID MIDBRAIN DOPAMINE NEURONS; BASOLATERAL AMYGDALA; COCAINE-SEEKING; BEHAVIOR; CORE; RELEASE; DISCONNECTION; INVOLVEMENT; MOTIVATION; INTERFACE AB The basolateral amygdala (BLA) has a crucial role in emotional learning irrespective of valence(1-5,21-23). The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours(4,6,7,24,25), but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibres from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. Here we show that optical stimulation of the pathway from the BLA to the NAc in mice reinforces behavioural responding to earn additional optical stimulation of these synaptic inputs. Optical stimulation of these glutamatergic fibres required intra-NAc dopamine D1-type receptor signalling, but not D2-type receptor signalling. Brief optical inhibition of fibres from the BLA to the NAc reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behaviour. Moreover, although optical stimulation of glutamatergic fibres from the medial prefrontal cortex to the NAc also elicited reliable excitatory synaptic responses, optical self-stimulation behaviour was not observed by activation of this pathway. These data indicate that whereas the BLA is important for processing both positive and negative affect, the glutamatergic pathway from the BLA to the NAc, in conjunction with dopamine signalling in the NAc, promotes motivated behavioural responding. Thus, optogenetic manipulation of anatomically distinct synaptic inputs to the NAc reveals functionally distinct properties of these inputs in controlling reward-seeking behaviours. C1 [Stuber, Garret D.; Sparta, Dennis R.; Stamatakis, Alice M.] Univ N Carolina, UNC Neurosci Ctr, Dept Psychiat, Chapel Hill, NC 27599 USA. [Stuber, Garret D.; Sparta, Dennis R.; Stamatakis, Alice M.] Univ N Carolina, UNC Neurosci Ctr, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Stuber, Garret D.; Sparta, Dennis R.; van Leeuwen, Wieke A.; Hardjoprajitno, Juanita E.; Cho, Saemi; Tye, Kay M.; Kempadoo, Kimberly A.; Bonci, Antonello] Univ Calif San Francisco, Wheeler Ctr Neurobiol Drug Addict, Dept Neurol, Ernest Gallo Clin & Res Ctr, San Francisco, CA 94608 USA. [Tye, Kay M.; Zhang, Feng; Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Tye, Kay M.; Zhang, Feng; Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Bonci, Antonello] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Stuber, GD (reprint author), Univ N Carolina, UNC Neurosci Ctr, Dept Psychiat, Chapel Hill, NC 27599 USA. EM gstuber@med.unc.edu RI Tye, Kay/J-6158-2013; Stuber, Garret/E-1160-2011 OI Tye, Kay/0000-0002-2435-0182; FU NARSAD; ABMRF; Foundation of Hope; NIDA [DA029325]; Psychiatry Department at UNC Chapel Hill; State of California through the University of California at San Francisco; [F32AA018610] FX We thank J. Phillips, V. Kharazia, A. Adamantidis and H.-C. Tsai for assistance and advice. We also thank V. Gukassyan and the UNC Neuroscience Center microscopy core facility. This study was supported by funds from NARSAD, ABMRF, The Foundation of Hope, and NIDA (DA029325), by startup funds provided by the Psychiatry Department at UNC Chapel Hill (G. D. S.) and by the State of California through the University of California at San Francisco (A. B.). D. R. S. was supported by F32AA018610. NR 26 TC 276 Z9 280 U1 6 U2 59 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 21 PY 2011 VL 475 IS 7356 BP 377 EP U129 DI 10.1038/nature10194 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794PA UT WOS:000292911200042 PM 21716290 ER PT J AU Hessa, T Sharma, A Mariappan, M Eshleman, HD Gutierrez, E Hegde, RS AF Hessa, Tara Sharma, Ajay Mariappan, Malaiyalam Eshleman, Heather D. Gutierrez, Erik Hegde, Ramanujan S. TI Protein targeting and degradation are coupled for elimination of mislocalized proteins SO NATURE LA English DT Article ID SIGNAL RECOGNITION PARTICLE; CYTOSOLIC PRION PROTEIN; QUALITY-CONTROL PATHWAY; ENDOPLASMIC-RETICULUM; TRANSLOCATION CHANNEL; MEMBRANE; NEURODEGENERATION; ER; CONTRIBUTES; SEQUENCE AB A substantial proportion of the genome encodes membrane proteins that are delivered to the endoplasmic reticulum by dedicated targeting pathways(1). Membrane proteins that fail targeting must be rapidly degraded to avoid aggregation and disruption of cytosolic protein homeostasis(2,3). The mechanisms of mislocalized protein (MLP) degradation are unknown. Here we reconstitute MLP degradation in vitro to identify factors involved in this pathway. We find that nascent membrane proteins tethered to ribosomes are not substrates for ubiquitination unless they are released into the cytosol. Their inappropriate release results in capture by the Bag6 complex, a recently identified ribosome-associating chaperone(4). Bag6-complex-mediated capture depends on the presence of unprocessed or non-inserted hydrophobic domains that distinguish MLPs from potential cytosolic proteins. A subset of these Bag6 complex 'clients' are transferred to TRC40 for insertion into the membrane, whereas the remainder are rapidly ubiquitinated. Depletion of the Bag6 complex selectively impairs the efficient ubiquitination of MLPs. Thus, by its presence on ribosomes that are synthesizing nascent membrane proteins, the Bag6 complex links targeting and ubiquitination pathways. We propose that such coupling allows the fast tracking of MLPs for degradation without futile engagement of the cytosolic folding machinery. C1 [Hessa, Tara; Sharma, Ajay; Mariappan, Malaiyalam; Eshleman, Heather D.; Gutierrez, Erik; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Gutierrez, Erik] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Hegde, RS (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 0QH, England. EM hegde.science@gmail.com RI mariappan, malaiyalam/K-9024-2012; OI Hegde, Ramanujan/0000-0001-8338-852X FU National Institutes of Health; Wenner-Gren Foundations FX We are grateful to E. Whiteman and X. Li for carrying out the initial experiments for parts of this project, S. W. Kang, S. Shao, and Z. Zhang for discussions, P. Sengupta, J. Magadan, and C. Ott for constructs, J. Taunton and J. Garrison for cotransin, S. Shao for comments on the manuscript, and Y. Ye for discussions and sharing results before publication. This work was supported by the Intramural Research Program of the National Institutes of Health (R. S. H.) and a postdoctoral fellowship from The Wenner-Gren Foundations (T.H.). NR 38 TC 94 Z9 95 U1 4 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 21 PY 2011 VL 475 IS 7356 BP 394 EP U154 DI 10.1038/nature10181 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794PA UT WOS:000292911200046 PM 21743475 ER PT J AU Polak, JF Pencina, MJ Pencina, KM O'Donnell, CJ Wolf, PA D'Agostino, RB AF Polak, Joseph F. Pencina, Michael J. Pencina, Karol M. O'Donnell, Christopher J. Wolf, Philip A. D'Agostino, Ralph B., Sr. TI Carotid-Wall Intima-Media Thickness and Cardiovascular Events SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; ATHEROSCLEROSIS RISK; ARTERIAL-WALL; MYOCARDIAL-INFARCTION; FRAMINGHAM RISK; PREDICTION; STROKE; COMMUNITIES; POPULATION; PLAQUE AB Background Intima-media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events. Methods We measured the mean intima-media thickness of the common carotid artery and the maximum intima-media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima-media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima-media thickness values. Results A total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima-media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima-media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima-media thickness of the internal carotid artery (7.6%, P<0.001) but not intima-media thickness of the common carotid artery (0.0%, P = 0.99). With the presence of plaque, defined as intima-media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P = 0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025). Conclusions The maximum internal and mean common carotid-artery intima-media thicknesses both predict cardiovascular outcomes, but only the maximum intima-media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. C1 [Polak, Joseph F.] Tufts Med Ctr, Dept Radiol, Boston, MA 02111 USA. [Pencina, Michael J.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Pencina, Karol M.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Wolf, Philip A.] Boston Univ, Dept Med & Neurol, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. RP Polak, JF (reprint author), Tufts Med Ctr, Dept Radiol, 800 Washington St,Box 299, Boston, MA 02111 USA. EM jpolak@tuftsmedicalcenter.org FU National Heart, Lung, and Blood Institute [R01 HL069003, HL081352, N01-HC-25195]; Abbott FX Supported by grants from the National Heart, Lung, and Blood Institute (R01 HL069003 and HL081352, to Dr. Polak) and its Framingham Heart Study (N01-HC-25195).; Dr. Pencina reports receiving fees for board membership from Abbott. No other potential conflict of interest relevant to this article was reported. NR 36 TC 281 Z9 295 U1 3 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 21 PY 2011 VL 365 IS 3 BP 213 EP 221 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 794QI UT WOS:000292915500005 PM 21774709 ER PT J AU Kim, S Bolton, EE Bryant, SH AF Kim, Sunghwan Bolton, Evan E. Bryant, Stephen H. TI PubChem3D: Shape compatibility filtering using molecular shape quadrupoles SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID GAUSSIAN DESCRIPTION; MOLAR VOLUMES; INFORMATION AB Background: PubChem provides a 3-D neighboring relationship, which involves finding the maximal shape overlap between two static compound 3-D conformations, a computationally intensive step. It is highly desirable to avoid this overlap computation, especially if it can be determined with certainty that a conformer pair cannot meet the criteria to be a 3-D neighbor. As such, PubChem employs a series of pre-filters, based on the concept of volume, to remove approximately 65% of all conformer neighbor pairs prior to shape overlap optimization. Given that molecular volume, a somewhat vague concept, is rather effective, it leads one to wonder: can the existing PubChem 3-D neighboring relationship, which consists of billions of shape similar conformer pairs from tens of millions of unique small molecules, be used to identify additional shape descriptor relationships? Or, put more specifically, can one place an upper bound on shape similarity using other "fuzzy" shape-like concepts like length, width, and height? Results: Using a basis set of 4.18 billion 3-D neighbor pairs identified from single conformer per compound neighboring of 17.1 million molecules, shape descriptors were computed for all conformers. These steric shape descriptors included several forms of molecular volume and shape quadrupoles, which essentially embody the length, width, and height of a conformer. For a given 3-D neighbor conformer pair, the volume and each quadrupole component (Q(x), Q(y), and Q(z)) were binned and their frequency of occurrence was examined. Per molecular volume type, this effectively produced three different maps, one per quadrupole component (Q(x), Q(y), and Q(z)), of allowed values for the similarity metric, shape Tanimoto (ST) >= 0.8. The efficiency of these relationships (in terms of true positive, true negative, false positive and false negative) as a function of ST threshold was determined in a test run of 13.2 billion conformer pairs not previously considered by the 3-D neighbor set. At an ST >= 0.8, a filtering efficiency of 40.4% of true negatives was achieved with only 32 false negatives out of 24 million true positives, when applying the separate Q(x), Q(y), and Q(z) maps in a series (Q(xyz)). This efficiency increased linearly as a function of ST threshold in the range 0.8-0.99. The Q(x) filter was consistently the most efficient followed by Q(y) and then by Q(z). Use of a monopole volume showed the best overall performance, followed by the self-overlap volume and then by the analytic volume. Application of the monopole-based Q(xyz) filter in a "real world" test of 3-D neighboring of 4,218 chemicals of biomedical interest against 26.1 million molecules in PubChem reduced the total CPU cost of neighboring by between 24-38% and, if used as the initial filter, removed from consideration 48.3% of all conformer pairs at almost negligible computational overhead. Conclusion: Basic shape descriptors, such as those embodied by size, length, width, and height, can be highly effective in identifying shape incompatible compound conformer pairs. When performing a 3-D search using a shape similarity cut-off, computation can be avoided by identifying conformer pairs that cannot meet the result criteria. Applying this methodology as a filter for PubChem 3-D neighboring computation, an improvement of 31% was realized, increasing the average conformer pair throughput from 154,000 to 202,000 per second per CPU core. C1 [Kim, Sunghwan; Bolton, Evan E.; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Bolton, EE (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services FX We are grateful to the NCBI Systems staff, especially Ron Patterson, Charlie Cook, and Don Preuss, whose efforts helped make the PubChem3D project possible. This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. NR 20 TC 7 Z9 7 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD JUL 20 PY 2011 VL 3 AR 25 DI 10.1186/1758-2946-3-25 PG 14 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 891OX UT WOS:000300227600001 PM 21774809 ER PT J AU Yedavalli, VSRK Jeang, KT AF Yedavalli, Venkat S. R. K. Jeang, Kuan-Teh TI Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression SO RETROVIROLOGY LA English DT Article DE Matrin 3; HIV-1; Rev; RNA export; nuclear matrix protein ID HUMAN-IMMUNODEFICIENCY-VIRUS; CONSTITUTIVE TRANSPORT ELEMENT; MESSENGER-RNA EXPORT; NUCLEAR-PORE COMPLEX; PROTEIN INTERACTIONS; SPLICING FACTOR; TYPE-1; ORGANIZATION; ARCHITECTURE; MICROENVIRONMENTS AB Post-transcriptional regulation of HIV-1 gene expression is mediated by interactions between viral transcripts and viral/cellular proteins. For HIV-1, post-transcriptional nuclear control allows for the export of intron-containing RNAs which are normally retained in the nucleus. Specific signals on the viral RNAs, such as instability sequences (INS) and Rev responsive element (RRE), are binding sites for viral and cellular factors that serve to regulate RNA-export. The HIV-1 encoded viral Rev protein binds to the RRE found on unspliced and incompletely spliced viral RNAs. Binding by Rev directs the export of these RNAs from the nucleus to the cytoplasm. Previously, Rev co-factors have been found to include cellular factors such as CRM1, DDX3, PIMT and others. In this work, the nuclear matrix protein Matrin 3 is shown to bind Rev/RRE-containing viral RNA. This binding interaction stabilizes unspliced and partially spliced HIV-1 transcripts leading to increased cytoplasmic expression of these viral RNAs. C1 [Yedavalli, Venkat S. R. K.; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU NIAID; office of the Director, NIH FX Work in KTJ's laboratory was supported in part by Intramural funds from NIAID, and by the Intramural AIDS Targeted Antiviral Program (IATAP) from the office of the Director, NIH. We thank members of KTJ's laboratory for reading and commenting on the manuscript, and Barbara Felber for sharing several critical reagents. We are grateful to Anna Kula and Alessandro Marcello for sharing data in their paper prior to publication [75]. NR 75 TC 25 Z9 25 U1 0 U2 9 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 JUL 20 PY 2011 VL 8 AR 61 DI 10.1186/1742-4690-8-61 PG 10 WC Virology SC Virology GA 813FY UT WOS:000294353400002 PM 21771347 ER PT J AU Ro, HJ Dawid, IB AF Ro, Hyunju Dawid, Igor B. TI Modulation of Tcf3 repressor complex composition regulates cdx4 expression in zebrafish SO EMBO JOURNAL LA English DT Article DE caudal body domain; Cdx4; E4f1; Tcf3; Wnt signalling ID HOX GENE-EXPRESSION; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; E3 UBIQUITIN LIGASE; TRANSCRIPTION FACTOR; BETA-CATENIN; CELL FATE; OVERLAPPING FUNCTIONS; AXIS SPECIFICATION; IN-VIVO AB The caudal homeobox (cdx) gene family is critical for specification of caudal body formation and erythropoiesis. In zebrafish, cdx4 expression is controlled by the Wnt pathway, but the molecular mechanism of this regulation is not fully understood. Here, we provide evidence that Tcf3 suppresses cdx4 expression through direct binding to multiple sites in the cdx4 gene regulatory region. Tcf3 requires corepressor molecules such as Groucho (Gro)/TLE and HDAC1 for activity. Using zebrafish embryos and cultured mammalian cells, we show that the transcription factor E4f1 derepresses cdx4 by dissociating corepressor proteins from Tcf3 without inhibiting its binding to cis-regulatory sites in the DNA. Further, the E3 ubiquitin ligase Lnx2b, acting as a scaffold protein irrespective of its enzymatic activity, counteracts the effects of E4f1. We propose that the modulation of Tcf3 repressor function by E4f1 assures precise and robust regulation of cdx4 expression in the caudal domain of the embryo. The EMBO Journal ( 2011) 30, 2894- 2907. doi:10.1038/emboj.2011.184; Published online 10 June 2011 C1 [Ro, Hyunju; Dawid, Igor B.] NICHHD, Mol Genet Lab, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, Program Genom Differentiat, NIH, Bldg 6,Rm 413,9000 Rockville Pike, Bethesda, MD 20892 USA. EM idawid@nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health FX We thank M Rath and J Gonzales for help with fish maintenance. We especially thank Dr RI Dorsky for the Tcf3a antibody and Drs S-Y Choi, DE Ayer and A Chitnis for other reagents. This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 74 TC 12 Z9 13 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 20 PY 2011 VL 30 IS 14 BP 2894 EP 2907 DI 10.1038/emboj.2011.184 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 808HZ UT WOS:000293970100015 PM 21666599 ER PT J AU Berezhkovskii, AM Lizunov, VA Zimmerberg, J Bezrukov, SM AF Berezhkovskii, Alexander M. Lizunov, Vladimir A. Zimmerberg, Joshua Bezrukov, Sergey M. TI Functional Role for Transporter Isoforms in Optimizing Membrane Transport SO BIOPHYSICAL JOURNAL LA English DT Article ID CHANNELS; BINDING AB Quantitative analysis of carrier parameters demonstrates that with decreasing substrate concentration the optimal strength of substrate-carrier interaction which maximizes the flux across the membrane increases and requires less fine-tuning than at higher concentrations of the substrate. C1 [Lizunov, Vladimir A.; Zimmerberg, Joshua; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Berezhkovskii, Alexander M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol,NIH, Bethesda, MD USA. RP Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM bezrukos@mail.nih.gov FU National Institutes of Health; Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was supported by the Intramural Research Program of the National Institutes of Health, Center for Information Technology, and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 15 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUL 20 PY 2011 VL 101 IS 2 BP L14 EP L16 DI 10.1016/j.bpj.2011.06.004 PG 3 WC Biophysics SC Biophysics GA 797VT UT WOS:000293158900004 PM 21767474 ER PT J AU Benko, W Ries, M Wiggs, EA Brady, RO Schiffmann, R FitzGibbon, EJ AF Benko, William Ries, Markus Wiggs, Edythe A. Brady, Roscoe O. Schiffmann, Raphael FitzGibbon, Edmond J. TI The Saccadic and Neurological Deficits in Type 3 Gaucher Disease SO PLOS ONE LA English DT Article ID OPTOKINETIC NYSTAGMUS; SUPERIOR COLLICULUS; CLINICAL-TRIALS; NORMATIVE DATA; CHILDREN; PATHOPHYSIOLOGY; ABNORMALITIES; MOVEMENTS; MIGLUSTAT; ENZYME AB Our objective was to characterize the saccadic eye movements in patients with type 3 Gaucher disease (chronic neuronopathic) in relationship to neurological and neurophysiological abnormalities. For approximately 4 years, we prospectively followed a cohort of 15 patients with Gaucher type 3, ages 8-28 years, by measuring saccadic eye movements using the scleral search coil method. We found that patients with type 3 Gaucher disease had a significantly higher regression slope of duration vs amplitude and peak duration vs amplitude compared to healthy controls for both horizontal and vertical saccades. Saccadic latency was significantly increased for horizontal saccades only. Downward saccades were more affected than upward saccades. Saccade abnormalities increased over time in some patients reflecting the slowly progressive nature of the disease. Phase plane plots showed individually characteristic patterns of abnormal saccade trajectories. Oculo-manual dexterity scores on the Purdue Pegboard test were low in virtually all patients, even in those with normal cognitive function. Vertical saccade peak duration vs amplitude slope significantly correlated with IQ and with the performance on the Purdue Pegboard but not with the brainstem and somatosensory evoked potentials. We conclude that, in patients with Gaucher disease type 3, saccadic eye movements and oculo-manual dexterity are representative neurological functions for longitudinal studies and can probably be used as endpoints for therapeutic clinical trials. Trial Registration: ClinicalTrials.gov NCT00001289 C1 [Benko, William; Wiggs, Edythe A.; Brady, Roscoe O.; Schiffmann, Raphael] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. [Ries, Markus] Univ Childrens Hosp, Heidelberg, Germany. [Schiffmann, Raphael] Baylor Res Inst, Inst Metab Dis, Dallas, TX USA. [FitzGibbon, Edmond J.] NEI, NIH, Bethesda, MD 20892 USA. RP Benko, W (reprint author), Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. EM Raphael.Schiffmann@Baylorhealth.edu OI Ries, Markus/0000-0002-5054-5741 FU National Institutes of Health (NINDS, NEI); Genzyme Corporation; Shire HGT; Amicus Therapeutics FX This work was supported only by the Intramural Program of the National Institutes of Health (NINDS, NEI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Research grants and honoraria from Genzyme Corporation, Shire HGT and Amicus Therapeutics. NR 29 TC 10 Z9 10 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 20 PY 2011 VL 6 IS 7 AR e22410 DI 10.1371/journal.pone.0022410 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794WE UT WOS:000292931200052 PM 21799847 ER PT J AU Schleicher, SM Thotala, DK Linkous, AG Hu, R Leahy, KM Yazlovitskaya, EM Hallahan, DE AF Schleicher, Stephen M. Thotala, Dinesh K. Linkous, Amanda G. Hu, Rong Leahy, Kathleen M. Yazlovitskaya, Eugenia M. Hallahan, Dennis E. TI Autotaxin and LPA Receptors Represent Potential Molecular Targets for the Radiosensitization of Murine Glioma through Effects on Tumor Vasculature SO PLOS ONE LA English DT Article ID LYSOPHOSPHATIDIC ACID RECEPTORS; CANCER METASTASIS; CELL MOTILITY; AKT; PATHWAY; IDENTIFICATION; ANGIOGENESIS; MECHANISMS; INVASION; ANALOGS AB Despite wide margins and high dose irradiation, unresectable malignant glioma (MG) is less responsive to radiation and is uniformly fatal. We previously found that cytosolic phospholipase A2 (cPLA(2)) is a molecular target for radiosensitizing cancer through the vascular endothelium. Autotaxin (ATX) and lysophosphatidic acid (LPA) receptors are downstream from cPLA(2) and highly expressed in MG. Using the ATX and LPA receptor inhibitor, alpha-bromomethylene phosphonate LPA (BrP-LPA), we studied ATX and LPA receptors as potential molecular targets for the radiosensitization of tumor vasculature in MG. Treatment of Human Umbilical Endothelial cells (HUVEC) and mouse brain microvascular cells bEND. 3 with 5 mu mol/L BrP-LPA and 3 Gy irradiation showed decreased clonogenic survival, tubule formation, and migration. Exogenous addition of LPA showed radioprotection that was abrogated in the presence of BrP-LPA. In co-culture experiments using bEND. 3 and mouse GL-261 glioma cells, treatment with BrP-LPA reduced Akt phosphorylation in both irradiated cell lines and decreased survival and migration of irradiated GL-261 cells. Using siRNA to knock down LPA receptors LPA1, LPA2 or LPA3 in HUVEC, we demonstrated that knockdown of LPA2 but neither LPA1 nor LPA3 led to increased viability and proliferation. However, knockdown of LPA1 and LPA3 but not LPA2 resulted in complete abrogation of tubule formation implying that LPA1 and LPA3 on endothelial cells are likely targets of BrP-LPA radiosensitizing effect. Using heterotopic tumor models of GL-261, mice treated with BrP-LPA and irradiation showed a tumor growth delay of 6.8 days compared to mice treated with irradiation alone indicating that inhibition of ATX and LPA receptors may significantly improve malignant glioma response to radiation therapy. These findings identify ATX and LPA receptors as molecular targets for the development of radiosensitizers for MG. C1 [Schleicher, Stephen M.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Yazlovitskaya, Eugenia M.] Vanderbilt Univ, Dept Med, Div Nephrol, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Linkous, Amanda G.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Thotala, Dinesh K.; Hu, Rong; Leahy, Kathleen M.; Hallahan, Dennis E.] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA. [Hallahan, Dennis E.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. [Hallahan, Dennis E.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Schleicher, SM (reprint author), Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. EM dhallahan@radonc.wustl.edu FU U.S. National Cancer Institute [1R01CA140220-02, 5R01CA125757-06, 7R01CA112385-0]; Siteman Cancer Research Award; Elizabeth and James McDonnell III Endowment; Howard Hughes Medical Institute-Ivy Foundation; Department of Radiation Oncology Startup Funds FX This work was supported by U.S. National Cancer Institute grants 1R01CA140220-02, 5R01CA125757-06, 7R01CA112385-0, Siteman Cancer Research Award, Elizabeth and James McDonnell III Endowment (D. Hallahan), Howard Hughes Medical Institute-Ivy Foundation Research Training Fellowship (www.hhmi.org) (S. Schleicher), and Department of Radiation Oncology Startup Funds (D. Thotala). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 25 Z9 26 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 20 PY 2011 VL 6 IS 7 AR e22182 DI 10.1371/journal.pone.0022182 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794WE UT WOS:000292931200033 PM 21799791 ER PT J AU van Bemmel, DM Boffetta, P Liao, LM Berndt, SI Menashe, I Yeager, M Chanock, S Karami, S Zaridze, D Matteev, V Janout, V Kollarova, H Bencko, V Navratilova, M Szeszenia-Dabrowska, N Mates, D Slamova, A Rothman, N Han, SS Rosenberg, PS Brennan, P Chow, WH Moore, LE AF van Bemmel, Dana M. Boffetta, Paolo Liao, Linda M. Berndt, Sonja I. Menashe, Idan Yeager, Meredith Chanock, Stephen Karami, Sara Zaridze, David Matteev, Vsevolod Janout, Vladimir Kollarova, Hellena Bencko, Vladimir Navratilova, Marie Szeszenia-Dabrowska, Neonilia Mates, Dana Slamova, Alena Rothman, Nathaniel Han, Summer S. Rosenberg, Philip S. Brennan, Paul Chow, Wong-Ho Moore, Lee E. TI Comprehensive Analysis of 5-Aminolevulinic Acid Dehydrogenase (ALAD) Variants and Renal Cell Carcinoma Risk among Individuals Exposed to Lead SO PLOS ONE LA English DT Article ID AMINOLEVULINATE DEHYDRATASE POLYMORPHISM; BLOOD LEAD; GENETIC SUSCEPTIBILITY; KIDNEY CANCER; WORKERS; POPULATION; PORPHYRIA; SMOKING; EASTERN; EUROPE AB Background: Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead. Methods: The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results: The adjusted risk associated with the ALAD variant rs8177796(CT/TT) was increased (OR = 1.35, 95%CI = 1.05-1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles ((OR)-O-GG = 2.68, 95%CI = 1.17-6.12, p = 0.01; (OR)-O-GA = 1.79, 95%CI = 1.06-3.04 with an interaction approaching significance (p(int) = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435((K68N)). Haplotype analysis identified a region associated with risk supporting tagging SNP results. Conclusion: A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure. C1 [van Bemmel, Dana M.] NCI, Canc Prevent Fellowship Program, Off Director, Bethesda, MD 20892 USA. [van Bemmel, Dana M.; Liao, Linda M.; Berndt, Sonja I.; Menashe, Idan; Karami, Sara; Rothman, Nathaniel; Han, Summer S.; Rosenberg, Philip S.; Chow, Wong-Ho; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, Gaithersburg, MD USA. [Boffetta, Paolo; Brennan, Paul] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo; Brennan, Paul] Int Prevent Res Inst, Lyon, France. [Zaridze, David; Matteev, Vsevolod] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Janout, Vladimir; Kollarova, Hellena] Palacky Univ, Dept Prevent Med, Fac Med, CR-77147 Olomouc, Czech Republic. [Bencko, Vladimir; Slamova, Alena] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Navratilova, Marie] Masaryk Mem Canc Inst, Brno, Czech Republic. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. RP van Bemmel, DM (reprint author), NCI, Canc Prevent Fellowship Program, Off Director, Bethesda, MD 20892 USA. EM vanbemmeld@mail.nih.gov RI Liao, Linda/B-3960-2011; Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; OI Liao, Linda/0000-0002-1923-5294; mates, dana/0000-0002-6219-9807 FU NIH (National Cancer Institute Division of Cancer Epidemiology and Genetics and the National Institute of Environmental Health Sciences) FX This research was supported by the Intramural Research Program of the NIH (National Cancer Institute Division of Cancer Epidemiology and Genetics and the National Institute of Environmental Health Sciences). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 6 Z9 6 U1 1 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 JUL 20 PY 2011 VL 6 IS 7 AR e20432 DI 10.1371/journal.pone.0020432 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794WE UT WOS:000292931200002 PM 21799727 ER PT J AU Trunova, S Baek, B Giniger, E AF Trunova, Svetlana Baek, Brian Giniger, Edward TI Cdk5 Regulates the Size of an Axon Initial Segment-Like Compartment in Mushroom Body Neurons of the Drosophila Central Brain SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; CELL-ADHESION MOLECULE; K+ CHANNEL; IN-VIVO; MEMBRANE; POLARITY; ANKYRIN; P35; LOCALIZATION; EXCITABILITY AB The axon initial segment (AIS) is the specialized compartment of vertebrate axons where action potentials are initiated. Despite longtime attention to the unique functions of this compartment, the mechanisms that regulate AIS formation and maintenance are not known. Here, we identify a novel compartment in Drosophila mushroom body neurons that mirrors the molecular hallmarks of the vertebrate AIS as judged by accumulation of the anchoring protein Ankyrin1, presence of a specialized actin cytoskeleton, exclusion of both axon-specific and somatodendritic-specific cell surface proteins, and accumulation of a unique combination of voltage-gated ion channels. Using pharmacological treatments, we show that, similar to the vertebrate AIS, the integrity of this region of gamma-neurons and its ability to tether membrane proteins depends on an intact actin cytoskeleton. We further show that Cdk5/p35 kinase regulates the formation and maintenance of the putative AIS by controlling the position of its distal boundary. Thus, boosting Cdk5 activity in gamma-neurons extends the AIS by as much as 100%, while eliminating Cdk5 activity causes the domain to shrink proximally or disappear altogether. These data demonstrate that Cdk5/p35 kinase is a key regulator of the development and maintenance of the AIS in Drosophila. C1 [Trunova, Svetlana; Baek, Brian; Giniger, Edward] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Giniger, E (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, 35 Convent Dr,Room 1C1002, Bethesda, MD 20892 USA. EM ginigere@ninds.nih.gov RI Giniger, Edward/C-1764-2015 OI Giniger, Edward/0000-0002-8340-6158 FU NINDS, NIH [Z01 NS003106] FX This work was supported by the Basic Neuroscience Program of the NINDS Intramural Research Program, NIH Grant Z01 NS003106. We thank Morgan Sheng and Bruce Tempel for helpful discussion; Stephen Wincovitch for help with confocal microscopy; and Ben White, Mark Stopfer, Julie Simpson, Chi-hon Lee, and the Giniger Laboratory for comments on this manuscript. We also thank Ben White, Ron Dubreuil, Liqun Luo, Yasushi Hiromi, and Andreas Prokop for providing reagents and especially thank Julie Simpson for sharing unpublished Elk and Shal transgenic strains. NR 41 TC 20 Z9 20 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 20 PY 2011 VL 31 IS 29 BP 10451 EP 10462 DI 10.1523/JNEUROSCI.0117-11.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 794SH UT WOS:000292921100006 PM 21775591 ER PT J AU Murata, K Imai, M Nakanishi, S Watanabe, D Pastan, I Kobayashi, K Nihira, T Mochizuki, H Yamada, S Mori, K Yamaguchi, M AF Murata, Koshi Imai, Maki Nakanishi, Shigetada Watanabe, Dai Pastan, Ira Kobayashi, Kazuto Nihira, Tomoko Mochizuki, Hideki Yamada, Shuichi Mori, Kensaku Yamaguchi, Masahiro TI Compensation of Depleted Neuronal Subsets by New Neurons in a Local Area of the Adult Olfactory Bulb SO JOURNAL OF NEUROSCIENCE LA English DT Article ID METABOTROPIC GLUTAMATE-RECEPTOR; CELL-ADHESION MOLECULE; CENTRAL-NERVOUS-SYSTEM; GRANULE CELLS; SUBVENTRICULAR ZONE; INTERNEURON SUBTYPES; SYNAPTIC INTEGRATION; NEWBORN NEURONS; STEM-CELLS; NEUROGENESIS AB In the olfactory bulb (OB), loss of preexisting granule cells (GCs) and incorporation of adult-born new GCs continues throughout life. GCs consist of distinct subsets. Here, we examined whether the loss and incorporation of GC subsets are coordinated in the OB. We classified GCs into mGluR2-expressing and -negative subsets and selectively ablated mGluR2-expressing GCs in a local area of the OB with immunotoxin-mediated cell ablation method. The density of mGluR2-expressing GCs showed considerable recovery within several weeks after the ablation. During recovery, an mGluR2-expressing new GC subset was preferentially incorporated over an mGluR2-negative new GC subset in the area of ablation, whereas the preferential incorporation was not observed in the intact area. The area-specific preferential incorporation of mGluR2-expressing new GCs occurred for BrdU analog-and retrovirus-labeled adult-born cells as well as for neonate-derived transplanted cells. The mGluR2-expressing new GCs in the ablated area were synaptically incorporated into the local bulbar circuit. The spine size of mGluR2-expressing new GCs in the ablated area was larger than that of those in the intact area. In contrast, mGluR2-negative new GCs did not show ablated area-specific spine enlargement. These results indicate that local OB areas have a mechanism to coordinate the loss and incorporation of GC subsets by compensatory incorporation of new GC subsets, which involves subset-specific cellular incorporation and subset-specific regulation of spine size. C1 [Yamaguchi, Masahiro] Univ Tokyo, Grad Sch Med, Dept Physiol, Bunkyo Ku, Tokyo 1130033, Japan. [Nakanishi, Shigetada] Osaka Biosci Inst, Dept Syst Biol, Osaka 5650874, Japan. [Watanabe, Dai] Kyoto Univ, Fac Med, Dept Biol Sci, Kyoto 6068501, Japan. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kobayashi, Kazuto] Med Univ, Sch Med, Inst Biomed Sci, Dept Mol Genet, Fukushima 9601295, Japan. [Nihira, Tomoko; Mochizuki, Hideki] Kitasato Univ, Sch Med, Dept Neurol, Kanagawa 2520374, Japan. [Yamada, Shuichi] Kyoto Univ, Inst Virus Res, Dept Cell Biol, Lab Signal Transduct, Kyoto 6068507, Japan. [Murata, Koshi; Mori, Kensaku; Yamaguchi, Masahiro] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Tokyo 1130033, Japan. RP Yamaguchi, M (reprint author), Univ Tokyo, Grad Sch Med, Dept Physiol, Bunkyo Ku, Hongo 7-3-1, Tokyo 1130033, Japan. EM yamaguti@m.u-tokyo.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology, Japan; Japan Society for the Promotion of Science (JSPS), Japan; JSPS; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (K.Mo., M.Y.) and a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (JSPS), Japan (K.Mo., M.Y.). K. Mu. was supported by JSPS Research Fellowship for Young Scientists. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. K. Sawamoto and Dr. N. Kaneko for technical assistance with cell transplantation, Dr. M. Onodera for retroviral vectors, and the members of the Department of Physiology at the University of Tokyo for valuable discussion and comments. NR 60 TC 9 Z9 11 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 JUL 20 PY 2011 VL 31 IS 29 BP 10540 EP 10557 DI 10.1523/JNEUROSCI.1285-11.2011 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 794SH UT WOS:000292921100014 PM 21775599 ER PT J AU Rudebeck, PH Murray, EA AF Rudebeck, Peter H. Murray, Elisabeth A. TI Dissociable Effects of Subtotal Lesions within the Macaque Orbital Prefrontal Cortex on Reward-Guided Behavior SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FRONTAL-LOBE DAMAGE; ORBITOFRONTAL CORTEX; DECISION-MAKING; RHESUS-MONKEYS; NEUROTOXIC LESIONS; AMYGDALA; PERFORMANCE; EXTINCTION; CHOICES; TASK AB The macaque orbital prefrontal cortex (PFo) has been implicated in a wide range of reward-guided behaviors essential for efficient foraging. The PFo, however, is not a homogeneous structure. Two major subregions, distinct by their cytoarchitecture and connections to other brain structures, compose the PFo. One subregion encompasses Walker's areas 11 and 13 and the other centers on Walker's area 14. Although it has been suggested that these subregions play dissociable roles in reward-guided behavior, direct neuropsychological evidence for this hypothesis is limited. To explore the independent contributions of PFo subregions to behavior, we studied rhesus monkeys (Macaca mulatta) with restricted excitotoxic lesions targeting either Walker's areas 11/13 or area 14. The performance of these two groups was compared to that of a group of unoperated controls on a series of reward-based tasks that has been shown to be sensitive to lesions of the PFo as a whole (Walker's areas 11, 13, and 14). Lesions of areas 11/13, but not area 14, disrupted the rapid updating of object value during selective satiation. In contrast, lesions targeting area 14, but not areas 11/13, impaired the ability of monkeys to learn to stop responding to a previously rewarded object. Somewhat surprisingly, neither lesion disrupted performance on a serial object reversal learning task, although aspiration lesions of the entire PFo produce severe deficits on this task. Our data indicate that anatomically defined subregions within macaque PFo make dissociable contributions to reward-guided behavior. C1 [Rudebeck, Peter H.; Murray, Elisabeth A.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Rudebeck, PH (reprint author), NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bldg 49,Suite 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM rudebeckp@mail.nih.gov RI Rudebeck, Peter/G-7931-2012; OI Rudebeck, Peter/0000-0002-1411-7555; Murray, Elisabeth/0000-0003-1450-1642 FU National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. We thank Dawn Lundgren, Emily Howland, and Anna Prescott for assistance with data collection, Richard Saunders and Rachel Reoli for help performing surgery, and Steve Wise and Janine Simmons for useful comments on the manuscript. We also thank the staff of the Nuclear Magnetic Resonance Facility, National Institute of Neurological Disorder and Stroke, and the Laboratory of Diagnostic and Radiology Research, as well as Megan Malloy for assistance in obtaining the MR scans. NR 40 TC 69 Z9 69 U1 1 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 20 PY 2011 VL 31 IS 29 BP 10569 EP 10578 DI 10.1523/JNEUROSCI.0091-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 794SH UT WOS:000292921100016 PM 21775601 ER PT J AU Wendler, D AF Wendler, David TI Research Enrollment and Informed Consent Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 20 PY 2011 VL 306 IS 3 BP 266 EP 266 DI 10.1001/jama.2011.986 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 794BS UT WOS:000292870500015 ER PT J AU Hadigan, C Kottilil, S AF Hadigan, Colleen Kottilil, Shyamasundaran TI Hepatitis C Virus Infection and Coinfection With Human Immunodeficiency Virus Challenges and Advancements in Management SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PLACEBO-CONTROLLED TRIAL; ALPHA-2A PLUS RIBAVIRIN; CHRONIC HCV INFECTION; GENOTYPE 1 INFECTION; PEGINTERFERON ALPHA-2A; UNITED-STATES; DOUBLE-BLIND; PEGYLATED INTERFERON-ALPHA-2A; NONALCOHOLIC STEATOHEPATITIS; FIBROSIS PROGRESSION AB Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) both emerged in the second half of the 20th century, and chronic infection with these agents is among the greatest challenges facing health care in the United States and worldwide. Despite tremendous advances in treatment and management of HIV and HCV, individuals with HIV/HCV coinfection experience a more complicated disease course and treatment. Recognition of the important role that host factors, such as IL28B genotype, have in response to HCV therapy and the emergence of new effective therapies for HCV are actively reshaping the standard of care. These advances may translate into more effective treatment and management of patients with chronic HCV and HIV coinfection in the years ahead. C1 [Hadigan, Colleen; Kottilil, Shyamasundaran] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Hadigan, C (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Room 11C103, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX The National Institute of Allergy and Infectious Diseases Intramural Research Program funded preparation of the manuscript. NR 63 TC 29 Z9 29 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 20 PY 2011 VL 306 IS 3 BP 294 EP 301 DI 10.1001/jama.2011.975 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 794BS UT WOS:000292870500022 PM 21771990 ER PT J AU Kristinsson, SY Bjorkholm, M Hultcrantz, M Derolf, AR Landgren, O Goldin, LR AF Kristinsson, Sigurdur Y. Bjorkholm, Magnus Hultcrantz, Malin Derolf, Asa R. Landgren, Ola Goldin, Lynn R. TI Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID THERAPY-RELATED MYELODYSPLASIA; WALDENSTROM MACROGLOBULINEMIA; HEMATOPOIETIC MALIGNANCIES; RHEUMATOID-ARTHRITIS; HODGKIN-LYMPHOMA; RISK-FACTORS; AUTOIMMUNE; DISORDERS; SWEDEN; TRANSFORMATION AB Purpose Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases. Patients and Methods By using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases. Results Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS. Conclusion Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions. J Clin Oncol 29:2897-2903. (C) 2011 by American Society of Clinical Oncology C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Hultcrantz, Malin; Derolf, Asa R.; Landgren, Ola] Karolinska Univ Hosp Solna, Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Hultcrantz, Malin; Derolf, Asa R.; Landgren, Ola] Karolinska Inst, Stockholm, Sweden. [Landgren, Ola; Goldin, Lynn R.] NCI, NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; National Cancer Institute, National Institutes of Health; Adolf H. Lundin Charitable foundation FX Supported by grants from the Swedish Cancer Society, the Stockholm County Council, the Karolinska Institutet Foundations, the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and the Adolf H. Lundin Charitable foundation. NR 31 TC 58 Z9 62 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 JUL 20 PY 2011 VL 29 IS 21 BP 2897 EP 2903 DI 10.1200/JCO.2011.34.8540 PG 7 WC Oncology SC Oncology GA 793KF UT WOS:000292819700019 PM 21690473 ER PT J AU Simon, R AF Simon, Richard TI Does Topoisomerase II-Alpha Gene Amplification Provide Useful Information for Treatment Selection in Patients With Breast Carcinoma? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 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 JUL 20 PY 2011 VL 29 IS 21 BP 2941 EP 2941 DI 10.1200/JCO.2011.34.9795 PG 1 WC Oncology SC Oncology GA 793KF UT WOS:000292819700025 PM 21670460 ER PT J AU Daher, M Lacouture, ME Rathkopf, D Maki, RG Keohan, ML Gansukh, B Chen, H Abou-Alfa, GK AF Daher, May Lacouture, Mario E. Rathkopf, Dana Maki, Robert G. Keohan, Mary Louise Gansukh, Bolorsukh Chen, Helen Abou-Alfa, Ghassan K. TI Case Series of Dermatologic Events Associated With the Insulin-Like Growth Factor Receptor 1 Inhibitor Cixutumumab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IRON-DEFICIENCY ANEMIA; FACTOR-I RECEPTOR; PYCNODYSOSTOSIS; KOILONYCHIA; HORMONE; DISEASE; CANCER; SKIN; IGF C1 [Daher, May] Amer Univ Beirut, Beirut, Lebanon. [Lacouture, Mario E.; Rathkopf, Dana; Maki, Robert G.; Keohan, Mary Louise; Gansukh, Bolorsukh; Abou-Alfa, Ghassan K.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Chen, Helen] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Daher, M (reprint author), Amer Univ Beirut, Beirut, Lebanon. OI Rathkopf, Dana/0000-0002-4503-7582 FU National Cancer Institute (NCI) [3U01CA069856-15S1, CA148260, CA008747, NO1-CM62206]; American Society of Clinical Oncology Foundation-NCI FX Supported by Grant No. 3U01CA069856-15S1, National Cancer Institute (NCI) ACTNOW funding award, Early Clinical Trials of New Anti-Cancer Agents With Phase I Emphasis (D. R.), NCI Grants No. CA148260, CA008747, American Society of Clinical Oncology Foundation-NCI Clinical Team Leader Award (R. G. M.), and Grant No. NO1-CM62206, NCI Phase II Contract (Memorial Sloan-Kettering Cancer Center; G. K. A., R. G. M.) NR 18 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2011 VL 29 IS 21 BP E638 EP E640 DI 10.1200/JCO.2010.34.5116 PG 3 WC Oncology SC Oncology GA 793KF UT WOS:000292819700008 PM 21606420 ER PT J AU Liu, CL Liu, AY Halabi, S AF Liu, Chunling Liu, Aiyi Halabi, Susan TI A min-max combination of biomarkers to improve diagnostic accuracy SO STATISTICS IN MEDICINE LA English DT Article DE area under curves; linear combinations; receiver operating characteristic (ROC) curve; robustness; sensitivity; specificity ID CHARACTERISTIC ROC CURVES; TESTS; AREA; MARKERS; CANCER AB Diagnostic accuracy can be improved considerably by combining multiple biomarkers. Although the likelihood ratio provides optimal solution to combination of biomarkers, the method is sensitive to distributional assumptions which are often difficult to justify. Alternatively simple linear combinations can be considered whose empirical solution may encounter intensive computation when the number of biomarkers is relatively large. Moreover, the optimal linear combinations derived under multivariate normality may suffer substantial loss of efficiency if the distributions are apart from normality. In this paper, we propose a new approach that linearly combines the minimum and maximum values of the biomarkers. Such combination only involves searching for a single combination coefficient that maximizes the area under the receiver operating characteristic (ROC) curves and is thus computation-effective. Simulation results show that the min-max combination may yield larger partial or full area under the ROC curves and is more robust against distributional assumptions. The methods are illustrated using the growth-related hormones data from the Growth and Maturation in Children with Autism or Autistic Spectrum Disorder Study (Autism/ASD Study). Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Liu, Chunling; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Halabi, Susan] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27708 USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. EM liua@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH) FX Research of the first two authors was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health (NIH). The authors thank Dr James L. Mills and Dr Kai F. Yu for helpful discussions on the autism data example. The authors thank the Editor, Associate Editor, and two referees for their constructive comments, and Dr Paul Albert for helpful discussions. NR 14 TC 15 Z9 15 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 20 PY 2011 VL 30 IS 16 BP 2005 EP 2014 DI 10.1002/sim.4238 PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 791UH UT WOS:000292691300006 PM 21472763 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, Jennifer TI Bridging Structure and Process in Developmental Biology through New Imaging Technologies SO DEVELOPMENTAL CELL LA English DT Editorial Material ID LEFT-RIGHT ASYMMETRY; ILLUMINATION MICROSCOPY; FLUORESCENT PROTEIN; LIVING CELLS; PLANE ILLUMINATION; RESOLUTION; RECONSTRUCTION; MORPHOGENESIS; CANCER; PROBES AB Many unexpected discoveries in developmental biology have depended on advancement of imaging technologies to visualize developmental processes as they unfold across multiple spatial and temporal scales. This essay surveys the recent advances in imaging, highlighting emerging capabilities with an eye toward those poised to have the greatest impact on developmental biology. C1 Eunice Kennedy Shriver Inst Child Hlth & Human De, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Inst Child Hlth & Human De, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov FU Intramural NIH HHS [ZIA HD001609-19] NR 45 TC 10 Z9 10 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JUL 19 PY 2011 VL 21 IS 1 SI SI BP 5 EP 10 DI 10.1016/j.devcel.2011.06.030 PG 6 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 799TY UT WOS:000293310200003 PM 21763598 ER PT J AU Martinou, JC Youle, RJ AF Martinou, Jean-Claude Youle, Richard J. TI Mitochondria in Apoptosis: Bcl-2 Family Members and Mitochondrial Dynamics SO DEVELOPMENTAL CELL LA English DT Review ID CYTOCHROME-C RELEASE; PROGRAMMED CELL-DEATH; OUTER-MEMBRANE PERMEABILIZATION; STRESS-INDUCED APOPTOSIS; LIPIDIC PORE FORMATION; BAX-DERIVED PEPTIDE; PROAPOPTOTIC BAX; BH3-ONLY PROTEINS; SUBCELLULAR-LOCALIZATION; EMBRYONIC-DEVELOPMENT AB Mitochondria participate in apoptosis through a range of mechanisms that vary between vertebrates and invertebrates. In vertebrates, they release intermembrane space proteins, such as cytochrome c, to promote caspase activation in the cytosol. This process is the result of the loss of integrity of the outer mitochondrial membrane caused by proapoptotic members of the Bcl-2 family. This event is always accompanied by a fissioning of the organelle. Fission of mitochondria has also been reported to participate in apoptosis in Drosophila and Caenorhabditis elegans. However, in these organisms, mitochondrial membrane permeabilization does not occur and the mechanism by which mitochondrial dynamics participates in cell death remains elusive. C1 [Martinou, Jean-Claude] Univ Geneva, Dept Cell Biol, Fac Sci, CH-1211 Geneva 4, Switzerland. [Martinou, Jean-Claude; Youle, Richard J.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Martinou, JC (reprint author), Univ Geneva, Dept Cell Biol, Fac Sci, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland. EM jean-claude.martinou@unige.ch; youler@ninds.nih.gov FU Swiss National Foundation [31003A-124968/1]; Oncosuisse; Geneva Department of Education; NINDS, NIH FX We thank Drs. Megan Cleland and Soojay Banerjee for help with artwork. J.-C.M is supported by the Swiss National Foundation (subsidy 31003A-124968/1), Oncosuisse, and the Geneva Department of Education. R.J.Y. is supported by the Intramural Program of the NINDS, NIH. NR 116 TC 501 Z9 568 U1 21 U2 152 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JUL 19 PY 2011 VL 21 IS 1 SI SI BP 92 EP 101 DI 10.1016/j.devcel.2011.06.017 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 799TY UT WOS:000293310200016 PM 21763611 ER PT J AU De Leon, JT Iwai, A Feau, C Garcia, Y Balsiger, HA Storer, CL Suro, RM Garza, KM Lee, S Kim, YS Chen, Y Ning, YM Riggs, DL Fletterick, RJ Guy, RK Trepel, JB Neckers, LM Cox, MB AF De Leon, Johanny Tonos Iwai, Aki Feau, Clementine Garcia, Yenni Balsiger, Heather A. Storer, Cheryl L. Suro, Raquel M. Garza, Kristine M. Lee, Sunmin Kim, Yeong Sang Chen, Yu Ning, Yang-Min Riggs, Daniel L. Fletterick, Robert J. Guy, R. Kiplin Trepel, Jane B. Neckers, Leonard M. Cox, Marc B. TI Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunophilin; FKBP4; steroid hormone receptor ID HSP90; COMPENDIUM; EXPRESSION; REPORTER; BINDING; LINES; OLD AB Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation. C1 [De Leon, Johanny Tonos; Garcia, Yenni; Balsiger, Heather A.; Storer, Cheryl L.; Suro, Raquel M.; Garza, Kristine M.; Cox, Marc B.] Univ Texas El Paso, Dept Biol Sci, El Paso, TX 79968 USA. [De Leon, Johanny Tonos; Garcia, Yenni; Balsiger, Heather A.; Storer, Cheryl L.; Suro, Raquel M.; Garza, Kristine M.; Cox, Marc B.] Univ Texas El Paso, Border Biomed Res Ctr, El Paso, TX 79968 USA. [Iwai, Aki; Neckers, Leonard M.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Feau, Clementine; Guy, R. Kiplin] St Jude Childrens Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA. [Lee, Sunmin; Kim, Yeong Sang; Trepel, Jane B.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Chen, Yu] Univ S Florida, Dept Mol Med, Tampa, FL 33612 USA. [Ning, Yang-Min] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Riggs, Daniel L.] Mayo Clin Arizona, Scottsdale, AZ 85259 USA. [Fletterick, Robert J.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. RP Cox, MB (reprint author), Univ Texas El Paso, Dept Biol Sci, El Paso, TX 79968 USA. EM mbcox@utep.edu RI Guy, Rodney/J-7107-2013 OI Guy, Rodney/0000-0002-9638-2060 FU Border Biomedical Research Center's [National Center for Research Resources/National Institutes of Health (NIH)] [5G12RR008124]; National Institute of General Medical Sciences, NIH [SC1GM084863]; Research Initiative for Scientific Enhancement [R25GM069621]; National Science Foundation [HRD-0832951]; American Lebanese Syrian Associated Charities; St. Jude Children's Research Hospital; NIH [DK58080]; Department of Defense [PC060344-W81XWH-07-1-0073]; National Cancer Institute FX We thank Brian Freeman, Charles Sawyers, Robert Reiter, David Toft, and Donald Tindall for providing reagents. The authors are grateful to David Smith and Charles Miller for critically reading the manuscript. We thank the Border Biomedical Research Center's [Grant 5G12RR008124, National Center for Research Resources/National Institutes of Health (NIH)] Biomolecule Analysis Core Facility, Tissue Culture Core Facility, and the DNA Analysis Core Facility for the use of the instruments. This project was also supported in part by American Recovery and Reinvestment Act funds through Grant SC1GM084863 to M. B. C. from the National Institute of General Medical Sciences, NIH. J.T.D.L. was supported by Research Initiative for Scientific Enhancement (R25GM069621) and National Science Foundation Louis Stokes Alliances for Minority Participation (HRD-0832951) fellowships. R. K. G. and C. F. were supported by the American Lebanese Syrian Associated Charities, St. Jude Children's Research Hospital, the NIH (DK58080), and the Department of Defense Prostate Cancer Research Program (PC060344-W81XWH-07-1-0073). A. I., S. L., Y.S.K., Y.N., J.B.T., and L.M.N. were supported by funds from the Intramural Research Program of the National Cancer Institute. NR 20 TC 54 Z9 54 U1 0 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 JUL 19 PY 2011 VL 108 IS 29 BP 11878 EP 11883 DI 10.1073/pnas.1105160108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900038 PM 21730179 ER PT J AU Kimble, JB Sorrell, E Shao, HX Martin, PL Perez, DR AF Kimble, J. Brian Sorrell, Erin Shao, Hongxia Martin, Philip L. Perez, Daniel Roberto TI Compatibility of H9N2 avian influenza surface genes and 2009 pandemic H1N1 internal genes for transmission in the ferret model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TRIG cassette; preparedness; infection; pathology; ecology ID A VIRUS; HUMAN INFECTION; SWINE; HEMAGGLUTININ; ORIGIN; REASSORTMENT; PATHOGENESIS; REPLICATION; POULTRY; H3N2 AB In 2009, a novel H1N1 influenza (pH1N1) virus caused the first influenza pandemic in 40 y. The virus was identified as a triple reassortant between avian, swine, and human influenza viruses, highlighting the importance of reassortment in the generation of viruses with pandemic potential. Previously, we showed that a reassortant virus composed of wild-type avian H9N2 surface genes in a seasonal human H3N2 backbone could gain efficient respiratory droplet transmission in the ferret model. Here we determine the ability of the H9N2 surface genes in the context of the internal genes of a pH1N1 virus to efficiently transmit via respiratory droplets in ferrets. We generated reassorted viruses carrying the HA gene alone or in combination with the NA gene of a prototypical H9N2 virus in the background of a pH1N1 virus. Four reassortant viruses were generated, with three of them showing efficient respiratory droplet transmission. Differences in replication efficiency were observed for these viruses; however, the results clearly indicate that H9N2 avian influenza viruses and pH1N1 viruses, both of which have occasionally infected pigs, have the potential to reassort and generate novel viruses with respiratory transmission potential in mammals. C1 [Kimble, J. Brian; Sorrell, Erin; Shao, Hongxia; Perez, Daniel Roberto] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Kimble, J. Brian; Sorrell, Erin; Shao, Hongxia; Perez, Daniel Roberto] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Martin, Philip L.] NCI, Ctr Adv Preclin Res, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Perez, DR (reprint author), Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. EM dperez1@umd.edu RI Wei, Jianjian/F-7788-2011; OI Wei, Jianjian/0000-0001-8859-8462; Perez, Daniel/0000-0002-6569-5689 FU Centers for Disease Control and Prevention-Department of Health and Human Services [1U01CI000355-01]; National Institute of Food and Agriculture-US Department of Agriculture [2007-04981]; National Institute of Allergy and Infectious Diseases-National Institutes of Health [HHSN266200700010C]; US Department of Agriculture-Agricultural Research Service FX We thank Troy Sutton, Lindomar Pena, and Yonas Araya for their help with animal studies; Jianqiang Ye for assistance with the ELISA assays; Amy Vincent for her assistance with the immunohistochemistry protocol; and Theresa Wolter-Marth and Andrea Ferrero for coordination of animal studies. This research was funded by Grants 1U01CI000355-01 from the Centers for Disease Control and Prevention-Department of Health and Human Services and 2007-04981 from the National Institute of Food and Agriculture-US Department of Agriculture, and Contract HHSN266200700010C from the National Institute of Allergy and Infectious Diseases-National Institutes of Health, and a Cooperative Agreement from the US Department of Agriculture-Agricultural Research Service. NR 27 TC 66 Z9 68 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2011 VL 108 IS 29 BP 12084 EP 12088 DI 10.1073/pnas.1108058108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900073 PM 21730147 ER PT J AU Zhou, XM Izumi, Y Burg, MB Ferraris, JD AF Zhou, Xiaoming Izumi, Yuichiro Burg, Maurice B. Ferraris, Joan D. TI Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-gamma 1 to activation of the osmoprotective transcription factor NFAT5 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE osmotic stress; MAPK ID OSMOTIC RESPONSE ELEMENT; NACL-INDUCED ACTIVATION; FACTOR TONEBP/OREBP; INDUCED PHOSPHORYLATION; NUCLEAR-LOCALIZATION; GROWTH-FACTOR; KIDNEY-CELLS; P38 KINASE; PROTEIN; RAC1 AB Separate reports that hypertonicity activates p38 via a Rac1-OSMMEKK3- MKK3-p38 pathway and that p38a contributes to activation of TonEBP/OREBP led us to the hypothesis that Rac1 might activate TonEBP/OREBP via p38. The present studies examine that possibility. High NaCl is hypertonic. We find that siRNA knockdown of Rac1 reduces high NaCl-induced increase of TonEBP/OREBP transcriptional activity (by reducing its transactivating activity but not its nuclear localization). Similarly, siRNA knockdown of osmosensing scaffold for MEKK3 (OSM) also reduces high NaCl-dependent TonEBP/OREBP transcriptional and transactivating activities. Simultaneous siRNA knockdown of Rac1 and OSM is not additive in reduction of TonEBP/OREBP transcriptional activity, indicating a common pathway. However, siRNA knockdown of MKK3 does not reduce TonEBP/OREBP transcriptional activity, although siRNA knockdown of MKK6 does. Nevertheless, the effect of Rac1 on TonEBP/OREBP is also independent of MKK6 because it occurs in MKK6-null cells. Furthermore, we find that siRNA knockdown of Rac1 or OSM actually increases activity (phosphorylation) of p38, rather than decreasing it, as previously reported. Thus, the effect of Rac1 on TonEBP/OREBP is independent of p38. We find instead that phospholipase C-gamma 1 (PLC-gamma 1) is involved. When transfected into PLC gamma 1- null mouse embryonic fibroblast cells, catalytically active Rac1 does not increase TonEBP/OREBP transcriptional activity unless PLC-gamma 1 is reconstituted. Similarly, dominant-negative Rac1 also does not inhibit TonEBP/OREBP in PLC-gamma 1-null cells unless PLC-gamma 1 is reconstituted. We conclude that Rac1/OSM supports TonEBP/OREBP activity and that this activity is mediated via PLC-gamma 1, not p38. C1 [Zhou, Xiaoming] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Izumi, Yuichiro; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Zhou, XM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, Room A3060, Bethesda, MD 20814 USA. EM xiazhou@usuhs.mil; maurice_burg@nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services; Uniformed Services University of the Health Sciences, Department of Defense [CO83WU] FX We thank Dr. Roger J. Davis for MKK6-/- MEFs, Dr. Graham Carpenter for PLC-gamma 1+/+ and PLC-gamma 1-/- MEFs, Dr. Andras Kapus for Rac1 mutant constructs, and Dr. Norman P. Curthoys for pTRE2-Flag-dnMKK6 plasmid. This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services and by Grant CO83WU from the Uniformed Services University of the Health Sciences, Department of Defense. NR 40 TC 14 Z9 15 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2011 VL 108 IS 29 BP 12155 EP 12160 DI 10.1073/pnas.1108107108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900085 PM 21712438 ER PT J AU Dalet, A Robbins, PF Stroobant, V Vigneron, N Li, YF El-Gamil, M Hanada, K Yang, JC Rosenberg, SA Van den Eynde, BJ AF Dalet, Alexandre Robbins, Paul F. Stroobant, Vincent Vigneron, Nathalie Li, Yong F. El-Gamil, Mona Hanada, Ken-ichi Yang, James C. Rosenberg, Steven A. Van den Eynde, Benoit J. TI An antigenic peptide produced by reverse splicing and double asparagine deamidation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antigen processing; peptide splicing; tumor antigen ID CYTOLYTIC T-LYMPHOCYTES; TUMOR-INFILTRATING LYMPHOCYTES; I-RESTRICTED EPITOPE; OPEN READING FRAME; ENDOPLASMIC-RETICULUM; HLA-A2 MELANOMAS; ENVELOPE GLYCOPROTEIN; PROCESSING PATHWAY; TYROSINASE EPITOPE; INTERFERON-GAMMA AB A variety of unconventional translational and posttranslational mechanisms contribute to the production of antigenic peptides, thereby increasing the diversity of the peptide repertoire presented by MHC class I molecules. Here, we describe a class I-restricted peptide that combines several posttranslational modifications. It is derived from tyrosinase and recognized by tumor-infiltrating lymphocytes isolated from a melanoma patient. This unusual antigenic peptide is made of two noncontiguous tyrosinase fragments that are spliced together in the reverse order. In addition, it contains two aspartate residues that replace the asparagines encoded in the tyrosinase sequence. We confirmed that this peptide is naturally presented at the surface of melanoma cells, and we showed that its processing sequentially requires translation of tyrosinase into the endoplasmic reticulum and its retrotranslocation into the cytosol, where deglycosylation of the two asparagines by peptide-N-glycanase turns them into aspartates by deamidation. This process is followed by cleavage and splicing of the appropriate fragments by the standard proteasome and additional transport of the resulting peptide into the endoplasmic reticulum through the transporter associated with antigen processing (TAP). C1 [Dalet, Alexandre; Stroobant, Vincent; Vigneron, Nathalie; Van den Eynde, Benoit J.] Catholic Univ Louvain, Ludwig Inst Canc Res, Brussels Branch, B-1200 Brussels, Belgium. [Dalet, Alexandre; Stroobant, Vincent; Vigneron, Nathalie; Van den Eynde, Benoit J.] Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium. [Robbins, Paul F.; Li, Yong F.; El-Gamil, Mona; Hanada, Ken-ichi; Yang, James C.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20854 USA. RP Van den Eynde, BJ (reprint author), Catholic Univ Louvain, Ludwig Inst Canc Res, Brussels Branch, B-1200 Brussels, Belgium. EM Benoit.Vandeneynde@bru.licr.org RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 FU European Community [LSHC-2006-518234]; Walloon Region Programme d'Excellence CIBLES; Fonds J. Maisin (Belgium); Fondation contre le Cancer (Belgium); Fonds National de la Recherche Scientifique (FNRS; Belgium); FNRS FX We thank Luc Pilotte and Aline Depasse for excellent technical assistance and Julie Klein for editorial assistance. This work was supported by the European Community under Sixth Framework Program Grant LSHC-2006-518234 (Cancer Immunotherapy), the Walloon Region Programme d'Excellence CIBLES, the Fonds J. Maisin (Belgium), the Fondation contre le Cancer (Belgium), and the Fonds National de la Recherche Scientifique (FNRS; Belgium). A.D. is supported by a Televie fellowship from the FNRS, and N.V. is a post-doctoral researcher with the FNRS. NR 55 TC 25 Z9 25 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2011 VL 108 IS 29 BP E323 EP E331 DI 10.1073/pnas.1101892108 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 794DY UT WOS:000292876900009 PM 21670269 ER PT J AU Combs, GF Watts, JC Jackson, MI Johnson, LK Zeng, HW Scheett, AJ Uthus, EO Schomburg, L Hoeg, A Hoefig, CS Davis, CD Milner, JA AF Combs, Gerald F., Jr. Watts, Jennifer C. Jackson, Matthew I. Johnson, LuAnn K. Zeng, Huawei Scheett, Angela J. Uthus, Eric O. Schomburg, Lutz Hoeg, Antonia Hoefig, Carolin S. Davis, Cindy D. Milner, John A. TI Determinants of selenium status in healthy adults SO NUTRITION JOURNAL LA English DT Article ID GLUTATHIONE-PEROXIDASE-ACTIVITY; SELENOPROTEIN-P; CANCER PREVENTION; 3'-UNTRANSLATED REGION; PLASMA SELENIUM; PROSTATE-CANCER; VITAMIN-E; SUPPLEMENTATION; EXPRESSION; TRIAL AB Background: Selenium (Se) status in non-deficient subjects is typically assessed by the Se contents of plasma/serum. That pool comprises two functional, specific selenoprotein components and at least one non-functional, non-specific components which respond differently to changes in Se intake. A more informative means of characterizing Se status in non-deficient individuals is needed. Methods: Multiple biomarkers of Se status (plasma Se, serum selenoprotein P [SEPP1], plasma glutathione peroxidase activity [GPX3], buccal cell Se, urinary Se) were evaluated in relation to selenoprotein genotypes (GPX1, GPX3, SEPP1, SEP15), dietary Se intake, and parameters of single-carbon metabolism in a cohort of healthy, non-Se-deficient men (n = 106) and women (n = 155). Conclusions: Plasma Se concentration was 142.0 +/- 23.5 ng/ml, with GPX3 and serum-derived SEPP1 calculated to comprise 20% and 34%, respectively, of that total. The balance, comprised of non-specific components, accounted for virtually all of the interindividual variation in total plasma Se. Buccal cell Se was associated with age and plasma homocysteine (hCys), but not plasma Se. SEPP1 showed a quadratic relationship with body mass index, peaking at BMI 25-30. Urinary Se was greater in women than men, and was associated with metabolic body weight (kg(0.75)), plasma folate, vitamin B-12 and hCys (negatively). One GPX1 genotype (679T/T) was associated with significantly lower plasma Se levels than other allelic variants. Selenium intake, estimated from food frequency questionnaires, did not predict Se status as indicated by any biomarker. These results show that genotype, methyl-group status and BMI contribute to variation in Se biomarkers in Se-adequate individuals. C1 [Combs, Gerald F., Jr.; Watts, Jennifer C.; Jackson, Matthew I.; Johnson, LuAnn K.; Zeng, Huawei; Scheett, Angela J.; Uthus, Eric O.] 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. [Davis, Cindy D.; Milner, John A.] NCI, Nutr Sci Res Grp, Nutr & Canc Program, Bethesda, MD 20892 USA. RP Combs, GF (reprint author), USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. EM gerald.combs@ars.usda.gov NR 53 TC 47 Z9 47 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD JUL 18 PY 2011 VL 10 AR 75 DI 10.1186/1475-2891-10-75 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 812CY UT WOS:000294266500001 PM 21767397 ER PT J AU Xiao, S Kumar, M Yang, XL Akkoyunlu, M Collins, PL Samal, SK Pal, U AF Xiao, Sa Kumar, Manish Yang, Xiuli Akkoyunlu, Mustafa Collins, Peter L. Samal, Siba K. Pal, Utpal TI A host-restricted viral vector for antigen-specific immunization against Lyme disease pathogen SO VACCINE LA English DT Article DE Borrelia burgdorferi; Newcastle disease virus; Lyme disease; Immunization; Vaccine ID OUTER-SURFACE PROTEIN; AVIAN INFLUENZA-VIRUS; NEWCASTLE-DISEASE; BORRELIA-BURGDORFERI; VACCINE VECTOR; ACTIVE IMMUNIZATION; RESPIRATORY-TRACT; FOREIGN GENE; OSPC; MICE AB Newcastle disease virus (NDV) is an avian virus that is attenuated in primates and is a potential vaccine vector for human use. We evaluated NDV as a vector for expressing selected antigens of the Lyme disease pathogen Borrelia burgdorferi. A series of recombinant NDVs were generated that expressed intracellular or extracellular forms of two B. burgdorferi antigens: namely, the basic membrane protein A (BmpA) and the outer surface protein C (OspC). Expression of the intracellular and extracellular forms of these antigens was confirmed in cultured chicken cells. C3H or Balb/C mice that were immunized intranasally with the NDV vectors mounted vigorous serum antibody responses against the NDV vector, but failed to mount a robust response against either the intracellular or extracellular forms of BmpA or OspC. By contrast, a single immunization of hamsters with the NDV vectors via the intranasal, intramuscular, or intraperitoneal route resulted in rapid and rigorous antibody responses against the intracellular or extracellular forms of BmpA and OspC. When groups of hamsters were separately inoculated with various NDV vectors and challenged with B. burgdorferi (10(8) cells/animal), immunization with vector expressing either intracellular or extracellular BmpA was associated with a significant reduction of the pathogen load in the joints. Taken together, our studies highlighted the importance of NDV as vaccine vector that can be used for simple yet effective immunization of hosts against bacterial infections including Lyme disease. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Xiao, Sa; Kumar, Manish; Yang, Xiuli; Samal, Siba K.; Pal, Utpal] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Akkoyunlu, Mustafa] US FDA, Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Dept Vet Med, Bldg 795,Room 1341, College Pk, MD 20742 USA. EM ssamal@umd.edu; upal@umd.edu RI Akkoyunlu, Mustafa/I-5712-2012; Pal, Utpal/I-5265-2015 FU NIH/NIAID [AI080615, AR055323, N01A060009]; NIH FX This research was supported in part by NIH/NIAID Awards (AI080615 and AR055323), NIH/NIAID Contract N01A060009 and NIH Intramural Research Program. We sincerely thank Alexis Smith for her excellent assistance with this study. NR 65 TC 7 Z9 8 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 18 PY 2011 VL 29 IS 32 BP 5294 EP 5303 DI 10.1016/j.vaccine.2011.05.010 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 808OB UT WOS:000293987200028 PM 21600949 ER PT J AU Ellong, EN Soni, KG Bui, QT Sougrat, R Golinelli-Cohen, MP Jackson, CL AF Ellong, Emy Njoh Soni, Krishnakant G. Quynh-Trang Bui Sougrat, Rachid Golinelli-Cohen, Marie-Pierre Jackson, Catherine L. TI Interaction between the Triglyceride Lipase ATGL and the Arf1 Activator GBF1 SO PLOS ONE LA English DT Article ID NUCLEOTIDE EXCHANGE FACTORS; CHANARIN-DORFMAN-SYNDROME; ADP-RIBOSYLATION FACTORS; TRANS-GOLGI NETWORK; LIPID DROPLETS; SACCHAROMYCES-CEREVISIAE; PROTEIN; LIPOLYSIS; FAMILY; PATATIN AB The Arf1 exchange factor GBF1 (Golgi Brefeldin A resistance factor 1) and its effector COPI are required for delivery of ATGL (adipose triglyceride lipase) to lipid droplets (LDs). Using yeast two hybrid, co-immunoprecipitation in mammalian cells and direct protein binding approaches, we report here that GBF1 and ATGL interact directly and in cells, through multiple contact sites on each protein. The C-terminal region of ATGL interacts with N-terminal domains of GBF1, including the catalytic Sec7 domain, but not with full-length GBF1 or its entire N-terminus. The N-terminal lipase domain of ATGL (called the patatin domain) interacts with two C-terminal domains of GBF1, HDS (Homology downstream of Sec7) 1 and HDS2. These two domains of GBF1 localize to lipid droplets when expressed alone in cells, but not to the Golgi, unlike the full-length GBF1 protein, which localizes to both. We suggest that interaction of GBF1 with ATGL may be involved in the membrane trafficking pathway mediated by GBF1, Arf1 and COPI that contributes to the localization of ATGL to lipid droplets. C1 [Ellong, Emy Njoh; Quynh-Trang Bui; Golinelli-Cohen, Marie-Pierre; Jackson, Catherine L.] CNRS, Lab Enzymol & Biochim Struct, Gif Sur Yvette, France. [Soni, Krishnakant G.; Sougrat, Rachid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. RP Ellong, EN (reprint author), CNRS, Lab Enzymol & Biochim Struct, Bat 34, Gif Sur Yvette, France. EM jackson@ijm.univ-paris-diderot.fr RI Jackson, Catherine/A-3421-2013; Golinelli, Marie-Pierre/K-4287-2013; OI Jackson, Catherine/0000-0002-0843-145X; Golinelli, Marie-Pierre/0000-0002-6738-8631; Sougrat, Rachid/0000-0001-6476-1886 FU ANR; CNRS; Fondation pour la Recherche Medicale (FRM); NICHD; Ministere de l'Enseignement Superieur et de la Recherche FX This work was funded by a grant from the ANR (Chaire d'Excellence), the CNRS, the Fondation pour la Recherche Medicale (FRM), and the Intramural Program of NICHD. ENE was supported by a fellowship from the Ministere de l'Enseignement Superieur et de la Recherche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 20 Z9 21 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2011 VL 6 IS 7 AR e21889 DI 10.1371/journal.pone.0021889 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HY UT WOS:000292812400019 PM 21789191 ER PT J AU Taha, TE James, MM Hoover, DR Sun, J Laeyendecker, O Mullis, CE Kumwenda, JJ Lingappa, JR Auvert, B Morrison, CS Mofensen, LM Taylor, A Fowler, MG Kumenda, NI Eshleman, SH AF Taha, E. Taha James, Maria M. Hoover, Donald R. Sun, Jin Laeyendecker, Oliver Mullis, Caroline E. Kumwenda, Johnstone J. Lingappa, Jairam R. Auvert, Bertran Morrison, Charles S. Mofensen, Lynne M. Taylor, Allan Fowler, Mary G. Kumenda, Newton I. Eshleman, Susan H. TI Association of recent HIV infection and in-utero HIV-1 transmission SO AIDS LA English DT Article DE HIV; incidence; Malawi; mother-to-child transmission; multiassay algorithm ID CAPTURE ENZYME-IMMUNOASSAY; TO-CHILD TRANSMISSION; PERINATAL TRANSMISSION; PREGNANT-WOMEN; PREVENTION; RISK; AFRICA; TRIAL; RNA; PROPHYLAXIS AB Objective: We previously developed a multiassay algorithm (MAA) to identify recent HIV infection that includes the BED-capture enzyme immunoassay, an avidity assay based on the Genetic Systems HIV-1/HIV-2+O enzyme immunoassay, CD4 cell count, and HIV viral load. We used this MAA to evaluate the association between recent maternal HIV infection and in-utero transmission of HIV. Methods: Plasma samples were collected at delivery from 2561 HIV-infected women in the postexposure prophylaxis of infants-Malawi trial. The MAA described above was used to identify women with recent HIV infection. Logistic regression models assessed association between recent HIV infection and in-utero HIV transmission (defined as a positive infant HIV DNA test at birth). Results: Seventy-three women were identified as recently infected using the MAA. Those women were younger and had lower parity than women who were identified as not recently infected using the MAA (P<0.0001 for age and parity). The frequency of in-utero HIV transmission was 17.8% among women identified as recently infected, compared with 6.7% among women identified as not recently infected (13/73 vs. 166/2488, P = 0.001). In a multivariate model, three factors were independently associated with in-utero HIV transmission: recent infection [adjusted odds ratio (AOR): 2.49, 95% confidence interval (CI): 1.30-4.78, P = 0.006], log(10) HIV viral load at delivery (AOR: 2.01, 95% CI: 1.60-2.51, P<0.0001), and younger age (per 10 year increase, AOR: 0.66, 95% CI: 0.43-0.93, P = 0.02). Conclusion: Results obtained using a MAA suggest that recent maternal HIV acquisition is strongly associated with in-utero HIV transmission, independent of HIV viral load at delivery. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [James, Maria M.; Fowler, Mary G.; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Taha, E. Taha; Sun, Jin; Kumenda, Newton I.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Healthcare Policy & Aging Res, Piscataway, NJ USA. [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Mullis, Caroline E.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Kumwenda, Johnstone J.] Univ Malawi, Dept Med, Coll Med, Blantyre, Malawi. [Lingappa, Jairam R.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Lingappa, Jairam R.] Univ Washington, Dept Med, Seattle, WA USA. [Lingappa, Jairam R.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Auvert, Bertran] INSERM, U1018, CESP, Villejuif, France. [Auvert, Bertran] Hop Ambroise Pare, AP HP, Boulogne, France. [Auvert, Bertran] Univ Versailles, Guyancourt, France. [Morrison, Charles S.] Family Hlth Int, Clin Sci, Durham, NC USA. [Mofensen, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Taylor, Allan] Ctr Dis Control & Prevent, Epidemiol Branch, Div HIV AIDS Prevent, Atlanta, GA USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Ross Bldg,Room 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group [U01-AI068633]; American Recovery and Reinvestment Act award [3U01AI068632-05S3]; National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); National Institute on Drug Abuse, National Institutes of Health (NIH); National Institute of Mental Health, National Institutes of Health (NIH); Office of AIDS Research, National Institutes of Health (NIH); Department of Health and Human Services (DHHS) [U01AI068613]; Centers for Disease Control and Prevention [U50/CCU022061]; Partners in Prevention HSV/HIV Transmission Study [26469]; Hormonal Contraception and HIV Acquisition (HC-HIV) Study [N01-HD-0-3310]; Division of Intramural Research, NIAID, NIH FX The sources of support are as follows: First, International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, American Recovery and Reinvestment Act award (cooperative agreement 3U01AI068632-05S3). Second, The HPTN sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) (U01AI068613). Third, The Centers for Disease Control and Prevention (cooperative agreement U50/CCU022061). Fourth, IMPAACT Group (U01-AI068633). Fifth, The Partners in Prevention HSV/HIV Transmission Study (grant #26469, Bill and Melinda Gates Foundation). Sixth, the Hormonal Contraception and HIV Acquisition (HC-HIV) Study (contract N01-HD-0-3310 through Family Health International, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, DHHS). Seventh, The Division of Intramural Research, NIAID, NIH. NR 43 TC 10 Z9 10 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 17 PY 2011 VL 25 IS 11 BP 1357 EP 1364 DI 10.1097/QAD.0b013e3283489d45 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 784UO UT WOS:000292183900002 PM 21572305 ER PT J AU Chandwani, S Beeler, J Li, H Audet, S Smith, B Moye, J Nalin, D Krasinski, K AF Chandwani, Sulachni Beeler, Judy Li, Hong Audet, Susette Smith, Betsy Moye, John Nalin, David Krasinski, Keith CA PACTG 225 Study Team TI Safety and Immunogenicity of Early Measles Vaccination in Children Born to HIV-Infected Mothers in the United States: Results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 225 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Global Technical Consultation to Assess the Feasibility of Measles Eradication CY JUL 28-30, 2010 CL Washington, DC ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; MATERNAL ANTIBODY; IMMUNE-RESPONSES; IMMUNIZATION; INFANTS; VACCINES; CELL; REVACCINATION; TITERS AB Background. PACTG (Pediatric AIDS Clinical Trials Group) 225, a multicenter, randomized, open-label trial in the United States evaluated reactogenicity and immunogenicity of 2 vaccination regimens: monovalent measles vaccine (Attenuvax) at 6 months of age and measles, mumps, and rubella, live attenuated (MMRII) vaccine at 12 months of age (2D), or only MMRII at 12 months of age (1D) in human immunodeficiency virus infected (HIV-infected) (POS) and uninfected (NEC) children in the pre-highly active antiretroviral therapy (pre-HAART) period. Methods. Plaque-reduction neutralization (PRN) of measles-neutralizing antibody titers were evaluated at study weeks 0, 6, 26, 32, 52, and 130 (similar to 3 years of age). Results. The 110 subjects included: 65 2DNEG; 30 1DNEG; 7 2DPOS and 8 1DPOS. Vaccinations (n = 175) were associated with no adverse experiences >Grade 2 except for Grade 3 fever (n = 2, 1 1DPOS and 1 1DNEG). Six weeks after Attenuvax, all 2DPOS subjects (7/7) seroresponded (PRN titers >= 120 mlU/mL) with median titers significantly exceeding 2DNEG titers (2115 vs 628 mlU/mL, respectively; P = .023). At similar to 3 years of age, 67% 1DPOS (4/6) and 83% 2DPOS (4/5) subjects maintained titers >= 120 mlU/mL. Prevaccination titers >= 25 mlU/mL among 2DNEG subjects correlated inversely with the likelihood of achieving titers >= 120 mlU/mL (56% vs 90%; P = .004). Conclusions. Among HIV-infected children pre-HAART, Attenuvax at 6 months was well tolerated and immunogenic. These data support the current World Health Organization (WHO) recommendation to administer a first dose of measles vaccine at 6 months of age to HIV-infected children. C1 [Chandwani, Sulachni; Krasinski, Keith] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Li, Hong] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Beeler, Judy; Audet, Susette] US FDA, Bethesda, MD 20014 USA. [Smith, Betsy] NIAID, Bethesda, MD 20892 USA. [Moye, John] NICHHD, Bethesda, MD 20892 USA. [Nalin, David] Merck Vaccine Div, West Point, PA USA. RP Chandwani, S (reprint author), NYU, Dept Pediat, Sch Med, 550 1st Ave,8W46 NB Bldg, New York, NY 10016 USA. EM sulachni.chandwani@nyumc.org OI moye, john/0000-0001-9976-8586 FU NIAID [U01 AI068632]; Division of Microbiology and Infectious Diseases (DMID); Centers for Disease Control and Prevention; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; PACTG; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group [1 U01 AI068616]; National Institutes of Health (NIH); NICHD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; NICHD [N01-DK-9-001/HHSN267200800001C] FX J. B. is employed by CBER and FDA and receives financial support from NIAID and Division of Microbiology and Infectious Diseases (DMID) for other activities outside of this study. D. N. is a retired director of Vaccine Scientific Affairs, Merck Vaccine Division, and holds stocks and stock options in Merck Pharmaceuticals.; This article is part of a supplement entitled "Global Progress Toward Measles Eradication and Prevention of Rubella and Congenital Rubella Syndrome," which was sponsored by the Centers for Disease Control and Prevention.; 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 PACTG, and #1 U01 AI068616 with the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, and was also supported in part by a grant from National Institutes of Health (NIH) and NICHD (K. K.). 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). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Support of the sites was provided by the NIAID and NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). Merck Vaccine Division supplied the Attenuvax and MMRII vaccines. NR 40 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2011 VL 204 SU 1 BP S179 EP S189 DI 10.1093/infdis/jir089 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 802YT UT WOS:000293547600023 PM 21666159 ER PT J AU de Mendizabal, NV Carneiro, J Sole, RV Goni, J Bragard, J Martinez-Forero, I Martinez-Pasamar, S Sepulcre, J Torrealdea, J Bagnato, F Garcia-Ojalvo, J Villoslada, P AF Velez de Mendizabal, Nieves Carneiro, Jorge Sole, Ricard V. Goni, Joaquin Bragard, Jean Martinez-Forero, Ivan Martinez-Pasamar, Sara Sepulcre, Jorge Torrealdea, Javier Bagnato, Francesca Garcia-Ojalvo, Jordi Villoslada, Pablo TI Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis SO BMC SYSTEMS BIOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SELF-TOLERANCE; DISEASE; ACTIVATION; INFECTION; FOXP3; EXACERBATIONS; GLYCOPROTEIN; INFLAMMATION; SUPPRESSION AB Background: The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e. g. failure in central tolerance, activation by pathogens) that are able to trigger the immune system. Results: The model represents five concepts: central tolerance (T-cell generation by the thymus), T-cell activation, T-cell memory, cross-regulation (negative feedback) between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion: The relapsing dynamic in MS derives from the emergent properties of the immune system operating in a pathological state, a fact that has implications for predicting disease course and developing new therapies for MS. C1 [Martinez-Pasamar, Sara; Villoslada, Pablo] Hosp Clin Barcelona, Ctr Neuroimmunol, Dept Neurosci, Inst Biomed Res August Pi Sunyer IDIBAPS, E-08036 Barcelona, Spain. [Velez de Mendizabal, Nieves; Goni, Joaquin; Bragard, Jean; Martinez-Forero, Ivan; Sepulcre, Jorge] Univ Navarra, CIMA, Div Neurosci, Pamplona 31008, Spain. [Velez de Mendizabal, Nieves; Torrealdea, Javier] Univ Basque Country, Comp Sci & Artificial Intelligence Dept, San Sebastian 20018, Spain. [Carneiro, Jorge] Inst Gulbenkian Ciencias, Theoret Immunol Grp, P-2780156 Oeiras, Portugal. [Sole, Ricard V.] Univ Pompeu Fabra, Complex Syst Lab, Barcelona 08003, Spain. [Bagnato, Francesca] NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Garcia-Ojalvo, Jordi] Univ Politecn Cataluna, Dept Fis & Engn Nucl, Terrassa 08222, Spain. RP Villoslada, P (reprint author), Hosp Clin Barcelona, Ctr Neuroimmunol, Dept Neurosci, Inst Biomed Res August Pi Sunyer IDIBAPS, Villarroel 170, E-08036 Barcelona, Spain. EM pvilloslada@clinic.ub.es RI Garcia-Ojalvo, Jordi/A-4574-2009; BRAGARD, Jean/C-8086-2012; Carneiro, Jorge/E-1369-2013; Sole, Ricard/I-3379-2015; OI Garcia-Ojalvo, Jordi/0000-0002-3716-7520; BRAGARD, Jean/0000-0003-3450-9609; Carneiro, Jorge/0000-0002-7520-3406; Villoslada, Pablo/0000-0002-8735-6119 FU European Commission [043241, 212877]; Spanish Ministry of Health [PI060117, RD07/0060/0000-01]; MEC [FIS2005-06912-C02]; NINDS-NIH FX This work was supported by the European Commission (NEST-Pathfinder program: "ComplexDis" grant, contract number: 043241 and ITNMC program: "UEPHA*MS" grant, contract number: 212877) and the Spanish Ministry of Health (PI060117 and RD07/0060/0000-01) to PV and JGO. NV is a fellow of the Programa de Formacion de Investigadores del Departamento de Educacion, Universidades e Investigacion, Gobierno Vasco (BFI05.9 AE). JB acknowledges the support of the MEC through the grant: FIS2005-06912-C02, DINCARD. JG is a fellow of Government of Navarra. Dr Bagnato's contribution to this work was supported by the Intramural Research Program of the NINDS-NIH. All authors read and approved the final manuscript. The authors have no conflicting financial interests to disclose. NR 61 TC 9 Z9 9 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD JUL 15 PY 2011 VL 5 AR 114 DI 10.1186/1752-0509-5-114 PG 15 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 807NJ UT WOS:000293905400001 ER PT J AU Liu, BY Wei, L Meyerle, C Tuo, JS Sen, HN Li, ZY Chakrabarty, S Agron, E Chan, CC Klein, ML Chew, E Ferris, F Nussenblatt, RB AF Liu, Baoying Wei, Lai Meyerle, Catherine Tuo, Jingsheng Sen, H. Nida Li, Zhiyu Chakrabarty, Sagarika Agron, Elvira Chan, Chi-Chao Klein, Michael L. Chew, Emily Ferris, Frederick Nussenblatt, Robert B. TI Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID GROWTH-FACTOR-BETA; FACTOR-H POLYMORPHISM; CHOROIDAL NEOVASCULARIZATION; FACTOR-B; DIFFERENTIATION; ACTIVATION; GAMMA; RISK; INTERLEUKIN-6; INFLAMMATION AB Background: Age related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH), the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a) have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD. Methods: Human peripheral blood mononuclear cells (PBMCs) were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500. Results: We show that C5a promotes interleukin (IL)-22 and IL-17 expression by human CD4(+) T cells. This effect is dependent on B7, IL-1 beta and IL-6 expression from monocytes. We have also found that C5a could protect human CD4(+) cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls. Conclusions: Our results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD. C1 [Liu, Baoying; Wei, Lai; Tuo, Jingsheng; Sen, H. Nida; Li, Zhiyu; Chakrabarty, Sagarika; Chan, Chi-Chao; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Meyerle, Catherine; Agron, Elvira; Chew, Emily; Ferris, Frederick] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Macular Degenerat Ctr, Casey Eye Inst, Portland, OR 97239 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Leonard Christensen Eye Pathol Lab, Casey Eye Inst, Portland, OR 97239 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov RI Wei, Lai/D-1088-2014; OI Tuo, Jingsheng/0000-0002-1372-7810 FU NIH, National Eye Institute FX We thank Dr. Anthony Adamis for kindly providing the C5aR antagonist; Rafael Villasmil for assistance with flow cytometric cell sorting; This research was supported by the Intramural Research Program of NIH, National Eye Institute. NR 44 TC 49 Z9 50 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 15 PY 2011 VL 9 AR 111 DI 10.1186/1479-5876-9-111 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 807RP UT WOS:000293917700001 PM 21762495 ER PT J AU Chikkaveeraiah, BV Mani, V Patel, V Gutkind, JS Rusling, JF AF Chikkaveeraiah, Bhaskara V. Mani, Vigneshwaran Patel, Vyomesh Gutkind, J. Silvio Rusling, James F. TI Microfluidic electrochemical immunoarray for ultrasensitive detection of two cancer biomarker proteins in serum SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Microfluidics; Immunoarray; Cancer biomarkers; Off-line protein capture; Gold nanoparticles; Paramagnetic beads ID PROSTATE-SPECIFIC ANTIGEN; CARBON NANOTUBE FOREST; SIGNAL AMPLIFICATION; IMMUNOSENSOR; IMMUNOASSAYS; TECHNOLOGY; SYSTEMS; ARRAYS; SENSOR; CHIP AB A microfluidic electrochemical immunoassay system for multiplexed detection of protein cancer biomarkers was fabricated using a molded polydimethylsiloxane channel and routine machined parts interfaced with a pump and sample injector. Using off-line capture of analytes by heavily-enzyme-labeled 1 mu m superparamagnetic particle (MP)-antibody bioconjugates and capture antibodies attached to an 8-electrode measuring chip, simultaneous detection of cancer biomarker proteins prostate specific antigen (PSA) and interleukin-6 (IL-6) in serum was achieved at sub-pg mL(-1) levels. MPs were conjugated with similar to 90,000 antibodies and similar to 200,000 horseradish peroxidase (HRP) labels to provide efficient off-line capture and high sensitivity. Measuring electrodes feature a layer of 5 nm glutathione-decorated gold nanoparticles to attach antibodies that capture MP-analyte bioconjugates. Detection limits of 0.23 pg mL(-1) for PSA and 0.30 pg mL(-1) for IL-6 were obtained in diluted serum mixtures. PSA and IL-6 biomarkers were measured in serum of prostate cancer patients in total assay time 1.15 h and sensor array results gave excellent correlation with standard enzyme-linked immunosorbent assays (ELISA). These microfluidic immunosensors employing nanostructured surfaces and off-line analyte capture with heavily labeled paramagnetic particles hold great promise for accurate, sensitive multiplexed detection of diagnostic cancer biomarkers. (C) 2011 Elsevier B.V. All rights reserved. C1 [Chikkaveeraiah, Bhaskara V.; Mani, Vigneshwaran; Rusling, James F.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Rusling, James F.] Univ Connecticut Hlth Ctr, Sch Chem, Dept Cell Biol, Farmington, CT 06032 USA. [Rusling, James F.] Natl Univ Ireland, Galway, Ireland. RP Rusling, JF (reprint author), Univ Connecticut, Dept Chem, 55 N Eagleville Rd, Storrs, CT 06269 USA. EM james.rusling@uconn.edu RI Gutkind, J. Silvio/A-1053-2009 FU NIEHS/NIH [ES013557]; Science Foundation Ireland FX This work was supported by PHS grant ES013557 from NIEHS/NIH, and by a Walton Research Fellowship awarded by Science Foundation Ireland to JFR. We thank Debra Rood and Lawrence K. Silbart for assistance with ELISA measurements. NR 59 TC 92 Z9 92 U1 16 U2 193 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD JUL 15 PY 2011 VL 26 IS 11 BP 4477 EP 4483 DI 10.1016/j.bios.2011.05.005 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 797DG UT WOS:000293104100035 PM 21632234 ER PT J AU Morris, AM Masur, H AF Morris, Alison M. Masur, Henry TI A Serologic Test to Diagnose Pneumocystis Pneumonia: Are We There Yet? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID BETA-D-GLUCAN; OPPORTUNISTIC INFECTIONS; ANTIRETROVIRAL THERAPY; JIROVECII; SERUM; AIDS; CARINII; UTILITY; WALL C1 [Masur, Henry] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Morris, Alison M.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Masur, H (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Rm 2C145, Bethesda, MD 20892 USA. EM hmasur@nih.gov NR 15 TC 8 Z9 9 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 JUL 15 PY 2011 VL 53 IS 2 BP 203 EP 204 DI 10.1093/cid/cir348 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 796BA UT WOS:000293024000015 PM 21690629 ER PT J AU Rope, AF Wang, K Evjenth, R Xing, JC Johnston, JJ Swensen, JJ Johnson, WE Moore, B Huff, CD Bird, LM Carey, JC Opitz, JM Stevens, CA Jiang, T Schank, C Fain, HD Robison, R Dalley, B Chin, S South, ST Pysher, TJ Jorde, LB Hakonarson, H Lillehaug, JR Biesecker, LG Yandell, M Arnesen, T Lyon, GJ AF Rope, Alan F. Wang, Kai Evjenth, Rune Xing, Jinchuan Johnston, Jennifer J. Swensen, Jeffrey J. Johnson, W. Evan Moore, Barry Huff, Chad D. Bird, Lynne M. Carey, John C. Opitz, John M. Stevens, Cathy A. Jiang, Tao Schank, Christa Fain, Heidi Deborah Robison, Reid Dalley, Brian Chin, Steven South, Sarah T. Pysher, Theodore J. Jorde, Lynn B. Hakonarson, Hakon Lillehaug, Johan R. Biesecker, Leslie G. Yandell, Mark Arnesen, Thomas Lyon, Gholson J. TI Using VAAST to Identify an X-Linked Disorder Resulting in Lethality in Male Infants Due to N-Terminal Acetyltransferase Deficiency SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ALPHA-ACETYLTRANSFERASE; SEQUENCING DATA; HUMAN GENOME; MUTATIONS; ARD1; VARIANTS; PROTEINS; CANCER; YEAST; MAP AB We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA 10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans. C1 [Rope, Alan F.; Carey, John C.; South, Sarah T.] Univ Utah, Sch Med, Dept Pediat Med Genet, Salt Lake City, UT 84112 USA. [Wang, Kai; Hakonarson, Hakon] Univ Utah, Sch Med, Ctr Appl Genom, Salt Lake City, UT 84112 USA. [Evjenth, Rune; Lillehaug, Johan R.; Arnesen, Thomas] Univ Bergen, Dept Mol Biol, N-5020 Bergen, Norway. [Xing, Jinchuan; Moore, Barry; Huff, Chad D.; Opitz, John M.; Jorde, Lynn B.; Yandell, Mark] Univ Utah, Eccles Inst Human Genet, Salt Lake City, UT 84112 USA. [Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Swensen, Jeffrey J.; Opitz, John M.; Chin, Steven; Pysher, Theodore J.] Univ Utah, Dept Pathol, Salt Lake City, UT 84112 USA. [Swensen, Jeffrey J.; South, Sarah T.] ARUP Labs, Salt Lake City, UT 84112 USA. [Johnson, W. Evan; Schank, Christa] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. [Bird, Lynne M.] Rady Childrens Hosp, San Diego, CA 92123 USA. [Bird, Lynne M.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92123 USA. [Opitz, John M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84112 USA. [Opitz, John M.] Univ Utah, Dept Neurol, Salt Lake City, UT 84112 USA. [Stevens, Cathy A.] Univ Tennessee, Coll Med, Dept Pediat, Chattanooga, TN 38163 USA. [Jiang, Tao] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Jiang, Tao] Shenzhen Univ, Sch Med, Genome Res Inst, Shenzhen 510860, Peoples R China. [Fain, Heidi Deborah; Robison, Reid] Univ Utah, Dept Psychiat, Salt Lake City, UT 84112 USA. [Dalley, Brian] Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Arnesen, Thomas] Haukeland Hosp, Dept Surg, N-5021 Bergen, Norway. [Lyon, Gholson J.] New York Univ Child Study Ctr, New York, NY 10016 USA. RP Lyon, GJ (reprint author), Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. EM lyong1@email.chop.edu RI Xing, Jinchuan/A-2489-2012; Lyon, Gholson/D-2765-2014; OI Lyon, Gholson/0000-0002-5869-0716; Arnesen, Thomas/0000-0002-3005-147X FU CCTS at the University of Utah [UL1RR025764]; National Cancer Institute [P30CA042014]; Research Council of Norway [197136]; Norwegian Cancer Society; National Human Genome Research Institute (NHGRI) [1RC2HG005619]; NIH/National Center for Research Resources [UL1 RR025774]; NIH/NHGRI [K99HG005846]; NHGRI [5R01HG5692]; NHGRI, NIH FX We express our gratitude to the families for their extraordinary cooperation and assistance. We also thank David Nix, Nina Glomnes, and Whitney Fitts for advice and/or technical assistance with family 1. Exon capture and sequencing for family 1 was paid for by the Department of Psychiatry, University of Utah (to G.J.L.). Collection of DNA and phenotyping for family 1 was supported by the Clinical Genetics Research Program: Phenotyping Core, under CCTS grant UL1RR025764 at the University of Utah. The University of Utah Microarray and Genomic Analysis core facility was supported by award number P30CA042014 from the National Cancer Institute. Functional analyses were supported by the Research Council of Norway (grant 197136 to T.A.) and the Norwegian Cancer Society (to J.R.L. and T.A.). B.M. and M.Y. were supported by National Human Genome Research Institute (NHGRI) 1RC2HG005619, K.W. by a pilot/methodological study award from NIH/National Center for Research Resources grant UL1 RR025774, J.X. by NIH/NHGRI K99HG005846, and W.E.J. by NHGRI 5R01HG5692. The research on family 2 was supported by Intramural Funds of the NHGRI, NIH (L.G.B.). These authors thank Danielle Brinkman for the initial consenting and records gathering for family 2 and Caitlin Krause and Jamie Teer for technical support. NR 48 TC 90 Z9 95 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 15 PY 2011 VL 89 IS 1 BP 28 EP 43 DI 10.1016/j.ajhg.2011.05.017 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 796HF UT WOS:000293041700003 PM 21700266 ER PT J AU Kullo, IJ Ding, KY Shameer, K McCarty, CA Jarvik, GR Denny, JC Ritchie, MD Ye, Z Crosslin, DR Chisholm, RL Manolio, TA Chute, CG AF Kullo, Iftikhar J. Ding, Keyue Shameer, Khader McCarty, Catherine A. Jarvik, Gail R. Denny, Joshua C. Ritchie, Marylyn D. Ye, Zi Crosslin, David R. Chisholm, Rex L. Manolio, Teri A. Chute, Christopher G. TI Complement Receptor 1 Gene Variants Are Associated with Erythrocyte Sedimentation Rate SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MALARIA; DISEASE; PROTEIN; INFLAMMATION; POLYMORPHISM; EXPRESSION; PROTECTION; REGULATOR AB The erythrocyte sedimentation rate (ESR), a commonly performed test of the acute phase response, is the rate at which erythrocytes sediment in vitro in 1 hr. The molecular basis of erythrocyte sedimentation is unknown. To identify genetic variants associated with ESR, we carried out a genome-wide association study of 7607 patients in the Electronic Medical Records and Genomics (eMERGE) network. The discovery cohort consisted of 1979 individuals from the Mayo Clinic, and the replication cohort consisted of 5628 individuals from the remaining four eMERGE sites. A nonsynonymous SNP, rs6691117 (Val -> IIe), in the complement receptor 1 gene (CR1) was associated with ESR (discovery cohort p = 7 x 10(-12), replication cohort p = 3 x 10(-14), combined cohort p = 9 x 10(-24)). We imputed 61 SNPs in CR1, and a "possibly damaging" SNP (rs2274567, His -> Arg) in linkage disequilibrium (r(2) = 0.74) with rs6691117 was also associated with ESR (discovery p = 5 x 10(-11), replication p = 7 x 10(-17), and combined cohort p = 2 x 10(-25)). The two nonsynonymous SNPs in CR1 are near the C3b/C4b binding site, suggesting a possible mechanism by which the variants may influence ESR. In conclusion, genetic variation in CR1, which encodes a protein that clears complement-tagged inflammatory particles from the circulation, influences interindividual variation in ESR, highlighting an association between the innate immunity pathway and erythrocyte interactions. C1 [Kullo, Iftikhar J.; Ding, Keyue; Shameer, Khader; Ye, Zi] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [McCarty, Catherine A.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA. [Jarvik, Gail R.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail R.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. [Ritchie, Marylyn D.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet, Nashville, TN 37231 USA. [Crosslin, David R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Chisholm, Rex L.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Chute, Christopher G.] Mayo Clin, Rochester, MN 55905 USA. RP Kullo, IJ (reprint author), Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. EM kullo.iftikhar@mayo.edu RI Ritchie, Marylyn/C-1114-2012; Jarvik, Gail/N-6476-2014; Khader, Shameer/J-2564-2016 OI Jarvik, Gail/0000-0002-6710-8708; FU National Human Genome Research Institute (NHGRI); National Institute of General Medical Sciences (NIGMS) [U01-HG-04599, U01-HG-004610, U01-HG-004608, U01HG004609, U01-HG-04603] FX The authors acknowledge Elizabeth Pugh for helpful discussions. The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI), with additional funding from National Institute of General Medical Sciences (NIGMS) through the following grants: U01-HG-04599 (Mayo Clinic), U01-HG-004610 (Group Health Cooperative), U01-HG-004608 (Marshfield Clinic), U01HG004609 (Northwestern University), and U01-HG-04603 (Vanderbilt University, also serving as the Administrative Coordinating Center). NR 37 TC 37 Z9 37 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 15 PY 2011 VL 89 IS 1 BP 131 EP 138 DI 10.1016/j.ajhg.2011.05.019 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 796HF UT WOS:000293041700011 PM 21700265 ER PT J AU Hanson, D Murray, PG O'Sullivan, J Urquhart, J Daly, S Bhaskar, SS Biesecker, LG Skae, M Smith, C Cole, T Kirk, J Chandler, K Kingston, H Donnai, D Clayton, PE Black, GCM AF Hanson, Dan Murray, Philip G. O'Sullivan, James Urquhart, Jill Daly, Sarah Bhaskar, Sanjeev S. Biesecker, Leslie G. Skae, Mars Smith, Claire Cole, Trevor Kirk, Jeremy Chandler, Kate Kingston, Helen Donnai, Dian Clayton, Peter E. Black, Graeme C. M. TI Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID OBSCURIN-LIKE-1; DOMAIN; P53 AB 3-M syndrome, a primordial growth disorder, is associated with mutations in CUL7 and OBSL1. Exome sequencing now identifies mutations in CCDC8 as a cause of 3-M syndrome. CCDC8 is a widely expressed gene that is transcriptionally associated to CUL7 and OBSL1 and coimmunoprecipitation indicates a physical interaction between CCDC8 and OBSL1 but not CUL7. We propose that CUL7, OBSL1, and CCDC8 are members of a pathway controlling mammalian growth. C1 [Hanson, Dan; Murray, Philip G.; O'Sullivan, James; Urquhart, Jill; Daly, Sarah; Bhaskar, Sanjeev S.; Chandler, Kate; Kingston, Helen; Donnai, Dian; Black, Graeme C. M.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Biomed Res Ctr, Genet Med Res Grp, Manchester M13 9WL, Lancs, England. [Hanson, Dan; Murray, Philip G.; O'Sullivan, James; Urquhart, Jill; Daly, Sarah; Bhaskar, Sanjeev S.; Chandler, Kate; Kingston, Helen; Donnai, Dian; Black, Graeme C. M.] Cent Manchester Fdn Trust, St Marys Hosp, Manchester M13 9WL, Lancs, England. [Hanson, Dan; Murray, Philip G.; Clayton, Peter E.] Univ Manchester, Sch Biomed, Dept Endocrinol, MAHSC, Manchester M13 9WL, Lancs, England. [Murray, Philip G.; O'Sullivan, James; Urquhart, Jill; Daly, Sarah; Bhaskar, Sanjeev S.; Skae, Mars; Chandler, Kate; Kingston, Helen; Donnai, Dian; Clayton, Peter E.; Black, Graeme C. M.] Cent Manchester Univ Hosp Fdn Trust, Manchester M13 9WL, Lancs, England. [Biesecker, Leslie G.] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20814 USA. [Smith, Claire] E Lancashire Hosp NHS Trust, Royal Blackburn Hosp, Blackburn BB2 3HH, Lancs, England. [Cole, Trevor] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England. [Kirk, Jeremy] Birmingham Childrens Hosp, Dept Paediat Endocrinol, Birmingham B4 6NH, W Midlands, England. RP Black, GCM (reprint author), Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Biomed Res Ctr, Genet Med Res Grp, Manchester M13 9WL, Lancs, England. EM graeme.black@manchester.ac.uk RI Urquhart, Jill/G-2282-2015; OI Urquhart, Jill/0000-0002-5788-5511; Murray, Philip/0000-0002-1480-1576; Clayton, Peter/0000-0003-1225-4537; Black, Graeme/0000-0001-8727-6592 FU National Institute of Health Research Manchester Biomedical Research Centre; National Human Genome Research Institute of the NIH FX We thank all healthcare professionals contributing to the care of families described here. Support from the National Institute of Health Research Manchester Biomedical Research Centre is acknowledged. P.G.M. is a Medical Research Council (UK) Clinical Research Fellow. The NISC Comparative Sequencing Program and the ClinSeq study are funded by the National Human Genome Research Institute of the NIH. NR 21 TC 43 Z9 49 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 15 PY 2011 VL 89 IS 1 BP 148 EP 153 DI 10.1016/j.ajhg.2011.05.028 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 796HF UT WOS:000293041700013 PM 21737058 ER PT J AU Lynch, CD Louis, GMB Lahti, MC Pekow, PS Nasca, PC Cohen, B AF Lynch, Courtney D. Louis, Germaine M. Buck Lahti, Maureen C. Pekow, Penelope S. Nasca, Philip C. Cohen, Bruce TI The Birth Certificate as an Efficient Means of Identifying Children Conceived With the Help of Infertility Treatment SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE birth certificates; child development; epidemiologic methods; fertility agents, female; fertilization in vitro ID ASSISTED REPRODUCTIVE TECHNOLOGY; HEALTH; STATE AB Recent work suggests that infertility treatment is associated with adverse child health outcomes. In exploring various methods of assembling a cohort of children conceived by infertility treatment, the authors conducted a validation study of the assisted reproductive technology and infertility drug use check boxes on the Massachusetts birth certificate. Using 2001 and 2002 data, the authors conducted telephone interviews with 399 women whose child's birth certificate had at least one of the boxes checked along with 185 women who were over age 42 years or who delivered twins or higher order multiples to compare the check box information with maternal report. Among the 579 women with available information, the birth certificate was fully concordant with respect to infertility treatment status for 271 (47%) women, partially concordant for 248 (43%) women, and discordant for 60 (10%) women. Agreement between the birth certificate and maternal report was good for singletons (weighted kappa = 0.66) but was found to be very poor among twins and higher order multiples (weighted kappa = 0.05). The authors concluded that birth certificates are an efficient means of locating children conceived with the help of infertility treatment but that they are not appropriate for identifying type of treatment. C1 [Lynch, Courtney D.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Lahti, Maureen C.; Pekow, Penelope S.] Univ Massachusetts, Amherst, NY USA. [Nasca, Philip C.] SUNY Albany, Albany, NY 12222 USA. [Cohen, Bruce] Massachusetts Dept Publ Hlth, Boston, MA USA. RP Lynch, CD (reprint author), Ohio State Univ, Coll Med, Dept Obstet & Gynecol, 395 W 12th Ave,Room 580, Columbus, OH 43210 USA. EM courtney.lynch@osumc.edu OI Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Funding for this project was provided by intramural research funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 13 TC 7 Z9 7 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2011 VL 174 IS 2 BP 211 EP 218 DI 10.1093/aje/kwr036 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 792VN UT WOS:000292778600011 PM 21705488 ER PT J AU Meyer, TE Fox, SD Issaq, HJ Xu, X Chu, LW Veenstra, TD Hsing, AW AF Meyer, Tamra E. Fox, Stephen D. Issaq, Haleem J. Xu, Xia Chu, Lisa W. Veenstra, Timothy D. Hsing, Ann W. TI A Reproducible and High-Throughput HPLC/MS Method To Separate Sarcosine from alpha- and beta-Alanine and To Quantify Sarcosine in Human Serum and Urine SO ANALYTICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; PROSTATE-CANCER; LIQUID-CHROMATOGRAPHY; MARKER AB While sarcosine was recently identified as a potential urine biomarker for prostate cancer, further studies have cast doubt on its utility to diagnose this condition. The inconsistent results may be due to the fact that alanine and sarcosine coelute on an HPLC reversed-phase column and the mass spectrometer cannot differentiate between the two isomers, since the same parent/product ions are generally used to measure them. In this study, we developed a high-throughput liquid chromatography-mass spectrometry (LC-MS) method that resolves sarcosine from alanine isomers, allowing its accurate quantification in human serum and urine. Assay reproducibility was determined using the coefficient of variation (CV) and intraclass correlation coefficient (ICC) in serum aliquots from 10 subjects and urine aliquots from 20 subjects across multiple analytic runs. Paired serum/urine samples from 42 subjects were used to evaluate sarcosine serum/urine correlation. Both urine and serum assays gave high sensitivity (limit of quantitation of 5 ng/mL) and reproducibility (serum assay, intra- and interassay CVs < 3% and ICCs > 99%; urine assay, intra-assay CV = 7.7% and ICC = 98.2% and interassay CV = 12.3% and ICC = 94.2%). In conclusion, this high-throughput LC-MS method is able to resolve sarcosine from alpha- and beta-alanine and is useful for quantifying sarcosine in serum and urine samples. C1 [Meyer, Tamra E.; Chu, Lisa W.; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fox, Stephen D.; Issaq, Haleem J.; Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Meyer, TE (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM Tamra.E.Meyer@us.army.mil; foxsd@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Shelley Niwa and Ann Truelove of Westat for their help with study and sample management. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. T.E.M. and S.D.F. contributed equally to this work. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 11 TC 30 Z9 30 U1 1 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUL 15 PY 2011 VL 83 IS 14 BP 5735 EP 5740 DI 10.1021/ac201003r PG 6 WC Chemistry, Analytical SC Chemistry GA 794JN UT WOS:000292892000036 PM 21635006 ER PT J AU de Groot, JF Piao, Y Tran, H Gilbert, M Wu, HK Liu, J Bekele, BN Cloughesy, T Mehta, M Robins, HI Lassman, A DeAngelis, L Camphausen, K Chen, A Yung, WKA Prados, M Wen, PY Heymach, JV AF de Groot, John F. Piao, Yuji Hai Tran Gilbert, Mark Wu, Hua-Kang Liu, Jun Bekele, B. Nebiyou Cloughesy, Tim Mehta, Minesh Robins, H. Ian Lassman, Andrew DeAngelis, Lisa Camphausen, Kevin Chen, Alice Yung, W. K. A. Prados, Michael Wen, Patrick Y. Heymach, John V. TI Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CARBONIC-ANHYDRASE-IX; PHASE-II; IN-VIVO; TUMOR ANGIOGENESIS; MALIGNANT GLIOMA; CANCER-PATIENTS; RECTAL-CANCER; BEVACIZUMAB; CELLS AB Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma. Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients. Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9. Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872-81. (C) 2011 AACR. C1 [de Groot, John F.; Piao, Yuji; Gilbert, Mark; Yung, W. K. A.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Hai Tran; Wu, Hua-Kang; Heymach, John V.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Liu, Jun; Bekele, B. Nebiyou] Univ Texas MD Anderson Canc Ctr, Dept Appl Math & Biostat, Houston, TX 77030 USA. [Cloughesy, Tim] Univ Calif Los Angeles, Los Angeles, CA USA. [Mehta, Minesh; Robins, H. Ian] Univ Wisconsin, Madison, WI USA. [Lassman, Andrew; DeAngelis, Lisa] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Prados, Michael] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP de Groot, JF (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. EM jdegroot@mdanderson.org OI mehta, minesh/0000-0002-4812-5713 FU AstraZeneca; Adnexus; Exelixis; Genentech; Bayer; Merck; Schering Plough; Tomotherapy; Keryx; Bristol Myers-Squibb; Campus Bio LP; Cephalon; Eisai; Imclone; Novartis; Merck/EMD; NIH: NABTC [U01-CA62399]; ASCO; [1R21A126127] FX J.F. de Groot: commercial research grants, AstraZeneca, Adnexus, Exelixis; consultant/advisory board, Genentech. M. Gilbert: consultant/advisory board, Genentech. M. Mehta: stock options, Tomotherapy, Pharmacyclics; consultant/advisory board, Genentech, Adnexus, Bayer, Merck, Schering Plough, Tomotherapy, Stemina. A. Lassman: commercial research grants, Genentech, Keryx; consultant/advisory board, Bristol Myers-Squibb, Campus Bio LP, Cephalon, Eisai, Genentech, Imclone, Merck, Schering Plough. WKA Yung: commercial research grant, Novartis; consultant/advisory board, Genentech, Merck/EMD, Schering Plough. The other authors disclosed no potential conflicts of interest.; The clinical trial was funded by the NIH: NABTC # U01-CA62399. Correlative studies supported in part by 1R21A126127 and an ASCO Career Development Award, both to J.F. de Groot. NR 38 TC 28 Z9 29 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2011 VL 17 IS 14 BP 4872 EP 4881 DI 10.1158/1078-0432.CCR-11-0271 PG 10 WC Oncology SC Oncology GA 793JI UT WOS:000292816900027 PM 21632852 ER PT J AU Meissner, HI Klabunde, CN Han, PK Benard, VB Breen, N AF Meissner, Helen I. Klabunde, Carrie N. Han, Paul K. Benard, Vicki B. Breen, Nancy TI Breast Cancer Screening Beliefs, Recommendations, and Practices SO CANCER LA English DT Article DE breast cancer; mammography; primary care; physicians; screening ID NATIONAL-SURVEY; MAMMOGRAPHY USE; UNITED-STATES; PHYSICIANS; US; TRENDS; PERCEPTIONS; LITIGATION; EXPERIENCE; IMPACT AB BACKGROUND: Primary care physicians (PCPs) play a key role in breast cancer screening, yet no current data exist regarding PCP practices. METHODS: The authors analyzed a nationally representative survey of PCPs that was fielded during September 2006 to May 2007 to investigate PCP breast cancer screening beliefs, recommendations, and practices. RESULTS: Most of the 1212 PCPs who participated in the survey (80%) reported that mammography for average-risk women aged >= 50 years was very effective in reducing cancer mortality, and 54% reported that it was very effective for women ages 40 to 49 years. Fewer respondents reported that clinical breast examination (CBE) or breast self-examination (BSE) was very effective, but the majority rated CBE and BSE as somewhat effective. The majority of PCPs routinely recommended mammography, CBE, and BSE to patients aged >= 40 years. In multivariate models, family/general practitioners (odds ratio [OR], 2.23; 95% confidence interval [Cl], 1.57-3.17 for mammography; OR, 4.42; 95% Cl, 2.60-7.52 for CBE) and internal medicine specialists (OR, 3.21; 95% Cl, 2.21-4.66 for mammography; OR, 5.34; 95% Cl, 3.21-8.88 for CBE) were more likely to recommend an upper age limit for screening than obstetrician/gynecologists. Physicians who reported that US Preventive Services Task Force guidelines were very influential were more likely to recommend an age at which they no longer recommend mammography and CBE. CONCLUSIONS: To the authors' knowledge, the current study is the first national study in over 2 decades to report the breast cancer screening practices of PCPs and provides baseline data for monitoring the impact of changes in clinical practice guidelines. The current findings suggested that virtually all PCPs routinely recommend mammography, CBE, and BSE to their patients aged >= 40 years, although recommendations vary by primary care specialty. Cancer 2011;117:3101-11. Published 2011 by the American Cancer Society* C1 [Meissner, Helen I.] NIH, Off Behav & Social Sci Res, Off Director, Bethesda, MD 20892 USA. [Klabunde, Carrie N.; Breen, Nancy] Natl Canc Inst Bethesda, Div Canc Control & Populat Sci, Bethesda, MD USA. [Han, Paul K.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Scarborough, ME USA. [Benard, Vicki B.] Ctr Dis Control & Prevent Atlanta, Div Canc Prevent & Control, Atlanta, GA USA. RP Meissner, HI (reprint author), NIH, Off Behav & Social Sci Res, Off Director, 31 Ctr Dr,Bldg 31,Room B1C19, Bethesda, MD 20892 USA. EM meissneh@od.nih.gov OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute [N02-PC-51308]; Centers for Disease Control and Prevention [Y3-PC-6017-01]; Agency for Healthcare Research and Quality [Y3-PC-5019-01, Y3-PC-5019-02] FX Funding support for the survey was provided by the National Cancer Institute (contract number N02-PC-51308), the Centers for Disease Control and Prevention (interagency agreement number Y3-PC-6017-01), and the Agency for Healthcare Research and Quality (interagency agreement numbers Y3-PC-5019-01 and Y3-PC-5019-02). NR 31 TC 33 Z9 38 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2011 VL 117 IS 14 BP 3101 EP 3111 DI 10.1002/cncr.25873 PG 11 WC Oncology SC Oncology GA 789SQ UT WOS:000292537000007 PM 21246531 ER PT J AU Du, XLL Lin, CC Johnson, NJ Altekruse, S AF Du, Xianglin L. Lin, Charles C. Johnson, Norman J. Altekruse, Sean TI Effects of Individual-Level Socioeconomic Factors on Racial Disparities in Cancer Treatment and Survival SO CANCER LA English DT Article DE cancer; socioeconomic status; racial disparities; treatment; survival ID AFRICAN-AMERICAN; BREAST-CANCER; OLDER WOMEN; DIAGNOSIS; METAANALYSIS; MORTALITY; HEALTH; RACE; EPIDEMIOLOGY; SURVEILLANCE AB BACKGROUND: This is the first study to use the linked National Longitudinal Mortality Study and Surveillance, Epidemiology, and End Results (SEER) data to determine the effects of individual-level socioeconomic factors (health insurance, education, income, and poverty status) on racial disparities in receiving treatment and in survival. METHODS: This study included 13,234 cases diagnosed with the 8 most common types of cancer (female breast, colorectal, prostate, lung and bronchus, uterine cervix, ovarian, melanoma, and urinary bladder) at age >= 25 years, identified from the National Longitudinal Mortality Study-SEER data during 1973 to 2003. Kaplan-Meier methods and Cox regression models were used for survival analysis. RESULTS: Three-year all-cause observed survival for cases diagnosed with local-stage cancers of the >= 8 leading tumors combined was >82% regardless of race/ethnicity. More favorable survival was associated with higher socioeconomic status. Compared with whites, blacks were less likely to receive first-course cancer-directed surgery, perhaps reflecting a less favorable stage distribution at diagnosis. Hazard ratio (HR) for cancer-specific mortality was significantly higher among blacks compared with whites (HR, 1.2; 95% confidence interval [Cl], 1.143) after adjusting for age, sex, and tumor stage, but not after further controlling for socioeconomic factors and treatment (HR, 1.0; 95% Cl, 0.9-1.1). HRs for all-cause mortality among patients with breast cancer and for cancer-specific mortality in patients with prostate cancer were significantly higher for blacks compared with whites after adjusting for socioeconomic factors, treatment, and patient and tumor characteristics. CONCLUSIONS: Favorable survival was associated with higher socioeconomic status. Racial disparities in survival persisted after adjusting for individual-level socioeconomic factors and treatment for patients with breast and prostate cancer. Cancer 2011;117:3242-51.0 (C) 2011 American Cancer Society. C1 [Du, Xianglin L.] Univ Texas Houston, Sch Publ Hlth, Div Epidemiol, Houston, TX 77030 USA. [Lin, Charles C.; Johnson, Norman J.] US Bur Census, Suitland, MD USA. [Altekruse, Sean] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Du, XLL (reprint author), Univ Texas Houston, Sch Publ Hlth, Div Epidemiol, 1200 Herman Pressler Dr, Houston, TX 77030 USA. EM Xianglin.L.Du@uth.tmc.edu FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [Y01 PC009021, Y01 PC009021-13] NR 25 TC 57 Z9 58 U1 2 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2011 VL 117 IS 14 BP 3242 EP 3251 DI 10.1002/cncr.25854 PG 10 WC Oncology SC Oncology GA 789SQ UT WOS:000292537000024 PM 21264829 ER PT J AU Purdue, MP Lan, Q Bagni, R Hocking, WG Baris, D Reding, DJ Rothman, N AF Purdue, Mark P. Lan, Qing Bagni, Rachel Hocking, William G. Baris, Dalsu Reding, Douglas J. Rothman, Nathaniel TI Prediagnostic Serum Levels of Cytokines and Other Immune Markers and Risk of Non-Hodgkin Lymphoma SO CANCER RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; B-CELL LYMPHOMA; INTERLEUKIN-1 RECEPTOR ANTAGONIST; SOLUBLE TNF RECEPTORS; IN-VIVO; INTERLYMPH-CONSORTIUM; RELEASE; CD27; AIDS; POLYMORPHISMS AB Although severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), it is unclear whether subclinical immune system function influences lymphomagenesis. To address this question, we conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to investigate whether circulating levels of cytokines and other immune markers are associated with future risk of NHL. Selected cytokines [interleukin (IL)-4, IL-6, IL-10, and TNF-alpha] and other immune markers [soluble TNF receptor 1 (sTNF-R1), sTNF-R2, C-reactive protein, and sCD27] were measured in prediagnostic serum specimens from 297 incident NHL cases and 297 individually matched controls. ORs and 95% confidence intervals (CI) relating quartiles of analyte concentration to NHL risk were calculated by using conditional logistic regression. Statistically significant associations with increased NHL risk were observed for elevated serum levels of sTNF-R1 (quartile 4 vs. quartile 1: OR 1.7, 95% CI: 1.1-2.8; P(trend) = 0.02) and sCD27 (OR = 5.3, 95% CI: 2.9-9.4; P(trend) < 0.0001). These associations remained in analyses of cases diagnosed longer than 6 years following blood collection (sTNF-R1: OR = 2.1, 95% CI: 1.0-4.0, P(trend) = 0.01; sCD27: OR 4.1, 95% CI: 1.9-8.5, P(trend) = 0.0001). Elevated levels of IL-10, TNF-alpha and sTNF-R2 were also significantly associated with increased risk of NHL overall; however, these associations weakened with increasing time from blood collection to case diagnosis and were null for cases diagnosed longer than 6 years postcollection. Our findings for sTNF-R1 and sCD27, possible markers for inflammatory and B-cell stimulatory states, respectively, support a role for subclinical inflammation and chronic B-cell stimulation in lymphomagenesis. Cancer Res; 71(14); 4898-907. (C) 2011 AACR. C1 [Purdue, Mark P.; Lan, Qing; Baris, Dalsu; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bagni, Rachel] NCI, Protein Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hocking, William G.; Reding, Douglas J.] Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol, Marshfield, WI USA. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, EPS 8114,6120 Execut Blvd, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Hocking, William/0000-0002-0690-3759 FU Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Cancer Institute, NIH [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH under Contract No. HHSN261200800001E. NR 49 TC 36 Z9 36 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2011 VL 71 IS 14 BP 4898 EP 4907 DI 10.1158/0008-5472.CAN-11-0165 PG 10 WC Oncology SC Oncology GA 792QN UT WOS:000292763700017 PM 21632552 ER PT J AU Chiu, WT Lee, HT Huang, FJ Aldape, KD Yao, J Steeg, PS Chou, CY Lu, ZM Xie, KP Huang, SY AF Chiu, Wen-Tai Lee, Hsueh-Te Huang, Feng-Ju Aldape, Kenneth D. Yao, Jun Steeg, Patricia S. Chou, Cheng-Yang Lu, Zhimin Xie, Keping Huang, Suyun TI Caveolin-1 Upregulation Mediates Suppression of Primary Breast Tumor Growth and Brain Metastases by Stat3 Inhibition SO CANCER RESEARCH LA English DT Article ID MAP KINASE CASCADE; CANCER-CELLS; DOWN-REGULATION; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; IN-VIVO; MICE; ACTIVATION; MELANOMA; INVASION AB Stat3 activation has been implicated as an important driver of brain metastasis in breast cancer, but the critical targets of Stat3 in this process are yet to be fully defined. In this study, we identified the lipid raft organizing protein Caveolin-1 (Cav-1) as a critical genetic target of Stat3 in this process. In human breast cancers, we found that activated Stat3 correlated with attenuation of Cav-1 in brain metastases relative to primary tumors. Cav-1 promoter activity and gene expression were increased by overexpressing an activated form of Stat3 but decreased by attenuation of Stat3 activity or expression. We identified putative Stat3-binding elements in the Cav-1 promoter and showed a direct repression of Cav-1 transcription by Stat3. Reciprocally, we showed that strategies to increase or decrease Cav-1 expression were sufficient to attenuate or promote breast cancer cell invasion. Furthermore, increased expression of Cav-1 phenocopied the effects of Stat3 activation in blocking primary tumor growth and abrogating formation of brain metastases. Collectively, our findings provide clinical and mechanistic evidence that Cav-1 is a critical target for suppression by Stat3 in driving invasion and metastasis of breast cancer cells. Cancer Res; 71(14); 4932-43. (C) 2011 AACR. C1 [Huang, Suyun] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Unit 1004, Houston, TX 77030 USA. [Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Yao, Jun; Lu, Zhimin] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Xie, Keping] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Huang, Feng-Ju; Xie, Keping; Huang, Suyun] Univ Texas Grad Sch Biomed Sci, Program Canc Biol, Houston, TX USA. [Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Chiu, Wen-Tai; Chou, Cheng-Yang] Natl Cheng Kung Univ, Coll Med, Dept Obstet & Gynecol, Tainan 70101, Taiwan. RP Huang, SY (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Unit 1004, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM suhuang@mdanderson.org FU U.S. Department of Defense [W81XWH-06-2-0033]; American Cancer Society; National Cancer Institute Cancer Center [CA 16672] FX The work was supported by U.S. Department of Defense Breast Cancer Research Program Center of Excellence Award Grant W81XWH-06-2-0033, American Cancer Society Research Scholar Grant, and National Cancer Institute Cancer Center Support Grant CA 16672. NR 49 TC 29 Z9 32 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2011 VL 71 IS 14 BP 4932 EP 4943 DI 10.1158/0008-5472.CAN-10-4249 PG 12 WC Oncology SC Oncology GA 792QN UT WOS:000292763700020 PM 21622714 ER PT J AU Yan, HH Pickup, M Pang, YL Gorska, AE Li, ZY Chytil, A Geng, YP Gray, JW Moses, HL Yang, L AF Yan, Hannah H. Pickup, Michael Pang, Yanli Gorska, Agnieszka E. Li, Zhaoyang Chytil, Anna Geng, Yipeng Gray, Jerome W. Moses, Harold L. Yang, Li TI Myeloid Suppressor Cells Regulate the Lung Environment-Response SO CANCER RESEARCH LA English DT Letter C1 [Yan, Hannah H.; Pang, Yanli; Li, Zhaoyang; Yang, Li] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20876 USA. [Pickup, Michael; Gorska, Agnieszka E.; Chytil, Anna; Geng, Yipeng; Moses, Harold L.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA. [Geng, Yipeng; Gray, Jerome W.] Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37212 USA. [Pickup, Michael; Gorska, Agnieszka E.; Chytil, Anna; Moses, Harold L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. RP Yang, L (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bldg 37,Room 3134C,37 Convent Dr,MSC 4258, Bethesda, MD 20876 USA. EM yangl3@mail.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2011 VL 71 IS 14 BP 5052 EP 5053 DI 10.1158/0008-5472.CAN-11-0688 PG 2 WC Oncology SC Oncology GA 792QN UT WOS:000292763700032 ER PT J AU Kochetov, AV Volkova, OA Poliakov, A Dubchak, I Rogozin, IB AF Kochetov, Alex V. Volkova, Oxana A. Poliakov, Alexander Dubchak, Inna Rogozin, Igor B. TI Tandem termination signal in plant mRNAs SO GENE LA English DT Article DE mRNA; Arabidopsis thaliana; Oryza sativa; Stop codon; Tandem terminators; Readthrough ID STOP CODON READTHROUGH; TRANSLATION START SITES; SACCHAROMYCES-CEREVISIAE; READ-THROUGH; HUMAN GENOME; DROSOPHILA-MELANOGASTER; PROTEIN; GENES; YEAST; IDENTIFICATION AB It was proposed that if some mRNA characteristics resulted in a low efficiency of termination signal, an additional closely located stop codon (tandem stop codons) could be used to prevent the harmful readthrough. However, the role of tandem terminators in higher eukaryotes was not verified and remains hypothetical. In this work the sequence features of Arabidopsis thaliana and Oryza sativa mRNAs were analyzed. It was found that plant mRNAs with UGA terminator were characterized by a higher frequency of nonsense codons in the first triplet position of 3'-UTR that could result from a weak natural selection for "reserve" stop signal. Interestingly, the presence of tandem stop codons positively correlated with a specific amino acid composition in the C-terminal position of the encoded proteins. In particular, C-terminal glycine positively correlated with significantly higher frequencies of reserve terminators at the beginning positions of 3'-UTR in UGA-containing mRNAs. This finding coincides with some earlier observations concerning the role of glycine and its codons in inefficient termination of translation and recoding (e.g., 2A oligopeptide). (C) 2011 Elsevier B.V. All rights reserved. C1 [Kochetov, Alex V.; Volkova, Oxana A.; Rogozin, Igor B.] Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Kochetov, Alex V.; Volkova, Oxana A.] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Poliakov, Alexander; Dubchak, Inna] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. [Poliakov, Alexander; Dubchak, Inna] DOE Joint Genome Inst, Walnut Creek, CA 94598 USA. [Rogozin, Igor B.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Kochetov, AV (reprint author), Russian Acad Sci, Inst Cytol & Genet, Lavrentieva Ave 10, Novosibirsk 630090, Russia. EM ak@bionet.nsc.ru; ov@bionet.nsc.ru; AVPoliakov@lbl.gov; ildubchak@lbl.gov; rogozin@ncbi.nlm.nih.gov RI Kochetov, Alex/R-9689-2016 OI Kochetov, Alex/0000-0003-3151-5181 FU Russian Ministry of Science Education [2.1.1/10551 (2.1.1/6382), 02.740.11.0705, 02.740.11.0277, P721]; Russian Academy of Sciences (Molecular and Cellular Biology); DHHS (NIH, National Library of Medicine); Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231] FX We are grateful to Prof. Lev L Kisselev for discussions. This work was supported by Russian Ministry of Science & Education (2.1.1/10551 (2.1.1/6382); 02.740.11.0705; 02.740.11.0277; P721), the Program of Russian Academy of Sciences (Molecular and Cellular Biology) and intramural funds of the DHHS (NIH, National Library of Medicine). The authors are also grateful to SD RAS Complex Integration Program for partial support. The work conducted by the U.S. Department of Energy Joint Genome Institute (ID. and A.P.) was supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. NR 45 TC 1 Z9 1 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUL 15 PY 2011 VL 481 IS 1 BP 1 EP 6 DI 10.1016/j.gene.2011.04.002 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 791NP UT WOS:000292672200001 PM 21539902 ER PT J AU Tebbenkamp, ATN Green, C Xu, GL Denovan-Wright, EM Rising, AC Fromholt, SE Brown, HH Swing, D Mandel, RJ Tessarollo, L Borchelt, DR AF Tebbenkamp, Andrew T. N. Green, Cameron Xu, Guilian Denovan-Wright, Eileen M. Rising, Aaron C. Fromholt, Susan E. Brown, Hilda H. Swing, Debbie Mandel, Ronald J. Tessarollo, Lino Borchelt, David R. TI Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative SO HUMAN MOLECULAR GENETICS LA English DT Article ID MOUSE MODEL; INTRANUCLEAR INCLUSIONS; REDUCES TOXICITY; CASPASE CLEAVAGE; MOTOR DEFICITS; DISEASE; POLYGLUTAMINE; GENE; AGGREGATION; REPEAT AB Recent studies have implicated an N-terminal caspase-6 cleavage product of mutant huntingtin (htt) as an important mediator of toxicity in Huntington's disease (HD). To directly assess the consequences of such fragments on neurologic function, we produced transgenic mice that express a caspase-6 length N-terminal fragment of mutant htt (N586) with both normal (23Q) and disease (82Q) length glutamine repeats. In contrast to mice expressing N586-23Q, mice expressing N586-82Q accumulate large cytoplasmic inclusion bodies that can be visualized with antibodies to epitopes throughout the N586 protein. However, biochemical analyses of aggregated mutant huntingtin in these mice demonstrated that the inclusion bodies are composed largely of a much smaller htt fragment (terminating before residue 115), with lesser amounts of full-length N586-82Q fragments. Mice expressing the N586-82Q fragment show symptoms typical of previously generated mice expressing mutant huntingtin fragments, including failure to maintain weight, small brain weight and reductions in specific mRNAs in the striatum. Uniquely, these N586-82Q mice develop a progressive movement disorder that includes dramatic deficits in motor performance on the rotarod and ataxia. Our findings suggest that caspase-6-derived fragments of mutant htt are capable of inducing novel HD-related phenotypes, but these fragments are not terminal cleavage products as they are subject to further proteolysis. In this scenario, mutant htt fragments derived from caspase 6, or possibly other proteases, could mediate HD pathogenesis via a 'hit and run' type of mechanism in which caspase-6, or other larger N-terminal fragments, mediate a neurotoxic process before being cleaved to a smaller fragment that accumulates pathologically. C1 [Tebbenkamp, Andrew T. N.; Green, Cameron; Xu, Guilian; Rising, Aaron C.; Fromholt, Susan E.; Brown, Hilda H.; Mandel, Ronald J.; Borchelt, David R.] Univ Florida, Dept Neurosci, Gainesville, FL 32610 USA. [Green, Cameron; Xu, Guilian; Fromholt, Susan E.; Brown, Hilda H.; Borchelt, David R.] Univ Florida, Santa Fe Hlth Alzheimers Dis Res Ctr, McKnight Brain Inst, Gainesville, FL 32610 USA. [Denovan-Wright, Eileen M.] Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 1X5, Canada. [Swing, Debbie; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Neural Dev Sect, Frederick, MD 21702 USA. RP Borchelt, DR (reprint author), Univ Florida, Dept Neurosci, 100 Newell Dr,Rm L1-100, Gainesville, FL 32610 USA. EM borchelt@mbi.ufl.edu OI Tebbenkamp, Andrew/0000-0002-9015-3427 FU Huntington's Disease Society of America; CHDI Coalition for a Cure; NIH, Center for Cancer Research, National Cancer Institute FX This work was supported by the Huntington's Disease Society of America and the CHDI Coalition for a Cure (A.T.N.T. and D.R.B.) and the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute (for D.S. and L.T.). NR 43 TC 23 Z9 24 U1 0 U2 1 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 JUL 15 PY 2011 VL 20 IS 14 BP 2770 EP 2782 DI 10.1093/hmg/ddr176 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 790AG UT WOS:000292560300007 PM 21515588 ER PT J AU Chung, CC Ciampa, J Yeager, M Jacobs, KB Berndt, SI Hayes, RB Gonzalez-Bosquet, J Kraft, P Wacholder, S Orr, N Yu, K Hutchinson, A Boland, J Chen, Q Feigelson, HS Thun, MJ Diver, WR Albanes, D Virtamo, J Weinstein, S Schumacher, FR Cancel-Tassin, G Cussenot, O Valeri, A Andriole, GL Crawford, ED Haiman, CA Henderson, BE Kolonel, L Le Marchand, L Siddiq, A Riboli, E Key, TJ Kaaks, R Isaacs, WB Isaacs, SD Gronberg, H Wiklund, F Xu, JF Vatten, LJ Hveem, K Njolstad, I Gerhard, DS Tucker, M Hoover, RN Fraumeni, JF Hunter, DJ Thomas, G Chatterjee, N Chanock, SJ AF Chung, Charles C. Ciampa, Julia Yeager, Meredith Jacobs, Kevin B. Berndt, Sonja I. Hayes, Richard B. Gonzalez-Bosquet, Jesus Kraft, Peter Wacholder, Sholom Orr, Nick Yu, Kai Hutchinson, Amy Boland, Joseph Chen, Quan Feigelson, Heather Spencer Thun, Michael J. Diver, W. Ryan Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Schumacher, Fredrick R. Cancel-Tassin, Geraldine Cussenot, Olivier Valeri, Antoine Andriole, Gerald L. Crawford, E. David Haiman, Christopher A. Henderson, Brian E. Kolonel, Laurence Le Marchand, Loic Siddiq, Afshan Riboli, Elio Key, Tim J. Kaaks, Rudolf Isaacs, William B. Isaacs, Sarah D. Gronberg, Henrik Wiklund, Fredrik Xu, Jianfeng Vatten, Lars J. Hveem, Kristian Njolstad, Inger Gerhard, Daniela S. Tucker, Margaret Hoover, Robert N. Fraumeni, Joseph F., Jr. Hunter, David J. Thomas, Gilles Chatterjee, Nilanjan Chanock, Stephen J. TI Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; RECOMBINATION HOTSPOTS; LINKAGE DISEQUILIBRIUM; GENETIC-VARIATION; COMMON VARIANT; BREAST-CANCER; IDENTIFIES 5; POPULATION; MYEOV AB Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P < 10(-8)) with rs10896449 the most significant (P = 7.94 x 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P = 4.76 x 10(-5), adjusted P = 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2) = 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P = 5.92 x 10(-3), adjusted P = 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2) = 0.17; rs10896449-rs10896438, r(2) = 0.10; rs12793759-rs10896438, r(2) = 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across similar to 123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n = 31), rs10896438 (n = 24) and rs12793759 (n = 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals. C1 [Chung, Charles C.; Gonzalez-Bosquet, Jesus; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Adv Technol Ctr NCI,Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Chung, Charles C.; Ciampa, Julia; Yeager, Meredith; Jacobs, Kevin B.; Berndt, Sonja I.; Hayes, Richard B.; Gonzalez-Bosquet, Jesus; Wacholder, Sholom; Orr, Nick; Yu, Kai; Hutchinson, Amy; Boland, Joseph; Chen, Quan; Albanes, Demetrius; Weinstein, Stephanie; Tucker, Margaret; Hoover, Robert N.; Fraumeni, Joseph F., Jr.; Hunter, David J.; Thomas, Gilles; Chatterjee, Nilanjan; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Gerhard, Daniela S.] NCI, Off Canc Genom, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Yeager, Meredith; Jacobs, Kevin B.; Hutchinson, Amy; Boland, Joseph; Chen, Quan] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hayes, Richard B.] NYU Sch Med, Dept Environm Med, New York, NY USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Feigelson, Heather Spencer; Thun, Michael J.; Diver, W. Ryan] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine] Hop Tenon, AP HP, Ctr Rech Pathol Prostat, F-75970 Paris, France. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Crawford, E. David] Univ Colorado, Dept Surg, Denver, CO 80202 USA. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Kolonel, Laurence; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Siddiq, Afshan; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Key, Tim J.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Kaaks, Rudolf] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany. [Isaacs, William B.; Isaacs, Sarah D.] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Vatten, Lars J.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth, N-7034 Trondheim, Norway. [Njolstad, Inger] Univ Tromso, Inst Community Med, Tromso, Norway. [Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Channing Lab, Sch Med, Boston, MA 02115 USA. [Thomas, Gilles] Univ Lyon 1, F-69365 Lyon, France. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Adv Technol Ctr NCI,Dept Hlth & Human Serv,NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; OI Hayes, Richard/0000-0002-0918-661X; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH); [CA129684]; [HHSN261200800001E] FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH). The project was partially funded in part using grant CA129684 to J.X. and Contract Number HHSN261200800001E. NR 41 TC 25 Z9 25 U1 0 U2 5 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 JUL 15 PY 2011 VL 20 IS 14 BP 2869 EP 2878 DI 10.1093/hmg/ddr189 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 790AG UT WOS:000292560300015 PM 21531787 ER PT J AU Tse, KP Su, WH Yang, ML Cheng, HY Tsang, NM Chang, KP Hao, SP Shugart, YY Chang, YS AF Tse, Ka-Po Su, Wen-Hui Yang, Min-lee Cheng, Hsiao-Yun Tsang, Ngan-Ming Chang, Kai-Ping Hao, Sheng-Po Shugart, Yin Yao Chang, Yu-Sun TI A gender-specific association of CNV at 6p21.3 with NPC susceptibility SO HUMAN MOLECULAR GENETICS LA English DT Article ID COPY NUMBER VARIATION; GENOME-WIDE ASSOCIATION; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; NASOPHARYNGEAL CARCINOMA; GENETIC POLYMORPHISMS; RISK; CANCER; EPIDEMIOLOGY; POPULATION AB Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases and neurological disorders. Nasopharyngeal carcinoma (NPC) is a multifactorial tumor closely associated with genetic background and with a male preponderance over female (3:1). Previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are associated with NPC susceptibility. Here, we sought to explore the possible association of CNVs with NPC predisposition. Utilizing genome-wide SNP-based arrays and five CNV-prediction algorithms, we identified eight regions with CNV that were significantly overrepresented in NPC patients compared with healthy controls. These CNVs included six deletions (on chromosomes 3, 6, 7, 8 and 19), and two duplications (on chromosomes 7 and 12). Among them, the CNV located at chromosome 6p21.3, with single-copy deletion of the MICA and HCP5 genes, showed the highest association with NPC. Interestingly, it was more specifically associated with an increased NPC risk among males. This gender-specific association was replicated in an independent case-control sample using a self-established deletion-specific polymerase chain reaction strategy. To the best of our knowledge, this is the first study to explore the role of constitutional CNVs in NPC, using a genome-wide platform. Moreover, we identified eight novel candidate regions with CNV that merit future investigation, and our results suggest that similar to neuroblastoma and prostate cancer, genetic structural variations might contribute to NPC predisposition. C1 [Tse, Ka-Po; Su, Wen-Hui; Yang, Min-lee; Cheng, Hsiao-Yun; Chang, Yu-Sun] Chang Gung Univ, Chang Gung Mol Med Res Ctr, Tao Yuan 333, Taiwan. [Su, Wen-Hui] Chang Gung Univ, Dept Biomed Sci, Grad Inst Biomed Sci, Tao Yuan 333, Taiwan. [Yang, Min-lee] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48105 USA. [Yang, Min-lee] Univ Michigan, Dept Stat, Ann Arbor, MI 48105 USA. [Tsang, Ngan-Ming] Chang Gung Mem Hosp Lin Kou, Dept Radiat Oncol, Tao Yuan 333, Taiwan. [Chang, Kai-Ping; Hao, Sheng-Po] Chang Gung Mem Hosp Lin Kou, Dept Otolaryngol, Tao Yuan 333, Taiwan. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Shugart, Yin Yao] Johns Hopkins Med Sch, Dept Pediat, Baltimore, MD 21205 USA. RP Chang, YS (reprint author), 259 Wen Hwa 1st Rd, Tao Yuan 333, Taiwan. EM ysc@mail.cgu.edu.tw FU Ministry of Education; National Science Council [NSC 94-2314-B-182A-188, 94-3112-B-182-005, 95-2320-B-182-001, 97-3112-B-182-008]; Chang Gung Memorial Hospital, Taiwan [CMRPD150961, CMRPG360221] FX This work was supported by grants from the Ministry of Education (to Chang Gung University), the National Science Council (NSC 94-2314-B-182A-188, 94-3112-B-182-005, 95-2320-B-182-001 and 97-3112-B-182-008) and Chang Gung Memorial Hospital (CMRPD150961 and CMRPG360221), Taiwan. NR 35 TC 21 Z9 22 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 15 PY 2011 VL 20 IS 14 BP 2889 EP 2896 DI 10.1093/hmg/ddr191 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 790AG UT WOS:000292560300017 PM 21536588 ER PT J AU Phillips, MD Mukhopadhyay, M Poscablo, C Westphal, H AF Phillips, Matthew D. Mukhopadhyay, Mahua Poscablo, Cristina Westphal, Heiner TI Dkk1 and Dkk2 regulate epicardial specification during mouse heart development SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Mouse; Heart; Congenital; Dkk1; Dkk2; Wnt ID BETA-CATENIN; WNT; DIFFERENTIATION; DISEASE; PROGENITORS; INDUCTION; DICKKOPF1; SIGNALS; FAMILY; CELLS AB Background: Dkk1 and Dkk2 interact with LRP5 and LRP6 to modulate canonical Wnt signaling during development, and are known to be expressed in the developing heart. However, a loss-of-function mutation in either gene by itself produces no discernable heart phenotype. Methods: Using standard husbandry techniques, Dkk1 null and Dkk2 null mouse lines were crossed to create double null embryos, which we examined using histological and immunohistochemical methods. Results: Double null embryos die perinatally, with a gross head phenotype reminiscent of Dkk1 null embryos. Upon examination of late stage hearts, we observe myocardial defects including ventricular septal defects. At earlier stages, double mutant hearts show myocardial and epicardial hyperplasia. Myocardial hypertrophy is associated with a moderate increase in cell proliferation, but epicardial hypercellularity is not. Rather, the field of proepicardial precursor cells near the liver shows a broadening of expression for the cardiac-specific gap junction protein Connexin 43. Conclusions: Dkk1 and Dkk2 both inhibit Wnt signaling to regulate early myocardial proliferation and each can compensate for the loss of the other in that role. Wnt signaling regulates myocardial proliferation in both heart fields at early stages. Additionally, Wnt signaling is sufficient to increase proepicardial specification as measured by Connexin 43 expression, resulting in a hypercellular epicardium and perhaps contributing to later defects. Published by Elsevier Ireland Ltd. C1 [Phillips, Matthew D.; Mukhopadhyay, Mahua; Poscablo, Cristina; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Program Genom Dev, NIH,HHS, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHD, Lab Mammalian Genes & Dev, NIH, 6B-4B413 Ctr Dr, Bethesda, MD 20892 USA. EM hw@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We thank Mrs. Rui Lin for genotyping and Dr. Margaret Kirby for helpful discussions. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [25]. NR 25 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2011 VL 150 IS 2 BP 186 EP 192 DI 10.1016/j.ijcard.2010.04.007 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 789VO UT WOS:000292545700027 PM 20439124 ER PT J AU Taubenberger, JK Morens, DM Krause, RM Fauci, AS AF Taubenberger, Jeffery K. Morens, David M. Krause, Richard M. Fauci, Anthony S. TI In Memoriam: Edwin D. Kilbourne, MD, 1920-2011 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID RECOMBINANT INFLUENZA-VIRUS; PULMONARY COMPLICATIONS; VACCINE; INFECTION; IMMUNITY C1 [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Morens, David M.; Fauci, Anthony S.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. [Krause, Richard M.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis Sect, Infect Dis Lab, NIH, Bldg 33,Room 3E19A-2, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov NR 24 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2011 VL 204 IS 2 BP 185 EP 187 DI 10.1093/infdis/jir245 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AZ UT WOS:000292562200004 ER PT J AU West, SK Munoz, B Mkocha, H Gaydos, CA Quinn, TC AF West, Sheila K. Munoz, Beatriz Mkocha, Harran Gaydos, Charlotte A. Quinn, Thomas C. TI Number of Years of Annual Mass Treatment With Azithromycin Needed to Control Trachoma in Hyper-endemic Communities in Tanzania SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CHLAMYDIA-TRACHOMATIS; HYPERENDEMIC COMMUNITY; ANTIBIOTIC-TREATMENT; INFECTIOUS TRACHOMA; REDUCTION AB Background. The World Health Organization recommends mass treatment as part of a trachoma control strategy. However, scant empirical data from hyperendemic communities exist on the number of rounds of treatment needed to reach a goal of <5% prevalence in children. We determined the prevalence of trachoma and infection with Chlamydia trachomatis in communities after 3-7 years of annual mass treatment in Tanzania. Methods. Seventy-one communities with trachoma and annual azithromycin coverage data were enrolled. A cross-sectional survey of >= 100 randomly selected children aged <5 years in each community was performed. Children were examined for clinical trachoma, and swab samples were taken for determination of ocular C. trachomatis infection. Results. After 3 years of mass treatment, the prevalence of trachoma decreased in a linear fashion with number of years of mass treatment, whereas decreased prevalences of C. trachomatis infection were related to the extent of the previous year's azithromycin coverage. Our model suggests that, for communities with baseline trachoma prevalence of 50% and annual treatment coverage of 75%, >7 years of annual mass treatment will be needed to reach a prevalence of trachoma of <5%. Conclusions. Country programs in trachoma-endemic regions must realistically expect that several years of annual mass treatment may be necessary to eliminate trachoma. C1 [West, Sheila K.; Munoz, Beatriz] Johns Hopkins Med Inst, Dept Opthalmol, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21205 USA. [Gaydos, Charlotte A.; Quinn, Thomas C.] Johns Hopkins Med Inst, Int Chlamydia Lab, Div Infect Dis, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Mkocha, Harran] Kongwa Trachoma Project, Kongwa, Tanzania. RP West, SK (reprint author), Johns Hopkins Univ Hosp, Wilmer Eye Inst, Wilmer Rm 129,600 N Wolfe St, Baltimore, MD 21287 USA. EM shwest@jhmi.edu FU National Eye Institute [EY16429]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was funded by a grant from the National Eye Institute (EY16429) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. S. K. W. is a Research to Prevent Blindness Senior Scientific Investigator. NR 19 TC 15 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2011 VL 204 IS 2 BP 268 EP 273 DI 10.1093/infdis/jir257 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AZ UT WOS:000292562200016 PM 21673038 ER PT J AU Imamichi, H DeGray, G Dewar, RL Mannon, P Yao, M Chairez, C Sereti, I Kovacs, JA AF Imamichi, Hiromi DeGray, Gerald Dewar, Robin L. Mannon, Peter Yao, Michael Chairez, Cheryl Sereti, Irini Kovacs, Joseph A. TI Lack of Compartmentalization of HIV-1 Quasispecies Between the Gut and Peripheral Blood Compartments SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; INTESTINAL-MUCOSA; LYMPHOID-TISSUE; T-CELLS; INFECTION; EXPRESSION; LYMPHOCYTES; ACTIVATION AB Compartmental differences in human immunodeficiency virus type 1 (HIV-1) between the gut and peripheral blood and within the gut were examined. Biopsy specimens from the colon and ileum and peripheral blood samples were collected from chronically HIV-1-infected individuals. HIV-1 envelope sequences were examined from cell-associated DNA and RNA and virion RNA. Phylogenetic analysis revealed no evidence of compartmentalization of HIV-1 between the gut and peripheral blood and within the gut (colon and ileum). HIV-1 sequences detected in the gut were transcriptionally active and were also found in peripheral blood from matching time points, providing evidence of ongoing virus production in the gut and equilibrium of HIV-1 between the gut and peripheral blood compartments. C1 [Imamichi, Hiromi; Chairez, Cheryl; Sereti, Irini] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [DeGray, Gerald; Dewar, Robin L.] NCI, Clin Serv Program, SAIC Frederick, Frederick, MD 21701 USA. [Mannon, Peter; Yao, Michael] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Imamichi, H (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bldg 550,Room 201-A,POB B, Frederick, MD 21702 USA. EM himamichi@nih.gov FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; National Institute of Allergy and Infectious Disease (NIAID), NIH [HHSN261200800001E]; NIAID; NIH Clinical Center FX This work was supported by the National Cancer Institute, National Institutes of Health (NIH; contract HHSN261200800001E); the National Institute of Allergy and Infectious Disease (NIAID), NIH (contract HHSN261200800001E); and the Intramural Research Program of NIAID and the NIH Clinical Center. NR 16 TC 16 Z9 16 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2011 VL 204 IS 2 BP 309 EP 314 DI 10.1093/infdis/jir259 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AZ UT WOS:000292562200021 PM 21673043 ER PT J AU Dahiya, N Becker, KG Wood, WH Zhang, YQ Morin, PJ AF Dahiya, Neetu Becker, Kevin G. Wood, William H., III Zhang, Yongqing Morin, Patrice J. TI Claudin-7 Is Frequently Overexpressed in Ovarian Cancer and Promotes Invasion SO PLOS ONE LA English DT Article ID JUNCTION PROTEIN CLAUDIN-7; PROSTATE-SPECIFIC ANTIGEN; SQUAMOUS-CELL CARCINOMA; REDUCED EXPRESSION; COLORECTAL-CANCER; EPITHELIAL-CELLS; TIGHT JUNCTIONS; ADHESION MOLECULE; BARRIER FUNCTION; GENE-EXPRESSION AB Background: Claudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC. Methodology/Principal Findings: A total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression. In real-time RT-PCR analysis, the gene for claudin-7, CLDN7, was found to be upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Small interfering RNA-mediated knockdown of claudin-7 in ovarian cancer cells led to significant changes in gene expression as measured by microarrays and validated by RT-PCR and immunoblotting. Analyses of the genes differentially expressed revealed that the genes altered in response to claudin-7 knockdown were associated with pathways implicated in various molecular and cellular functions such as cell cycle, cellular growth and proliferation, cell death, development, and cell movement. Through functional experiments in vitro, we found that both migration and invasion were altered in cells where CLDN7 had been knocked down or overexpressed. Interestingly, claudin-7 expression was associated with a net increase in invasion, but also with a decrease in migration. Conclusion/Significance: Our work shows that claudin-7 is significantly upregulated in EOC and that it may be functionally involved in ovarian carcinoma invasion. CLDN7 may therefore represent potential marker for ovarian cancer detection and a target for therapy. C1 [Dahiya, Neetu; Morin, Patrice J.] NIA, Lab Cellular & Mol Biol, Baltimore, MD 21224 USA. [Becker, Kevin G.; Wood, William H., III; Zhang, Yongqing] NIA, Res Resource Branch, Baltimore, MD 21224 USA. [Morin, Patrice J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Dahiya, N (reprint author), NIA, Lab Cellular & Mol Biol, Baltimore, MD 21224 USA. EM morinp@mail.nih.gov RI Dahiya, Neetu/E-5208-2011; OI Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 22 Z9 22 U1 1 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 JUL 15 PY 2011 VL 6 IS 7 AR e22119 DI 10.1371/journal.pone.0022119 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HT UT WOS:000292811700025 PM 21789222 ER PT J AU Glesner, J Wunschmann, S Li, M Gustchina, A Wlodawer, A Himly, M Chapman, MD Pomes, A AF Glesner, Jill Wuenschmann, Sabina Li, Mi Gustchina, Alla Wlodawer, Alexander Himly, Martin Chapman, Martin D. Pomes, Anna TI Mechanisms of Allergen-Antibody Interaction of Cockroach Allergen Bla g 2 with Monoclonal Antibodies That Inhibit IgE Antibody Binding SO PLOS ONE LA English DT Article ID MAGNETIC-RESONANCE STRUCTURE; FLUORESCENT MULTIPLEX ARRAY; SITE-DIRECTED MUTAGENESIS; DUST-MITE ALLERGEN; MAJOR ALLERGEN; CARBOHYDRATE DETERMINANTS; MUTATIONAL ANALYSIS; CRYSTAL-STRUCTURE; GRASS-POLLEN; AMINO-ACID AB Background: Cockroach allergy is strongly associated with asthma, and involves the production of IgE antibodies against inhaled allergens. Reports of conformational epitopes on inhaled allergens are limited. The conformational epitopes for two specific monoclonal antibodies (mAb) that interfere with IgE antibody binding were identified by X-ray crystallography on opposite sites of the quasi-symmetrical cockroach allergen Bla g 2. Methodology/Principal Findings: Mutational analysis of selected residues in both epitopes was performed based on the Xray crystal structures of the allergen with mAb Fab/Fab9 fragments, to investigate the structural basis of allergen-antibody interactions. The epitopes of Bla g 2 for the mAb 7C11 or 4C3 were mutated, and the mutants were analyzed by SDS-PAGE, circular dichroism, and/or mass spectrometry. Mutants were tested for mAb and IgE antibody binding by ELISA and fluorescent multiplex array. Single or multiple mutations of five residues from both epitopes resulted in almost complete loss of mAb binding, without affecting the overall folding of the allergen. Preventing glycosylation by mutation N268Q reduced IgE binding, indicating a role of carbohydrates in the interaction. Cation-p interactions, as well as electrostatic and hydrophobic interactions, were important for mAb and IgE antibody binding. Quantitative differences in the effects of mutations on IgE antibody binding were observed, suggesting heterogeneity in epitope recognition among cockroach allergic patients. Conclusions/Significance: Analysis by site-directed mutagenesis of epitopes identified by X-ray crystallography revealed an overlap between monoclonal and IgE antibody binding sites and provided insight into the B cell repertoire to Bla g 2 and the mechanisms of allergen-antibody recognition, including involvement of carbohydrates. C1 [Glesner, Jill; Wuenschmann, Sabina; Chapman, Martin D.; Pomes, Anna] INDOOR Biotechnol Inc, Charlottesville, VA USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Himly, Martin] Salzburg Univ, Div Allergy & Immunol, Dept Mol Biol, A-5020 Salzburg, Austria. RP Glesner, J (reprint author), INDOOR Biotechnol Inc, Charlottesville, VA USA. EM apomes@inbio.com RI Himly, Martin/D-1568-2015; OI Himly, Martin/0000-0001-5416-085X; Pomes, Anna/0000-0002-8729-1829 FU National Institute of Allergy and Infectious Diseases [RO1AI077653]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E]; NIAID/NIH FX This project was supported in part by Award Number RO1AI077653 from the National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov), in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part with Federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors JG, SW, MDC and AP are employed by Indoor Biotechnologies, Inc. MDC is the president and owner of the company. AP is the contact PI of the RO1 from the NIAID/NIH that finances this study. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 38 TC 19 Z9 19 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2011 VL 6 IS 7 AR e22223 DI 10.1371/journal.pone.0022223 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HT UT WOS:000292811700035 PM 21789239 ER PT J AU Luo, AH Tahsili-Fahadan, P Wise, RA Lupica, CR Aston-Jones, G AF Luo, Alice H. Tahsili-Fahadan, Pouya Wise, Roy A. Lupica, Carl R. Aston-Jones, Gary TI Linking Context with Reward: A Functional Circuit from Hippocampal CA3 to Ventral Tegmental Area SO SCIENCE LA English DT Article ID DOPAMINE NEURONS; COCAINE-SEEKING; NUCLEUS; RAT; REPRESENTATIONS; STIMULATION; PROJECTIONS; AFFERENTS; RELAPSE; MEMORY AB Reward-motivated behavior is strongly influenced by the learned significance of contextual stimuli in the environment. However, the neural pathways that mediate context-reward relations are not well understood. We have identified a circuit from area CA3 of dorsal hippocampus to ventral tegmental area (VTA) that uses lateral septum (LS) as a relay. Theta frequency stimulation of CA3 excited VTA dopamine (DA) neurons and inhibited non-DA neurons. DA neuron excitation was likely mediated by disinhibition because local antagonism of g-aminobutyric acid receptors blocked responses to CA3 stimulation. Inactivating components of the CA3-LS-VTA pathway blocked evoked responses in VTA and also reinstatement of cocaine-seeking by contextual stimuli. This transsynaptic link between hippocampus and VTA appears to be an important substrate by which environmental context regulates goal-directed behavior. C1 [Luo, Alice H.; Wise, Roy A.] Natl Inst Drug Abuse, Behav Neurosci Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Tahsili-Fahadan, Pouya; Aston-Jones, Gary] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Lupica, Carl R.] Natl Inst Drug Abuse, Electrophysiol Res Sect, Cellular Neurobiol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Luo, AH (reprint author), Natl Inst Drug Abuse, Behav Neurosci Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. EM alice_luo@hotmail.com RI Wise, Roy/A-6465-2012 FU U.S. Public Health Service [R37-DA006214, F31-MH071093]; National Institute on Drug Abuse FX We thank B. Bingham and J. See for assistance with the initial anatomical experiments; R. Fallon, G. Sartor, L. Zhang, S. Mahler, K. Moussawi, R. Smith, and T. Smith for assistance with behavioral studies; C. Backman and W. Freed for use of their microscopy equipment; and C. Mejias-Aponte for his programming expertise and thoughtful comments. This work was supported by U.S. Public Health Service grant awards R37-DA006214 and F31-MH071093, and the National Institute on Drug Abuse Intramural Research Program. The anatomical data were gathered at the University of Pennsylvania. NR 17 TC 130 Z9 134 U1 5 U2 32 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 15 PY 2011 VL 333 IS 6040 BP 353 EP 357 DI 10.1126/science.1204622 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 792HF UT WOS:000292732000046 PM 21764750 ER PT J AU Jiang, WZ Chai, NR Maric, D Bielekova, B AF Jiang, Wenzheng Chai, Noo Ri Maric, Dragan Bielekova, Bibiana TI Unexpected Role for Granzyme K in CD56(bright) NK Cell-Mediated Immunoregulation of Multiple Sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; REGULATORY T-CELLS; PERIPHERAL-BLOOD; DIFFERENTIAL EXPRESSION; INTERFERON-BETA; LYMPH-NODES; PERFORIN; DACLIZUMAB AB Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis. NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity toward immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56(bright) NK cell subset, which is selectively expanded by daclizumab, a CD25-blocking Ab that suppresses multiple sclerosis-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. Although both granzyme A and granzyme K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56(bright) NK cells, profoundly inhibited the ability of NK-92 cells to kill activated syngeneic T cells. Finally, we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56(bright) NK cells. Our study describes the important physiological role that GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity. The Journal of Immunology, 2011, 187: 781-790. C1 [Jiang, Wenzheng; Chai, Noo Ri; Bielekova, Bibiana] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Jiang, Wenzheng] E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU National Institute of Neurological Disorders and Stroke/National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke/National Institutes of Health. NR 46 TC 45 Z9 45 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 JUL 15 PY 2011 VL 187 IS 2 BP 781 EP 790 DI 10.4049/jimmunol.1100789 PG 10 WC Immunology SC Immunology GA 788NF UT WOS:000292451000024 PM 21666061 ER PT J AU Choi, S Schwartz, RH AF Choi, Seeyoung Schwartz, Ronald H. TI Impairment of Immunological Synapse Formation in Adaptively Tolerant T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MEDIATES RAP1-INDUCED ADHESION; MICROTUBULE-ORGANIZING CENTER; ANTIGEN-PRESENTING CELLS; INTEGRIN ACTIVATION; IMMUNE SYNAPSE; CYTOSKELETAL REORGANIZATION; RECEPTOR MICROCLUSTERS; ACTIN POLYMERIZATION; SIGNALING PROTEINS; ADAPTER PROTEIN AB Adaptive tolerance is a hyporesponsive state in which lymphocyte Ag receptor signaling becomes desensitized after prolonged in vivo encounter with Ag. The molecular mechanisms underlying this hyporesponsive state in T cells are not fully understood, although a major signaling block has been shown to be present at the level of ZAP70 phosphorylation of linker for activation of T cells (LAT). In this study, we investigated the ability of adaptively tolerant mouse T cells to form conjugates with Ag-bearing APCs and to translocate signaling molecules into the interface between the T cells and APCs. Compared with naive or preactivated T cells, adaptively tolerant T cells showed no dramatic impairment in their formation of conjugates with APCs. In contrast, there was a large impairment in immunological synapse formation. Adaptively tolerant T cells were defective in their translocation of signaling molecules, such as ZAP70, LAT, and phospholipase C gamma 1, into the T cell-APC contact sites. Although Ag-induced activation of VAV1 was normal, VAV's recruitment into the synapse was also impaired. Interestingly, expressions of both IL-2-inducible T cell kinase and growth factor receptor-bound protein 2-related adaptor downstream of SHC were decreased by 60-80% in adaptively tolerant T cells. These decreases, in addition to the impairment in LAT phosphorylation by ZAP70, appear to be the major impediments to the phosphorylation of SLP76 (SRC homology 2 domain-containing leukocyte protein of 76 kDa) and the recruitment of VAV1, which are important for stable immunological synapse formation. The Journal of Immunology, 2011, 187: 805-816. C1 [Schwartz, Ronald H.] NIAID, Cellular & Mol Immunol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Schwartz, RH (reprint author), NIAID, Cellular & Mol Immunol Lab, Dept Hlth & Human Serv, NIH, Bldg 4,Room 111,MSC 0420, Bethesda, MD 20892 USA. EM rs34r@niaid.nih.gov FU National Institutes of Health FX This work was supported by the National Institutes of Health Intramural Research Program. NR 69 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2011 VL 187 IS 2 BP 805 EP 816 DI 10.4049/jimmunol.1003314 PG 12 WC Immunology SC Immunology GA 788NF UT WOS:000292451000026 PM 21685322 ER PT J AU Killebrew, JR Perdue, N Kwan, A Thornton, AM Shevach, EM Campbell, DJ AF Killebrew, Justin R. Perdue, Nikole Kwan, Alan Thornton, Angela M. Shevach, Ethan M. Campbell, Daniel J. TI A Self-Reactive TCR Drives the Development of Foxp3(+) Regulatory T Cells That Prevent Autoimmune Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR TRANSGENIC MICE; DENDRITIC CELLS; PERIPHERAL TOLERANCE; CLONAL DELETION; IN-VIVO; ANTIGEN; MAINTENANCE; THYMUS; HOMEOSTASIS; EXPRESSION AB Although Foxp3(+) regulatory T cells (Tregs) are thought to express autoreactive TCRs, it is not clear how individual TCRs influence Treg development, phenotype, and function in vivo. We have generated TCR transgenic mice (termed SFZ70 mice) using Tcra and Tcrb genes cloned from an autoreactive CD4(+) T cell isolated from a Treg-deficient scurfy mouse. The SFZ70 TCR recognizes a cutaneous autoantigen and drives development of both conventional CD4(+) Foxp3(-) T cells (T-conv) and Foxp3(+) Tregs. SFZ70 Tregs display an activated phenotype evidenced by robust proliferation and expression of skin-homing molecules such as CD103 and P-selectin ligand. Analysis of Foxp3-deficient SFZ70 mice demonstrates that Tregs inhibit T-conv cell expression of tissue-homing receptors and their production of proinflammatory cytokines. In addition, Treg suppression of SFZ70 T-conv cells can be overcome by nonspecific activation of APCs. These results provide new insights into the differentiation and function of tissue-specific Tregs in vivo and provide a tractable system for analyzing the molecular requirements of Treg-mediated tolerance toward a cutaneous autoantigen. The Journal of Immunology, 2011, 187: 861-869. C1 [Killebrew, Justin R.; Perdue, Nikole; Kwan, Alan; Campbell, Daniel J.] Benaroya Res Inst, Program Immunol, Seattle, WA 98101 USA. [Killebrew, Justin R.; Campbell, Daniel J.] Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98195 USA. [Thornton, Angela M.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Campbell, DJ (reprint author), Benaroya Res Inst, Program Immunol, 1201 9th Ave, Seattle, WA 98101 USA. EM campbell@benaroyaresearch.org FU National Institutes of Health [AR055695, DK072295, AI067750]; Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology FX This work was supported by National Institutes of Health Grants AR055695, DK072295, and AI067750 (to D.J.C.). J.R.K. was supported in part by the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology. NR 45 TC 17 Z9 20 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2011 VL 187 IS 2 BP 861 EP 869 DI 10.4049/jimmunol.1004009 PG 9 WC Immunology SC Immunology GA 788NF UT WOS:000292451000032 PM 21690323 ER PT J AU Li, F Folk, JE Cheng, KJ Kurimura, M Deck, JA Deschamps, JR Rothman, RB Dersch, CM Jacobson, AE Rice, KC AF Li, Feng Folk, John E. Cheng, Kejun Kurimura, Muneaki Deck, Jason A. Deschamps, Jeffrey R. Rothman, Richard B. Dersch, Christina M. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena. 43. Synthesis of the ortho-a and para-a, and improved synthesis and optical resolution of the ortho-b and para-b oxide-bridged phenylmorphans: Compounds with moderate to low opioid-receptor affinity SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE ortho-a and ortho-b oxide-bridged; phenylmorphans; para-a and para-b oxide-bridged; phenylmorphans; Synthesis; Optical resolution ID N-PHENETHYL ANALOGS; ISOMERS AB N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for mu- and kappa-opioid receptors than their N-methyl relatives (e. g., K(i) = 167 nM and 171 nM at mu- and kappa-receptors vs > 2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for mu- and kappa-receptors (K(i) = 49 and 42 nM, respectively, and it was found to also have moderate mu- and kappa-opioid antagonist activity in the [(35)S]GTP-gamma-S assay (K(e) = 31 and 26 nM). (C) 2011 Published by Elsevier C1 [Li, Feng; Folk, John E.; Cheng, Kejun; Kurimura, Muneaki; Deck, Jason A.; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Li, Feng; Folk, John E.; Cheng, Kejun; Kurimura, Muneaki; Deck, Jason A.; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. [Deschamps, Jeffrey R.] NIH, Ctr Mol Modeling, Div Computat Biosci, CIT,DHHS, Bethesda, MD 20892 USA. NIDA, Addict Res Ctr, Clin Psychopharmacol Sect, Chem Biol Res Branch,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, 5625 Fishers Lane,Room 4N03, Bethesda, MD 20892 USA. EM kr21f@nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 FU NIH of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism; NIDA through Naval Research Laboratory (NRL) [Y1-DA1101] FX The work of the Drug Design and Synthesis Section, CBRB, NIDA, & NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism. The Clinical Psychopharmacology Section, CBRB, NIDA, was supported by the NIH Intramural Research Program of the National Institute on Drug Abuse (NIDA). We thank the Averica Discovery Services, J.P. Kiplinger, President, Worcester, MA, for carrying out the supercritical fluid chromatography used to obtain the enantiomers of 16 and 19. We also thank Dr. Klaus Gawrisch and Dr. Walter Teague (Laboratory of Membrane Biochemistry and Biophysics, NIAAA, for NMR spectral data. The authors express their thanks to Noel Whittaker and Wesley White, Laboratory of Analytical Chemistry, NIDDK, for mass spectral data and 1H NMR spectral data. The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). NR 17 TC 3 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2011 VL 19 IS 14 BP 4330 EP 4337 DI 10.1016/j.bmc.2011.05.035 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 786JD UT WOS:000292301200018 PM 21684752 ER PT J AU Ahmed, SK Etoga, JLG Patel, SA Bridges, RJ Thompson, CM AF Ahmed, S. Kaleem Etoga, Jean-Louis G. Patel, Sarjubhai A. Bridges, Richard J. Thompson, Charles M. TI Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system x(c)(-) SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Hydantoin scaffolds; Glutamate; System x(c)(-); Inhibitor; VGLUT ID QUINOLINE-2,4-DICARBOXYLIC ACIDS; BRAIN-FUNCTION; RECEPTORS AB Evidence was acquired prior to suggest that the vesicular glutamate transporter (VGLUT) but not other glutamate transporters were inhibited by structures containing a weakly basic a-amino group. To test this hypothesis, a series of analogs using a hydantoin (pK(a) similar to 9.1) isostere were synthesized and analyzed as inhibitors of VGLUT and the obligate cystine-glutamate transporter (system x(c)(-)). Of the hydantoin analogs tested, a thiophene-5-carboxaldehyde analog 2l and a bis-hydantoin 4b were relatively strong inhibitors of VGLUT reducing uptake to less than 6% of control at 5 mM but few inhibited system x(c)(-) greater than 50% of control. The benzene-2,4-disulfonic acid analog 2b and p-diaminobenzene analog 2e were also good hydantoin-based inhibitors of VGLUT reducing uptake by 11% and 23% of control, respectively, but neither analog was effective as a system x(c)(-) inhibitor. In sum, a hydantoin isostere adds the requisite chemical properties needed to produce selective inhibitors of VGLUT. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Ahmed, S. Kaleem; Thompson, Charles M.] Univ Montana, Core Lab Neuromol Prod, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Etoga, Jean-Louis G.] Univ Montana, Dept Chem & Biochem, Missoula, MT 59812 USA. [Patel, Sarjubhai A.; Bridges, Richard J.; Thompson, Charles M.] Univ Montana, COBRE Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Thompson, Charles M.] ATERIS Technol LLC, Missoula, MT 59802 USA. RP Thompson, CM (reprint author), Univ Montana, Core Lab Neuromol Prod, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. EM charles.thompson@umontana.edu RI Ahmed, Syed/I-5530-2013 FU Core Laboratory for Neuromolecular Production [P30 NS055022, NS058229, NS30570, NS42077]; COBRE Center for Structural and Functional Neuroscience [NIH P20-RR015583]; [NS38248] FX This research was supported by NS38248 (CMT), the Core Laboratory for Neuromolecular Production P30 NS055022 (CMT), NS058229 (ATERIS Technologies LLC), NS30570 (RJB), NS42077 (RJB) and the COBRE Center for Structural and Functional Neuroscience (NIH P20-RR015583). NR 31 TC 8 Z9 8 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUL 15 PY 2011 VL 21 IS 14 BP 4358 EP 4362 DI 10.1016/j.bmcl.2011.05.018 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 784VM UT WOS:000292186400052 PM 21669531 ER PT J AU Yang, X Beason-Held, L Resnick, SM Landman, BA AF Yang, Xue Beason-Held, Lori Resnick, Susan M. Landman, Bennett A. TI Biological parametric mapping with robust and non-parametric statistics SO NEUROIMAGE LA English DT Article DE Structure-function relationships; Statistical parametric mapping; Biological parametric mapping; Robust regression; Non-parametric regression ID LEAST-SQUARES; BRAIN; REGRESSION; IMAGES; UNIVARIATE; SERIES; TESTS AB Mapping the quantitative relationship between structure and function in the human brain is an important and challenging problem. Numerous volumetric, surface, regions of interest and voxelwise image processing techniques have been developed to statistically assess potential correlations between imaging and non-imaging metrices. Recently, biological parametric mapping has extended the widely popular statistical parametric mapping approach to enable application of the general linear model to multiple image modalities (both for regressors and regressands) along with scalar valued observations. This approach offers great promise for direct, voxelwise assessment of structural and functional relationships with multiple imaging modalities. However, as presented, the biological parametric mapping approach is not robust to outliers and may lead to invalid inferences (e.g., artifactual low p-values) due to slight mis-registration or variation in anatomy between subjects. To enable widespread application of this approach, we introduce robust regression and non-parametric regression in the neuroimaging context of application of the general linear model. Through simulation and empirical studies, we demonstrate that our robust approach reduces sensitivity to outliers without substantial degradation in power. The robust approach and associated software package provide a reliable way to quantitatively assess voxelwise correlations between structural and functional neuroimaging modalities. (C) 2011 Elsevier Inc. All rights reserved. C1 [Yang, Xue; Landman, Bennett A.] Vanderbilt Univ, Nashville, TN 37235 USA. [Beason-Held, Lori; Resnick, Susan M.] NIA, NIH, Baltimore, MD 21224 USA. [Landman, Bennett A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Landman, BA (reprint author), Vanderbilt Univ EECS, 2301 Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. EM bennett.landman@vanderbilt.edu FU NIH/NINDS [1R01NS056307, 1R21NS064534]; NIH, National Institute on Aging and by Research and Development [N01-AG-3-2124] FX Grant Support: NIH/NINDS 1R01NS056307 and NIH/NINDS 1R21NS064534. This project was supported in part by grants NIH/NINDS1R01 NS056307 and NIH/NINDS1R21NS064534, the Intramural Research Program of the NIH, National Institute on Aging and by Research and Development Contract N01-AG-3-2124. NR 27 TC 11 Z9 11 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2011 VL 57 IS 2 BP 423 EP 430 DI 10.1016/j.neuroimage.2011.04.046 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 781TU UT WOS:000291960200017 PM 21569856 ER PT J AU Goldsmith, J Crainiceanu, CM Caffo, BS Reich, DS AF Goldsmith, Jeff Crainiceanu, Ciprian M. Caffo, Brian S. Reich, Daniel S. TI Penalized functional regression analysis of white-matter tract profiles in multiple sclerosis SO NEUROIMAGE LA English DT Article DE Multiple sclerosis; Diffusion tensor imaging; Magnetization transfer ratio; Regression methods; Functional data analysis ID DIFFUSION TENSOR TRACTOGRAPHY; CORTICOSPINAL TRACT; QUANTITATIVE MRI; CORPUS-CALLOSUM; DISABILITY; IMPAIRMENT; MORPHOMETRY; STATISTICS; TRACKING; DISEASE AB Diffusion tensor imaging (DTI) enables noninvasive parcellation of cerebral white matter into its component fiber bundles or tracts. These tracts often subserve specific functions, and damage to the tracts can therefore result in characteristic forms of disability. Attempts to quantify the extent of tract-specific damage have been limited in part by substantial spatial variation of imaging properties from one end of a tract to the other, variation that can be compounded by the effects of disease. Here, we develop a "penalized functional regression" procedure to analyze spatially normalized tract profiles, which powerfully characterize such spatial variation. The central idea is to identify and emphasize portions of a tract that are more relevant to a clinical outcome score, such as case status or degree of disability. The procedure also yields a "tract abnormality score" for each tract and MRI index studied. Importantly, the weighting function used in this procedure is constrained to be smooth, and the statistical associations are estimated using generalized linear models. We test the method on data from a cross-sectional MRI and functional study of 115 multiple-sclerosis cases and 42 healthy volunteers, considering a range of quantitative MRI indices, white-matter tracts, and clinical outcome scores, and using training and testing sets to validate the results. We show that attention to spatial variation yields up to 15% (mean across all tracts and MRI indices: 6.4%) improvement in the ability to discriminate multiple sclerosis cases from healthy volunteers. Our results confirm that comprehensive analysis of white-matter tract-specific imaging data improves with knowledge and characterization of the normal spatial variation. Published by Elsevier Inc. C1 [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Goldsmith, Jeff; Crainiceanu, Ciprian M.; Caffo, Brian S.] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Reich, Daniel S.] Johns Hopkins Sch Med, Dept Radiol, Bethesda, MD 20892 USA. [Reich, Daniel S.] Johns Hopkins Sch Med, Dept Neurol, Bethesda, MD 20892 USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, 10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM jgoldsmi@jhsph.edu; ccrainic@jhsph.edu; bcaffo@jhsph.edu; daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU National Institutes of Health (National Institute of Neurological Disorders and Stroke) [K99NS064098, R01NS060910, R01EB012547, P41RR015241]; National Multiple Sclerosis Society [TR3760A3]; EMD Serono FX The authors thank Peter Calabresi, Peter van Zijl, Seth Smith, Eliza Gordon-Lipkin, Sheena Farrell, Terri Brawner, Kathleen Kahl, and Ivana Kusevic, all of whom were instrumental in collecting the data for this study. Jonathan Farrell and Bennett Landman provided assistance with image processing. The study was supported by the National Institutes of Health (the Intramural Research Program of the National Institute of Neurological Disorders and Stroke as well as grants K99NS064098, R01NS060910, R01EB012547, and P41RR015241); the National Multiple Sclerosis Society (grant TR3760A3): and an unrestricted grant from EMD Serono to support data collection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 36 TC 13 Z9 13 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2011 VL 57 IS 2 BP 431 EP 439 DI 10.1016/j.neuroimage.2011.04.044 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 781TU UT WOS:000291960200018 PM 21554962 ER PT J AU Goloshevsky, AG Wu, CWH Dodd, SJ Koretsky, AP AF Goloshevsky, Artem G. Wu, Carolyn W. -H. Dodd, Stephen J. Koretsky, Alan P. TI Mapping cortical representations of the rodent forepaw and hindpaw with BOLD fMRI reveals two spatial boundaries SO NEUROIMAGE LA English DT Article DE BOLD; CBV; fMRI; Rat; Electrical stimulation; Cortical representation; Induced cortical plasticity; Peripheral denervation; Histochemical staining ID PRIMARY SOMATOSENSORY CORTEX; CEREBRAL-BLOOD-FLOW; ISO-ORIENTATION COLUMNS; LEVEL-DEPENDENT SIGNAL; FUNCTIONAL MRI; GRADIENT-ECHO; SPIN-ECHO; CYTOCHROME-OXIDASE; NEURONAL-ACTIVITY; VISUAL-CORTEX AB Electrical stimulation of the rat forepaw and hindpaw was employed to study the spatial distribution of BOLD fMRI. Averaging of multiple fMRI sessions significantly improved the spatial stability of the BOLD signal and enabled quantitative determination of the boundaries of the BOLD fMRI maps. The averaged BOLD fMRI signal was distributed unevenly over the extent of the map and the data at the boundaries could be modeled with major and minor spatial components. Comparison of three-dimensional echo-planar imaging (EPI) fMRI at isotropic 300 pm resolution demonstrated that the border locations of the major spatial component of BOLD signal did not overlap between the forepaw and hindpaw maps. Interestingly, the border positions of the minor BOLD fMRI spatial components extended significantly into neighboring representations. Similar results were found for cerebral blood volume (CBV) weighted fMRI obtained using iron oxide particles, suggesting that the minor spatial components may not be due to vascular mislocalization typically associated with BOLD fMRI. Comparison of the BOLD fMRI maps of the forepaw and hindpaw to histological determination of these representations using cytochrome oxidase (CO) staining demonstrated that the major spatial component of the BOLD fMRI activation maps accurately localizes the borders. Finally, 2-3 weeks following peripheral nerve denervation, cortical reorganization/plasticity at the boundaries of somatosensory limb representations in adult rat brain was studied. Denervation of the hindpaw caused a growth in the major component of forepaw representation into the adjacent border of hindpaw representation, such that fitting to two components no longer led to a better fit as compared to using one major component. The border of the representation after plasticity was the same as the border of its minor component in the absence of any plasticity. It is possible that the minor components represent either vascular effects that extend from the real neuronal representations or the neuronal communication between neighboring regions. Either way the results will be useful for studying mechanisms of plasticity that cause alterations in the boundaries of neuronal representations. Published by Elsevier Inc. C1 [Koretsky, Alan P.] NINDS, LFMI, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, LFMI, NIH, Bldg 10,Rm B1D728,10 Ctr Dr, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NINDS, NIH FX The authors would like to thank Nadia Bouraoud for animal preparation and physiology. This work was supported by the intramural research program of NINDS, NIH. NR 75 TC 5 Z9 5 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2011 VL 57 IS 2 BP 526 EP 538 DI 10.1016/j.neuroimage.2011.04.002 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 781TU UT WOS:000291960200027 PM 21504796 ER PT J AU Hurst, FP Belur, P Nee, R Agodoa, LY Patel, P Abbott, KC Jindal, RM AF Hurst, Frank P. Belur, Pallavi Nee, Robert Agodoa, Lawrence Y. Patel, Purav Abbott, Kevin C. Jindal, Rahul M. TI Poor Outcomes Associated With Neutropenia After Kidney Transplantation: Analysis of United States Renal Data System SO TRANSPLANTATION LA English DT Article DE Neutropenia after kidney transplantation; Granulocyte colony-stimulating factors; United States Renal Data System ID MYCOPHENOLATE-MOFETIL; ALLOGRAFT RECIPIENTS; RISK-FACTORS; LEUKOPENIA; THROMBOCYTOPENIA; MANAGEMENT; THERAPY; DISEASE AB Background. Posttransplant neutropenia (PTN) is relatively common after kidney transplantation, and may result in a reduction of immunosuppression, which may precipitate acute rejection. Granulocyte colony-stimulating factors (GCSF) have been used to treat PTN, although outcomes associated with use of this medication in this population are unknown. Methods. In a retrospective cohort of 41,705 adult Medicare primary patients transplanted from January 2001 to June 2006, we assessed Medicare claims for neutropenia, leukopenia, and GCSF use, respectively. Outcomes included allograft loss and death. Results. There were 6043 (14.5%) patients with claims for PTN. Factors associated with PTN included female gender, Caucasian ethnicity, ischemic heart disease, donor cytomegalovirus positive, deceased donor, expanded donor criteria, delayed graft function, elevated panel reactive antibody, higher human leukocyte antigen mismatch, and later year of transplant. Thymoglobulin induction, tacrolimus, and mycophenolate mofetil were also associated. PTN was less frequent among patients with congestive heart failure, recipient cytomegalovirus positive, and interleukin-2 induction. PTN was associated with increased risk of allograft loss (adjusted hazard ratio, 1.59; 95% confidence interval, 1.43-1.76; P<0.001) and death (adjusted hazard ratio, 1.74; 95% confidence interval, 1.59-1.90; P<0.001). Of the 6043 patients with PTN, 740 (12.2%) received GCSF. Patients who received GCSF had a lower risk of death on unadjusted analysis, but this only trended towards significance after adjustment. Conclusions. Neutropenia after renal transplantation is common and is associated with an increased risk of allograft loss and death. GCSF was used in 12% of cases and did not increase risk of allograft loss. Strategies to avoid PTN and greater use of GCSF may be indicated to prevent graft loss and death. C1 [Jindal, Rahul M.] Walter Reed AMC, Div Organ Transplant, Washington, DC USA. [Hurst, Frank P.; Belur, Pallavi; Nee, Robert; Abbott, Kevin C.] Walter Reed Army Med Ctr, Div Nephrol, Washington, DC 20307 USA. [Agodoa, Lawrence Y.] NIDDK, NIH, Bethesda, MD USA. [Patel, Purav] Med Univ Lublin, Lublin, Poland. [Jindal, Rahul M.] George Washington Univ, Dept Med, Washington, DC USA. RP Jindal, RM (reprint author), Walter Reed AMC, Div Organ Transplant, Washington, DC USA. EM jindalr@msn.com OI Abbott, Kevin/0000-0003-2111-7112 NR 24 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2011 VL 92 IS 1 BP 36 EP 40 DI 10.1097/TP.0b013e31821c1e70 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 780JY UT WOS:000291853300009 PM 21512429 ER PT J AU Makarova, KS Aravind, L Wolf, YI Koonin, EV AF Makarova, Kira S. Aravind, L. Wolf, Yuri I. Koonin, Eugene V. TI Unification of Cas protein families and a simple scenario for the origin and evolution of CRISPR-Cas systems SO BIOLOGY DIRECT LA English DT Article ID T7 RNA-POLYMERASE; DNA-POLYMERASES; ANTIVIRAL DEFENSE; GENETIC ELEMENTS; STRUCTURAL BASIS; IMMUNE-SYSTEM; PROKARYOTES; IDENTIFICATION; SUPERFAMILY; SEQUENCE AB Background: The CRISPR-Cas adaptive immunity systems that are present in most Archaea and many Bacteria function by incorporating fragments of alien genomes into specific genomic loci, transcribing the inserts and using the transcripts as guide RNAs to destroy the genome of the cognate virus or plasmid. This RNA interference-like immune response is mediated by numerous, diverse and rapidly evolving Cas (CRISPR-associated) proteins, several of which form the Cascade complex involved in the processing of CRISPR transcripts and cleavage of the target DNA. Comparative analysis of the Cas protein sequences and structures led to the classification of the CRISPR-Cas systems into three Types (I, II and III). Results: A detailed comparison of the available sequences and structures of Cas proteins revealed several unnoticed homologous relationships. The Repeat-Associated Mysterious Proteins (RAMPs) containing a distinct form of the RNA Recognition Motif (RRM) domain, which are major components of the CRISPR-Cas systems, were classified into three large groups, Cas5, Cas6 and Cas7. Each of these groups includes many previously uncharacterized proteins now shown to adopt the RAMP structure. Evidence is presented that large subunits contained in most of the CRISPR-Cas systems could be homologous to Cas10 proteins which contain a polymerase-like Palm domain and are predicted to be enzymatically active in Type III CRISPR-Cas systems but inactivated in Type I systems. These findings, the fact that the CRISPR polymerases, RAMPs and Cas2 all contain core RRM domains, and distinct gene arrangements in the three types of CRISPR-Cas systems together provide for a simple scenario for origin and evolution of the CRISPR-Cas machinery. Under this scenario, the CRISPR-Cas system originated in thermophilic Archaea and subsequently spread horizontally among prokaryotes. Conclusions: Because of the extreme diversity of CRISPR-Cas systems, in-depth sequence and structure comparison continue to reveal unexpected homologous relationship among Cas proteins. Unification of Cas protein families previously considered unrelated provides for improvement in the classification of CRISPR-Cas systems and a reconstruction of their evolution. Open peer review: This article was reviewed by Malcolm White (nominated by Purficacion Lopez-Garcia), Frank Eisenhaber and Igor Zhulin. For the full reviews, see the Reviewers' Comments section. C1 [Makarova, Kira S.; Aravind, L.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU 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 69 TC 189 Z9 199 U1 17 U2 82 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUL 14 PY 2011 VL 6 AR 38 DI 10.1186/1745-6150-6-38 PG 27 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 803DW UT WOS:000293562600001 PM 21756346 ER PT J AU Skinner, J Kotliarov, Y Varma, S Mine, KL Yambartsev, A Simon, R Huyen, Y Morgun, A AF Skinner, Jeff Kotliarov, Yuri Varma, Sudhir Mine, Karina L. Yambartsev, Anatoly Simon, Richard Huyen, Yentram Morgun, Andrey TI Construct and Compare Gene Coexpression Networks with DAPfinder and DAPview SO BMC BIOINFORMATICS LA English DT Article ID FALSE DISCOVERY RATE; RECEPTOR GENE; BRAIN-TUMORS; EXPRESSION; GROWTH; CANCER; AMPLIFICATION; DEPENDENCY; PROFILES; EGFR AB Background: DAPfinder and DAPview are novel BRB-ArrayTools plug-ins to construct gene coexpression networks and identify significant differences in pairwise gene-gene coexpression between two phenotypes. Results: Each significant difference in gene-gene association represents a Differentially Associated Pair (DAP). Our tools include several choices of filtering methods, gene-gene association metrics, statistical testing methods and multiple comparison adjustments. Network results are easily displayed in Cytoscape. Analyses of glioma experiments and microarray simulations demonstrate the utility of these tools. Conclusions: DAPfinder is a new friendly-user tool for reconstruction and comparison of biological networks. C1 [Skinner, Jeff; Varma, Sudhir; Huyen, Yentram] NIAID, BCBB, OCICB, NIH, Bethesda, MD 20892 USA. [Kotliarov, Yuri] NCI, Neurooncol Branch CHIAI, NINDS, NIH, Bethesda, MD 20892 USA. [Mine, Karina L.] Univ Fed Sao Paulo, Dept Pediat, Setor Imunogenet, Sao Paulo, Brazil. [Yambartsev, Anatoly] Univ Sao Paulo, IME, Sao Paulo, Brazil. [Simon, Richard] NCI, BRB, DCTD, NIH, Bethesda, MD 20892 USA. [Morgun, Andrey] NIAID, Ghost Lab, TCTMS, LCMI,NIH, Bethesda, MD 20892 USA. RP Huyen, Y (reprint author), NIAID, BCBB, OCICB, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huyeny@niaid.nih.gov; anemorgun@hotmail.com RI Varma, Sudhir/N-8763-2014; Kotliarov, Yuri/B-6938-2017; OI Varma, Sudhir/0000-0002-4096-4782; Skinner, Jeff/0000-0001-5697-0442 FU Department of Intramural Research (DIR); Office of the Director (OD) at NIAID, NIH FX This work was supported by funding from the Department of Intramural Research (DIR) and the Office of the Director (OD) at NIAID, NIH. Vivek Gopalan, Supriya Menezes and Ming-Chung Li helped with the initial coding of DAPfinder. Vijay Nagarajan and Michael Dolan helped produce and edit the figures. Natalia Shulzenko discussed biological questions motivating our tool. NR 37 TC 9 Z9 9 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUL 14 PY 2011 VL 12 AR 286 DI 10.1186/1471-2105-12-286 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 801DN UT WOS:000293416700001 PM 21756334 ER PT J AU Cooper, KG Winfree, S Malik-Kale, P Jolly, C Ireland, R Knodler, LA Steele-Mortimer, O AF Cooper, Kendal G. Winfree, Seth Malik-Kale, Preeti Jolly, Carrie Ireland, Robin Knodler, Leigh A. Steele-Mortimer, Olivia TI Activation of Akt by the Bacterial Inositol Phosphatase, SopB, is Wortmannin Insensitive SO PLOS ONE LA English DT Article ID PROTEIN-KINASE B; PLECKSTRIN-HOMOLOGY DOMAINS; INTESTINAL EPITHELIAL-CELLS; HOST-CELL; PLASMA-MEMBRANE; SALMONELLA-TYPHIMURIUM; SUSTAINED ACTIVATION; INHIBITORS; PATHWAY; SIGD AB Salmonella enterica uses effector proteins translocated by a Type III Secretion System to invade epithelial cells. One of the invasion-associated effectors, SopB, is an inositol phosphatase that mediates sustained activation of the pro-survival kinase Akt in infected cells. Canonical activation of Akt involves membrane translocation and phosphorylation and is dependent on phosphatidyl inositide 3 kinase (PI3K). Here we have investigated these two distinct processes in Salmonella infected HeLa cells. Firstly, we found that SopB-dependent membrane translocation and phosphorylation of Akt are insensitive to the PI3K inhibitor wortmannin. Similarly, depletion of the PI3K regulatory subunits p85 alpha and p85 beta by RNAi had no inhibitory effect on SopB-dependent Akt phosphorylation. Nevertheless, SopB-dependent phosphorylation does depend on the Akt kinases, PDK1 and rictor-mTOR. Membrane translocation assays revealed a dependence on SopB for Akt recruitment to Salmonella ruffles and suggest that this is mediated by phosphoinositide (3,4) P(2) rather than phosphoinositide (3,4,5) P(3). Altogether these data demonstrate that Salmonella activates Akt via a wortmannin insensitive mechanism that is likely a class I PI3K-independent process that incorporates some essential elements of the canonical pathway. C1 [Cooper, Kendal G.; Winfree, Seth; Malik-Kale, Preeti; Jolly, Carrie; Ireland, Robin; Knodler, Leigh A.; Steele-Mortimer, Olivia] NIAID, Intracellular Parasites Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. RP Cooper, KG (reprint author), Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. EM omortimer@niaid.nih.gov FU National Institutes of Allergy and Infectious Disease, National Institutes of Health FX Work in the laboratory was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Disease, National Institutes of Health. No other current external funding sources supported this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 11 Z9 12 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2011 VL 6 IS 7 AR e22260 DI 10.1371/journal.pone.0022260 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HP UT WOS:000292811300059 PM 21779406 ER PT J AU Robidart, JC Roque, A Song, PF Girguis, PR AF Robidart, Julie C. Roque, Annelys Song, Pengfei Girguis, Peter R. TI Linking Hydrothermal Geochemistry to Organismal Physiology: Physiological Versatility in Riftia pachyptila from Sedimented and Basalt-hosted Vents SO PLOS ONE LA English DT Article ID EAST PACIFIC RISE; TUBE-WORM; GUAYMAS BASIN; ROSE GARDEN; CHEMOAUTOTROPHIC SYMBIONTS; CARBONIC-ANHYDRASE; METABOLITE UPTAKE; INORGANIC CARBON; ACID CYCLE; SULFIDE AB Much of what is known regarding Riftia pachyptila physiology is based on the wealth of studies of tubeworms living at diffuse flows along the fast-spreading, basalt-hosted East Pacific Rise (EPR). These studies have collectively suggested that Riftia pachyptila and its chemoautotrophic symbionts are physiologically specialized, highly productive associations relying on hydrogen sulfide and oxygen to generate energy for carbon fixation, and the symbiont's nitrate reduction to ammonia for energy and biosynthesis. However, Riftia also flourish in sediment-hosted vents, which are markedly different in geochemistry than basalt-hosted systems. Here we present data from shipboard physiological studies and global quantitative proteomic analyses of Riftia pachyptila trophosome tissue recovered from tubeworms residing in the EPR and the Guaymas basin, a sedimented, hydrothermal vent field. We observed marked differences in symbiont nitrogen metabolism in both the respirometric and proteomic data. The proteomic data further suggest that Riftia associations in Guaymas may utilize different sulfur compounds for energy generation, may have an increased capacity for energy storage, and may play a role in degrading exogenous organic carbon. Together these data reveal that Riftia symbionts are far more physiologically plastic than previously considered, and that contrary to previous assertions-Riftia do assimilate reduced nitrogen in some habitats. These observations raise new hypotheses regarding adaptations to the geochemical diversity of habitats occupied by Riftia, and the degree to which the environment influences symbiont physiology and evolution. C1 [Robidart, Julie C.] Univ Calif Santa Cruz, Dept Ocean Sci, Santa Cruz, CA 95064 USA. [Roque, Annelys] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Song, Pengfei; Girguis, Peter R.] Harvard Univ, Cambridge, MA 02138 USA. RP Robidart, JC (reprint author), Univ Calif Santa Cruz, Dept Ocean Sci, Santa Cruz, CA 95064 USA. EM pgirguis@oeb.harvard.edu FU National Science Foundation [OCE-0623383, OCE-0732369] FX This project was supported by grants from the National Science Foundation to PRG (OCE-0623383 and OCE-0732369, http://www.nsf.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 10 Z9 10 U1 5 U2 40 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2011 VL 6 IS 7 AR e21692 DI 10.1371/journal.pone.0021692 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 793HP UT WOS:000292811300012 PM 21779334 ER PT J AU Srinivasula, S Lempicki, RA Adelsberger, JW Huang, CY Roark, J Lee, PI Rupert, A Stevens, R Sereti, I Lane, HC Di Mascio, M Kovacs, JA AF Srinivasula, Sharat Lempicki, Richard A. Adelsberger, Joseph W. Huang, Chiung-Yu Roark, Joshua Lee, Philip I. Rupert, Adam Stevens, Randy Sereti, Irini Lane, H. Clifford Di Mascio, Michele Kovacs, Joseph A. TI Differential effects of HIV viral load and CD4 count on proliferation of naive and memory CD4 and CD8 T lymphocytes SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; INFECTED PATIENTS; TYPE-1 INFECTION; RHESUS MACAQUES; CELL TURNOVER; KINETICS; TRANSLOCATION; DYNAMICS AB We previously showed that HIV infection leads to expansion of a rapidly proliferating pool (s(1)) of CD4 and CD8 T lymphocytes. In the current study, we used in vivo labeling with bromodeoxyuridine to characterize the kinetics of naive, memory, and activated (HLA-DR(+)/CD38(+)) subpopulations of CD4 and CD8 T lymphocytes, and to examine the relationship between kinetic parameters and baseline CD4 counts, HIV viral load, potential markers of microbial translocation, and cytokine levels. Activated cells showed the highest proliferation rates, followed by effector and central memory cells, with naive cells showing the lowest rates, for both CD4 and CD8 T cells. HIV viral load correlated with s(1) of CD4 and CD8 effector memory cells, as well as CD8 naive cells, whereas CD4 cell counts correlated inversely with naive CD4 s(1). Endotoxin levels showed a weak negative association with CD4 but not CD8 s(1). INF-gamma and TNF-alpha were associated with s(1) for CD4 and CD8 cells, respectively. Thus, HIV is the primary driving force behind the activation and proliferation of most subsets of both CD4 and CD8 T lymphocytes, whereas naive CD4 cell proliferation likely represents a homeostatic response. Microbial translocation does not appear to play an important role in this proliferation. (Blood.2011;118(2):262-270) C1 [Srinivasula, Sharat; Roark, Joshua] NCI, Biostat Res Branch, SAIC Frederick Inc, Frederick, MD 21701 USA. [Lempicki, Richard A.; Adelsberger, Joseph W.; Rupert, Adam; Stevens, Randy] NCI, Appl & Dev Res Directorate, SAIC Frederick Inc, Frederick, MD 21701 USA. [Huang, Chiung-Yu; Di Mascio, Michele] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Lee, Philip I.; Sereti, Irini; Lane, H. Clifford] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH Clin Ctr, Crit Care Med Dept, NIH, Bethesda, MD USA. RP Srinivasula, S (reprint author), 6700A Rockledge Dr,Rm 5227, Bethesda, MD 20817 USA. EM srinivasulas@mail.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Programs of the National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases and supported in part by the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 35 TC 27 Z9 29 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 14 PY 2011 VL 118 IS 2 BP 262 EP 270 DI 10.1182/blood-2011-02-335174 PG 9 WC Hematology SC Hematology GA 792IB UT WOS:000292735100010 PM 21562041 ER PT J AU Hanash, AM Kappel, LW Yim, NL Nejat, RA Goldberg, GL Smith, OM Rao, UK Dykstra, L Na, IK Holland, AM Dudakov, JA Liu, C Murphy, GF Leonard, WJ Heller, G van den Brink, MRM AF Hanash, Alan M. Kappel, Lucy W. Yim, Nury L. Nejat, Rebecca A. Goldberg, Gabrielle L. Smith, Odette M. Rao, Uttam K. Dykstra, Lindsay Na, Il-Kang Holland, Amanda M. Dudakov, Jarrod A. Liu, Chen Murphy, George F. Leonard, Warren J. Heller, Glenn van den Brink, Marcel R. M. TI Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; CHRONIC VIRAL-INFECTION; TUMOR ACTIVITY; INTERLEUKIN-21; LEUKEMIA; CANCER; DIFFERENTIATION; EXPRESSION; ORGAN AB IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastro-intestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity againstA20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes. (Blood. 2011; 118(2): 446-455) C1 [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Zuckerman Res Ctr 1419, Dept Med, New York, NY 10021 USA. [Kappel, Lucy W.; Yim, Nury L.; Nejat, Rebecca A.; Goldberg, Gabrielle L.; Smith, Odette M.; Rao, Uttam K.; Dykstra, Lindsay; Na, Il-Kang; Holland, Amanda M.; Dudakov, Jarrod A.; van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10021 USA. [Kappel, Lucy W.; Holland, Amanda M.; van den Brink, Marcel R. M.] Weill Cornell Med Coll, Dept Immunol & Microbial Pathogenesis, New York, NY USA. [Na, Il-Kang] Charite CBF Univ Med Berlin, Dept Hematol & Oncol, Berlin, Germany. [Liu, Chen] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. [Murphy, George F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Program Dermatopathol, Boston, MA 02115 USA. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Heller, Glenn] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP van den Brink, MRM (reprint author), Mem Sloan Kettering Canc Ctr, Zuckerman Res Ctr 1419, Dept Med, 418 E 69th St, New York, NY 10021 USA. EM vandenbm@mskcc.org OI Murphy, George/0000-0003-3464-793X; Dudakov, Jarrod/0000-0001-6220-5632 FU National Institutes of Health [RO1-HL069929, RO1-CA107096, RO1-AI080455, PO1-CA33049, R01-HL095075]; NHLBI; Lymphoma Foundation; Alex's Lemonade Stand; Leukemia and Lymphoma Society; Ryan Gibson Foundation; Elsa U. Pardee Foundation; Byrne Fund; Emerald Foundation; Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center; Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research FX This work was supported by the National Institutes of Health (awards RO1-HL069929, RO1-CA107096, RO1-AI080455, PO1-CA33049, and R01-HL095075 (M.R.M.v.d.B.), as well the NHLBI Intramural Research Program (W.J.L.) and by the Lymphoma Foundation, Alex's Lemonade Stand, the Leukemia and Lymphoma Society, the Ryan Gibson Foundation, the Elsa U. Pardee Foundation, the Byrne Fund, the Emerald Foundation, and The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by Mr William H. Goodwin and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research (M.R.M.v.d.B.). A. M. Hanash was supported through the Research Training Award for Fellows from the American Society of Hematology. NR 54 TC 33 Z9 35 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 14 PY 2011 VL 118 IS 2 BP 446 EP 455 DI 10.1182/blood-2010-07-294785 PG 10 WC Hematology SC Hematology GA 792IB UT WOS:000292735100031 PM 21596854 ER PT J AU Gu, ZL Yakel, JL AF Gu, Zhenglin Yakel, Jerrel L. TI Timing-Dependent Septal Cholinergic Induction of Dynamic Hippocampal Synaptic Plasticity SO NEURON LA English DT Article ID LONG-TERM POTENTIATION; CENTRAL-NERVOUS-SYSTEM; AMYLOID-BETA-PEPTIDE; ALPHA-7-CONTAINING NICOTINIC RECEPTORS; ALZHEIMERS-DISEASE; ACETYLCHOLINE-RECEPTORS; PYRAMIDAL CELLS; SK CHANNELS; MEMORY; INHIBITION AB Cholinergic modulation of hippocampal synaptic plasticity has been studied extensively by applying receptor agonists or blockers; however, the effect of rapid physiological cholinergic stimuli on plasticity is largely unknown. Here, we report that septal cholinergic input, activated either by electrical stimulation or via an optogenetic approach, induced different types of hippocampal Schaffer collateral (SC) to CA1 synaptic plasticity, depending on the timing of cholinergic input relative to the SC input. When the cholinergic input was activated 100 or 10 ms prior to SC stimulation, it resulted in alpha 7 nAChR-dependent long-term potentiation (LTP) or short-term depression, respectively. When the cholinergic stimulation was delayed until 10 ms after the SC stimulation, a muscarinic AChR-dependent LTP was induced. Moreover, these various forms of plasticity were disrupted by A beta exposure. These results have revealed the remarkable temporal precision of cholinergic functions, providing a novel mechanism for information processing in cholinergic-dependent higher cognitive functions. C1 [Gu, Zhenglin; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX We thank Patricia Lamb for animal genotyping and plasmid preparation, Drs. Negin Martin and Charles Romeo for virus packaging, Dr. James M. Wilson at University of Pennsylvania for providing the AAV serotype 9 helper plasmid, and Charles J. Tucker and Agnus Janoshazi for assistance with fluorescent microscopy. We also thank Drs. Serena Dudek, David Armstrong, Patricia Jensen, and Lutz Birnbaumer for discussions and critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 55 TC 104 Z9 105 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 14 PY 2011 VL 71 IS 1 BP 155 EP 165 DI 10.1016/j.neuron.2011.04.026 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 793FQ UT WOS:000292806200014 PM 21745645 ER PT J AU Burch, LH AF Burch, Lauranell H. TI MUC5B Promoter Polymorphism and Pulmonary Fibrosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Burch, LH (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. EM burchl@niehs.nih.gov NR 2 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2011 VL 365 IS 2 BP 178 EP 178 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 791SP UT WOS:000292685500022 PM 21751916 ER PT J AU Chung, SM Himmel, DM Jiang, JK Wojtak, K Bauman, JD Rausch, JW Wilson, JA Beutler, JA Thomas, CJ Arnold, E Le Grice, SFJ AF Chung, Suhman Himmel, Daniel M. Jiang, Jian-Kang Wojtak, Krzysztof Bauman, Joseph D. Rausch, Jason W. Wilson, Jennifer A. Beutler, John A. Thomas, Craig J. Arnold, Eddy Le Grice, Stuart F. J. TI Synthesis, Activity, and Structural Analysis of Novel alpha-Hydroxytropolone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIV RNASE-H; SMALL-MOLECULE INHIBITORS; MAXIMUM-LIKELIHOOD; CRYSTAL-STRUCTURE; PROTEIN MODELS; MUTATIONS; MECHANISM; ACID; SITE; REPLACEMENT AB The alpha-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating alpha-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51. HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified alpha-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved alpha-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use. C1 [Chung, Suhman; Rausch, Jason W.; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Himmel, Daniel M.; Wojtak, Krzysztof; Bauman, Joseph D.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Himmel, Daniel M.; Wojtak, Krzysztof; Bauman, Joseph D.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Jiang, Jian-Kang; Thomas, Craig J.] NIH Chem Genom Ctr, Rockville, MD 20850 USA. [Wilson, Jennifer A.; Beutler, John A.] NCI, Mol Discovery Program, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM legrices@mail.nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU National Cancer Institute, National Institutes of Health; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; National Human Genome Research Institute; NIH [AI 27690] FX S.C., J.R., J.B., J.W., and S.L.G. are supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. J.J. and C.T. were supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute. D. M.H. and E.A. were supported by NIH MERIT Award AI 27690. NR 53 TC 44 Z9 45 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 14 PY 2011 VL 54 IS 13 BP 4462 EP 4473 DI 10.1021/jm2000757 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 788YF UT WOS:000292479600012 PM 21568335 ER PT J AU Buckholtz, NS AF Buckholtz, Neil S. TI PERSPECTIVE In search of biomarkers SO NATURE LA English DT Editorial Material ID ALZHEIMERS ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; RECOMMENDATIONS; DISEASE C1 NIA, Dementias Aging Branch, Div Neurosci, Bethesda, MD 20892 USA. RP Buckholtz, NS (reprint author), NIA, Dementias Aging Branch, Div Neurosci, Bethesda, MD 20892 USA. EM buckholn@nia.nih.gov NR 3 TC 15 Z9 15 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 14 PY 2011 VL 475 IS 7355 BP S8 EP S8 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791UA UT WOS:000292690500004 PM 21760582 ER PT J AU Hunt, PR Son, TG Wilson, MA Yu, QS Wood, WH Zhang, YQ Becker, KG Greig, NH Mattson, MP Camandola, S Wolkow, CA AF Hunt, Piper R. Son, Tae Gen Wilson, Mark A. Yu, Quian-Sheng Wood, William H. Zhang, Yongqing Becker, Kevin G. Greig, Nigel H. Mattson, Mark P. Camandola, Simonetta Wolkow, Catherine A. TI Extension of Lifespan in C. elegans by Naphthoquinones That Act through Stress Hormesis Mechanisms SO PLOS ONE LA English DT Article ID NEMATODE CAENORHABDITIS-ELEGANS; HEAT-SHOCK PROTEINS; OXIDATIVE-STRESS; SACCHAROMYCES-CEREVISIAE; ADAPTIVE RESPONSE; GENE-EXPRESSION; FACTOR SKN-1; LONGEVITY; RESISTANCE; DAF-16 AB Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap'n'collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway. C1 [Hunt, Piper R.; Son, Tae Gen; Wilson, Mark A.; Mattson, Mark P.; Camandola, Simonetta; Wolkow, Catherine A.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Yu, Quian-Sheng; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wood, William H.; Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hunt, PR (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM camandolasi@grc.nia.nih.gov; wolkowca@gmail.com RI Mattson, Mark/F-6038-2012; Hunt, Piper/G-1555-2012; OI Hunt, Piper/0000-0003-0538-7606; Becker, Kevin/0000-0002-6794-6656 FU National Institute of Aging [Z01 AG000320] FX This work was funded by the National Institute of Aging Intramural Research Program, Z01 AG000320. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 23 Z9 26 U1 1 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 13 PY 2011 VL 6 IS 7 AR e21922 DI 10.1371/journal.pone.0021922 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 792WQ UT WOS:000292781500023 PM 21765926 ER PT J AU Ma, BY Tsai, CJ Haliloglu, T Nussinov, R AF Ma, Buyong Tsai, Chung-Jung Haliloglu, Turkan Nussinov, Ruth TI Dynamic Allostery: Linkers Are Not Merely Flexible SO STRUCTURE LA English DT Review ID MEDIATOR SUBUNIT MED1/TRAP220; HSP70 MOLECULAR CHAPERONES; SCF UBIQUITIN LIGASE; GLUCOCORTICOID-RECEPTOR; ENERGY LANDSCAPE; DNA-BINDING; TRANSCRIPTIONAL ACTIVATION; CONFORMATIONAL SELECTION; DIHYDROFOLATE-REDUCTASE; STRUCTURAL INSIGHTS AB Most proteins consist of multiple domains. How do linkers efficiently transfer information between sites that are on different domains to activate the protein? Mere flexibility only implies that the conformations would be sampled. For fast timescales between triggering events and cellular response, which often involves large conformational change, flexibility on its own may not constitute a good solution. We posit that successive conformational states along major allosteric propagation pathways are pre-encoded in linker sequences where each state is encoded by the previous one. The barriers between these states that are hierarchically populated are lower, achieving faster timescales even for large conformational changes. We further propose that evolution has optimized the linker sequences and lengths for efficiency, which explains why mutations in linkers may affect protein function and review the literature in this light. C1 [Ma, Buyong; Tsai, Chung-Jung; Nussinov, Ruth] NCI Frederick, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Haliloglu, Turkan] Bogazici Univ, Polymer Res Ctr, TR-34342 Bebek, Turkey. [Haliloglu, Turkan] Bogazici Univ, Dept Chem Engn, TR-34342 Bebek, Turkey. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI Frederick, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU TUBA (Turkish Academy of Sciences); State Planning organization DPT [2009K120520]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX T.H. acknowledges support from TUBA (Turkish Academy of Sciences) and State Planning organization DPT (2009K120520). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 117 TC 109 Z9 109 U1 6 U2 55 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUL 13 PY 2011 VL 19 IS 7 BP 907 EP 917 DI 10.1016/j.str.2011.06.002 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 792ZO UT WOS:000292789300004 PM 21742258 ER PT J AU Schweimer, K Prasch, S Sujatha, PS Bubunenko, M Gottesman, ME Rosch, P AF Schweimer, Kristian Prasch, Stefan Sujatha, Pagadala Santhanam Bubunenko, Mikhail Gottesman, Max E. Roesch, Paul TI NusA Interaction with the alpha Subunit of E-coli RNA Polymerase Is via the UP Element Site and Releases Autoinhibition SO STRUCTURE LA English DT Article ID ESCHERICHIA-COLI NUSA; ELONGATION-FACTOR NUSA; CARBOXY-TERMINAL DOMAINS; PROTEIN CONTACT SITE; LAMBDA N PROTEIN; DNA-BINDING; PHAGE-LAMBDA; MYCOBACTERIUM-TUBERCULOSIS; TRANSCRIPTION TERMINATION; CRYSTAL-STRUCTURE AB Elongating Escherichia coli RNAP is modulated by NusA protein. The C-terminal domain (CTD) of the RNAP alpha subunit (alpha CTD) interacts with the acidic CTD 2 (AR2) of NusA, releasing the autoinhibitory blockade of the NusA S1-KH1-KH2 motif and allowing NusA to bind nascent nut spacer RNA. We determined the solution conformation of the AR2:alpha CTD complex. The alpha CTD residues that interface with AR2 are identical to those that recognize UP promoter elements A nusA-Delta AR2 mutation does not affect UP-dependent rrnH transcription initiation in vivo. Instead, the mutation inhibits Rho-dependent transcription termination at phage gamma tR1, which lies adjacent to the gamma nutR sequence. The Rho-dependent gamma timm terminator, which is not preceded by a nut sequence, is fully functional. We propose that constitutive binding of NusA-Delta AR2 to gamma nutR occludes Rho. In addition, the mutation confers a dominant defect in exiting stationary phase. C1 [Gottesman, Max E.] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Schweimer, Kristian; Prasch, Stefan; Sujatha, Pagadala Santhanam; Roesch, Paul] Univ Bayreuth, Lehrstuhl Biopolymere, D-95447 Bayreuth, Germany. [Schweimer, Kristian; Prasch, Stefan; Sujatha, Pagadala Santhanam; Roesch, Paul] Univ Bayreuth, Forschungszentrum Biomakromol, D-95447 Bayreuth, Germany. [Bubunenko, Mikhail] NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Bubunenko, Mikhail] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Gottesman, Max E.] Columbia Univ, Med Ctr, Inst Canc Res, New York, NY 10032 USA. RP Gottesman, ME (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. EM meg8@columbia.edu; roesch@unibt.de RI Rosch, Paul/I-5445-2014 OI Rosch, Paul/0000-0003-3330-2446 FU Deutsche Forschungsgemeinschaft [Ro617/17-1]; NIH [GM037219]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Trans National Institutes of Health/Food and Drug Administration; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Financial support by the Deutsche Forschungsgemeinschaft to PR (Ro617/17-1) and by NIH to M.E.G. (GM037219) is gratefully acknowledged. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and in part by a Trans National Institutes of Health/Food and Drug Administration Intramural Biodefense Program Grant of National Institutes of Allergy and Infectious Disease (to Donald L. Court). This project has been also partly funded 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 16 Z9 16 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 13 PY 2011 VL 19 IS 7 BP 945 EP 954 DI 10.1016/j.str.2011.03.024 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 792ZO UT WOS:000292789300007 PM 21742261 ER PT J AU Ziogas, A Horick, NK Kinney, AY Lowery, JT Domchek, SM Isaacs, C Griffin, CA Moorman, PG Edwards, KL Hill, DA Berg, JS Tomlinson, GE Anton-Culver, H Strong, LC Kasten, CH Finkelstein, DM Plon, SE AF Ziogas, Argyrios Horick, Nora K. Kinney, Anita Y. Lowery, Jan T. Domchek, Susan M. Isaacs, Claudine Griffin, Constance A. Moorman, Patricia G. Edwards, Karen L. Hill, Deirdre A. Berg, Jonathan S. Tomlinson, Gail E. Anton-Culver, Hoda Strong, Louise C. Kasten, Carol H. Finkelstein, Dianne M. Plon, Sharon E. TI Clinically Relevant Changes in Family History of Cancer Over Time SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BREAST-CANCER; COLORECTAL-CANCER; HIGH-RISK; INHERITANCE; ONSET; WOMEN AB Context Knowledge of family cancer history is important for assessing cancer risk and guiding screening recommendations. Objective To quantify how often throughout adulthood clinically significant changes occur in cancer family history that would result in recommendations for earlier or intense screening. Design and Setting Descriptive study examining baseline and follow-up family history data from participants in the Cancer Genetics Network (CGN), a US national population-based cancer registry, between 1999 and 2009. Participants Adults with a personal history, family history, or both of cancer enrolled in the CGN through population-based cancer registries. Retrospective colorectal, breast, and prostate cancer screening-specific analyses included 9861, 2547, and 1817 participants, respectively; prospective analyses included 1533, 617, and 163 participants, respectively. Median follow-up was 8 years (range, 0-11 years). Screening-specific analyses excluded participants with the cancer of interest. Main Outcome Measures Percentage of individuals with clinically significant family histories and rate of change over 2 periods: (1) retrospectively, from birth until CGN enrollment and (2) prospectively, from enrollment to last follow-up. Results Retrospective analysis revealed that the percentages of participants who met criteria for high-risk screening based on family history at ages 30 and 50 years, respectively, were as follows: for colorectal cancer, 2.1% (95% confidence interval [CI], 1.8%-2.4%) and 7.1%(95% CI, 6.5%-7.6%); for breast cancer, 7.2%(95% CI, 6.1%-8.4%) and 11.4% (95% CI, 10.0%-12.8%); and for prostate cancer, 0.9%(95% CI, 0.5%-1.4%) and 2.0% (95% CI, 1.4%-2.7%). In prospective analysis, the numbers of participants who newly met criteria for high-risk screening based on family history per 100 persons followed up for 20 years were 2 (95% CI, 0-7) for colorectal cancer, 6 (95% CI, 2-13) for breast cancer, and 8 (95% CI, 3-16) for prostate cancer. The rate of change in cancer family history was similar for colorectal and breast cancer between the 2 analyses. Conclusion Clinically relevant family history of colorectal, breast, and prostate cancer that would result in recommendations for earlier or intense cancer screening increases between ages 30 and 50 years, although the absolute rate is low for prostate cancer. JAMA. 2011; 306(2): 172-178 C1 [Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Irvine, CA 92717 USA. [Horick, Nora K.; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Finkelstein, Dianne M.] Harvard Univ, Boston, MA 02115 USA. [Kinney, Anita Y.] Huntsman Canc Inst, Salt Lake City, UT USA. [Kinney, Anita Y.] Univ Utah, Salt Lake City, UT USA. [Lowery, Jan T.] Univ Colorado, Aurora, CO USA. [Domchek, Susan M.] Univ Penn, Philadelphia, PA 19104 USA. [Isaacs, Claudine] Georgetown Univ, Washington, DC USA. [Griffin, Constance A.] Johns Hopkins Univ, Baltimore, MD USA. [Moorman, Patricia G.] Duke Univ, Med Ctr, Durham, NC USA. [Edwards, Karen L.] Univ Washington, Seattle, WA 98195 USA. [Hill, Deirdre A.] Univ New Mexico, Albuquerque, NM 87131 USA. [Berg, Jonathan S.] Univ N Carolina, Chapel Hill, NC USA. [Tomlinson, Gail E.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Tomlinson, Gail E.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Strong, Louise C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Plon, Sharon E.] Baylor Coll Med, Houston, TX 77030 USA. [Kasten, Carol H.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Finkelstein, DM (reprint author), 50 Staniford St,Ste 560, Boston, MA 02114 USA. EM dfinkel-stein@partners.org FU National Cancer Institute [U01CA078284, U24CA078134, U24CA078164, U24CA078156, U24CA078148, U24CA078146, U24CA078174, U24CA078157, U24CA078142, HHSN2612007440000C] FX The CGN is supported by grants U01CA078284, U24CA078134, U24CA078164, U24CA078156, U24CA078148, U24CA078146, U24CA078174, U24CA078157, and U24CA078142 and contract HHSN2612007440000C from the National Cancer Institute. NR 21 TC 16 Z9 17 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 13 PY 2011 VL 306 IS 2 BP 172 EP 178 DI 10.1001/jama.2011.955 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 791CO UT WOS:000292639400024 PM 21750294 ER PT J AU Suffredini, AF Munford, RS AF Suffredini, Anthony F. Munford, Robert S. TI Novel Therapies for Septic Shock Over the Past 4 Decades SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GRAM-NEGATIVE BACTEREMIA; ACTIVATED PROTEIN-C; RANDOMIZED CONTROLLED-TRIAL; ILL ADULT PATIENTS; SEVERE SEPSIS; SURVIVING SEPSIS; SYSTEMIC INFLAMMATION; ENDOTOXIN; CAMPAIGN; EFFICACY AB Infections that result in shock and organ failure are a major public health problem worldwide. Severe sepsis and septic shock affect patients of all ages and often complicate chronic diseases. They are the major causes of death in critical care units and contribute substantially to hospital inpatient costs. Translating the scientific advances of the last 4 decades into clinical practice has been challenging. Despite many attempts to develop new therapies, the basic elements of treatment have not changed since the 1960s. In this Grand Rounds, we summarize the results of the clinical trials conducted during the last 4 decades, discuss some lessons learned, and suggest possible directions for future investigation. JAMA. 2011;306(2):194-199 www.jama.com C1 [Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Munford, Robert S.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Suffredini, AF (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM asuffredini@cc.nih.gov FU Clinical Center, Intramural Research and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by the Clinical Center, Intramural Research Program and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 49 TC 47 Z9 52 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 13 PY 2011 VL 306 IS 2 BP 194 EP 199 DI 10.1001/jama.2011.909 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 791CO UT WOS:000292639400027 PM 21750297 ER PT J AU Cereda, V Vergati, M Huen, NY di Bari, MG Jochems, C Intrivici, C Gulley, JL Apelian, D Schlom, J Tsang, KY AF Cereda, Vittore Vergati, Matteo Huen, Ngar-Yee di Bari, Maria Giovanna Jochems, Caroline Intrivici, Chiara Gulley, James L. Apelian, David Schlom, Jeffrey Tsang, Kwong Y. TI Maturation of human dendritic cells with Saccharomyces cerevisiae (yeast) reduces the number and function of regulatory T cells and enhances the ratio of antigen-specific effectors to regulatory T cells SO VACCINE LA English DT Article DE Saccharomyces cerevisiae; Regulatory T cells; Human dendritic cells ID WHOLE RECOMBINANT YEAST; PERIPHERAL-BLOOD; CARCINOEMBRYONIC ANTIGEN; COSTIMULATORY MOLECULES; IMMUNE TOLERANCE; FOXP3 EXPRESSION; TUMOR-ANTIGENS; GENE-TRANSFER; CANCER; RESPONSES AB We compared the effects of yeast-treated human dendritic cells (DCs) with CD40L-matured human DCs for the induction of effector cells and the number and functionality of CD4(+)CD25(+)CD127(-)FoxP3(+) regulatory T cells (Tregs). DCs were treated with yeast or CD40L and cocultured with isolated autologous CD4(+) T cells. CD4(+)CD25(+)CD127(-) T cells isolated from the coculture of CD4(+) T cells plus yeast-treated DCs (yeast coculture) had a lower expression of FoxP3 and decreased suppressive function compared to CD4(+)CD25(+)CD127(-) T cells isolated from the coculture of CD4(+) T cells plus CD40L-treated DCs (CD40L coculture). Also, compared to the CD4OL coculture, the yeast coculture showed increases in the ratio of CD4(+)CD25(+) activated T cells to Tregs and in the production of Th1-related cytokines (IL-2, TNF-alpha, IFN-gamma) and IL-6. In addition, yeast-treated DCs used as antigen-presenting cells (APCs) incubated with the tumor antigen CEA enhanced the proliferation of CEA-specific CD4(+) T cells compared to the use of CD40L-matured DCs used as APCs. This is the first study to report on the role of yeast-treated/matured human DCs in reducing Treg frequency and functionality and in enhancing effector to Treg ratios. These results provide an additional rationale for the use of yeast as a vector in cancer vaccines. Published by Elsevier Ltd. C1 [Cereda, Vittore; Vergati, Matteo; Huen, Ngar-Yee; di Bari, Maria Giovanna; Jochems, Caroline; Intrivici, Chiara; Gulley, James L.; Schlom, Jeffrey; Tsang, Kwong Y.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Apelian, David] GlobeImmune Inc, Louisville, CO USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Center for Cancer Research, National Cancer Institute, NIH FX Grant support: Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 50 TC 10 Z9 10 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 12 PY 2011 VL 29 IS 31 BP 4992 EP 4999 DI 10.1016/j.vaccine.2011.04.101 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 796HX UT WOS:000293043500016 PM 21569810 ER PT J AU Yao, X Hamilton, RG Weng, NP Xue, QL Bream, JH Li, HF Tian, J Yeh, SH Resnick, B Xu, XY Walston, J Fried, LP Leng, SX AF Yao, Xu Hamilton, Robert G. Weng, Nan-ping Xue, Qian-Li Bream, Jay H. Li, Huifen Tian, Jing Yeh, Shu-Hui Resnick, Barbara Xu, Xiyan Walston, Jeremy Fried, Linda P. Leng, Sean X. TI Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults SO VACCINE LA English DT Article DE Frailty; Influenza immunization; Antibody response; Influenza infection; Influenza-like illness; Older adults ID CELLULAR IMMUNE-RESPONSES; MORTALITY BENEFITS; CONTROLLED TRIAL; SERUM INTERLEUKIN-6; GERIATRIC SYNDROME; ELDERLY-PEOPLE; UNITED-STATES; INFLAMMATION; PROTECTION; WOMEN AB Annual immunization with a trivalent inactivated vaccine (TIV) is considered efficacious for prevention of seasonal influenza in older adults. However, significant controversy exists in the current literature regarding the clinical effectiveness of TIV immunization in this highly heterogeneous population. Frailty is an important geriatric syndrome characterized by decreased physiologic reserve and increased vulnerability to stressors. Using a validated set of frailty criteria, we conducted a prospective observational study to evaluate TIV-induced strain-specific hemagglutination inhibition (HI) antibody titers and post-vaccination rates of influenza-like illness (ILI) and infection in frail and nonfrail older adults. The results indicate that frailty was associated with significant impairment in TIV-induced strain-specific HI titers and increased rates of ILI and laboratory-confirmed influenza infection. These findings suggest that assessing frailty status in the elderly may identify those who are less likely to respond to TIV immunization and be at higher risk for seasonal influenza and its complications. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Yao, Xu; Xue, Qian-Li; Li, Huifen; Tian, Jing; Walston, Jeremy; Leng, Sean X.] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med, Baltimore, MD 21224 USA. [Yao, Xu; Xue, Qian-Li; Li, Huifen; Tian, Jing; Walston, Jeremy; Leng, Sean X.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21224 USA. [Bream, Jay H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Resnick, Barbara] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [Xu, Xiyan] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Leng, SX (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Div Geriatr Med & Gerontol,Dept Med, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM sleng1@jhmi.edu FU National Institute on Aging; American Federation for Aging Research; John A. Hartford Foundation; Atlantic Philanthropies; Starr Foundation FX Sean Leng is a current recipient of the Paul Beeson Career Development Award in Aging Research, K23 AG028963, (supported by the National Institute on Aging, the American Federation for Aging Research, The John A. Hartford Foundation, The Atlantic Philanthropies, The Starr Foundation and an anonymous donor). NR 45 TC 39 Z9 40 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 12 PY 2011 VL 29 IS 31 BP 5015 EP 5021 DI 10.1016/j.vaccine.2011.04.077 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 796HX UT WOS:000293043500019 PM 21565245 ER PT J AU Koshiol, J Gulley, ML Zhao, Y Rubagotti, M Marincola, FM Rotunno, M Tang, W Bergen, AW Bertazzi, PA Roy, D Pesatori, AC Linnoila, I Dittmer, D Goldstein, AM Caporaso, NE McShane, LM Wang, E Landi, MT AF Koshiol, J. Gulley, M. L. Zhao, Y. Rubagotti, M. Marincola, F. M. Rotunno, M. Tang, W. Bergen, A. W. Bertazzi, P. A. Roy, D. Pesatori, A. C. Linnoila, I. Dittmer, D. Goldstein, A. M. Caporaso, N. E. McShane, L. M. Wang, E. Landi, M. T. TI Epstein-Barr virus microRNAs and lung cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE Epstein-Barr virus; lung cancer; microRNA; microarray; qPCR ID PRIMARY EFFUSION LYMPHOMA; PARAFFIN-EMBEDDED TISSUE; IN-SITU HYBRIDIZATION; CELL-LINES; EXPRESSION; CARCINOMAS; SURVIVAL; INFLAMMATION; ANTIBODIES; NEOPLASMS AB BACKGROUND: We conducted the first analysis of viral microRNAs (miRNAs) in lung cancer, with a focus on Epstein-Barr virus (EBV). METHODS: We evaluated viral miRs with a two-channel oligo-array targeting mature, anti-sense miRNAs in 290 cases. In 48 cases, we compared microarray and real-time quantitative PCR (qPCR) expression for three EBV miRNAs. We tested for EBV DNA, RNA, and protein in tumour tissue from six cases with and six cases without strong qPCR-based evidence of EBV miRNAs. RESULTS: The EBV miRNAs strongly differentiated between adenocarcinoma and squamous cell carcinoma using the microarray (P<0.01 for 9 out of 16 EBV miRNAs). However, microarray and qPCR measurements of BART1, BART2, and BHRF1-3 expression were not significantly correlated (P = 0.53, 0.94, and 0.47, respectively). Although qPCR provided substantial evidence of EBV miRNAs in 7 out of 48 cases, only 1 of these 7 cases had detectable EBV DNA in tumour tissue. None had detectable EBV RNA or protein by histochemical stains. CONCLUSION: In a comprehensive evaluation of EBV miRNA, DNA, RNA, and protein in lung cancer, we found little evidence of EBV in lung tumour tissue. Discrepancies between microarray- and qPCR-based strategies highlight the difficulty of validating molecular markers of disease. Our results do not support a role of EBV in lung cancer. British Journal of Cancer (2011) 105, 320-326. doi: 10.1038/bjc.2011.221 www.bjcancer.com Published online 7 June 2011 (C) 2011 Cancer Research UK C1 [Koshiol, J.; Goldstein, A. M.; Caporaso, N. E.; Landi, M. T.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gulley, M. L.; Tang, W.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Gulley, M. L.; Tang, W.] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC USA. [Zhao, Y.; McShane, L. M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rubagotti, M.; Bertazzi, P. A.; Pesatori, A. C.] Univ Milan, Dept Occupat & Environm Hlth, EPOCA Epidemiol Res Ctr, Milan, Italy. [Rubagotti, M.; Bertazzi, P. A.; Pesatori, A. C.; Wang, E.] Fdn IRCCS Osped Maggiore Policlin, Epidemiol Unit, Milan, Italy. [Marincola, F. M.] NIH, IDIS, Dept Transfus Med, Ctr Clin,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rotunno, M.; Dittmer, D.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bergen, A. W.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Roy, D.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Linnoila, I.] NIH, Natl Inst Hlth Clin Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Marincola, F. M.] NIH, CHI, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Koshiol, J (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov RI bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Bergen, Andrew/0000-0002-1237-7644; pesatori, angela/0000-0002-0261-3252 FU NCI NIH HHS [P01 CA019014] NR 49 TC 8 Z9 9 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 12 PY 2011 VL 105 IS 2 BP 320 EP 326 DI 10.1038/bjc.2011.221 PG 7 WC Oncology SC Oncology GA 791SE UT WOS:000292684200018 PM 21654679 ER PT J AU Bergsagel, PL Kuehl, WM AF Bergsagel, P. Leif Kuehl, W. Michael TI Comprehensive Identification of Somatic Mutations in Chronic Lymphocytic Leukemia SO CANCER CELL LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; DNMT3A; GENOME C1 [Kuehl, W. Michael] NCI, Genet Branch, Bethesda, MD 20892 USA. [Bergsagel, P. Leif] Mayo Clin Arizona, Comprehens Canc Ctr, Scottsdale, AZ USA. RP Kuehl, WM (reprint author), NCI, Genet Branch, Bethesda, MD 20892 USA. EM wmk@helix.nih.gov FU Intramural NIH HHS [Z99 CA999999, ZIA BC010910-03]; NCI NIH HHS [R01 CA133966]; NIA NIH HHS [R01 AG020686] NR 9 TC 3 Z9 3 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 12 PY 2011 VL 20 IS 1 BP 5 EP 7 DI 10.1016/j.ccr.2011.06.023 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 793CK UT WOS:000292797800003 PM 21741593 ER PT J AU Gupta, N Stopfer, M AF Gupta, Nitin Stopfer, Mark TI Olfactory Coding: Giant Inhibitory Neuron Governs Sparse Odor Codes SO CURRENT BIOLOGY LA English DT Editorial Material ID MUSHROOM BODY; SYSTEM; OSCILLATIONS; INTERNEURON; LOCUST; CORTEX AB Electrophysiological investigations in locusts have revealed that the sparseness of odor representations, in the brain region expected to mediate olfactory learning, is shaped by a unique inhibitory neuron. C1 [Gupta, Nitin; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. RP Gupta, N (reprint author), NICHHD, NIH, Bldg 35,35 Lincoln Dr,Rm 3A-102,Msc 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov OI Gupta, Nitin/0000-0002-8408-3848 NR 14 TC 2 Z9 2 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUL 12 PY 2011 VL 21 IS 13 BP R504 EP R506 DI 10.1016/j.cub.2011.05.044 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 793FI UT WOS:000292805400010 PM 21741586 ER PT J AU Shiao, YH Leighty, RM Wang, CJ Ge, X Crawford, EB Spurrier, JM McCann, SD Fields, JR Fornwald, L Riffle, L Driver, C Quinones, OA Wilson, RE Kasprzak, KS Travlos, GS Alvord, WG Anderson, LM AF Shiao, Yih-Horng Leighty, Robert M. Wang, Cuiju Ge, Xin Crawford, Erik B. Spurrier, Joshua M. McCann, Sean D. Fields, Janet R. Fornwald, Laura Riffle, Lisa Driver, Craig Quinones, Octavio A. Wilson, Ralph E. Kasprzak, Kazimierz S. Travlos, Gregory S. Alvord, W. Gregory Anderson, Lucy M. TI Ontogeny-Driven rDNA Rearrangement, Methylation, and Transcription, and Paternal Influence SO PLOS ONE LA English DT Article ID RNA-POLYMERASE-I; RIBOSOMAL-RNA; EPIGENETIC INHERITANCE; GENE-EXPRESSION; EVOLUTION; MICE; MECHANISMS; COMPONENT; PROMOTER; DISEASE AB Gene rearrangement occurs during development in some cell types and this genome dynamics is modulated by intrinsic and extrinsic factors, including growth stimulants and nutrients. This raises a possibility that such structural change in the genome and its subsequent epigenetic modifications may also take place during mammalian ontogeny, a process undergoing finely orchestrated cell division and differentiation. We tested this hypothesis by comparing single nucleotide polymorphism-defined haplotype frequencies and DNA methylation of the rDNA multicopy gene between two mouse ontogenic stages and among three adult tissues of individual mice. Possible influences to the genetic and epigenetic dynamics by paternal exposures were also examined for Cr(III) and acid saline extrinsic factors. Variables derived from litters, individuals, and duplicate assays in large mouse populations were examined using linear mixed-effects model. We report here that active rDNA rearrangement, represented by changes of haplotype frequencies, arises during ontogenic progression from day 8 embryos to 6-week adult mice as well as in different tissue lineages and is modifiable by paternal exposures. The rDNA methylation levels were also altered in concordance with this ontogenic progression and were associated with rDNA haplotypes. Sperm showed highest level of methylation, followed by lungs and livers, and preferentially selected haplotypes that are positively associated with methylation. Livers, maintaining lower levels of rDNA methylation compared with lungs, expressed more rRNA transcript. In vitro transcription demonstrated haplotype-dependent rRNA expression. Thus, the genome is also dynamic during mammalian ontogeny and its rearrangement may trigger epigenetic changes and subsequent transcriptional controls, that are further influenced by paternal exposures. C1 [Shiao, Yih-Horng; Wang, Cuiju; Crawford, Erik B.; Spurrier, Joshua M.; McCann, Sean D.; Fields, Janet R.; Kasprzak, Kazimierz S.; Anderson, Lucy M.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. [Leighty, Robert M.; Quinones, Octavio A.; Alvord, W. Gregory] Data Management Serv Inc, Frederick, MD USA. [Ge, Xin; Fornwald, Laura; Riffle, Lisa; Driver, Craig] Sci Applicat Int Corp Frederick, Frederick, MD USA. [Wilson, Ralph E.; Travlos, Gregory S.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Shiao, YH (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. EM shiaoy@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. 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 35 TC 8 Z9 8 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 12 PY 2011 VL 6 IS 7 AR e22266 DI 10.1371/journal.pone.0022266 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791WM UT WOS:000292699000034 PM 21765958 ER PT J AU Stone, N Pangilinan, F Molloy, AM Shane, B Scott, JM Ueland, PM Mills, JL Kirke, PN Sethupathy, P Brody, LC AF Stone, Nicole Pangilinan, Faith Molloy, Anne M. Shane, Barry Scott, John M. Ueland, Per Magne Mills, James L. Kirke, Peader N. Sethupathy, Praveen Brody, Lawrence C. TI Bioinformatic and Genetic Association Analysis of MicroRNA Target Sites in One-Carbon Metabolism Genes SO PLOS ONE LA English DT Article ID NEURAL-TUBE DEFECTS; METHYLENETETRAHYDROFOLATE REDUCTASE; CHROMOSOMAL LOCALIZATION; MICROBIOLOGICAL ASSAY; METHIONINE SYNTHASE; FOLATE-DEFICIENCY; CELLULAR UPTAKE; MITOCHONDRIAL; EXPRESSION; RECEPTOR AB One-carbon metabolism (OCM) is linked to DNA synthesis and methylation, amino acid metabolism and cell proliferation. OCM dysfunction has been associated with increased risk for various diseases, including cancer and neural tube defects. MicroRNAs (miRNAs) are similar to 22 nt RNA regulators that have been implicated in a wide array of basic cellular processes, such as differentiation and metabolism. Accordingly, mis-regulation of miRNA expression and/or activity can underlie complex disease etiology. We examined the possibility of OCM regulation by miRNAs. Using computational miRNA target prediction methods and Monte-Carlo based statistical analyses, we identified two candidate miRNA "master regulators" (miR-22 and miR-125) and one candidate pair of "master co-regulators" (miR-344-5p/484 and miR-488) that may influence the expression of a significant number of genes involved in OCM. Interestingly, miR-22 and miR-125 are significantly up-regulated in cells grown under low-folate conditions. In a complementary analysis, we identified 15 single nucleotide polymorphisms (SNPs) that are located within predicted miRNA target sites in OCM genes. We genotyped these 15 SNPs in a population of healthy individuals (age 18-28, n = 2,506) that was previously phenotyped for various serum metabolites related to OCM. Prior to correction for multiple testing, we detected significant associations between TCblR rs9426 and methylmalonic acid (p = 0.045), total homocysteine levels (tHcy) (p = 0.033), serum B12 (p < 0.0001), holo transcobalamin (p < 0.0001) and total transcobalamin (p < 0.0001); and between MTHFR rs1537514 and red blood cell folate (p < 0.0001). However, upon further genetic analysis, we determined that in each case, a linked missense SNP is the more likely causative variant. Nonetheless, our Monte-Carlo based in silico simulations suggest that miRNAs could play an important role in the regulation of OCM. C1 [Stone, Nicole; Pangilinan, Faith; Sethupathy, Praveen; Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Molloy, Anne M.; Scott, John M.] Trinity Coll Dublin, Sch Immunol & Biochem, Dublin, Ireland. [Shane, Barry] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Ueland, Per Magne] Univ Bergen, Pharmacol Sect, Inst Med, Bergen, Norway. [Ueland, Per Magne] Univ Bergen, Haukeland Univ Hosp, Bergen, Norway. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Kirke, Peader N.] Hlth Res Board Ireland, Child Hlth Epidemiol Unit, Dublin, Ireland. RP Stone, N (reprint author), Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA. EM sethupathyp@mail.nih.gov; lbrody@mail.nih.gov RI Ueland, Per/C-7340-2013; OI Molloy, Anne/0000-0002-1688-9049 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute FX This study was supported by the Intramural Research Programs of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Human Genome Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 13 Z9 17 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 12 PY 2011 VL 6 IS 7 AR e21851 DI 10.1371/journal.pone.0021851 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791WM UT WOS:000292699000013 PM 21765920 ER PT J AU Engel, A Shewmaker, F Edskes, HK Dyda, F Wickner, RB AF Engel, Abbi Shewmaker, Frank Edskes, Herman K. Dyda, Fred Wickner, Reed B. TI Amyloid of the Candida albicans Ure2p Prion Domain Is Infectious and Has an In-Register Parallel beta-Sheet Structure SO BIOCHEMISTRY LA English DT Article ID SOLID-STATE NMR; SACCHAROMYCES-CEREVISIAE; YEAST PRION; SUP35 PROTEIN; PSI+ PRION; PROPAGATION; GENERATION; CHAPERONE; HSP104; CONSERVATION AB Ure2p of Candida albicans (Ure2(albicans) or CaUre2p) can be a prion in Saccharomyces cerevisiae, but Ure2p of Candida glabrata (Ure2(glabrata)) cannot, even though the Ure2(glabrata) N-terminal. domain is more similar to that of the S. cerevisiae Ure2p (Ure2(cerevisiae)) than Ure2(albicans) is. We show that the N-terminal N/Q-rich prion domain of Ure2(albicans) forms amyloid that is infectious, transmitting [URE3alb] to S. cerevisiae cells expressing only C. albicans Ure2p. Using solid-state nuclear magnetic resonance of selectively labeled C. albicans Ure2p(1-9), we show that this infectious amyloid has an in-register parallel beta-sheet structure, like that of the S. cerevisiae Ure2p prion domain and other S. cerevisiae prion amyloids. In contrast, the N/Q-rich N-terminal domain of Ure2(glabrata) does not readily form amyloid, and that formed upon prolonged incubation is not infectious. C1 [Engel, Abbi; Shewmaker, Frank; Edskes, Herman K.; Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Engel, Abbi] Georgetown Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20057 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 64 TC 12 Z9 15 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 12 PY 2011 VL 50 IS 27 BP 5971 EP 5978 DI 10.1021/bi200142x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 788FK UT WOS:000292430600001 PM 21634787 ER PT J AU Sharma, S Findlay, GM Bandukwala, HS Oberdoerffer, S Baust, B Li, ZG Schmidt, V Hogan, PG Sacks, DB Rao, A AF Sharma, Sonia Findlay, Gregory M. Bandukwala, Hozefa S. Oberdoerffer, Shalini Baust, Beate Li, Zhigang Schmidt, Valentina Hogan, Patrick G. Sacks, David B. Rao, Anjana TI Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LONG NONCODING RNAS; GENE-EXPRESSION; CHROMATIN; IQGAP1; COACTIVATOR; CALCIUM; BINDING; FAMILY AB Nuclear factor of activated T cells (NFAT) proteins are Ca(2+)-regulated transcription factors that control gene expression in many cell types. NFAT proteins are heavily phosphorylated and reside in the cytoplasm of resting cells; when cells are stimulated by a rise in intracellular Ca(2+), NFAT proteins are dephosphorylated by the Ca(2+)/calmodulin-dependent phosphatase calcineurin and translocate to the nucleus to activate target gene expression. Here we show that phosphorylated NFAT1 is present in a large cytoplasmic RNA-protein scaffold complex that contains a long intergenic noncoding RNA (lincRNA), NRON [noncoding (RNA) repressor of NFAT]; a scaffold protein, IQ motif containing GTPase activating protein (IQGAP); and three NFAT kinases, casein kinase 1, glycogen synthase kinase 3, and dual specificity tyrosine phosphorylation regulated kinase. Combined knockdown of NRON and IQGAP1 increased NFAT dephosphorylation and nuclear import exclusively after stimulation, without affecting the rate of NFAT rephosphorylation and nuclear export; and both NRON-depleted T cells and T cells from IQGAP1-deficient mice showed increased production of NFAT-dependent cytokines. Our results provide evidence that a complex of lincRNA and protein forms a scaffold for a latent transcription factor and its regulatory kinases, and support an emerging consensus that lincRNAs that bind transcriptional regulators have a similar scaffold function. C1 [Sharma, Sonia; Findlay, Gregory M.; Bandukwala, Hozefa S.; Oberdoerffer, Shalini; Baust, Beate; Hogan, Patrick G.; Rao, Anjana] Harvard Univ, Sch Med, Immune Dis Inst, Dept Pathol, Boston, MA 02115 USA. [Sharma, Sonia; Findlay, Gregory M.; Bandukwala, Hozefa S.; Oberdoerffer, Shalini; Baust, Beate; Hogan, Patrick G.; Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Schmidt, Valentina] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM arao@idi.harvard.edu OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health (NIH) [AI40127, AI84167, CA93645, DK62040]; American Cancer Society; Canadian Institutes of Health Research; Leukemia and Lymphoma Society; Lady Tata Memorial Fund; Children's Hospital, Boston FX We thank Danya Machnes for technical support and members of the Rao lab for valuable discussions. This work was funded by National Institutes of Health (NIH) grants AI40127 and AI84167 (to A. R.), NIH Grant CA93645 (to D. B. S.) and NIH Grant DK62040 and a Research Scholar Grant from the American Cancer Society (to V. S.), a Fellowship from the Canadian Institutes of Health Research and a Special Fellowship from the Leukemia and Lymphoma Society (S. S.), a fellowship from the Lady Tata Memorial Fund (H. S. B.), and a postdoctoral training grant from the Joint Program in Transfusion Biology and Medicine, Children's Hospital, Boston (S.O.). NR 34 TC 78 Z9 87 U1 3 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11381 EP 11386 DI 10.1073/pnas.1019711108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200024 PM 21709260 ER PT J AU Harris, A Borgnia, MJ Shi, D Bartesaghi, A He, HF Pejchal, R Kang, Y Depetris, R Marozsan, AJ Sanders, RW Klasse, PJ Milne, JLS Wilson, IA Olson, WC Moore, JP Subramaniam, S AF Harris, Audray Borgnia, Mario J. Shi, Dan Bartesaghi, Alberto He, Haifeng Pejchal, Robert Kang, Yun (Kenneth) Depetris, Rafael Marozsan, Andre J. Sanders, Rogier W. Klasse, Per Johan Milne, Jacqueline L. S. Wilson, Ian A. Olson, William C. Moore, John P. Subramaniam, Sriram TI Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE viral entry; cryoelectron microscopy; HIV spike; HIV vaccine; AIDS vaccine ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; GP120; COMPLEX; ELICITATION; REVEALS; SUBTYPE; BINDING; TARGET AB The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined with subvolume averaging, we have analyzed the structure of SOSIP gp140 trimers, which are cleaved, solubilized versions of the ectodomain of trimeric HIV-1 Env. We show that unliganded gp140 trimers adopt a quaternary arrangement similar to that displayed by native unliganded trimers on the surface of intact HIV-1 virions. When complexed with soluble CD4, Fab 17b, which binds to gp120 at its chemokine coreceptor binding site, or both soluble CD4 and 17b Fab, gp140 trimers display an open conformation in which there is an outward rotation and displacement of each gp120 protomer. We demonstrate that the molecular arrangements of gp120 trimers in the closed and open conformations of the soluble trimer are the same as those observed for the closed and open states, respectively, of trimeric gp120 on intact HIV-1 BaL virions, establishing that soluble gp140 trimers can be designed to mimic the quaternary structural transitions displayed by native trimeric Env. C1 [Harris, Audray; Borgnia, Mario J.; Shi, Dan; Bartesaghi, Alberto; Milne, Jacqueline L. S.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [He, Haifeng] FEI Co, Hillsboro, OR 97124 USA. [Pejchal, Robert; Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Pejchal, Robert; Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Kang, Yun (Kenneth); Marozsan, Andre J.; Olson, William C.] Progen Pharmaceut, Tarrytown, NY 10591 USA. [Depetris, Rafael; Sanders, Rogier W.; Klasse, Per Johan; Moore, John P.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov FU National Cancer Institute; NIH [AI36082, 45463]; International AIDS Vaccine Initiative; NIH HIV Vaccine Research and Design [P01 AI-082362] FX We thank Steven Fellini and colleagues for assistance with use of the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (NIH) (http://biowulf.nih.gov); Dr. Dennis Burton (The Scripps Research Institute) for providing 17b antibody; and A. M. Cupo, A.A. Ouattara, and L. Pagel for excellent technical assistance. This work was supported by the Center for Cancer Research at the National Cancer Institute, NIH and by NIH Grants AI36082 and 45463; by the International AIDS Vaccine Initiative; and by NIH HIV Vaccine Research and Design Grant P01 AI-082362. NR 30 TC 93 Z9 95 U1 1 U2 21 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11440 EP 11445 DI 10.1073/pnas.1101414108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200034 PM 21709254 ER PT J AU Johmura, Y Soung, NK Park, JE Yu, LR Zhou, M Bang, JK Kim, BY Veenstra, TD Erikson, RL Lee, KS AF Johmura, Yoshikazu Soung, Nak-Kyun Park, Jung-Eun Yu, Li-Rong Zhou, Ming Bang, Jeong K. Kim, Bo-Yeon Veenstra, Timothy D. Erikson, Raymond L. Lee, Kyung S. TI Regulation of microtubule-based microtubule nucleation by mammalian polo-like kinase 1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mitosis; spindle assembly; polo-box domain; distributive phosphorylation; Ser/Thr protein kinase ID MITOTIC SPINDLE; GAMMA-TUBULIN; BOX DOMAIN; HUMAN-CELLS; COMPLEX; PLK1; CENTROSOME; CYTOKINESIS; RECRUITMENT; AUGMIN AB Bipolar spindle formation is pivotal for accurate segregation of mitotic chromosomes during cell division. A growing body of evidence suggests that, in addition to centrosome-and chromatin-based microtubule (MT) nucleation, MT-based MT nucleation plays an important role for proper bipolar spindle formation in various eukaryotic organisms. Although a recently discovered Augmin complex appears to play a central role in this event, how Augmin is regulated remains unknown. Here we provide evidence that a mammalian polo-like kinase 1 (Plk1) localizes to mitotic spindles and promotes MT-based MT nucleation by directly regulating Augmin. Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a gamma-tubulin ring complex (gamma-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction. This step appeared to be critical to allow Plk1 to phosphorylate the Hice1 subunit of the Augmin complex to promote the Augmin-MT interaction and MT-based MT nucleation from within the spindle. Loss of either the Nedd1 S460 function or the Plk1-dependent Hice1 phosphorylation impaired both the Augmin-MT interaction and gamma-tubulin recruitment to the spindles, thus resulting in improper bipolar spindle formation that ultimately leads to mitotic arrest and apoptotic cell death. Thus, via the formation of the Nedd1-Plk1 complex and subsequent Augmin phosphorylation, Plk1 regulates spindle MT-based MT nucleation to accomplish normal bipolar spindle formation and mitotic progression. C1 [Erikson, Raymond L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Johmura, Yoshikazu; Soung, Nak-Kyun; Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Soung, Nak-Kyun; Kim, Bo-Yeon] Korea Res Inst Biosci & Biotechnol, Chem Biol Res Ctr, Ochang 363883, Chung Buk, South Korea. [Yu, Li-Rong] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Ctr Prote, Jefferson, AR 72079 USA. [Zhou, Ming; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. [Bang, Jeong K.] Korean Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Bak, South Korea. RP Erikson, RL (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM erikson@mcb.harvard.edu; kyunglee@mail.nih.gov FU National Cancer Institute; Food and Drug Administration (FDA); Korea Basic Science Institute [T3022B]; Ministry of Education, Science and Technology of Korea FX We are grateful to Mary Dasso, Dan L. Sackett, and Yasuhiko Terada for critical reading of the manuscript; Gohta Goshima, Jens Luders, Andreas Merdes, Dan L. Sackett, Tim Stearns, Ryota Uehara, and Michael B. Yaffe for reagents and technical assistance; and Susan Garfield, Valarie Barr, Brian Svedberg, and Elise Shumsky for their assistance in confocal and time-lapse microscopies. This work was supported in part by National Cancer Institute intramural grants (to K. S. L. and T. D. V.), a Food and Drug Administration (FDA) grant (to L.-R.Y.), Korea Basic Science Institute's high field NMR research program Grant T3022B (To J.K.B.), and the World Class Institute research program of the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology of Korea (B.Y.K.). NR 27 TC 35 Z9 36 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11446 EP 11451 DI 10.1073/pnas.1106223108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200035 PM 21690413 ER PT J AU Grati, M Kachar, B AF Grati, M'hamed Kachar, Bechara TI Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VESTIBULAR HAIR-CELLS; INNER-EAR; ADAPTATION; ACTIN; MUTATIONS; HARMONIN; BUNDLE; TRANSDUCTION; CADHERIN-23; MECHANISMS AB In the most accepted model for hair cell mechanotransduction, a cluster of myosin motors located at the stereocilia upper tip-link density (UTLD) keeps the tip-link under tension at rest. Both myosin VIIa (MYO7A) and myosin 1c have been implicated in mechanotransduction based on functional studies. However, localization studies are conflicting, leaving open the question of which myosin localizes at the UTLD and generates the tip-link resting tension. Using immunofluorescence, we now show that MYO7A and sans, a MYO7A-interacting protein, cluster at the UTLD. Analysis of the immunofluorescence intensity indicates that eight or more MYO7A molecules are present at each UTLD, consistent with a direct role for MYO7A in maintaining tip-link tension. MYO7A and sans localization at the UTLD is confirmed by transfection of hair cells with GFP-tagged constructs for these proteins. Cotransfection studies in a heterologous system show that MYO7A, sans, and the UTLD protein harmonin-b form a tripartite complex and that each protein is capable of interacting with one another independently. We propose that MYO7A, sans, and harmonin-b form the core components of the UTLD molecular complex. In this complex, MYO7A is likely the motor element that pulls on CDH23 to exert tension on the tip-link. C1 [Grati, M'hamed; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. EM kacharb@nidcd.nih.gov FU National Institute on Deafness and Other Communication Disorders-National Institutes of Health FX We thank Drs. L. Andrade, F. Salles, S. Ebrahim, U. Manor, and Y. Dai for help with experiments and with the manuscript. This work was supported by the Intramural Program of the National Institute on Deafness and Other Communication Disorders-National Institutes of Health. NR 42 TC 73 Z9 79 U1 3 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 JUL 12 PY 2011 VL 108 IS 28 BP 11476 EP 11481 DI 10.1073/pnas.1104161108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200040 PM 21709241 ER PT J AU Dahirel, V Shekhar, K Pereyra, F Miura, T Artyomov, M Talsania, S Allen, TM Altfeld, M Carrington, M Irvine, DJ Walker, BD Chakraborty, AK AF Dahirel, Vincent Shekhar, Karthik Pereyra, Florencia Miura, Toshiyuki Artyomov, Mikita Talsania, Shiv Allen, Todd M. Altfeld, Marcus Carrington, Mary Irvine, Darrell J. Walker, Bruce D. Chakraborty, Arup K. TI Coordinate linkage of HIV evolution reveals regions of immunological vulnerability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytotoxic T-lymphocyte response; elite controllers; random matrix theory ID T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS TYPE-1; ELITE CONTROLLERS; VACCINE DESIGN; RHESUS-MONKEYS; INFECTION; DETERMINANTS; ASSOCIATIONS; MUTATIONS; PROTEINS AB Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses. C1 [Dahirel, Vincent; Shekhar, Karthik; Pereyra, Florencia; Allen, Todd M.; Altfeld, Marcus; Carrington, Mary; Irvine, Darrell J.; Walker, Bruce D.; Chakraborty, Arup K.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA. [Dahirel, Vincent; Shekhar, Karthik; Pereyra, Florencia; Allen, Todd M.; Altfeld, Marcus; Carrington, Mary; Irvine, Darrell J.; Walker, Bruce D.; Chakraborty, Arup K.] Harvard Univ, Boston, MA 02129 USA. [Dahirel, Vincent; Shekhar, Karthik; Talsania, Shiv; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Dahirel, Vincent; Artyomov, Mikita; Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Irvine, Darrell J.; Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Artyomov, Mikita] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia. [Talsania, Shiv] Univ Loughborough, Dept Chem Engn, Loughborough LE11 3TU, Leics, England. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Irvine, Darrell J.; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Miura, Toshiyuki] Univ Tokyo, Inst Med Sci, Tokyo 1088639, Japan. RP Walker, BD (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA. EM bwalker@partners.org; arupc@mit.edu RI Allen, Todd/F-5473-2011 FU Ragon Institute; National Institutes of Health [RO130914, PO1 AI074415, HHSN261200800001E]; Howard Hughes Medical Institute; Mark and Lisa Schwartz Foundation; National Cancer Institute FX We thank D. Barouch and H. Eisen for valuable discussions. Financial support was provided by the Ragon Institute, a National Institutes of Health Director's Pioneer Award (to A. K. C.), National Institutes of Health Grants RO130914 (to B. D. W.) and PO1 AI074415 (to M. Altfeld and T. M. A.), The Howard Hughes Medical Institute (B. D. W.) and the Mark and Lisa Schwartz Foundation (B. D. W.) This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. NR 33 TC 92 Z9 92 U1 3 U2 22 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11530 EP 11535 DI 10.1073/pnas.1105315108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200049 PM 21690407 ER PT J AU Hwang, J Kita, R Kwon, HS Choi, EH Lee, SH Udey, MC Morasso, MI AF Hwang, Joonsung Kita, Ryosuke Kwon, Hyouk-Soo Choi, Eung Ho Lee, Seung Hun Udey, Mark C. Morasso, Maria I. TI Epidermal ablation of Dlx3 is linked to IL-17-associated skin inflammation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE barrier function; psoriasis; inflammatory diseases; homeobox transcription factor; mouse model ID LIVER-X-RECEPTORS; CORNIFIED ENVELOPE; ATOPIC-DERMATITIS; BARRIER FUNCTION; T-CELLS; MYCOBACTERIUM-TUBERCULOSIS; PSORIASIS PATHOGENESIS; MOUSE MODELS; IN-VIVO; KERATINOCYTES AB In an effort to understand the role of Distal-less 3 (Dlx3) in cutaneous biology and pathophysiology, we generated and characterized a mouse model with epidermal ablation of Dlx3. K14cre;Dlx3(Kin/f) mice exhibited epidermal hyperproliferation and abnormal differentiation of keratinocytes. Results from subsequent analyses revealed cutaneous inflammation that featured accumulation of IL-17-producing CD4(+) T, CD8(+) T, and gamma delta T cells in the skin and lymph nodes of K14cre;Dlx3(Kin/f) mice. The gene expression signature of K14cre; Dlx3(Kin/f) skin shared features with lesional psoriatic skin, and Dlx3 expression was markedly and selectively decreased in psoriatic skin. Interestingly, cultured Dlx3 null keratinocytes triggered cytokine production that is potentially linked to inflammatory responses in K14cre; Dlx3(Kin/f) mice. Thus, Dlx3 ablation in epidermis is linked to altered epidermal differentiation, barrier development, and IL-17-associated skin inflammation. This model provides a platform that will allow the systematic exploration of the contributions of keratinocytes to cutaneous inflammation. C1 [Hwang, Joonsung; Kita, Ryosuke; Morasso, Maria I.] NIAMSD, Dev Skin Biol Sect, NIH, Bethesda, MD 20892 USA. [Kwon, Hyouk-Soo; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Choi, Eung Ho] Yonsei Univ, Wonju Coll Med, Dept Dermatol, Wonju 220701, South Korea. [Lee, Seung Hun] Yonsei Univ, Coll Med, Dept Dermatol, Seoul 135720, South Korea. RP Morasso, MI (reprint author), NIAMSD, Dev Skin Biol Sect, NIH, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU NIAMS; Center for Cancer Research of the NCI at the National Institutes of Health FX We thank Dr. J. Chae, Dr. O. Duverger, Dr. J. Okano, and Mr. A. Lee of the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) and the NIAMS Light Imaging Section staff, for technical assistance; Dr. H. J. Kim, Dr. S. E. Lee, and Dr. H. J. Lee of Yonsei University for materials; Dr. S. Yuspa and Dr. C. Cataisson (NCI) for helpful comments on the manuscript; and Dr. A. Oshima and other members of the Laboratory of Cancer Biology and Genetics, National Cancer Institute (NCI) for helpful discussions. This study was supported by the NIAMS Intramural Research Program and the Center for Cancer Research of the NCI at the National Institutes of Health. NR 51 TC 18 Z9 18 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11566 EP 11571 DI 10.1073/pnas.1019658108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200055 PM 21709238 ER PT J AU Cohen, JE Lee, PR Chen, S Li, W Fields, RD AF Cohen, Jonathan E. Lee, Philip R. Chen, Shan Li, Wei Fields, R. Douglas TI MicroRNA regulation of homeostatic synaptic plasticity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE activity-dependent development; posttranscriptional gene regulation; presynaptic terminal ID DENDRITIC SPINE DEVELOPMENT; LONG-TERM POTENTIATION; VESICLE PROTEIN 2A; HIPPOCAMPAL-NEURONS; EXPRESSION; BRAIN; SYNAPSES; NEUROTRANSMISSION; IDENTIFICATION; INACTIVITY AB Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e. g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated. C1 [Cohen, Jonathan E.; Lee, Philip R.; Fields, R. Douglas] Eunice Kennedy Shriver Natl Inst Child & Human De, Sect Nervous Syst Dev & Plast, NIH, Bethesda, MD 20892 USA. [Chen, Shan; Li, Wei] NEI, Unit Retinal Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child & Human De, Sect Nervous Syst Dev & Plast, NIH, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov RI Moyal, Elizabeth/A-9802-2015 OI Moyal, Elizabeth/0000-0002-6593-9276 FU National Institute of Child Health and Human Development; National Eye Institute FX We are grateful to Drs. David Bredt and Robert J. Wenthold for PSD-95-GFP and Robert Malinow for pCl-SEP-GluR2(R) used in this study. This work was supported by the National Institute of Child Health and Human Development and the National Eye Institute Intramural Research Program. NR 45 TC 73 Z9 73 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2011 VL 108 IS 28 BP 11650 EP 11655 DI 10.1073/pnas.1017576108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791BO UT WOS:000292635200069 PM 21697510 ER PT J AU Yaniv, Y Juhaszova, M Wang, S Fishbein, KW Zorov, DB Sollott, SJ AF Yaniv, Yael Juhaszova, Magdalena Wang, Su Fishbein, Kenneth W. Zorov, Dmitry B. Sollott, Steven J. TI Analysis of Mitochondrial 3D-Deformation in Cardiomyocytes during Active Contraction Reveals Passive Structural Anisotropy of Orthogonal Short Axes SO PLOS ONE LA English DT Article ID PERMEABILITY TRANSITION PORE; RAT VENTRICULAR MYOCYTES; CARDIAC MYOCYTES; MATRIX VOLUME; HEART-MITOCHONDRIA; OSMOTIC STRENGTH; PAPILLARY-MUSCLE; LEFT ATRIUM; LENGTH; MEMBRANE AB The cardiomyocyte cytoskeleton, composed of rigid and elastic elements, maintains the isolated cell in an elongated cylindrical shape with an elliptical cross-section, even during contraction-relaxation cycles. Cardiomyocyte mitochondria are micron-sized, fluid-filled passive spheres distributed throughout the cell in a crystal-like lattice, arranged in pairs sandwiched between the sarcomere contractile machinery, both longitudinally and radially. Their shape represents the extant 3-dimensional (3D) force-balance. We developed a novel method to examine mitochondrial 3D-deformation in response to contraction and relaxation to understand how dynamic forces are balanced inside cardiomyocytes. The variation in transmitted light intensity induced by the periodic lattice of myofilaments alternating with mitochondrial rows can be analyzed by Fourier transformation along a given cardiomyocyte axis to measure mitochondrial deformation along that axis. This technique enables precise detection of changes in dimension of similar to 1% in similar to 1 mu m (long-axis) structures with 8 ms time-resolution. During active contraction (1 Hz stimulation), mitochondria deform along the length-and width-axes of the cell with similar deformation kinetics in both sarcomere and mitochondrial structures. However, significant deformation anisotropy (without hysteresis) was observed between the orthogonal short-axes (i.e., width and depth) of mitochondria during electrical stimulation. The same degree of deformation anisotropy was also found between the myocyte orthogonal short-axes during electrical stimulation. Therefore, the deformation of the mitochondria reflects the overall deformation of the cell, and the apparent stiffness and stress/strain characteristics of the cytoskeleton differ appreciably between the two cardiomyocyte orthogonal short-axes. This method may be applied to obtaining a better understanding of the dynamic force-balance inside cardiomyocytes and of changes in the spatial stiffness characteristics of the cytoskeleton that may accompany aging or pathological conditions. C1 [Yaniv, Yael; Juhaszova, Magdalena; Wang, Su; Zorov, Dmitry B.; Sollott, Steven J.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD USA. [Fishbein, Kenneth W.] NIA, Lab Clin Invest, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD USA. RP Yaniv, Y (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD USA. EM sollotts@mail.nih.gov RI Yaniv, Yael/B-3311-2015; OI Yaniv, Yael/0000-0002-5183-6284; Fishbein, Kenneth/0000-0002-6353-4603 FU National Institutes of Health, National Institute on Aging FX This work was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 13 Z9 13 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 JUL 11 PY 2011 VL 6 IS 7 AR e21985 DI 10.1371/journal.pone.0021985 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791QY UT WOS:000292680900021 PM 21779362 ER PT J AU Finkel, T AF Finkel, Toren TI Signal transduction by reactive oxygen species SO JOURNAL OF CELL BIOLOGY LA English DT Review ID ELEGANS LIFE-SPAN; MN SUPEROXIDE-DISMUTASE; TYROSINE-PHOSPHATASE 1B; EPIDERMAL-GROWTH-FACTOR; STEM-CELL HOMEOSTASIS; ATM-DEFICIENT MICE; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; MITOCHONDRIAL DYSFUNCTION; ATAXIA-TELANGIECTASIA AB Although historically viewed as purely harmful, recent evidence suggests that reactive oxygen species (ROS) function as important physiological regulators of intracellular signaling pathways. The specific effects of ROS are modulated in large part through the covalent modification of specific cysteine residues found within redox-sensitive target proteins. Oxidation of these specific and reactive cysteine residues in turn can lead to the reversible modification of enzymatic activity. Emerging evidence suggests that ROS regulate diverse physiological parameters ranging from the response to growth factor stimulation to the generation of the inflammatory response, and that dysregulated ROS signaling may contribute to a host of human diseases. C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU National Institutes of Health; Ellison Medical Foundation FX This work was supported by National Institutes of Health Intramural funds and a grant from the Ellison Medical Foundation. NR 98 TC 596 Z9 624 U1 18 U2 116 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUL 11 PY 2011 VL 194 IS 1 BP 7 EP 15 DI 10.1083/jcb.201102095 PG 9 WC Cell Biology SC Cell Biology GA 792RZ UT WOS:000292768200003 PM 21746850 ER PT J AU Schuster, SJ Neelapu, SS Gause, BL Janik, JE Muggia, FM Gockerman, JP Winter, JN Flowers, CR Nikcevich, DA Sotomayor, EM McGaughey, DS Jaffe, ES Chong, EA Reynolds, CW Berry, DA Santos, CF Popa, MA McCord, AM Kwak, LW AF Schuster, Stephen J. Neelapu, Sattva S. Gause, Barry L. Janik, John E. Muggia, Franco M. Gockerman, Jon P. Winter, Jane N. Flowers, Christopher R. Nikcevich, Daniel A. Sotomayor, Eduardo M. McGaughey, Dean S. Jaffe, Elaine S. Chong, Elise A. Reynolds, Craig W. Berry, Donald A. Santos, Carlos F. Popa, Mihaela A. McCord, Amy M. Kwak, Larry W. TI Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; COLONY-STIMULATING FACTOR; B-CELL LYMPHOMA; IDIOTYPE VACCINATION; PHASE-III; IMMUNE-RESPONSES; MYELOMA PROTEINS; STAGE-III; TRIAL; CYCLOPHOSPHAMIDE AB Purpose Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial. Patients and Methods Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control. Results Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients. Conclusion Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials. C1 [Kwak, Larry W.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. [Schuster, Stephen J.; Chong, Elise A.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Gause, Barry L.; Janik, John E.; Jaffe, Elaine S.; Reynolds, Craig W.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Muggia, Franco M.] NYU, Sch Med, Inst Canc, New York, NY USA. [Gockerman, Jon P.] Duke Univ, Ctr Comprehens Canc, Durham, NC USA. [Winter, Jane N.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Flowers, Christopher R.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Nikcevich, Daniel A.] SMDC Canc Ctr, Duluth, MN USA. [Nikcevich, Daniel A.] Duluth Community Clin Oncol, Duluth, MN USA. [Sotomayor, Eduardo M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Santos, Carlos F.; Popa, Mihaela A.; McCord, Amy M.] Biovest Int, Tampa, FL USA. [McGaughey, Dean S.] Virginia Oncol Associates, Norfolk, VA USA. RP Kwak, LW (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, 1515 Holcombe Blvd,Unit 429, Houston, TX 77030 USA. EM lkwak@mdanderson.org RI Flowers, Christopher/F-1953-2010; OI Flowers, Christopher/0000-0002-9524-3990; Jaffe, Elaine/0000-0003-4632-0301; Muggia, Franco/0000-0003-0703-9146 FU National Cancer Institute; Biovest International; Millennium Pharmaceuticals; Berlex/Bayer Pharmaceuticals; Celgene FX Supported by the National Cancer Institute and Biovest International.; Research Funding: Stephen J. Schuster, Biovest International; Sattva S. Neelapu, Biovest International; Franco M. Muggia, Biovest International; Jane N. Winter, Biovest International; Christopher R. Flowers, Biovest International, Millennium Pharmaceuticals, Berlex/Bayer Pharmaceuticals; Larry W. Kwak, Celgene NR 37 TC 122 Z9 125 U1 1 U2 12 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2011 VL 29 IS 20 BP 2787 EP 2793 DI 10.1200/JCO.2010.33.3005 PG 7 WC Oncology SC Oncology GA 789IH UT WOS:000292508500019 PM 21632504 ER PT J AU Chen, Z Zhang, B Albert, PS AF Chen, Zhen Zhang, Bo Albert, Paul S. TI A joint modeling approach to data with informative cluster size: Robustness to the cluster size model SO STATISTICS IN MEDICINE LA English DT Article DE shared parameter models; non-ignorable dropout; developmental toxicity; random cluster size; informative number of observations ID SUBUNIT-SPECIFIC OUTCOMES; LINEAR MIXED MODELS; LONGITUDINAL DATA; LIKELIHOOD APPROACH; MISSPECIFICATION AB In many biomedical and epidemiological studies, data are often clustered due to longitudinal follow up or repeated sampling. While in some clustered data the cluster size is pre-determined, in others it may be correlated with the outcome of subunits, resulting in informative cluster size. When the cluster size is informative, standard statistical procedures that ignore cluster size may produce biased estimates. One attractive framework for modeling data with informative cluster size is the joint modeling approach in which a common set of random effects are shared by both the outcome and cluster size models. In addition to making distributional assumptions on the shared random effects, the joint modeling approach needs to specify the cluster size model. Questions arise as to whether the joint modeling approach is robust to misspecification of the cluster size model. In this paper, we studied both asymptotic and finite-sample characteristics of the maximum likelihood estimators in joint models when the cluster size model is misspecified. We found that using an incorrect distribution for the cluster size may induce small to moderate biases, while using a misspecified functional form for the shared random parameter in the cluster size model results in nearly unbiased estimation of outcome model parameters. We also found that there is little efficiency loss under this model misspecification. A developmental toxicity study was used to motivate the research and to demonstrate the findings. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Chen, Zhen; Zhang, Bo; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Chen, Z (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM chenzhe@mail.nih.gov FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research is support by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors thank the two anonymous referees and the Associate Editor for very useful comments that improved the presentation of the paper. They also thank the Center for Information Technology, the National Institutes of Health, for providing access to the high-performance computational capabilities of the Biowulf Linux cluster. NR 22 TC 6 Z9 6 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 10 PY 2011 VL 30 IS 15 BP 1825 EP 1836 DI 10.1002/sim.4239 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 777EM UT WOS:000291598600004 PM 21495060 ER PT J AU Melief, CJM O'Shea, JJ Stroncek, DF AF Melief, Cornelis J. M. O'Shea, John J. Stroncek, David F. TI Summit on cell therapy for cancer: The importance of the interaction of multiple disciplines to advance clinical therapy SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID NATURAL-KILLER-CELLS; TUMOR-INFILTRATING LYMPHOCYTES; CD8(+) T-CELLS; METASTATIC MELANOMA; ADOPTIVE IMMUNOTHERAPY; GENETIC-MODIFICATION; MYELOID-LEUKEMIA; VIVO EXPANSION; PHASE-II; NK CELLS AB The field of cellular therapy of cancer is moving quickly and the issues involved with its advancement are complex and wide ranging. The growing clinical applications and success of adoptive cellular therapy of cancer has been due to the rapid evolution of immunology, cancer biology, gene therapy and stem cell biology and the translation of advances in these fields from the research laboratory to the clinic. The continued development of this field is dependent on the exchange of ideas across these diverse disciplines, the testing of new ideas in the research laboratory and in animal models, the development of new cellular therapies and GMP methods to produce these therapies, and the testing of new adoptive cell therapies in clinical trials. The Summit on Cell Therapy for Cancer to held on November 1 and 2, 2011 at the National Institutes of Health (NIH) campus will include a mix of perspectives, concepts and ideas related to adoptive cellular therapy that are not normally presented together at any single meeting. This novel assembly will generate new ideas and new collaborations and possibly increase the rate of advancement of this field. C1 [Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Melief, Cornelis J. M.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands. [O'Shea, John J.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, 10 Ctr Dr MSC 1288,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Society for Immunotherapy of Cancer (SITC) FX This summit is sponsored by Society for Immunotherapy of Cancer (SITC) in conjunction with the following participating organizations: AABB (formerly the American Association of Blood Banks), American Society for Blood and Marrow Transplantation (ASBMT), American Society of Gene & Cell Therapy (ASGCT) and Cancer Immunotherapy Trials Network (CITN). NR 36 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 8 PY 2011 VL 9 AR 107 DI 10.1186/1479-5876-9-107 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 810UM UT WOS:000294153000001 PM 21740581 ER PT J AU Sviridov, DO Ikpot, IZ Stonik, J Drake, SK Amar, M Osei-Hwedieh, DO Piszczek, G Turner, S Remaley, AT AF Sviridov, D. O. Ikpot, I. Z. Stonik, J. Drake, S. K. Amar, M. Osei-Hwedieh, D. O. Piszczek, G. Turner, S. Remaley, A. T. TI Helix stabilization of amphipathic peptides by hydrocarbon stapling increases cholesterol efflux by the ABCA1 transporter SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Apolipoproteins; Peptides; Atherosclerosis; Cholesterol efflux; High density lipoproteins ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; MIMETIC PEPTIDES; CORONARY ATHEROSCLEROSIS; LIPID EFFLUX; SPECIFICITY; TRIAL; D-4F; MICE AB Apolipoprotein mimetic peptides are short amphipathic peptides that efflux cholesterol from cells by the ABCA1 transporter and are being investigated as therapeutic agents for cardiovascular disease. We examined the role of helix stabilization of these peptides in cholesterol efflux. A 23-amino acid long peptide (Ac-VLESFKVSFLSALEEYTKKLNTQ-NH2) based on the last helix of apoA-I (A10) was synthesized, as well as two variants, S1A10 and S2A10, in which the third and fourth and third and fifth turn of each peptide, respectively, were covalently joined by hydrocarbon staples. By CD spectroscopy, the stapled variants at 24 degrees C were more helical in aqueous buffer than A10 (A10 17%, S1A10 62%, S2A10 97%). S1A10 and S2A10 unlike A10 were resistant to proteolysis by pepsin and chymotrypsin. S1A10 and S2A10 showed more than a 10-fold increase in cholesterol efflux by the ABCA1 transporter compared to A10. In summary, hydrocarbon stapling of amphipathic peptides increases their helicity, makes them resistant to proteolysis and enhances their ability to promote cholesterol efflux by the ABCA1 transporter, indicating that this peptide modification may be useful in the development of apolipoprotein mimetic peptides. Published by Elsevier Inc. C1 [Sviridov, D. O.; Ikpot, I. Z.; Stonik, J.; Amar, M.; Osei-Hwedieh, D. O.; Remaley, A. T.] NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Drake, S. K.] NIH, Dept Crit Care Med, NIH Clin Ctr, Bethesda, MD 20892 USA. [Piszczek, G.] NHLBI, Biophys Core Facil, NIH, Bethesda, MD 20892 USA. [Turner, S.] KineMed Inc, Alameda, CA USA. RP Remaley, AT (reprint author), NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bldg 10,Room 2C-433,10 Ctr Dr, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov FU National Institutes of Health FX Research was supported by intramural NHLBI research funds from the National Institutes of Health. NR 33 TC 26 Z9 26 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 8 PY 2011 VL 410 IS 3 BP 446 EP 451 DI 10.1016/j.bbrc.2011.05.154 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 793CJ UT WOS:000292797700013 PM 21672528 ER PT J AU Tano, JY Smedlund, K Lee, R Abramowitz, J Birnbaumer, L Vazquez, G AF Tano, Jean-Yves Smedlund, Kathryn Lee, Robert Abramowitz, Joel Birnbaumer, Lutz Vazquez, Guillermo TI Impairment of survival signaling and efferocytosis in TRPC3-deficient macrophages SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE TRPC proteins; Calcium influx; Calcium channels; Macrophage survival; Apoptosis ID ENDOTHELIAL-CELLS; TRPC3 CHANNELS; ACTIVATION; ATHEROSCLEROSIS; APOPTOSIS; INCREASES; PROTEINS; CALCIUM; DISEASE AB We have recently shown that in macrophages proper operation of the survival pathways phosphatidylin-ositol-3-kinase (PI3K)/AKT and nuclear factor kappa B (NFkB) has an obligatory requirement for constitutive, non-regulated Ca(2+) influx. In the present work we examined if Transient Receptor Potential Canonical 3 (TRPC3), a member of the TRPC family of Ca(2+)-permeable cation channels, contributes to the constitutive Ca(2+) influx that supports macrophage survival. We used bone marrow-derived macrophages obtained from TRPC3(-/-) mice to determine the activation status of survival signaling pathways, apoptosis and their efferocytic properties. Treatment of TRPC3(+/+) macrophages with the pro-apoptotic cytokine TNF alpha induced time-dependent phosphorylation of I kappa B alpha, AKT and BAD, and this was drastically reduced in TRPC3(-/-) macrophages. Compared to TRPC3(+/+) cells TRPC3(-/-) macrophages exhibited reduced constitutive cation influx, increased apoptosis and impaired efferocytosis. The present findings suggest that macrophage TRPC3, presumably through its constitutive function, contributes to survival signaling and efferocytic properties. (C) 2011 Elsevier Inc. All rights reserved. C1 [Tano, Jean-Yves; Smedlund, Kathryn; Lee, Robert; Vazquez, Guillermo] Univ Toledo, Coll Med, Dept Physiol & Pharmacol, Toledo, OH 43614 USA. [Tano, Jean-Yves; Smedlund, Kathryn; Lee, Robert; Vazquez, Guillermo] Univ Toledo, Coll Med, Ctr Diabet & Endocrine Res, Toledo, OH 43614 USA. [Abramowitz, Joel; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Dept Signal Transduct, Lab Membrane Signaling, Res Triangle Pk, NC 27709 USA. RP Vazquez, G (reprint author), Univ Toledo, Coll Med, Dept Physiol & Pharmacol, 3000 Arlington Av,UTHSC Mail Stop 1008,Hlth Sci C, Toledo, OH 43614 USA. EM Guillermo.Vazquez@utoledo.edu RI Abramowitz, Joel/A-2620-2015; OI Smedlund, Kathryn/0000-0002-5746-8419 FU American Heart Association [SDG0635250N]; University of Toledo College of Medicine FX This work was supported by American Heart Association (SDG0635250N to G.V.) and University of Toledo College of Medicine. NR 20 TC 19 Z9 19 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 8 PY 2011 VL 410 IS 3 BP 643 EP 647 DI 10.1016/j.bbrc.2011.06.045 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 793CJ UT WOS:000292797700047 PM 21684255 ER PT J AU Zoabi, M Sadeh, R de Bie, P Marquez, VE Ciechanover, A AF Zoabi, Muhammad Sadeh, Ronen de Bie, Prim Marquez, Victor E. Ciechanover, Aaron TI PRAJA1 is a ubiquitin ligase for the polycomb repressive complex 2 proteins (vol 408, pg 393, 2011) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Correction C1 [Zoabi, Muhammad; Sadeh, Ronen; de Bie, Prim; Ciechanover, Aaron] Technion Israel Inst Technol, Rappaport Fac Med, Ctr Vasc & Tumor Biol, IL-31096 Haifa, Israel. [Zoabi, Muhammad; Sadeh, Ronen; de Bie, Prim; Ciechanover, Aaron] Technion Israel Inst Technol, Res Inst, IL-31096 Haifa, Israel. [Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Ciechanover, A (reprint author), Technion Israel Inst Technol, Rappaport Fac Med, Ctr Vasc & Tumor Biol, IL-31096 Haifa, Israel. EM c_tzachy@netvision.net.il NR 1 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 8 PY 2011 VL 410 IS 3 BP 705 EP 705 DI 10.1016/j.bbrc.2011.06.037 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 793CJ UT WOS:000292797700058 ER PT J AU Biddie, SC John, S Sabo, PJ Thurman, RE Johnson, TA Schiltz, RL Miranda, TB Sung, MH Trump, S Lightman, SL Vinson, C Stamatoyannopoulos, JA Hager, GL AF Biddie, Simon C. John, Sam Sabo, Pete J. Thurman, Robert E. Johnson, Thomas A. Schiltz, R. Louis Miranda, Tina B. Sung, Myong-Hee Trump, Saskia Lightman, Stafford L. Vinson, Charles Stamatoyannopoulos, John A. Hager, Gordon L. TI Transcription Factor AP1 Potentiates Chromatin Accessibility and Glucocorticoid Receptor Binding SO MOLECULAR CELL LA English DT Article ID NF-KAPPA-B; DNA-BINDING; IN-VIVO; RETINOIC ACID; C-JUN; PROTEIN; ACTIVATION; GENE; REPRESSION; SEQUENCE AB Ligand-dependent transcription by the nuclear receptor glucocorticoid receptor (GR) is mediated by interactions with coregulators. The role of these interactions in determining selective binding of GR to regulatory elements remains unclear. Recent findings indicate that a large fraction of genomic GR binding coincides with chromatin that is accessible prior to hormone treatment, suggesting that receptor binding is dictated by proteins that maintain chromatin in an open state. Combining DNasel accessibility and chromatin immunoprecipitation with high-throughput sequencing, we identify the activator protein 1 (AP1) as a major partner for productive GR-chromatin interactions. AP1 is critical for GR-regulated transcription and recruitment to co-occupied regulatory elements, illustrating an extensive AP1-GR interaction network. Importantly, the maintenance of baseline chromatin accessibility facilitates GR recruitment and is dependent on AP1 binding. We propose a model in which the basal occupancy of transcription factors acts to prime chromatin and direct inducible transcription factors to select regions in the genome. C1 [Biddie, Simon C.; John, Sam; Johnson, Thomas A.; Schiltz, R. Louis; Miranda, Tina B.; Sung, Myong-Hee; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Sabo, Pete J.; Thurman, Robert E.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Biddie, Simon C.; Lightman, Stafford L.] Univ Bristol, Henry Wellcome Labs Neurosci & Endocrinol, Fac Med & Dent, Bristol BS1 3NY, Avon, England. [Trump, Saskia] UFZ Helmholtz Ctr Environm Res, Dept Environm Immunol, D-04318 Leipzig, Germany. RP John, S (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, B602,Bldg 41,41 Lib Dr, Bethesda, MD 20892 USA. EM sam@mail.nih.gov; jstam@uw.edu; hagerg@exchange.nih.gov OI Biddie, Simon/0000-0002-8253-0253 FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; NIH [1RC2HG005654]; Needham Cooper Postgraduate Medicine Scholarship FX We thank Stephanie Morris, Lars Grontved, and Raffaella Nativio for critical reading of the manuscript. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and NIH Grant #1RC2HG005654 (to J.A.S.). S.C.B was supported, in part, by The Needham Cooper Postgraduate Medicine Scholarship. The authors thank Michael Radonovich for technical assistance and Richard Sandstrom for help with data submission. NR 42 TC 167 Z9 169 U1 6 U2 20 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 JUL 8 PY 2011 VL 43 IS 1 BP 145 EP 155 DI 10.1016/j.molcel.2011.06.016 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 792EN UT WOS:000292723400015 PM 21726817 ER PT J AU O'Brien, TR Everhart, JE Morgan, TR Lok, AS Chung, RT Shao, YW Shiffman, ML Dotrang, M Sninsky, JJ Bonkovsky, HL Pfeiffer, RM AF O'Brien, Thomas R. Everhart, James E. Morgan, Timothy R. Lok, Anna S. Chung, Raymond T. Shao, Yongwu Shiffman, Mitchell L. Dotrang, Myhanh Sninsky, John J. Bonkovsky, Herbert L. Pfeiffer, Ruth M. CA HALT-C Trial Grp TI An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C SO PLOS ONE LA English DT Article ID CHRONIC HCV INFECTION; LONG-TERM TREATMENT; INTERFERON-ALPHA; VIRUS-INFECTION; GENETIC-VARIATION; PEGYLATED INTERFERON; RIBAVIRIN; PEGINTERFERON; TELAPREVIR; THERAPY AB Background: Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. Methods: HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC). Results: Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p <.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p < 0.001). Subjects with a predicted probability of SVR < 10% had an observed SVR rate of 3.8%; subjects with a predicted probability > 10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. Conclusion: A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC. C1 [O'Brien, Thomas R.; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Everhart, James E.] NIDDKD, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit,Med Serv, Boston, MA USA. [Shao, Yongwu] Informat Management Serv Inc, Silver Spring, MD USA. [Shiffman, Mitchell L.] Bon Secours Hlth Syst, Liver Inst Virginia, Newport News, VA USA. [Dotrang, Myhanh] CSC, Rockville, MD USA. [Sninsky, John J.] Celera Corp, Alameda, CA USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute (NCI); National Center for Minority Health and Health Disparities; National Center for Research Resources, National Institutes of Health; Hoffmann-La Roche, Inc.; Celera Corporation through National Institutes of Health; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, CT [M01RR-06192]; Saint Louis University School of Medicine, St Louis, MO [N01-DK-w9-2324]; Massachusetts General Hospital, Boston, MA [N01-DK-9-2319, M01RR-01066, 1 UL1 RR025758-01]; University of Colorado Denver, School of Medicine, Aurora, CO [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; 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 Michigan Medical Center, Ann Arbor, MI [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; Vertex Pharmaceuticals; Merck; Schering Plough Corporation; WAKO Diagnostics; Bristol-Myers Squibb; Gilead and Eisai Pharmaceuticals; Novartis; Romark; Biolex; Conatus; Glaxo SmithKline; Globeimmune; Human Genome Sciences; Idenix; Roche; Tibotec; Valeant; Wyeth; Zymogenetics; Novartis Pharmaceuticals FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute (NCI), the National Center for Minority Health and Health Disparities, General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health. Employees of NIDDK and NCI played a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., and Celera Corporation through Cooperative Research and Development Agreements (CRADA) with the National Institutes of Health. The present study was also supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. 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. Yongwu Shao was employed by Information Management Services, Silver Spring; Myhanh Dotrang by CSC, Rockville; and John J. Sninsky by Celera Corporation, Alameda. These authors played a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Contract and grant numbers: University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326); University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192); Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-w9-2324); Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center); University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01); University of California Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827); 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); University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043); University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research); Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065).; The authors wish to report the following relationships that might appear to represent a potential conflict: John J. Sninsky is employed by Celera Corporation, Alameda. T. R. Morgan is on the speaker's bureau and receives research support from Hoffmann-La Roche, Inc.; is a consultant, serves on an advisory board, and receives research support from Vertex Pharmaceuticals; serves on an advisory board for Gilead Sciences; and receives research support from Merck, Schering Plough Corporation, and WAKO Diagnostics. A. S. Lok is a consultant for Hoffmann-La Roche, Inc., Abbott and Gilead; and receives research support from Schering-Plough Corporation, Bristol-Myers Squibb, Gilead and Eisai Pharmaceuticals. R. T. Chung receives research support from Hoffmann-La Roche, Inc.; receives research support from Schering-Plough, Novartis, and Romark; and is a consultant for Vertex Pharmaceuticals, Merck, Pfizer, Astellas, Novartis, and Gilead. M. L. Shiffman is a consultant for Celera Corporation, Hoffmann-La Roche, Inc., and National Genome Sciences; has attended advisor meetings with Anadys, Biolex, Bristol-Myers-Squibb, Conatus, Globeimmune, Human Genome Sciences, Novartis, Roche, Romark, Pfizer, Schering-Plough, Valeant, Vertex and Zymogenetics; is a speaker for Roche and Schering-Plough; is on the data safety monitoring boards with Abbott and Anadys; and has received research support from Biolex, Conatus, Glaxo SmithKline, Globeimmune, Human Genome Sciences, Idenix, Roche, Romark, Tibotec, Valeant, Vertex, Wyeth and Zymogenetics. J. J. Sninsky is an employee of Celera Corporation. H. L. Bonkovsky receives research support from Hoffmann-La Roche, Inc.; is a consultant for Boehringer-Ingelheim; is a consultant and on the advisory board for Clinuvel, Inc.; is a consultant, advisory board member and receives research support from Novartis Pharmaceuticals; is a consultant and on the speakers' bureau for Lundbeck Pharmaceuticals; and receives research support from Vertex Pharmaceuticals. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. Authors with no financial relationships related to this project are: T. R. O'Brien, J. E. Everhart, Y. Shao, M. Dotrang, and R. M. Pfeiffer. NR 27 TC 18 Z9 19 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 JUL 8 PY 2011 VL 6 IS 7 AR e20904 DI 10.1371/journal.pone.0020904 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791IA UT WOS:000292657200005 PM 21760886 ER PT J AU Cookson, MR AF Cookson, Mark R. TI A Feedforward Loop Links Gaucher and Parkinson's Diseases? SO CELL LA English DT Editorial Material ID ALPHA-SYNUCLEIN C1 NIA, Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Gene Express Unit, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov NR 10 TC 4 Z9 4 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 8 PY 2011 VL 146 IS 1 BP 9 EP 11 DI 10.1016/j.cell.2011.06.031 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 789TN UT WOS:000292539300001 PM 21729776 ER PT J AU Shao, SC Hegde, RS AF Shao, Sichen Hegde, Ramanujan S. TI A Flip Turn for Membrane Protein Insertion SO CELL LA English DT Editorial Material ID EXIT TUNNEL; RIBOSOME; INTEGRATION; TOPOLOGY C1 [Shao, Sichen; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Shao, Sichen] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Hegde, RS (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 0QH, England. EM hegde.science@gmail.com OI Shao, Sichen/0000-0003-2679-5537; Hegde, Ramanujan/0000-0001-8338-852X FU Intramural NIH HHS [ZIA HD008862-02] NR 10 TC 3 Z9 3 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 8 PY 2011 VL 146 IS 1 BP 13 EP 15 DI 10.1016/j.cell.2011.06.028 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 789TN UT WOS:000292539300003 PM 21729778 ER PT J AU Mazzulli, JR Xu, YH Sun, Y Knight, AL McLean, PJ Caldwell, GA Sidransky, E Grabowski, GA Krainc, D AF Mazzulli, Joseph R. Xu, You-Hai Sun, Ying Knight, Adam L. McLean, Pamela J. Caldwell, Guy A. Sidransky, Ellen Grabowski, Gregory A. Krainc, Dimitri TI Gaucher Disease Glucocerebrosidase and alpha-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies SO CELL LA English DT Article ID PARKINSONS-DISEASE; FIBRIL FORMATION; MOUSE MODELS; MUTATIONS; NEURODEGENERATION; DEFICIENCY; MECHANISM; OLIGOMERS; CATECHOLS; ENZYME AB Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of alpha-synuclein (alpha-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified alpha-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that alpha-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of alpha-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies. C1 [Mazzulli, Joseph R.; McLean, Pamela J.; Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [Xu, You-Hai; Sun, Ying; Grabowski, Gregory A.] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Xu, You-Hai; Sun, Ying; Grabowski, Gregory A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. [Knight, Adam L.; Caldwell, Guy A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Caldwell, Guy A.] Univ Alabama, Ctr Neurodegenerat & Expt Therapeut, Dept Neurol, Birmingham, AL 35294 USA. [Caldwell, Guy A.] Univ Alabama, Ctr Neurodegenerat & Expt Therapeut, Dept Neurobiol, Birmingham, AL 35294 USA. [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. EM krainc@mgh.helix.harvard.edu FU National Institutes of Health [R01NS051303, F32NS066730]; National Institute of Neurological Disorders and Stroke [R01DK36729]; National Human Genome Research Institute FX We thank Harry Ischiropoulos for pCDNA3.1 human alpha-syn plasmids and syn303 antibody, Benoit I. Giasson for the SNL-1 antibody, and Kimberly Kegel for technical advice on liposome formation. This work was supported by National Institutes of Health grants R01NS051303 (D.K.) and F32NS066730 (J.R.M.) from the National Institute of Neurological Disorders and Stroke, R01DK36729 (G.A.G.), and the Intramural Programs of the National Human Genome Research Institute and the National Institutes of Health (E.S.). NR 38 TC 356 Z9 361 U1 8 U2 37 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 8 PY 2011 VL 146 IS 1 BP 37 EP 52 DI 10.1016/j.cell.2011.06.001 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 789TN UT WOS:000292539300005 PM 21700325 ER PT J AU Chang, AHK Jeong, J Levine, RL AF Chang, Allen H. K. Jeong, Jinsook Levine, Rodney L. TI Iron Regulatory Protein 2 Turnover through a Nonproteasomal Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ELEMENT-BINDING-PROTEIN; DEPENDENT DEGRADATION; ACONITASE ACTIVITY; MOLECULAR CONTROL; RNA-BINDING; CELL-DEATH; HOMEOSTASIS; IRP2; TRANSFERRIN; INHIBITION AB Iron regulatory protein 2 (IRP2) controls the synthesis of many proteins involved in iron metabolism, and the level of IRP2 itself is regulated by varying the rate of its degradation. The proteasome is known to mediate degradation, with specificity conferred by an iron-sensing E3 ligase. Most studies on the degradation of IRP2 have employed cells overexpressing IRP2 and also rendered iron deficient to further increase IRP2 levels. We utilized a sensitive, quantitative assay for IRP2, which allowed study of endogenous IRP2 degradation in HEK293A cells under more physiologic conditions. We found that under these conditions, the proteasome plays only a minor role in the degradation of IRP2, with almost all the IRP2 being degraded by a nonproteasomal pathway. This new pathway is calcium-dependent but is not mediated by calpain. Elevating the cellular level of IRP2 by inducing iron deficiency or by transfection causes the proteasomal pathway to account for the major fraction of IRP2 degradation. We conclude that under physiological, iron-sufficient conditions, the steady-state level of IRP2 in HEK293A cells is regulated by the nonproteasomal pathway. C1 [Chang, Allen H. K.; Jeong, Jinsook; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), Bldg 50,Room 2351,MSC 8012, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU NHLBI, National Institutes of Health [1Z01 HL000225] FX This work was supported by the Intramural Research Program of the NHLBI, National Institutes of Health, (Project no. 1Z01 HL000225). NR 33 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 8 PY 2011 VL 286 IS 27 BP 23698 EP 23707 DI 10.1074/jbc.M110.216788 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786HO UT WOS:000292294900011 PM 21558272 ER PT J AU Ghosh, S Vassilev, AP Zhang, JM Zhao, YM DePamphilis, ML AF Ghosh, Soma Vassilev, Alex P. Zhang, Junmei Zhao, Yingming DePamphilis, Melvin L. TI Assembly of the Human Origin Recognition Complex Occurs through Independent Nuclear Localization of Its Components SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-REPLICATION; ORC6 PROTEIN; IN-VIVO; CELLS; BINDING; ARCHITECTURE; RECRUITMENT; CENTROSOME; INITIATION; SEQUENCE AB Initiation of eukaryotic genome duplication begins when a six-subunit origin recognition complex (ORC) binds to DNA. However, the mechanism by which this occurs in vivo and the roles played by individual subunits appear to differ significantly among organisms. Previous studies identified a soluble human ORC(2-5) complex in the nucleus, an ORC(1-5) complex bound to chromatin, and an Orc6 protein that binds weakly, if at all, to other ORC subunits. Here we show that stable ORC(1-6) complexes also can be purified from human cell extracts and that Orc6 and Orc1 each contain a single nuclear localization signal that is essential for nuclear localization but not for ORC assembly. The Orc6 nuclear localization signal, which is essential for Orc6 function, is facilitated by phosphorylation at its cyclin-dependent kinase consensus site and by association with Kpna6/1, nuclear transport proteins that did not co-purify with other ORC subunits. These and other results support a model in which Orc6, Orc1, and ORC(2-5) are transported independently to the nucleus where they can either assemble into ORC(1-6) or function individually. C1 [Ghosh, Soma; Vassilev, Alex P.; DePamphilis, Melvin L.] NICHD, NIH, Bethesda, MD 20892 USA. [Zhang, Junmei] Univ Texas SW Med Ctr Dallas, Prot Chem Technol Ctr, Dallas, TX 75390 USA. [Zhao, Yingming] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. RP DePamphilis, ML (reprint author), NICHD, NIH, Bldg 6-3A-15,9000 Rockville Pike, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU National Institutes of Health (NICHD) FX This work was supported, in whole or in part, by National Institutes of Health intramural research programs (NICHD). NR 41 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 8 PY 2011 VL 286 IS 27 BP 23831 EP 23841 DI 10.1074/jbc.M110.215988 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786HO UT WOS:000292294900026 PM 21555516 ER PT J AU Nady, N Lemak, A Walker, JR Avvakumov, GV Kareta, MS Achour, M Xue, S Duan, SL Allali-Hassani, A Zuo, XB Wang, YX Bronner, C Chedin, F Arrowsmith, CH Dhe-Paganon, S AF Nady, Nataliya Lemak, Alexander Walker, John R. Avvakumov, George V. Kareta, Michael S. Achour, Mayada Xue, Sheng Duan, Shili Allali-Hassani, Abdellah Zuo, Xiaobing Wang, Yun-Xing Bronner, Christian Chedin, Frederic Arrowsmith, Cheryl H. Dhe-Paganon, Sirano TI Recognition of Multivalent Histone States Associated with Heterochromatin by UHRF1 Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; EMBRYONIC STEM-CELLS; DNA METHYLATION; BINDING-PROTEIN; STRUCTURAL BASIS; PERICENTROMERIC HETEROCHROMATIN; MULTIDOMAIN PROTEIN; 3-WAY DECOMPOSITION; LYSINE METHYLATION; MAMMALIAN-CELLS AB Histone modifications and DNA methylation represent two layers of heritable epigenetic information that regulate eukaryotic chromatin structure and gene activity. UHRF1 is a unique factor that bridges these two layers; it is required for maintenance DNA methylation at hemimethylated CpG sites, which are specifically recognized through its SRA domain and also interacts with histone H3 trimethylated on lysine 9 (H3K9me3) in an unspecified manner. Here we show that UHRF1 contains a tandem Tudor domain (TTD) that recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). Solution NMR and crystallographic data reveal the TTD simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first Tudor subdomain and unmodified H3K4 within a groove between the tandem subdomains. The subdomains undergo a conformational adjustment upon peptide binding, distinct from previously reported mechanisms for dual histone mark recognition. Mutant UHRF1 protein deficient for H3K4me0/K9me3 binding shows altered localization to heterochromatic chromocenters and fails to reduce expression of a target gene, p16(INK4A), when overexpressed. Our results demonstrate a novel recognition mechanism for the combinatorial readout of histone modification states associated with gene silencing and add to the growing evidence for coordination of, and cross-talk between, the modification states of H3K4 and H3K9 in regulation of gene expression. C1 [Nady, Nataliya; Lemak, Alexander; Duan, Shili; Arrowsmith, Cheryl H.] Univ Toronto, Ontario Canc Inst, Campbell Family Canc Res Inst, Toronto, ON M5G 1L7, Canada. [Nady, Nataliya; Lemak, Alexander; Duan, Shili; Arrowsmith, Cheryl H.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [Walker, John R.; Avvakumov, George V.; Xue, Sheng; Allali-Hassani, Abdellah; Arrowsmith, Cheryl H.; Dhe-Paganon, Sirano] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [Kareta, Michael S.; Chedin, Frederic] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Achour, Mayada; Bronner, Christian] Fac Pharm, CNRS UMR7213, Lab Biophoton & Pharmacol, F-67401 Illkirch Graffenstaden, France. [Zuo, Xiaobing; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. [Dhe-Paganon, Sirano] Univ Toronto, Dept Physiol, Toronto, ON M5G 1L5, Canada. RP Arrowsmith, CH (reprint author), 101 Coll St,Ste 700, Toronto, ON M5G 1L7, Canada. EM carrow@uhnres.utoronto.ca; sirano.dhepaganon@utoronto.ca RI Zuo, Xiaobing/F-1469-2010; OI Kareta, Michael/0000-0002-6980-9065; Zuo, Xiaobing/0000-0002-0134-4804 FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886, DE-AC02-06CH11357]; Canadian Institutes for Health Research (CIHR) [1097737]; Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; MerckCo., Inc.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust; Ontario Ministry of Health and Long Term Care; Cancer Research Coordinating Committee; California Institute of Regenerative Medicine FX Use of the National Synchrotron Light Source, Brookhaven National Laboratory was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-98CH10886. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-06CH11357. The Structural Genomics Consortium is a registered charity (1097737) that receives funds from the Canadian Institutes for Health Research (CIHR), the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck&Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. This work was supported in part by the Ontario Ministry of Health and Long Term Care (to C. H. A.), the Cancer Research Coordinating Committee (to F. C.), a Stem Cell training grant from the California Institute of Regenerative Medicine (to M. S. K.). a Frederick Banting and Charles Best Canada Doctoral Research Award from the CIHR (to N. N.). NR 72 TC 65 Z9 68 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 8 PY 2011 VL 286 IS 27 BP 24300 EP 24311 DI 10.1074/jbc.M111.234104 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786HO UT WOS:000292294900071 PM 21489993 ER PT J AU Marshall, E Zarin, D AF Marshall, Eliot Zarin, Deborah TI Unseen World of Clinical Trials Emerges From U.S. Database SO SCIENCE LA English DT Editorial Material C1 [Zarin, Deborah] NIH, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 8 PY 2011 VL 333 IS 6039 BP 145 EP 145 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 789GG UT WOS:000292502700013 ER PT J AU Utreras, E Terse, A Keller, J Iadarola, MJ Kulkarni, AB AF Utreras, Elias Terse, Anita Keller, Jason Iadarola, Michael J. Kulkarni, Ashok B. TI Resveratrol inhibits Cdk5 activity through regulation of p35 expression SO MOLECULAR PAIN LA English DT Article DE Cdk5; resveratrol; TNF-alpha?alpha; pain; Egr-1; ERK1/2; analgesic ID NF-KAPPA-B; DIABETIC NEUROPATHIC PAIN; CYCLIN-DEPENDENT KINASES; INDUCED ACTIVATION; MAP KINASE; PC12 CELLS; MOUSE SKIN; TNF-ALPHA; HYPERALGESIA; TRANSCRIPTION AB Background: We have previously reported that cyclin-dependent kinase 5 (Cdk5) participates in the regulation of nociceptive signaling. Through activation of the ERK1/2 pathway, Tumor Necrosis Factor-alpha (TNF-alpha) induces expression of Egr-1. This results in the sustained and robust expression of p35, a coactivator of Cdk5, in PC12 cells, thereby increasing Cdk5 kinase activity. The aim of our present study was to test whether resveratrol, a polyphenolic compound with known analgesic activity, can regulate Cdk5/p35 activity. Results: Here we used a cell-based assay in which a p35 promoter-luciferase construct was stably transfected in PC12 cells. Our studies demonstrate that resveratrol inhibits p35 promoter activity and also blocks the TNF-alpha mediated increase in Cdk5 activity in PC12 cells. Resveratrol also inhibits p35 expression and blocks the TNF-alpha mediated increase in Cdk5 activity in DRG neurons. In the presence of resveratrol, the MEK inhibitor decreased p35 promoter activity, whereas the inhibitors of p38 MAPK, JNK and NF-kappa B increased p35 promoter activity, indicating that these pathways regulate p35 expression differently. The TNF-alpha-mediated increase in Egr-1 expression was decreased by resveratrol treatment with a concomitant reduction in p35 expression and protein levels, resulting in reduced Cdk5 kinase activity. Conclusions: We demonstrate here that resveratrol regulates p35 promoter activity in PC12 cells and DRG neurons. Most importantly, resveratrol blocks the TNF-alpha-mediated increase in p35 promoter activity, thereby reducing p35 expression and subsequent Cdk5 kinase activity. This new molecular mechanism adds to the known analgesic effects of resveratrol and confirms the need for identifying new analgesics based on their ability to inhibit Cdk5 activity for effective treatment of pain. C1 [Utreras, Elias; Terse, Anita; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Keller, Jason; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Bldg 30,Rm 130,MSC 4395, Bethesda, MD 20892 USA. EM ak40m@nih.gov RI utreras, elias/I-1038-2013 OI utreras, elias/0000-0002-1004-0466 FU Division of Intramural Research, NIDCR, NIH FX We would like to thank Dr. Michaela Prochazkova for helpful discussions and Shelagh Powers for expert editorial assistance. These studies were supported by the Division of Intramural Research, NIDCR, NIH. NR 50 TC 16 Z9 16 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD JUL 7 PY 2011 VL 7 AR 49 DI 10.1186/1744-8069-7-49 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 813BO UT WOS:000294341700001 PM 21736731 ER PT J AU Ko, SU Tolea, MI Hausdorff, JM Ferrucci, L AF Ko, Seung-uk Tolea, Magdalena I. Hausdorff, Jeffrey M. Ferrucci, Luigi TI Sex-specific differences in gait patterns of healthy older adults: Results from the Baltimore Longitudinal Study of Aging SO JOURNAL OF BIOMECHANICS LA English DT Article DE Sex difference in gait; Aging; Kinematics; Kinetics; Mechanical work expenditure ID GROUND REACTION FORCE; GENDER-DIFFERENCES; WALKING SPEED; KNEE OSTEOARTHRITIS; YOUNG-ADULTS; AGE; PARAMETERS AB The effects of normal aging and orthopedic conditions on gait patterns during customary walking have been extensively investigated. Empirical evidence supports the notion that sex differences exist in the gait patterns of young adults but it is unclear as to whether sex differences exist in older adults. The aim of this study was to investigate sex-specific differences in gait among older adults. Study participants were 336 adults (50-96 years; 162 women) enrolled in the Baltimore Longitudinal Study of Aging (BLSA) who completed walking tasks at self-selected speed without assistance. After adjusting for significant covariates, women walked with higher cadence (p=0.01) and shorter stride length (p=0.006) compared to men, while gait speed was not significantly related to sex. Women also had less hip range of motion (ROM: p=0.004) and greater ankle ROM (p<0.001) in the sagittal-plane, and greater hip ROM (p=0.004) in the frontal-plane. Hip absorptive mechanical work expenditure (MWE) of the women was greater in the sagittal-plane (p<0.001) and lower in the frontal-plane (p<0.001), compared to men. In summary, women's gait is characterized by greater ankle ROM than men while men tend to have greater hip ROM than women. Characterizing unique gait patterns of women and men with aging may be beneficial for detecting the early stages of gait abnormalities that may lead to pathology. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Ko, Seung-uk] Chonnam Natl Univ, Dept Mech Engn, Yeosu 550749, Jeonnam, South Korea. [Tolea, Magdalena I.; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Hausdorff, Jeffrey M.] Tel Aviv Univ, Sackler Fac Med, Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. [Hausdorff, Jeffrey M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Ko, SU (reprint author), Chonnam Natl Univ, Dept Mech Engn, 50 Daehak Ro, Yeosu 550749, Jeonnam, South Korea. EM seunguk.ko@gmail.com FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. NR 26 TC 24 Z9 24 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JUL 7 PY 2011 VL 44 IS 10 BP 1974 EP 1979 DI 10.1016/j.jbiomech.2011.05.005 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 796JQ UT WOS:000293048000021 PM 21601861 ER PT J AU Lanoy, E Rosenberg, PS Fily, F Lascaux, AS Martinez, V Partisani, M Poizot-Martin, I Rouveix, E Engels, EA Costagliola, D Goedert, JJ AF Lanoy, Emilie Rosenberg, Philip S. Fily, Fabien Lascaux, Anne-Sophie Martinez, Valerie Partisani, Maria Poizot-Martin, Isabelle Rouveix, Elisabeth Engels, Eric A. Costagliola, Dominique Goedert, James J. CA FHDH-ANRS Co4 TI HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECONSTITUTION INFLAMMATORY SYNDROME; UNITED-STATES; CANCER-RISK; PERIPHERAL-BLOOD; T-CELLS; AIDS; DISEASE; COHORT; ERA AB Hodgkin lymphoma (HL) incidence with HIV infection may have increased with the introduction of combination antiretroviral therapy (cART), suggesting that immune reconstitution may contribute to some cases. We evaluated HL risk with cART during the first months of treatment. With 187 HL cases among 64 368 HIV patients in France, relative rates (RRs) and 95% confidence intervals (CIs) of HL were estimated using Poisson models for duration of cART, CD4 count, and HIV load, with and without adjustment for demographic/clinical covariates. HL risk was unrelated to cART use overall, but it was related to time intervals after cART initiation (P = .006). Risk was especially and significantly elevated in months 1-3 on cART (RR 2.95, CI 1.64-5.31), lower in months 4-6 (RR 1.63), and null with longer use (RR 1.00). CD4 count was strongly associated with HL risk (P < 10(-6)), with the highest HL incidence at 50-99 CD4 cells/mm(3). With adjustment for CD4 count and covariates, HL risk was elevated, but not significantly (RR 1.42), in months 1-3 on cART. HIV load had no added effect. HL risk increased significantly soon after cART initiation, which was largely explained by the CD4 count. Further studies of HIV-associated HL are needed. (Blood. 2011;118(1):44-49) C1 [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD 20852 USA. [Lanoy, Emilie; Costagliola, Dominique] INSERM, Paris, France. [Lanoy, Emilie; Costagliola, Dominique] Univ Paris 06, Paris, France. [Fily, Fabien] Ctr Hosp Univ Pontchaillou, Serv Malad Infect & Reanimat Med, Rennes, France. [Lascaux, Anne-Sophie] Hop Henri Mondor, Dept Clin Immunol, F-94010 Creteil, France. [Martinez, Valerie] Hop Antoine Beclere, AP HP, Serv Med Interne, Clamart, France. [Partisani, Maria] Hop Univ, Ctr Soins Infect VIH, Strasbourg, France. [Poizot-Martin, Isabelle] Hop St Marguerite, Unite Le Ctr Informat & Soins Immunodeficience Hu, Marseille, France. [Rouveix, Elisabeth] Hop Ambroise Pare, Serv Med 5, Boulogne, France. [Costagliola, Dominique] Grp Hosp Pitie Salpetriere, AP HP, Serv Malad Infect & Trop, F-75634 Paris, France. RP Goedert, JJ (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, 6120 Executive Blvd,Rm 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov RI Lanoy, Emilie/A-8541-2011; Costagliola, Dominique/H-5849-2011 OI Lanoy, Emilie/0000-0002-4789-7770; Costagliola, Dominique/0000-0003-0765-0869 FU Agence Nationale de Recherches sur le SIDA et les hepatites (ANRS); INSERM; French Ministry of Health; National Cancer Institute, National Institutes of Health (Bethesda, MD) FX The French Hospital Database on HIV is supported by Agence Nationale de Recherches sur le SIDA et les hepatites (ANRS), INSERM, and the French Ministry of Health. This work was also supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (Bethesda, MD). NR 35 TC 32 Z9 32 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 7 PY 2011 VL 118 IS 1 BP 44 EP 49 DI 10.1182/blood-2011-02-339275 PG 6 WC Hematology SC Hematology GA 789HI UT WOS:000292505900010 PM 21551234 ER PT J AU Delabie, J Holte, H Vose, JM Ullrich, F Jaffe, ES Savage, KJ Connors, JM Rimsza, L Harris, NL Muller-Hermelink, K Rudiger, T Coiffier, B Gascoyne, RD Berger, F Tobinai, K Au, WY Liang, R Montserrat, E Hochberg, EP Pileri, S Federico, M Nathwani, B Armitage, JO Weisenburger, DD AF Delabie, Jan Holte, Harald Vose, Julie M. Ullrich, Fred Jaffe, Elaine S. Savage, Kerry J. Connors, Joseph M. Rimsza, Lisa Harris, Nancy L. Mueller-Hermelink, Konrad Ruediger, Thomas Coiffier, Bertrand Gascoyne, Randy D. Berger, Francoise Tobinai, Kensei Au, Wing Y. Liang, Raymond Montserrat, Emili Hochberg, Ephraim P. Pileri, Stefano Federico, Massimo Nathwani, Bharat Armitage, James O. Weisenburger, Dennis D. TI Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project SO BLOOD LA English DT Article ID NON-HODGKIN-LYMPHOMA; CELIAC-DISEASE; INTESTINAL LYMPHOMAS; MALIGNANCY; MODEL; SPRUE AB Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options. (Blood. 2011;118(1):148-155) C1 [Delabie, Jan] Univ Hosp Oslo, Dept Pathol, Oslo, Norway. [Holte, Harald] Univ Hosp Oslo, Dept Oncol, Oslo, Norway. [Vose, Julie M.; Armitage, James O.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Ullrich, Fred] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. [Jaffe, Elaine S.] NCI, Dept Pathol, Bethesda, MD 20892 USA. [Savage, Kerry J.; Connors, Joseph M.] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Rimsza, Lisa] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mueller-Hermelink, Konrad] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Ruediger, Thomas] Stadt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany. [Coiffier, Bertrand] Ctr Hosp Lyon Sud, Dept Hematol, Lyon, France. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Berger, Francoise] Ctr Hosp Lyon Sud, Dept Pathol, Lyon, France. [Tobinai, Kensei] Natl Canc Ctr, Hematol & Stem Cell Transplantat Div, Tokyo, Japan. [Au, Wing Y.; Liang, Raymond] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Montserrat, Emili] Univ Barcelona Hosp, Inst Hematol & Oncol, Barcelona, Spain. [Hochberg, Ephraim P.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA USA. [Pileri, Stefano] Univ Bologna Hosp, Dept Pathol, Bologna, Italy. [Federico, Massimo] Univ Modena & Reggio Emilia, Dept Oncol & Haematol, Modena, Italy. [Nathwani, Bharat] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Nathwani, Bharat] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. RP Delabie, J (reprint author), Univ Oslo, Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway. EM jan.delabie@medisin.uio.no RI Federico, Massimo/A-6801-2012; Federico, Massimo/J-5984-2014; OI Federico, Massimo/0000-0002-9889-3796; Federico, Massimo/0000-0002-5074-3262; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301 NR 34 TC 82 Z9 87 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 7 PY 2011 VL 118 IS 1 BP 148 EP 155 DI 10.1182/blood-2011-02-335216 PG 8 WC Hematology SC Hematology GA 789HI UT WOS:000292505900021 PM 21566094 ER PT J AU Bhat, KL Markham, GD Larkin, JD Bock, CW AF Bhat, Krishna L. Markham, George D. Larkin, Joseph D. Bock, Charles W. TI Thermodynamics of Boroxine Formation from the Aliphatic Boronic Acid Monomers R-B(OH)(2) (R = H, H3C, H2N, HO, and F): A Computational Investigation SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID POLARIZABLE CONTINUUM MODEL; QUADRATIC CONFIGURATION-INTERACTION; CORRELATED MOLECULAR CALCULATIONS; ORTHORHOMBIC METABORIC ACID; METHYL TRANSFER-REACTIONS; CROSS-COUPLING REACTIONS; INTERNAL LEWIS-BASE; GAUSSIAN-BASIS SETS; WAVE-FUNCTIONS; ORGANOBORON COMPOUNDS AB Boroxines are the six-membered cydotrimeric dehydration products of organoboronic acids, 3R-B(OH)(2) R3B3O3 + 3H(2)O, and in recent years have emerged as a useful class of organoboron molecules with applications in organic synthesis both as reagents and catalysts, as structural components in boronic-acid-derived pharmaceutical agents, and as anion acceptors and electrolyte additives for battery materials [Korich, A. L.; Iovine, P. M. Dalton Trans. 2010, 39, 1423 1431]. Second-order Moller-Plesset perturbation theory, in conjunction with the Dunning-Woon correlation-consistent cc-pVDZ, aug-cc-pVDZ, cc-pVTZ, and aug-cc-pVTZ basis sets, was used to investigate the structures and relative energies of the endo-exo, anti, and syn conformers of the aliphatic boronic acids R B(OH)(2) (R = H, H3C, H2N, HO, and F), as well as the thermodynamics of their boroxine formation; single-point calculations at the MP2/aug-cc-pVQZ, MP2/aug-cc-pV5Z, and CCSD(T)/aug-cc-pVTZ levels using the MP2/aug-cc-pVTZ optimized geometries were also performed in selected cases. The endo-exo conformer was generally lowest in energy in vacuo, as well as in PCM and CPCM models of aqueous and carbon tetrachloride media. The values of Delta H-298(0) for boroxine formation via dehydration from the endo-exo conformers of these aliphatic boronic acids ranged from -2.9 for (H2N)(3)B3O3 to +12.2 kcal/mol for H3B3O3 at the MP2/aug-cc-pVTZ level in vacuo; for H3B3O3, the corresponding values in PCM/UFF implicit carbon tetrachloride and aqueous media were +11.2 and +9.8 kcal/mol, respectively. On the basis of our calculations, we recommend that Delta H-f(298 K) for boroxine listed in the JANAF compilation needs to be revised from -290.0 to approximately -277.0 kcal/mol. C1 [Bock, Charles W.] Philadelphia Univ, Dept Chem & Biochem, Sch Sci & Hlth, Philadelphia, PA 19144 USA. [Bhat, Krishna L.] Widener Univ, Dept Chem, Chester, PA 19013 USA. [Markham, George D.] Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. [Larkin, Joseph D.] NHLBI, NIH, Bethesda, MD 20851 USA. RP Bock, CW (reprint author), Philadelphia Univ, Dept Chem & Biochem, Sch Sci & Hlth, Sch House Lane & Henry Ave, Philadelphia, PA 19144 USA. EM bock.charles@gmail.com FU NIH, NHLBI; NIH [GM31186]; NCI [CA06927]; Commonwealth of Pennsylvania FX This research was supported in part (J.D.L.) by the Intramural Research Program of the NIH, NHLBI. G.D.M. would like to thank the NIH (GM31186) and NCI (CA06927) for financial support of this work, which was also supported by an appropriation from the Commonwealth of Pennsylvania. The High Performance Computing Facility at the Fox Chase Cancer Center and the PQS Cluster Facility at Philadelphia University were used for the calculations described in this article. This study also utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 124 TC 17 Z9 17 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JUL 7 PY 2011 VL 115 IS 26 BP 7785 EP 7793 DI 10.1021/jp202409m PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 786CQ UT WOS:000292281300043 PM 21650154 ER PT J AU Pastor, RW MacKerell, AD AF Pastor, R. W. MacKerell, A. D., Jr. TI Development of the CHARMM Force Field for Lipids SO JOURNAL OF PHYSICAL CHEMISTRY LETTERS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; DEUTERIUM MAGNETIC-RESONANCE; FATTY ACYL CHAINS; COMPUTER-SIMULATION; SURFACE-TENSION; LIQUID/LIQUID INTERFACES; CONSTANT-PRESSURE; LIQUID-CRYSTAL; BILAYER; MEMBRANES AB The development of the CHARMM additive all-atom lipid force field (FF) is traced from the early 1990s to the most recent version (C36) published in 2010. Though simulations with early versions yielded useful results, they failed to reproduce two important quantities, a zero surface tension at the experimental bilayer surface area and the signature splitting of the deuterium order parameters in the glycerol and upper chain carbons. Systematic optimization of parameters based on high-level quantum mechanical data and free-energy simulations have resolved these issues, and bilayers with a wide range of lipids can be simulated in tensionless ensembles using C36. Issues associated with other all-atom lipid FFs, success and limitations in the C36 FF, and ongoing developments are also discussed. C1 [MacKerell, A. D., Jr.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP MacKerell, AD (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM alex@outerbanks.umaryland.edu OI MacKerell, Alex/0000-0001-8287-6804 FU NIH [GM070855, GM072558, GM015101]; University of Maryland Computer-Aided Drug Design Center; NIH, National Heart, Lung and Blood Institute FX We thank our many collaborators involved in this now two-decade project, especially Bernard Brooks, Scott Feller, Jeffery Klauda, Benoit Roux, Douglas Tobias, and Richard Venable. Experimentalists Michael Brown, Klaus Gawrisch, Stuart McLaughlin, John Nagle, and Stephen White have also been indispensible for providing data, often before publication, and helping us understand it. Financial support from the NIH (GM070855, GM072558, and GM015101 to A.D.M.) and the University of Maryland Computer-Aided Drug Design Center are appreciated. This research was supported in part by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. NR 50 TC 94 Z9 95 U1 3 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7185 J9 J PHYS CHEM LETT JI J. Phys. Chem. Lett. PD JUL 7 PY 2011 VL 2 IS 13 BP 1526 EP 1532 DI 10.1021/jz200167q PG 7 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Atomic, Molecular & Chemical SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 794JW UT WOS:000292893400007 PM 21760975 ER PT J AU Radoshitzky, SR Longobardi, LE Kuhn, JH Retterer, C Dong, L Clester, JC Kota, K Carra, J Bavari, S AF Radoshitzky, Sheli R. Longobardi, Lindsay E. Kuhn, Jens H. Retterer, Cary Dong, Lian Clester, Jeremiah C. Kota, Krishna Carra, John Bavari, Sina TI Machupo Virus Glycoprotein Determinants for Human Transferrin Receptor 1 Binding and Cell Entry SO PLOS ONE LA English DT Article ID HEMORRHAGIC-FEVER ARENAVIRUSES; GP-C; SUBTILASE SKI-1/S1P; SIGNAL PEPTIDE; IDENTIFICATION; CLEAVAGE; JUNIN AB Machupo virus (MACV) is a highly pathogenic New World arenavirus that causes hemorrhagic fever in humans. MACV, as well as other pathogenic New World arenaviruses, enter cells after their GP1 attachment glycoprotein binds to their cellular receptor, transferrin receptor 1 (TfR1). TfR1 residues essential for this interaction have been described, and a co-crystal of MACV GP1 bound to TfR1 suggests GP1 residues important for this association. We created MACV GP1 variants and tested their effect on TfR1 binding and virus entry to evaluate the functional significance of some of these and additional residues in human and simian cells. We found residues R111, D123, Y122, and F226 to be essential, D155, and P160 important, and D114, S116, D140, and K169 expendable for the GP1-TfR1 interaction and MACV entry. Several MACV GP1 residues that are critical for the interaction with TfR1 are conserved among other New World arenaviruses, indicating a common basis of receptor interaction. Our findings also open avenues for the rational development of viral entry inhibitors. C1 [Radoshitzky, Sheli R.; Longobardi, Lindsay E.; Retterer, Cary; Dong, Lian; Clester, Jeremiah C.; Kota, Krishna; Carra, John; Bavari, Sina] USAMRIID, Div Toxicol, Frederick, MD USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, Frederick, MD USA. RP Radoshitzky, SR (reprint author), USAMRIID, Div Toxicol, Frederick, MD USA. EM sina.bavari@amedd.army.mil RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU Joint Science and Technology Office Transformational Medical Technologies [TMTI0048_09_RD_T]; Defense Threat Reduction Agency [4.10022_08_RD_B]; NIAID [HHSN272200200016I] FX This research was partially supported by the Joint Science and Technology Office Transformational Medical Technologies (proposal # TMTI0048_09_RD_T) and Defense Threat Reduction Agency (proposal #4.10022_08_RD_B) to SB. JHK performed this work as an employee of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, Contract No. HHSN272200200016I. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 13 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2011 VL 6 IS 7 AR e21398 DI 10.1371/journal.pone.0021398 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791HI UT WOS:000292655400005 PM 21750710 ER PT J AU Wentzensen, N Black, A Jacobs, K Yang, HP Berg, CD Caporaso, N Peters, U Ragard, L Buys, SS Chanock, S Hartge, P AF Wentzensen, Nicolas Black, Amanda Jacobs, Kevin Yang, Hannah P. Berg, Christine D. Caporaso, Neil Peters, Ulrike Ragard, Lawrence Buys, Saundra S. Chanock, Stephen Hartge, Patricia TI Genetic Variation on 9p22 Is Associated with Abnormal Ovarian Ultrasound Results in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; RANDOMIZED-TRIAL; RISK-FACTORS AB Background: A recent ovarian cancer genome-wide association study (GWAS) identified a locus on 9p22 associated with reduced ovarian cancer risk. The single nucleotide polymorphism (SNP) markers localize to the BNC2 gene, which has been associated with ovarian development. Methods: We analyzed the association of 9p22 SNPs with transvaginal ultrasound (TVU) screening results and CA-125 blood levels from participants without ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO); 1,106 women with adequate ultrasound screening results and available genotyping information were included in the study. Results: We observed a significantly increased risk of abnormal suspicious TVU results for seven SNPs on 9p22, with odds ratios between 1.68 (95% CI: 1.04-2.72) for rs4961501 and 2.10 (95% CI: 1.31-3.38) for rs12379183. Associations were restricted to abnormal suspicious findings at the first TVU screen. We did not observe an association between 9p22 SNPs and CA-125 levels. Conclusions: Our findings suggest that 9p22 SNPs, which were found to be associated with decreased risk of ovarian cancer in a recent GWAS, are associated with sonographically detectable ovarian abnormalities. Our results corroborate the relevance of the 9p22 locus for ovarian biology. Further studies are required to understand the complex relationship between screening abnormalities and ovarian carcinogenesis and to evaluate whether this locus can influence the risk stratification of ovarian cancer screening. C1 [Wentzensen, Nicolas; Black, Amanda; Yang, Hannah P.; Caporaso, Neil; Chanock, Stephen; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Jacobs, Kevin; Chanock, Stephen] NCI, Core Genotyping Facil, Rockville, MD USA. [Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Ragard, Lawrence] Westat Corp, Rockville, MD USA. [Buys, Saundra S.] Huntsman Canc Inst, Div Oncol, Salt Lake City, UT USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM wentzenn@mail.nih.gov RI Berg , Christine/K-1047-2014 FU Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2011 VL 6 IS 7 AR e21731 DI 10.1371/journal.pone.0021731 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791HI UT WOS:000292655400014 PM 21750727 ER PT J AU Collins, PY Patel, V Joestl, SS March, D Insel, TR Daar, AS AF Collins, Pamela Y. Patel, Vikram Joestl, Sarah S. March, Dana Insel, Thomas R. Daar, Abdallah S. CA Sci Advisory Board Executive Comm Grand Challenges Gl TI Grand challenges in global mental health SO NATURE LA English DT Editorial Material ID PRIORITIES; CONSENSUS; SERVICES; DEMENTIA C1 [Collins, Pamela Y.; Joestl, Sarah S.; March, Dana] NIMH, Off Res Dispair & Global Mental Hlth, Bethesda, MD USA. [Patel, Vikram] London Sch Hyg & Trop Med UK, Ctr Global Mental Hlth, Sangath, Goa, India. [Daar, Abdallah S.] Univ Toronto, Toronto, ON, Canada. [Daar, Abdallah S.] McLaughlin Rotman Ctr Global Hlth, Toronto, ON, Canada. RP Collins, PY (reprint author), NIMH, Off Res Dispair & Global Mental Hlth, Bethesda, MD USA. EM pamela.collins@nih.gov; a.daar@utoronto.ca RI Hall, Wayne/A-3283-2008; Durkin, Maureen/B-7834-2015; OI Hall, Wayne/0000-0003-1984-0096; Kapur, Shitij/0000-0002-2231-2924; Patel, Vikram/0000-0003-1066-8584; Bordin, Isabel A./0000-0002-3173-5419 FU Intramural NIH HHS [Z99 MH999999]; NICHD NIH HHS [P30 HD003352]; Wellcome Trust [079113, 091834] NR 16 TC 577 Z9 595 U1 9 U2 81 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 7 PY 2011 VL 475 IS 7354 BP 27 EP 30 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 788RE UT WOS:000292461300013 PM 21734685 ER PT J AU Han, YH Kang, Y Torres-Jerez, I Cheung, F Town, CD Zhao, PX Udvardi, MK Monteros, MJ AF Han, Yuanhong Kang, Yun Torres-Jerez, Ivone Cheung, Foo Town, Christopher D. Zhao, Patrick X. Udvardi, Michael K. Monteros, Maria J. TI Genome-wide SNP discovery in tetraploid alfalfa using 454 sequencing and high resolution melting analysis SO BMC GENOMICS LA English DT Article ID MEDICAGO-TRUNCATULA; CROP LEGUMES; DNA; MARKERS; SATIVA; GENE; MAP AB Background: Single nucleotide polymorphisms (SNPs) are the most common type of sequence variation among plants and are often functionally important. We describe the use of 454 technology and high resolution melting analysis (HRM) for high throughput SNP discovery in tetraploid alfalfa (Medicago sativa L.), a species with high economic value but limited genomic resources. Results: The alfalfa genotypes selected from M. sativa subsp. sativa var. 'Chilean' and M. sativa subsp. falcata var. 'Wisfal', which differ in water stress sensitivity, were used to prepare cDNA from tissue of clonally-propagated plants grown under either well-watered or water-stressed conditions, and then pooled for 454 sequencing. Based on 125.2 Mb of raw sequence, a total of 54,216 unique sequences were obtained including 24,144 tentative consensus (TCs) sequences and 30,072 singletons, ranging from 100 bp to 6,662 bp in length, with an average length of 541 bp. We identified 40,661 candidate SNPs distributed throughout the genome. A sample of candidate SNPs were evaluated and validated using high resolution melting (HRM) analysis. A total of 3,491 TCs harboring 20,270 candidate SNPs were located on the M. truncatula (MT 3.5.1) chromosomes. Gene Ontology assignments indicate that sequences obtained cover a broad range of GO categories. Conclusions: We describe an efficient method to identify thousands of SNPs distributed throughout the alfalfa genome covering a broad range of GO categories. Validated SNPs represent valuable molecular marker resources that can be used to enhance marker density in linkage maps, identify potential factors involved in heterosis and genetic variation, and as tools for association mapping and genomic selection in alfalfa. C1 [Han, Yuanhong; Monteros, Maria J.] Samuel Roberts Noble Fdn Inc, Forage Improvement Div, Ardmore, OK 73401 USA. [Kang, Yun; Torres-Jerez, Ivone; Zhao, Patrick X.; Udvardi, Michael K.] Samuel Roberts Noble Fdn Inc, Div Plant Biol, Ardmore, OK 73401 USA. [Cheung, Foo] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Cheung, Foo; Town, Christopher D.] J Craig Venter Inst, Rockville, MD 20850 USA. RP Monteros, MJ (reprint author), Samuel Roberts Noble Fdn Inc, Forage Improvement Div, 2510 Sam Noble Pkwy, Ardmore, OK 73401 USA. EM mjmonteros@noble.org FU Samuel Roberts Noble Foundation; Oklahoma Bioenergy Center; Forage Genetics International FX This study was supported by The Samuel Roberts Noble Foundation, grants from the Oklahoma Bioenergy Center to M.J. Monteros and M. K. Udvardi, and a grant from Forage Genetics International to M.J. Monteros. We would like to thank Shelby Bidwell for uploading the 454 sequences to Genebank and assisting in sequence assembly, Cook Ly for assistance with preparing figures, and Mark Sorrells for providing comments on the manuscript. NR 36 TC 37 Z9 39 U1 4 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 6 PY 2011 VL 12 AR 350 DI 10.1186/1471-2164-12-350 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 806ZF UT WOS:000293856300001 ER PT J AU Basseville, A Preisser, L Trecesson, SD Boisdron-Celle, M Gamelin, E Coqueret, O Morel, A AF Basseville, Agnes Preisser, Laurence Trecesson, Sophie de Carne Boisdron-Celle, Michele Gamelin, Erick Coqueret, Olivier Morel, Alain TI Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells SO MOLECULAR CANCER LA English DT Article ID PREGNANE-X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; ST JOHNS WORT; NUCLEAR RECEPTOR; 7-ETHYL-10-HYDROXYCAMPTOTHECIN SN-38; GLUCOCORTICOID-RECEPTOR; MULTIDRUG-RESISTANCE; ANTICANCER AGENTS; HUMAN HEPATOCYTES; MALIGNANT GLIOMA AB Background: Resistance to chemotherapy remains one of the principle obstacles to the treatment of colon cancer. In order to identify the molecular mechanism of this resistance, we investigated the role of the steroid and xenobiotic receptor (SXR) in the induction of drug resistance. Indeed, this nuclear receptor plays an important role in response to xenobiotics through the upregulation of detoxification genes. Following drug treatments, SXR is activated and interacts with the retinoid X receptor (RXR) to induce expression of some genes involved in drug metabolism such as phase I enzyme (like CYP), phase II enzymes (like UGT) and transporters (e.g. MDR1). Results: In this study, we have shown that endogenous SXR is activated in response to SN-38, the active metabolite of the anticancer drug irinotecan, in human colon cancer cell lines. We have found that endogenous SXR translocates into the nucleus and associates with RXR upon SN-38 treatment. Using ChIP, we have demonstrated that endogenous SXR, following its activation, binds to the native promoter of the CYP3A4 gene to induce its expression. RNA interference experiments confirmed SXR involvement in CYP3A4 overexpression and permitted us to identify CYP3A5 and MRP2 transporter as SXR target genes. As a consequence, cells overexpressing SXR were found to be less sensitive to irinotecan treatment. Conclusions: Altogether, these results suggest that the SXR pathway is involved in colon cancer irinotecan resistance in colon cancer cell line via the upregulation of select detoxification genes. C1 [Basseville, Agnes; Preisser, Laurence; Trecesson, Sophie de Carne; Boisdron-Celle, Michele; Gamelin, Erick; Coqueret, Olivier; Morel, Alain] Univ Angers, Canc Ctr Paul Papin, INSERM, U892, F-49033 Angers, France. [Basseville, Agnes] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morel, A (reprint author), Univ Angers, Canc Ctr Paul Papin, INSERM, U892, 2 Rue Moll, F-49033 Angers, France. EM Alain.Morel@ico.unicancer.fr RI preisser, laurence/K-7583-2015; Coqueret, Olivier/K-9660-2015 OI Coqueret, Olivier/0000-0002-2843-7867 FU Ligue Contre le Cancer FX We wish to thank Anne Lise Poirier for her statistical expertise and Dr Susan Bates for allowing us to complete the experiments in her lab. This work was supported by grants from the Ligue Contre le Cancer (equipes labelisees 2007, O.C. and E.G. and comite du Maine et Loire). NR 55 TC 23 Z9 23 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUL 6 PY 2011 VL 10 AR 80 DI 10.1186/1476-4598-10-80 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 797PK UT WOS:000293139600001 PM 21733184 ER PT J AU Collins, FS AF Collins, Francis S. TI Reengineering Translational Science: The Time Is Right SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HUMAN-GENOME; DRUG DEVELOPMENT; DISEASE; TRIAL; PROTECTION; DISCOVERY; ONCOLOGY; LESSONS; IMPROVE; PROJECT AB Despite dramatic advances in the molecular pathogenesis of disease, translation of basic biomedical research into safe and effective clinical applications remains a slow, expensive, and failure-prone endeavor. To pursue opportunities for disruptive translational innovation, the U. S. National Institutes of Health (NIH) intends to establish a new entity, the National Center for Advancing Translational Sciences (NCATS). The mission of NCATS is to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of diseases and conditions. The new center's activities will complement, and not compete with, translational research being carried out at NIH and elsewhere in the public and private sectors. C1 NIH, Off Director, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM francis.collins@nih.gov NR 55 TC 141 Z9 145 U1 1 U2 34 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 6 PY 2011 VL 3 IS 90 AR 90cm17 DI 10.1126/scitranslmed.3002747 PG 6 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NZ UT WOS:000292982200001 PM 21734173 ER PT J AU Zustiak, SP Nossal, R Sackett, DL AF Zustiak, Silviya P. Nossal, Ralph Sackett, Dan L. TI Hindered Diffusion in Polymeric Solutions Studied by Fluorescence Correlation Spectroscopy SO BIOPHYSICAL JOURNAL LA English DT Article ID PROTEIN DIFFUSION; LIVING CELLS; CROWDED ENVIRONMENT; ANOMALOUS DIFFUSION; CYTOPLASM; BINDING; DISSOCIATION; MOBILITY; POLYELECTROLYTE; RIBONUCLEASE AB Diffusion of molecules in the crowded and charged interior of the cell has long been of interest for understanding cellular processes. Here, we introduce a model system of hindered diffusion that includes both crowding and binding. In particular, we obtained the diffusivity of the positively charged protein, ribonuclease A (RNase), in solutions of dextrans of various charges (binding) and concentrations (crowding), as well as combinations of both, in a buffer of physiological ionic strength. Using fluorescence correlation spectroscopy, we observed that the diffusivity of RNase was unaffected by the presence of positively charged or neutral dextrans in the dilute regime but was affected by crowding at higher polymer concentrations. Conversely, protein diffusivity was significantly reduced by negatively charged dextrans, even at 0.4 mu M (0.02% w/v) dextran. The diffusivity of RNase decreased with increasing concentrations of negative dextran, and the amount of bound RNase increased until it reached a plateau of similar to 80% bound RNase. High salt concentrations were used to establish the electrostatic nature of the binding. Binding of RNase to the negatively charged dextrans was further confirmed by ultrafiltration. C1 [Zustiak, Silviya P.; Nossal, Ralph; Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Dev, Program Phys Biol, NIH, Bethesda, MD USA. RP Zustiak, SP (reprint author), Eunice Kennedy Shriver Natl Inst Child Dev, Program Phys Biol, NIH, Bethesda, MD USA. EM zustiaksp@mail.mih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by funds from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 42 TC 20 Z9 20 U1 0 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL 6 PY 2011 VL 101 IS 1 BP 255 EP 264 DI 10.1016/j.bpj.2011.05.035 PG 10 WC Biophysics SC Biophysics GA 790EQ UT WOS:000292571700029 PM 21723836 ER PT J AU Yadav, H Quijano, C Kamaraju, AK Gavrilova, O Malek, R Chen, WP Zerfas, P Duan, ZG Wright, EC Stuelten, C Sun, P Lonning, S Skarulis, M Sumner, AE Finkel, T Rane, SG AF Yadav, Hariom Quijano, Celia Kamaraju, Anil K. Gavrilova, Oksana Malek, Rana Chen, Weiping Zerfas, Patricia Duan Zhigang Wright, Elizabeth C. Stuelten, Christina Sun, Peter Lonning, Scott Skarulis, Monica Sumner, Anne E. Finkel, Toren Rane, Sushil G. TI Protection from Obesity and Diabetes by Blockade of TGF-beta/Smad3 Signaling SO CELL METABOLISM LA English DT Article ID GROWTH-FACTOR-BETA; BROWN ADIPOSE-TISSUE; PLASMINOGEN-ACTIVATOR INHIBITOR-1; DIET-INDUCED OBESITY; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; ADIPOCYTE DIFFERENTIATION; TARGETED DISRUPTION; GENETIC-CONTROL; WHITE FAT AB Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1 alpha expression. We observe significant correlation between TGF-beta 1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta activity might be an effective treatment strategy for obesity and diabetes. C1 [Yadav, Hariom; Kamaraju, Anil K.; Malek, Rana; Skarulis, Monica; Sumner, Anne E.; Rane, Sushil G.] NIDDK, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Quijano, Celia; Finkel, Toren] NHLBI, Ctr Mol Med, Bethesda, MD 20892 USA. [Gavrilova, Oksana] Mouse Metab Core Lab, Bethesda, MD 20892 USA. [Chen, Weiping] Genom Core Facil, Bethesda, MD 20892 USA. [Zerfas, Patricia] Off Director, Off Res Serv, Bethesda, MD 20892 USA. [Duan Zhigang; Wright, Elizabeth C.] NIDDK, Off Res Serv, Bethesda, MD 20892 USA. [Stuelten, Christina] NCI, Bethesda, MD 20892 USA. [Sun, Peter] NIAID, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Lonning, Scott] Genzyme Corp, Framingham, MA 01701 USA. [Quijano, Celia] Univ Republica, Dept Bioquim, Fac Med, Montevideo, Uruguay. RP Rane, SG (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, South Dr & Old Georgetown Rd, Bethesda, MD 20892 USA. EM ranes@mail.nih.gov FU NIH FX This work is dedicated to the memory of G.S. Rane. The authors appreciate the support of members of the Rane laboratory. The authors thank Alexandra McPherron (NIDDK) for advice. The technical support provided by George Poy, Madia Ricks, Anita Tambay, Ugochi Ukegbu, Richard Chen, Alice Franks, Janet Lee, William Jou, Tatyana Chanturiya, and Kevin Wang is greatly appreciated. This work was supported by funds from the NIH intramural program. NR 47 TC 153 Z9 157 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL 6 PY 2011 VL 14 IS 1 BP 67 EP 79 DI 10.1016/j.cmet.2011.04.013 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 790JB UT WOS:000292583200010 PM 21723505 ER PT J AU Tang, M Pelkey, KA Ng, D Ivakine, E McBain, CJ Salter, MW McInnes, RR AF Tang, Man Pelkey, Kenneth A. Ng, David Ivakine, Evgueni McBain, Chris J. Salter, Michael W. McInnes, Roderick R. TI Neto1 Is an Auxiliary Subunit of Native Synaptic Kainate Receptors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MOSSY-FIBER SYNAPSES; LONG-TERM POTENTIATION; GLUTAMATE RECEPTORS; PYRAMIDAL CELLS; HIGH-AFFINITY; CAENORHABDITIS-ELEGANS; GLUR6-DEFICIENT MICE; EXCITATORY SYNAPSES; HIPPOCAMPAL-NEURONS; NMDA RECEPTORS AB Ionotropic glutamate receptors of AMPA, NMDA, and kainate receptor (KAR) subtypes mediate fast excitatory synaptic transmission in the vertebrate CNS. Auxiliary proteins have been identified for AMPA and NMDA receptor complexes, but little is known about KAR complex proteins. We previously identified the CUB (complement C1r/C1s, Uegf, Bmpl) domain protein, Neto1, as an NMDA receptor-associated polypeptide. Here, we show that Neto1 is also an auxiliary subunit for endogenous synaptic KARs. We found that Neto1 and KARs coimmunoprecipitated from brain lysates, from postsynaptic densities (PSDs) and, in a manner dependent on Neto1 CUB domains, when coexpressed in heterologous cells. In Neto1-null mice, there was an similar to 50% reduction in the abundance of GluK2-KARs in hippocampal PSDs. Neto1 strongly localized to CA3 stratum lucidum, and loss of Neto1 resulted in a selective deficit in KAR-mediated neurotransmission at mossy fiber-CA3 pyramidal cell (MF-CA3) synapses: KAR-mediated EPSCs in Neto1-null mice were reduced in amplitude and decayed more rapidly than did those in wild-type mice. In contrast, the loss of Neto2, which also localizes to stratum lucidum and interacts with KARs, had no effect on KAR synaptic abundance or MF-CA3 transmission. Indeed, MF-CA3 KAR deficits in Neto1/Neto2-double-null mutant mice were indistinguishable from Neto1 single-null mice. Thus, our findings establish Neto1 as an auxiliary protein required for synaptic function of KARs. The ability of Neto1 to regulate both NMDARs and KARs reveals a unique dual role in controlling synaptic transmission by serving as an auxiliary protein for these two classes of ionotropic glutamate receptors in a synapse-specific fashion. C1 [McInnes, Roderick R.] McGill Univ, Jewish Gen Hosp, Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada. [Tang, Man; Ng, David; Ivakine, Evgueni; McInnes, Roderick R.] Hosp Sick Children, Res Inst, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada. [Salter, Michael W.] Hosp Sick Children, Res Inst, Program Neurosci & Mental Hlth, Toronto, ON M5G 1X8, Canada. [Tang, Man; Ng, David; McInnes, Roderick R.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Salter, Michael W.] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada. [Pelkey, Kenneth A.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [McInnes, Roderick R.] McGill Univ, Jewish Gen Hosp, Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada. RP McInnes, RR (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada. EM mike.salter@utoronto.ca; rod.mcinnes@mcgill.ca FU Canadian Institutes of Health Research [MOP-7315, IOP-54037]; NICHD FX This study was supported by Grants MOP-7315 and IOP-54037 from the Canadian Institutes of Health Research to R.R.M., and an NICHD Intramural award to C.J.M.; R.R.M. and M.W.S. hold Canada Research Chairs; M.W.S. is an International Research Scholar of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank L. Ploder, R. Szilard, D. Mahuran, and R. Reithmeier for technical advice; and K. Roche for the FLAG-GluK2 plasmid construct. NR 63 TC 39 Z9 40 U1 0 U2 16 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 6 PY 2011 VL 31 IS 27 BP 10009 EP 10018 DI 10.1523/JNEUROSCI.6617-10.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 789OE UT WOS:000292524400024 PM 21734292 ER PT J AU Whitby, LR Ando, Y Setola, V Vogt, PK Roth, BL Boger, DL AF Whitby, Landon R. Ando, Yoshio Setola, Vincent Vogt, Peter K. Roth, Bryan L. Boger, Dale L. TI Design, Synthesis, and Validation of a beta-Turn Mimetic Library Targeting Protein-Protein and Peptide-Receptor Interactions SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHASE COMBINATORIAL SYNTHESIS; IMINODIACETIC ACID LIBRARIES; MOLECULAR-DYNAMICS METHODS; OLEFIN METATHESIS REACTION; SMALL ORGANIC-MOLECULES; DNA-BINDING MOLECULES; MU-OPIOID RECEPTOR; CONFORMATIONAL-ANALYSIS; PARALLEL SYNTHESIS; SOLID-PHASE AB The design and synthesis of a beta-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10 245 beta-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a beta-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K-i = 390 and 23 nM, respectively) for the K-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring beta-turn. Unique to the design and because of the C-2 symmetry of the template, a typical 20 x 20 x 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 x 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid liquid or liquid solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (>100-fold) and affinities (as low as = 80 nM for KOR). A key insight to emerge from the studies is that the phenol of Tyr in endogenous ligands bearing the H-Tyr-Pro-Trp/Phe-Phe-NH2 beta-turn is important for MOR binding but may not be important for KOR (accommodated, but not preferred) and that the resulting selectivity for KOR observed with its removal can be increased by replacing the phenol OH with a chlorine substituent, further enhancing KOR affinity. C1 [Whitby, Landon R.; Ando, Yoshio; Vogt, Peter K.; Boger, Dale L.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Whitby, Landon R.; Ando, Yoshio; Vogt, Peter K.; Boger, Dale L.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Setola, Vincent; Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27514 USA. RP Boger, DL (reprint author), Scripps Res Inst, Dept Chem, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM boger@scripps.edu RI Roth, Bryan/F-3928-2010; OI Vogt, Peter K/0000-0002-4519-7500 FU National Institutes of Health [CA078045, R01 DA017204, R01DA027170] FX We gratefully acknowledge the financial support of the National Institutes of Health (CA078045, D.L.B. and P.K.V.; R01 DA017204, R01DA027170, the Michael Hooker Distinguished Professorship and the NIMH Psychoactive Drug Screening Program Contract, BLit). L.RW. is a Skaggs Fellow. NR 118 TC 32 Z9 32 U1 0 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 6 PY 2011 VL 133 IS 26 BP 10184 EP 10194 DI 10.1021/ja201878v PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 792BN UT WOS:000292715600046 PM 21609016 ER PT J AU Stany, MP Vathipadiekal, V Ozbun, L Stone, RL Mok, SC Xue, H Kagami, T Wang, YW McAlpine, JN Bowtell, D Gout, PW Miller, DM Gilks, CB Huntsman, DG Ellard, SL Wang, YZ Vivas-Mejia, P Lopez-Berestein, G Sood, AK Birrer, MJ AF Stany, Michael P. Vathipadiekal, Vinod Ozbun, Laurent Stone, Rebecca L. Mok, Samuel C. Xue, Hui Kagami, Takashi Wang, Yuwei McAlpine, Jessica N. Bowtell, David Gout, Peter W. Miller, Dianne M. Gilks, C. Blake Huntsman, David G. Ellard, Susan L. Wang, Yu-Zhuo Vivas-Mejia, Pablo Lopez-Berestein, Gabriel Sood, Anil K. Birrer, Michael J. TI Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; INTERFERING RNA DELIVERY; IN-VIVO; FACTOR EXPRESSION; GENE-EXPRESSION; ANTITUMOR-ACTIVITY; TYROSINE KINASE; FACTOR RECEPTOR; CARCINOMA AB Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients. C1 [Stany, Michael P.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Vathipadiekal, Vinod; Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Vathipadiekal, Vinod; Birrer, Michael J.] Harvard Univ, Sch Med, Boston, MA USA. [Ozbun, Laurent] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stone, Rebecca L.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Mok, Samuel C.] Harvard Univ, Brigham & Womens Hosp, Sch Publ Hlth, Boston, MA 02115 USA. [Xue, Hui; Kagami, Takashi; Wang, Yuwei; Gout, Peter W.; Wang, Yu-Zhuo] British Columbia Canc Agcy, Living Tumor Lab, Vancouver, BC V5Z 4E6, Canada. [McAlpine, Jessica N.; Miller, Dianne M.] Univ British Columbia, Dept Obstet & Gynecol, Div Gynecol Oncol, Vancouver, BC V5Z 1M9, Canada. [Bowtell, David] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Gilks, C. Blake; Huntsman, David G.] British Columbia Canc Agcy, Ctr Translat & Appl Genom, Vancouver Gen Hosp, Dept Pathol,Genet Pathol Evaluat Ctr, Vancouver, BC V5Z 4E6, Canada. [Ellard, Susan L.] British Columbia Canc Agcy So Interior, Dept Med Oncol, Kelowna, BC, Canada. [Wang, Yu-Zhuo] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada. [Wang, Yu-Zhuo] Univ British Columbia, Vancouver Prostate Ctr, Vancouver, BC V5Z 1M9, Canada. [Vivas-Mejia, Pablo; Lopez-Berestein, Gabriel] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA. RP Stany, MP (reprint author), Walter Reed Army Med Ctr, Washington, DC 20307 USA. EM mbirrer@partners.org RI Bowtell, David/H-1007-2016; OI Bowtell, David/0000-0001-9089-7525; Vathipadiekal, Vinod/0000-0002-8181-6890 FU National Cancer Institute at the National Institutes of the Health; OvCaRe (an initiative of the Vancouver General Hospital and University of BC Hospital Foundation and the BC Cancer Foundation); BC Cancer Foundation; Pfizer Canada FX This work was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of the Health (MJB) and OvCaRe (an initiative of the Vancouver General Hospital and University of BC Hospital Foundation and the BC Cancer Foundation) (YZW), the BC Cancer Foundation and Pfizer Canada (Investigator-initiated project, SLE and YZW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 53 TC 37 Z9 37 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 6 PY 2011 VL 6 IS 7 AR e21121 DI 10.1371/journal.pone.0021121 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 791AK UT WOS:000292632000007 PM 21754983 ER PT J AU Liu, MH Eiden, MV AF Liu, Meihong Eiden, Maribeth V. TI The receptors for gibbon ape leukemia virus and amphotropic murine leukemia virus are not downregulated in productively infected cells SO RETROVIROLOGY LA English DT Article ID AMINO-ACID TRANSPORTER; AVIAN-LEUKOSIS VIRUS; ROUS SARCOMA VIRUS; SUPERINFECTION INTERFERENCE; ENVELOPE GLYCOPROTEIN; SURFACE RECEPTOR; HOST-RANGE; RETROVIRUSES; PARTICLES; PROTEINS AB Background: Over the last several decades it has been noted, using a variety of different methods, that cells infected by a specific gammaretrovirus are resistant to infection by other retroviruses that employ the same receptor; a phenomenon termed receptor interference. Receptor masking is thought to provide an earlier means of blocking superinfection, whereas receptor down regulation is generally considered to occur in chronically infected cells. Results: We used replication-competent GFP-expressing viruses containing either an amphotropic murine leukemia virus (A-MLV) or the gibbon ape leukemia virus (GALV) envelope. We also constructed similar viruses containing fluorescence-labeled Gag proteins for the detection of viral particles. Using this repertoire of reagents together with a wide range of antibodies, we were able to determine the presence and availability of viral receptors, and detect viral envelope proteins and particles presence on the cell surface of chronically infected cells. Conclusions: A-MLV or GALV receptors remain on the surface of chronically infected cells and are detectable by respective antibodies, indicating that these receptors are not downregulated in these infected cells as previously proposed. We were also able to detect viral envelope proteins on the infected cell surface and infected cells are unable to bind soluble A-MLV or GALV envelopes indicating that receptor binding sites are masked by endogenously expressed A-MLV or GALV viral envelope. However, receptor masking does not completely prevent A-MLV or GALV superinfection. C1 [Liu, Meihong; Eiden, Maribeth V.] NIMH, Sect Mol Virol, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Eiden, MV (reprint author), NIMH, Sect Mol Virol, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. EM eidenm@mail.nih.gov FU NIMH FX We thank Karen B. Farrell for technical advice; Jim Nagle and Debbie Kauffmann at the NINDS Sequencing Facility (National Institutes of Health) for sequencing; Parisa Moghaddam-Taaheri for experimental help; Jon Marsh and Jill Russ for supervising FACS operation and Vincent Schram and Lynne Holtzclaw in the Microscropy & Imaging Core, NICHD, NIH for technical guidance in confocal microscope and Wenqin Xu for her thoughtful comments and editorial assistance. NIMH intramural funding supported this work. NR 39 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 5 PY 2011 VL 8 AR 53 DI 10.1186/1742-4690-8-53 PG 14 WC Virology SC Virology GA 792FO UT WOS:000292726100001 PM 21729311 ER PT J AU Lam, CSP Lyass, A Kraigher-Krainer, E Massaro, JM Lee, DS Ho, JE Levy, D Redfield, MM Pieske, BM Benjamin, EJ Vasan, RS AF Lam, Carolyn S. P. Lyass, Asya Kraigher-Krainer, Elisabeth Massaro, Joseph M. Lee, Douglas S. Ho, Jennifer E. Levy, Daniel Redfield, Margaret M. Pieske, Burkert M. Benjamin, Emelia J. Vasan, Ramachandran S. TI Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community SO CIRCULATION LA English DT Article DE echocardiography; epidemiology; heart failure; risk factors ID OBSTRUCTIVE PULMONARY-DISEASE; DIASTOLIC DYSFUNCTION; SYSTOLIC DYSFUNCTION; ELDERLY-PATIENTS; NATURAL-HISTORY; OF-CARDIOLOGY; FRAMINGHAM; DIAGNOSIS; HEALTH; METAANALYSIS AB Background-Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF. Methods and Results-We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76 +/- 5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1:FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all P < 0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (P = 0.013). Conclusions-Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence. (Circulation. 2011;124:24-30.) C1 [Lam, Carolyn S. P.; Lyass, Asya; Massaro, Joseph M.; Lee, Douglas S.; Ho, Jennifer E.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Lyass, Asya] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Kraigher-Krainer, Elisabeth; Pieske, Burkert M.] Graz Univ, Dept Cardiol, Graz, Austria. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Toronto Gen Hosp, Toronto, ON M5G 1L7, Canada. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Lam, Carolyn S. P.; Redfield, Margaret M.] Mayo Clin, Rochester, MN USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM vasan@bu.edu RI Lee, Douglas/J-4315-2014; OI Massaro, Joseph/0000-0002-2682-4812; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute [NO1-HC-25195]; Canadian Institutes of Health Research FX This work was supported by the National Heart, Lung and Blood Institute (contract NO1-HC-25195). Dr Lee was supported by a clinician-scientist award from the Canadian Institutes of Health Research. NR 32 TC 91 Z9 95 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 5 PY 2011 VL 124 IS 1 BP 24 EP U85 DI 10.1161/CIRCULATIONAHA.110.979203 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 787KO UT WOS:000292375200016 PM 21670229 ER PT J AU Brindley, MA Hunt, CL Kondratowicz, AS Bowman, J Sinn, PL McCray, PB Quinn, K Weller, ML Chiorini, JA Maury, W AF Brindley, Melinda A. Hunt, Catherine L. Kondratowicz, Andrew S. Bowman, Jill Sinn, Patrick L. McCray, Paul B., Jr. Quinn, Kathrina Weller, Melodie L. Chiorini, John A. Maury, Wendy TI Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein SO VIROLOGY LA English DT Article DE Axl; Filovirus; Ebolavirus; Marburgvirus; Virus entry; Tyrosine kinase receptors ID VESICULAR STOMATITIS-VIRUS; VASCULAR SMOOTH-MUSCLE; HUMAN-IMMUNODEFICIENCY-VIRUS; DC-SIGN; ENDOTHELIAL-CELLS; CELLULAR ENTRY; GAS6; INFECTION; PROTEIN; ACTIVATION AB In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and alpha-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl. (C) 2011 Elsevier Inc. All rights reserved. C1 [Brindley, Melinda A.; Hunt, Catherine L.; Kondratowicz, Andrew S.; Bowman, Jill; Maury, Wendy] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Sinn, Patrick L.; McCray, Paul B., Jr.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Quinn, Kathrina; Weller, Melodie L.; Chiorini, John A.] NIH, Mol Physiol & Therapeut Branch, Natl Dent & Craniofacial Res Branch, Bethesda, MD 20892 USA. RP Maury, W (reprint author), Univ Iowa, Dept Microbiol, 3-750 Bowen Sci Bldg, Iowa City, IA 52242 USA. EM wendy-maury@uiowa.edu FU NIH NIDCR; NIH NIAID; [NIHAI064526]; [AI073330]; [NIHHL075363]; [NIHT32 A1007533] FX This work was supported by NIHAI064526 and AI073330 (W.M.), NIHHL075363 (P.B.M.) and intramural NIH NIAID biodefense and NIH NIDCR grants to J.A.C. M.A.B. and A.S.K. were supported through NIHT32 A1007533, a training grant in molecular virology. NR 55 TC 44 Z9 45 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL 5 PY 2011 VL 415 IS 2 BP 83 EP 94 DI 10.1016/j.virol.2011.04.002 PG 12 WC Virology SC Virology GA 778OH UT WOS:000291713500002 PM 21529875 ER PT J AU Joshi, A Garg, H Ablan, S Freed, EO Nagashima, K Manjunath, N Shankar, P AF Joshi, Anjali Garg, Himanshu Ablan, Sherimay Freed, Eric O. Nagashima, Kunio Manjunath, N. Shankar, Premlata TI Targeting the HIV entry, assembly and release pathways for anti-HIV gene therapy SO VIROLOGY LA English DT Article DE HIV; Gag; Envelope; Virus assembly; HIV entry; Dominant negative; Gene therapy ID IMMUNODEFICIENCY-VIRUS TYPE-1; WILD-TYPE VIRUS; GP41 CYTOPLASMIC TAIL; ZINC-FINGER NUCLEASES; GAG-MEMBRANE-BINDING; VIRAL MESSENGER-RNA; BYSTANDER APOPTOSIS; ENVELOPE GLYCOPROTEINS; PARTICLE-PRODUCTION; ENV PROTEINS AB Targeting the HIV entry and assembly pathways holds promise for development of novel anti-HIV gene therapy vectors. We characterized discrete dominant negative (DN) Gag and Envelope mutants for their anti-HIV-1 activity. We show here that capsid mutants (Q155N and Y164A) are more potent inhibitors of WT HIV than the matrix mutant 1GA. Both the Envelope mutants tested, V513E and R515A, were equally effective and a combination of Gag and Envelope DN genes significantly enhanced potency. Interestingly, the DN mutants acted at multiple steps in the virus life cycle rather than solely disrupting virus release or infection. Inhibition mediated by R515A could be partially attributed to the Envelope cytoplasmic tail, as deletion of R515A tail partially abrogated its DN effect. Finally, the Y164A/R515A double mutant expressed in a lentiviral vector was effective at inhibiting HIV replication in CD34+ hematopoietic stem cell-derived macrophages, demonstrating the therapeutic potential of our approach. Published by Elsevier Inc. C1 [Joshi, Anjali; Garg, Himanshu; Manjunath, N.; Shankar, Premlata] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Ctr Excellence Infect Dis, El Paso, TX 79905 USA. [Joshi, Anjali; Garg, Himanshu] Texas Tech Univ, Hlth Sci Ctr, Dept Pediat, El Paso, TX 79905 USA. [Ablan, Sherimay; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Nagashima, Kunio] NCI, Electron Microscope Lab, Res Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Joshi, A (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Ctr Excellence Infect Dis, El Paso, TX 79905 USA. EM anjali.joshi@ttuhsc.edu; premlata.shankar@ttuhsc.edu FU NIH [AI071882, AI08053] FX This work was supported by NIH grants AI071882 and AI08053 to P.S. We thank F. Soheilian for expert technical assistance and V. Bokyo and Wei-Shau Hu for kindly providing the pNL4-3/Gag-mRFP. The HIV-Ig, GFP expressing lentiviral vector TyefEGFP and TZM-bl cells were obtained from the NIH AIDS Research and Reference Reagent Program. A.J. and H.G. designed and conducted the experiments, performed the research, contributed reagents, analyzed the data, and wrote the paper. S.A. conducted the experiments and reviewed the manuscript, K.N. conducted the experiments, E.F. contributed vital expertise and critically reviewed the data and manuscript, and M.N. and P.S. contributed vital reagents and reviewed the manuscript. NR 49 TC 4 Z9 6 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 0042-6822 J9 VIROLOGY JI Virology PD JUL 5 PY 2011 VL 415 IS 2 BP 95 EP 106 DI 10.1016/j.virol.2011.03.028 PG 12 WC Virology SC Virology GA 778OH UT WOS:000291713500003 PM 21529874 ER PT J AU Young, TS Young, DD Ahmad, I Louis, JM Benkovic, SJ Schultz, PG AF Young, Travis S. Young, Douglas D. Ahmad, Insha Louis, John M. Benkovic, Stephen J. Schultz, Peter G. TI Evolution of cyclic peptide protease inhibitors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE unnatural amino acid; protein translation; bacterial selection ID ESCHERICHIA-COLI; IN-VIVO; BIOSYNTHESIS; ANTIBIOTICS; SELECTION; SYSTEM; DISCOVERY; LIBRARY; BINDING; SCREEN AB We report a bacterial system for the evolution of cyclic peptides that makes use of an expanded set of amino acid building blocks. Orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pairs, together with a split intein system were used to biosynthesize a library of ribosomal peptides containing amino acids with unique structures and reactivities. This peptide library was subsequently used to evolve an inhibitor of HIV protease using a selection based on cellular viability. Two of three cyclic peptides isolated after two rounds of selection contained the keto amino acid p-benzoylphenylalanine (pBzF). The most potent peptide (G12: GIXVSL; X = pBzF) inhibited HIV protease through the formation of a covalent Schiff base adduct of the pBzF residue with the.-amino group of Lys 14 on the protease. This result suggests that an expanded genetic code can confer an evolutionary advantage in response to selective pressure. Moreover, the combination of natural evolutionary processes with chemically biased building blocks provides another strategy for the generation of biologically active peptides using microbial systems. C1 [Benkovic, Stephen J.] Penn State Univ, Dept Chem, Wartik Lab 414, University Pk, PA 16802 USA. [Young, Travis S.; Young, Douglas D.; Ahmad, Insha; Schultz, Peter G.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Young, Travis S.; Young, Douglas D.; Ahmad, Insha; Schultz, Peter G.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Louis, John M.] NIH, Chem Phys Lab, NIDDK, Bethesda, MD 20892 USA. RP Benkovic, SJ (reprint author), Penn State Univ, Dept Chem, Wartik Lab 414, University Pk, PA 16802 USA. EM schultz@scripps.edu FU National Institutes of Health (NIH) [5R01GM062159, F32CA144213]; National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Office of the Director, NIH; Achievement Rewards for College Scientists Scholarship FX The authors would like to thank Xuemei Han and the Yates Lab for aid in MS characterization, as well as Virginia Seely and Emily Remba for manuscript preparation and submission. This work was funded by Grant 5R01GM062159 from the National Institutes of Health (NIH) (to P. G. S.) and supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH and the Intramural AIDS-Targeted Program of the Office of the Director, NIH. This is manuscript 21197 of The Scripps Research Institute. D.D.Y. is grateful for an NIH Fellowship F32CA144213 and T.S.Y. is grateful for an Achievement Rewards for College Scientists Scholarship. NR 37 TC 48 Z9 51 U1 0 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2011 VL 108 IS 27 BP 11052 EP 11056 DI 10.1073/pnas.1108045108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 787LC UT WOS:000292376700031 PM 21690365 ER PT J AU Burton, DR Hessell, AJ Keele, BF Klasse, PJ Ketas, TA Moldt, B Dunlop, DC Poignard, P Doyle, LA Cavacini, L Veazey, RS Moore, JP AF Burton, Dennis R. Hessell, Ann J. Keele, Brandon F. Klasse, Per Johan Ketas, Thomas A. Moldt, Brian Dunlop, D. Cameron Poignard, Pascal Doyle, Lara A. Cavacini, Lisa Veazey, Ronald S. Moore, John P. TI Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE binding antibodies; passive immunization ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; RHESUS MACAQUES; ENVELOPE GLYCOPROTEIN; HIV VACCINES; IN-VITRO; INFECTION; BINDING; TRANSMISSION; MONKEYS AB To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site (CD4bs) on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of simian HIV (SHIV)-162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120-binding properties, measured in vitro, but b12 is strongly neutralizing and b6 is not. F240 is nonneutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in seven of seven animals, b6 in zero of five animals, and F240 in two of five animals. Compared with control animals, the protection by b12 achieved statistical significance, whereas that caused by F240 did not. For two of three unprotected F240-treated animals there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, when data from all of the experiments were combined, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared with other nonprotected macaques. Thus, a gp120-binding, weakly neutralizing MAb to the CD4bs was, at best, completely ineffective at protection. A nonneutralizing antibody to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of potently neutralizing antibodies. C1 [Burton, Dennis R.; Hessell, Ann J.; Moldt, Brian; Dunlop, D. Cameron; Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.; Hessell, Ann J.; Moldt, Brian; Dunlop, D. Cameron; Poignard, Pascal] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Burton, Dennis R.; Dunlop, D. Cameron] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02114 USA. [Hessell, Ann J.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Keele, Brandon F.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Klasse, Per Johan; Ketas, Thomas A.; Moore, John P.] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. [Doyle, Lara A.; Veazey, Ronald S.] Tulane Univ, Sch Med, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Cavacini, Lisa] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu; jpm2003@med.cornell.edu RI poignard, pascal/N-6678-2013 FU International AIDS Vaccine Initiative; National Institutes of Health [U19 AI76982, R37 AI36082, AI33292, AI1055332]; National Cancer Institute, National Institutes of Health [HHSN266200400088C]; Alfred Benzon Foundation FX We thank Athe Tsibris and Steven Wolinsky for contributing founder virus data for the gel control group (Fig. 4); Leo Stamatatos for the SHIV-162P4 challenge stock; and Kelsi Rasmussen and Janell LeBlanc for their technical support. The animal studies were funded by the International AIDS Vaccine Initiative, with additional support by National Institutes of Health Cooperative Agreement U19 AI76982 (to J.P.M.); in vitro studies were also supported by National Institutes of Health Grants R37 AI36082 (to J.P.M.) and AI33292 and AI1055332 (to D.R.B.); sequencing and founder virus analysis was performed with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN266200400088C. B.M. was supported by the Alfred Benzon Foundation. NR 43 TC 149 Z9 150 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2011 VL 108 IS 27 BP 11181 EP 11186 DI 10.1073/pnas.1103012108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 787LC UT WOS:000292376700053 PM 21690411 ER PT J AU Josefsson, L King, MS Makitalo, B Brannstrom, J Shao, W Maldarelli, F Kearney, MF Hu, WS Chen, JB Gaines, H Mellors, JW Albert, J Coffin, JM Palmer, SE AF Josefsson, Lina King, Martin S. Makitalo, Barbro Brannstrom, Johan Shao, Wei Maldarelli, Frank Kearney, Mary F. Hu, Wei-Shau Chen, Jianbo Gaines, Hans Mellors, John W. Albert, Jan Coffin, John M. Palmer, Sarah E. TI Majority of CD4(+) T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DYNAMICS IN-VIVO; REVERSE-TRANSCRIPTASE; INFECTED INDIVIDUALS; MONONUCLEAR-CELLS; TYPE-1 INFECTION; RECOMBINATION; RESISTANCE; RNA; EVOLUTION AB Neither the number of HIV-1 proviruses within individual infected cells in HIV-1-infected patients nor their genetic relatedness within individual infected cells and between cells and plasma virus are well defined. To address these issues we developed a technique to quantify and genetically characterize HIV-1 DNA from single infected cells in vivo. Analysis of peripheral blood CD4(+) T cells from nine patients revealed that the majority of infected cells contain only one copy of HIV-1 DNA, implying a limited potential for recombination in virus produced by these cells. The genetic similarity between HIV populations in CD4(+) T cells and plasma implies ongoing exchange between these compartments both early and late after infection. C1 [Josefsson, Lina; Makitalo, Barbro; Brannstrom, Johan; Gaines, Hans; Palmer, Sarah E.] Swedish Inst Infect Dis Control, Dept Diagnost & Vaccinol, S-17182 Solna, Sweden. [Josefsson, Lina; Albert, Jan; Palmer, Sarah E.] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17182 Solna, Sweden. [Josefsson, Lina; Maldarelli, Frank; Kearney, Mary F.; Hu, Wei-Shau; Chen, Jianbo; Coffin, John M.; Palmer, Sarah E.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [King, Martin S.] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60069 USA. [Shao, Wei] SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Mellors, John W.] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. RP Josefsson, L (reprint author), Swedish Inst Infect Dis Control, Dept Diagnost & Vaccinol, S-17182 Solna, Sweden. EM Lina.Josefsson@smi.se; john.coffin@tufts.edu RI Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU NIH; National Cancer Institute (Center for Cancer Research, NIH) the Swedish Research Council; American Foundation for AIDS Research [107170-44-RGRL]; F. M. Kirby Foundation FX We acknowledge with gratitude the patients participating in this study, G. Bratt and A. Thalme for clinical assistance with patients in Sweden, Diane Rock for assistance with recruitment of the patients attending the clinic at the National Institutes of Health (NIH), and M. Mild for assistance in phylogenetic analysis. This study was supported by an NIH Bench to Bedside Award (to F. M.) in the HIV Drug Resistance Program, the Intramural Research Program of the National Cancer Institute (Center for Cancer Research, NIH) the Swedish Research Council, and American Foundation for AIDS Research Grant 107170-44-RGRL. J.M.C. was a research professor of the American Cancer Society with support from the F. M. Kirby Foundation. NR 34 TC 94 Z9 94 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2011 VL 108 IS 27 BP 11199 EP 11204 DI 10.1073/pnas.1107729108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 787LC UT WOS:000292376700056 PM 21690402 ER PT J AU Wykes, MN Kay, JG Manderson, A Liu, XQ Brown, DL Richard, DJ Wipasa, J Jiang, SHH Jones, MK Janse, CJ Waters, AP Pierce, SK Miller, LH Stow, JL Good, MF AF Wykes, Michelle N. Kay, Jason G. Manderson, Anthony Liu, Xue Q. Brown, Darren L. Richard, Derek J. Wipasa, Jiraprapa Jiang, Suhua H. Jones, Malcolm K. Janse, Chris J. Waters, Andrew P. Pierce, Susan K. Miller, Louis H. Stow, Jennifer L. Good, Michael F. TI Rodent blood-stage Plasmodium survive in dendritic cells that infect naive mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immune evasion; rodent malaria ID MALARIA PARASITE; QUARTAN MALARIA; MAMMALIAN HOST; SPOROZOITES; BERGHEI; YOELII; MOUSE; MEROZOITES; PLATELETS; ANTIGEN AB Plasmodium spp. parasites cause malaria in 300 to 500 million individuals each year. Disease occurs during the blood-stage of the parasite's life cycle, where the parasite is thought to replicate exclusively within erythrocytes. Infected individuals can also suffer relapses after several years, from Plasmodium vivax and Plasmodium ovale surviving in hepatocytes. Plasmodium falciparum and Plasmodium malariae can also persist after the original bout of infection has apparently cleared in the blood, suggesting that host cells other than erythrocytes (but not hepatocytes) may harbor these blood-stage parasites, thereby assisting their escape from host immunity. Using blood stage transgenic Plasmodium berghei-expressing GFP (PbGFP) to track parasites in host cells, we found that the parasite had a tropism for CD317(+) dendritic cells. Other studies using confocal microscopy, in vitro cultures, and cell transfer studies showed that blood-stage parasites could infect, survive, and replicate within CD317(+) dendritic cells, and that small numbers of these cells released parasites infectious for erythrocytes in vivo. These data have identified a unique survival strategy for blood-stage Plasmodium, which has significant implications for understanding the escape of Plasmodium spp. from immune-surveillance and for vaccine development. C1 [Wykes, Michelle N.; Liu, Xue Q.; Richard, Derek J.; Jiang, Suhua H.; Jones, Malcolm K.; Good, Michael F.] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Kay, Jason G.; Manderson, Anthony; Brown, Darren L.; Stow, Jennifer L.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Jones, Malcolm K.] Univ Queensland, Sch Vet Sci, Brisbane, Qld 4072, Australia. [Wipasa, Jiraprapa] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50200, Thailand. [Jiang, Suhua H.] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Immunol, Wuhan 430030, Hubei, Peoples R China. [Jiang, Suhua H.] Shihezi Univ, Sch Med, Dept Pathogen Biol & Immunol, Shihezi City 832002, Xinjiang, Peoples R China. [Janse, Chris J.] Leiden Univ, Med Ctr, Ctr Infect Dis, Dept Parasitol, NL-2333 ZA Leiden, Netherlands. [Waters, Andrew P.] Univ Glasgow, Wellcome Ctr Mol Parasitol, Glasgow G12 8TA, Lanark, Scotland. [Waters, Andrew P.] Univ Glasgow, Fac Biomed Life Sci, Glasgow Biomed Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Miller, Louis H.] NIAID, Malaria Cell Biol Sect, NIH, Rockville, MD 20852 USA. RP Wykes, MN (reprint author), Queensland Inst Med Res, Brisbane, Qld 4029, Australia. EM michelle.wykes@qimr.edu.au; lmiller@niaid.nih.gov; michael.good@griffith.edu.au RI Waters, Andy/C-9377-2009; Wykes, Michelle/G-6272-2013; Stow, Jennifer/I-4723-2013; Jones, Malcolm/A-1097-2009; OI Waters, Andy/0000-0001-8900-2982; Wykes, Michelle/0000-0002-7956-0144; Stow, Jennifer/0000-0002-5409-9101; Jones, Malcolm/0000-0002-0035-6141; Richard, Derek/0000-0002-4839-8471 FU National Health and Medical Research Council (Australia) FX We thank Drs. Denise Doolan, Christian Engwerda, and James McCarthy for their critical reading of the manuscript; Drs. Alan Sher and Leanne Tilley for their discussion of the data; Ms. Grace Chojnowski and Paula Hall for their excellent cell sorting skills; and Ms. Virginia McPhun for her technical assistance with some of the earlier developmental assays. This study was supported by the National Health and Medical Research Council (Australia). NR 29 TC 33 Z9 35 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2011 VL 108 IS 27 BP 11205 EP 11210 DI 10.1073/pnas.1108579108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 787LC UT WOS:000292376700057 PM 21690346 ER PT J AU Wynn, TA AF Wynn, Thomas A. TI Integrating mechanisms of pulmonary fibrosis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Review ID TUMOR-NECROSIS-FACTOR; INDUCED LUNG INJURY; BRONCHIOLITIS OBLITERANS SYNDROME; THYMIC STROMAL LYMPHOPOIETIN; MESENCHYMAL STEM-CELLS; GROWTH-FACTOR-BETA; FACTOR-ALPHA; IL-13-INDUCED INFLAMMATION; NALP3 INFLAMMASOME; MURINE LUNG AB Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options. Although research on the pathogenesis of pulmonary fibrosis has frequently focused on the mechanisms that regulate the proliferation, activation, and differentiation of collagen-secreting myofibroblasts, recent studies have identified new pathogenic mechanisms that are critically involved in the initiation and progression of fibrosis in a variety of settings. A more detailed and integrated understanding of the cellular and molecular mechanisms of pulmonary fibrosis could help pave the way for effective therapeutics for this devastating and complex disease. C1 [Wynn, Thomas A.] NIAID, Program Barrier Immun & Repair, NIH, Bethesda, MD 20892 USA. [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Program Barrier Immun & Repair, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU National Institute of Allergy and Infectious Disease/National Institutes of Health FX I would like to sincerely thank the past and present members of my laboratory for their guidance and support. The Wynn laboratory is supported by the intramural research program of the National Institute of Allergy and Infectious Disease/National Institutes of Health. NR 146 TC 309 Z9 326 U1 3 U2 36 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 4 PY 2011 VL 208 IS 7 BP 1339 EP 1350 DI 10.1084/jem.20110551 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 791BZ UT WOS:000292637000002 PM 21727191 ER PT J AU Nair, M Prabhakaran, D Narayan, KMV Sinha, R Lakshmy, R Devasenapathy, N Daniel, CR Gupta, R George, PS Mathew, A Tandon, N Reddy, KS AF Nair, Manisha Prabhakaran, Dorairaj Narayan, K. M. Venkat Sinha, Rashmi Lakshmy, Ramakrishnan Devasenapathy, Niveditha Daniel, Carrie R. Gupta, Ruby George, Preethi S. Mathew, Aleyamma Tandon, Nikhil Reddy, K. Srinath TI HbA(1c) values for defining diabetes and impaired fasting glucose in Asian Indians SO PRIMARY CARE DIABETES LA English DT Article DE HbA(1c); Diabetes; "Asian Indians" ID PLASMA-GLUCOSE; HIGH-RISK; GLYCOSYLATED HEMOGLOBIN; DIAGNOSTIC-CRITERIA; GLYCATED HEMOGLOBIN; US POPULATION; A1C-BASED DIAGNOSIS; HBA1C; MELLITUS; A1C AB Aim: To determine the glycosylated haemoglobin (HbA(1c)) cut-points for diabetes and impaired fasting glucose (IFG) among Asian Indians. Methods: Participants (n = 525) were a random sample selected from the India Health Study. Based on history and fasting plasma glucose (FPG), participants were classified into known diabetes, newly diagnosed diabetes (NDD), impaired fasting glucose (IFG) [ADA and WHO criteria] or normal fasting glucose (NFG). Receiver Operating Characteristic curves were used to identify the optimum sensitivity and specificity for defining HbA(1c), cut-points for NDD and IFG against the FPG criteria. Results: There were 64 participants with a known history of diabetes. Of the remaining 461, IFG was present in 44.7% (ADA) and 18.2% (WHO), and 10.4% were NDD. Mean HbA(1c) were 5.4 (+/-0.04)% for NFG; 5.7 (+/-0.06)% among IFG-ADA, 5.8 (+/-0.09)% among IFG-WHO; 7.5 (+/-0.33)% for NDD and 8.4 (+/-0.32)% for known diabetes. Optimal HbA(1c) cut-point for NOD was 5.8% (sensitivity = 75%, specificity = 75.5%, AUC = 0.819). Cut-point for IFG (ADA) was 5.5% (sensitivity = 59.7%, specificity = 59.9%, AUC = 0.628) and for IFG (WHO) was 5.6% (sensitivity = 60.7%, specificity =65.1%, AUC = 0.671). Conclusion: In this study population from north and south regions of India, the HbA(1c) cut-point that defines NDD (>= 5.8%) was much lower than that proposed by an international expert committee and the American Diabetes Association (>= 6.5%). A cut-point of >= 5.5% or >= 5.6% defined IFG, and was slightly lower than the >= 5.7% for high risk proposed, but accuracy was less than 70%. (C) 2011 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved. C1 [Nair, Manisha] Publ Hlth Fdn India, Fogarty Int Ctr, New Delhi 122002, India. [Nair, Manisha] Publ Hlth Fdn India, Ctr Excellence Ctr cArdiometab Risk Reduct S Asia, New Delhi 122002, India. [Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Narayan, K. M. Venkat] Emory Univ, Atlanta, GA 30322 USA. [Sinha, Rashmi; Daniel, Carrie R.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lakshmy, Ramakrishnan; Gupta, Ruby] All India Inst Med Sci, Dept Cardiac Biochem, New Delhi, India. [Devasenapathy, Niveditha] Indian Inst Publ Hlth, New Delhi, India. [George, Preethi S.; Mathew, Aleyamma] Reg Canc Ctr, Thiruvananthapuram, Kerala, India. [Tandon, Nikhil] All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India. RP Nair, M (reprint author), Publ Hlth Fdn India, Fogarty Int Ctr, New Delhi 122002, India. EM dr.manisha.das@gmail.com; dprabhakaran@ccdcindia.org; knaraya@emory.edu; sinhar@exchange.nih.gov; lakshmy_ram@yahoo.com; niveditha@iiphd.org; danielc3@mai1.nih.gov; g_ruby2123@yahoo.co.in; preethig@rcctvm.org; amathew@rcctvm.org; nikhil_tandon@hotmail.com; ksrinath.reddy@phfi.org RI Narayan, K.M. Venkat /J-9819-2012; Sinha, Rashmi/G-7446-2015; OI Narayan, K.M. Venkat /0000-0001-8621-5405; Sinha, Rashmi/0000-0002-2466-7462; Nair, Manisha/0000-0003-0660-5054; Prabhakaran, Dorairaj/0000-0002-3172-834X FU NIH FX Funded by: NIH. NR 48 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1751-9918 J9 PRIM CARE DIABETES JI Prim. Care Diabetes PD JUL PY 2011 VL 5 IS 2 BP 95 EP 102 DI 10.1016/j.pcd.2011.02.002 PG 8 WC Endocrinology & Metabolism; Primary Health Care SC Endocrinology & Metabolism; General & Internal Medicine GA 945MV UT WOS:000304279500005 PM 21474403 ER PT J AU Ahuja, K Bennett, F Cohen, J Edwards, R Pritchard, H Silver, A Sirlin, J Slee, J Abse, D Ashwood-Smith, MJ Bavister, B Bedford, JM Beier, HM Bronson, R Cattanach, B Daniel, JC Dawes, EA Ferguson-Smith, M Gardner, R Griffin, D Hunter, RHF Johnson, M Jones, H Lunenfeld, B Mittwoch, U Moor, R Rankin, B Schally, AV Sharpe, DJ Simpson, D Yanagimachi, R Ahuja, K Alexandre, H Bhargava, PM Cohen, J Dexter, A Diedrich, K Emperaire, JC Findlay, A Fishel, S Fox, NL Goddard, H Gomel, V Gore-Langton, RE Gosden, R Iritani, A Koskimies, AI MacDonald, G Menezo, Y Mettler, L Monk, M Mori, T Mortimer, D Papaioannou, VE Racowsky, C Surani, A Trounson, A Van Blerkom, J Vincent, P Walters, E Webster, J Williams, P Aboulghar, M Barri, PN Benagiano, G Blackwell, C Bolton, VN Brinsden, PR Bustillo, M Coulam, C Chaouat, G Crosignani, P Gardner, D Gianaroli, L Hamberger, L Hartshorne, G Hollands, P Howles, C Illmensee, K Jauniaux, E Kini, D Lee, S Lees, M Leese, H Mathews, T Moate, E Nygren, K Ockleford, C Palermo, GD Pandiyan, N Rizk, B Rosenwaks, Z Sallam, H Sathananthan, AH Saunders, DM Simpson, JL Sunde, A Tan, SL Ulloa-Aguirre, A Gosden, LV Veiga, A Albertini, DF Alikani, M Balaban, B Thornhill, A Beard, HK Ben-Shlomo, I Bennett, F Borini, A Carrell, D De Jonge, C Eichenlaub-Ritter, U Fleming, S Geber, S Gerris, J Golombok, S Leather, DS Nagy, ZP Nielsen, HI Oehninger, S Olivennes, F Patrizio, P Paulson, RJ de Fried, EP Pool, TB Risquez, F Sauer, MV Sciarra, JJ Basuray, R Boiso, I Bose, CK Cryan, B Falconer, A Hansis, C Kahraman, S Ko, MSH Korsak, V Loeffler, F Ludwig, M Magli, MC Robertson, JA Roche, LA Thornhill, A Wallberg-Henriksson, H Woo, G AF Ahuja, Kamal Bennett, Fiona Cohen, Jacques Edwards, Ruth Pritchard, Huw Silver, Ann Sirlin, Julio Slee, John Abse, Dannie Ashwood-Smith, M. J. Bavister, Barry Bedford, J. Michael Beier, Henning M. Bronson, Richard Cattanach, Bruce Daniel, Joseph C. Dawes, Edwin A. Ferguson-Smith, Malcolm Gardner, Richard Griffin, Dave Hunter, R. H. F. Johnson, Martin Jones, Howard Lunenfeld, Bruno Mittwoch, Ursula Moor, Robert Rankin, Barbara Schally, Andrew V. Sharpe, David J. Simpson, David Yanagimachi, Ryuzo 'Yana' Ahuja, Kamal Alexandre, Henri Bhargava, Pushpa M. Cohen, Jacques Dexter, Alan Diedrich, Klaus Emperaire, Jean-Claude Findlay, Alan Fishel, Simon Fox, Norma Lynn Goddard, Hester Gomel, Victor Gore-Langton, Robert E. Gosden, Roger Iritani, A. Koskimies, Aarne I. MacDonald, Grace Menezo, Yves Mettler, Liselotte Monk, Marilyn Mori, Takahide Mortimer, David Papaioannou, Virginia E. Racowsky, Catherine Surani, Azim Trounson, Alan Van Blerkom, Jonathan Vincent, Paul Walters, Eurof Webster, John Williams, Peter Aboulghar, M. Barri, Pedro N. Benagiano, Giuseppe Blackwell, Caroline Bolton, Virginia N. Brinsden, Peter R. Bustillo, Maria Coulam, Carolyn Chaouat, Gerard Crosignani, Piergiorgio Gardner, David Gianaroli, Luca Hamberger, Lars Hartshorne, Geraldine Hollands, Peter Howles, Colin Illmensee, Karl Jauniaux, Eric Kini, Dee Lee, Sammy Lees, Martin Leese, Henry Mathews, Thomas Moate, Elaine Nygren, Karl Ockleford, Colin Palermo, Gianpiero D. Pandiyan, N. Rizk, Botros Rosenwaks, Zev Sallam, Hassan Sathananthan, A. Henry Saunders, Douglas M. Simpson, Joe Leigh Sunde, Arne Tan, Seang Lin Ulloa-Aguirre, Alfredo Gosden, Lucinda Veeck Veiga, Anna Albertini, David F. Alikani, Mina Balaban, Basak Thornhill, Alan Beard, Helen K. Ben-Shlomo, Izhar Bennett, Fiona Borini, Andrea Carrell, Douglas De Jonge, Christopher Eichenlaub-Ritter, Ursula Fleming, Steven Geber, Selmo Gerris, Jan Golombok, Susan Leather, Dame Suzi Nagy, Zsolt Peter Nielsen, H. Ingolf Oehninger, Sergio Olivennes, Francois Patrizio, Pasquale Paulson, Richard J. Polak de Fried, Ester Pool, Thomas B. (Rusty) Risquez, Francisco Sauer, Mark V. Sciarra, John J. Basuray, Rita Boiso, Irene Bose, Chinmoy K. Cryan, Bob Falconer, Anthony Hansis, Christoph Kahraman, Semra Ko, Minoru S. H. Korsak, Vladislav Loeffler, Frank Ludwig, Michael Magli, M. Cristina Robertson, John A. Roche, Lady Alexandra Thornhill, A. Wallberg-Henriksson, Harriet Woo, George CA IVF Canada TI Salute to a giant ... Robert Geoffrey Edwards SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Biographical-Item C1 [Pritchard, Huw] York Univ, Dept Chem, N York, ON M3J 1P3, Canada. [Silver, Ann] Physiol Lab, Cambridge CB2 3EG, England. [Slee, John] Bangor Univ, Bangor, Gwynedd, Wales. [Slee, John] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Ashwood-Smith, M. J.] Univ Victoria, Victoria, BC, Canada. [Bedford, J. Michael] Cornell Univ, Weill Med Coll, Ithaca, NY 14853 USA. [Bronson, Richard] SUNY Stony Brook, Med Ctr, Stony Brook, NY USA. [Leese, Henry] Univ Hull, Hull York Med Sch, Kingston Upon Hull HU6 7RX, N Humberside, England. [Hunter, R. H. F.] Univ Cambridge Sidney Sussex Coll, Cambridge, England. [Lunenfeld, Bruno] Bar Ilan Univ, Ramat Gan, Israel. [Mittwoch, Ursula] UCL, Dept Genet Evolut & Environm, London, England. [Moor, Robert] Unit Reprod Physiol & Biochem, Cambridge, England. [Rankin, Barbara; Goddard, Hester] Marshall Lab, Marshall, AL USA. [Schally, Andrew V.] Univ Miami, Coral Gables, FL 33124 USA. [Yanagimachi, Ryuzo 'Yana'] Univ Hawaii, Sch Med, Honolulu, HI 96822 USA. [Ahuja, Kamal] London Womens Clin, London, England. [Alexandre, Henri] Univ Libre Brussels, Brussels, Belgium. [Alexandre, Henri] Univ Mons UMONS, Mons, Belgium. [Cohen, Jacques] Tyho Galileo Res & Reprogenet Labs, Livingston, NJ USA. [Diedrich, Klaus] Univ Lubeck, Lubeck, Germany. [Emperaire, Jean-Claude] IVF Ctr Clin Jean Villar, Bordeaux Bruges, France. [Findlay, Alan] Univ Cambridge Churchill Coll, Cambridge CB3 0DS, England. [Fox, Norma Lynn] Human Genome Sci Inc, Clin Res, Rockville, MD USA. [Gore-Langton, Robert E.] EMMES Corp, Rockville, MD USA. [Iritani, A.; Mori, Takahide] Kyoto Univ, Kyoto 6068501, Japan. [Koskimies, Aarne I.] Felicitas Clin, Helsinki, Finland. [Monk, Marilyn] UCL, Inst Child Hlth, London WC1E 6BT, England. [Mortimer, David] Oozoa Biomed Inc, Vancouver, BC, Canada. [Racowsky, Catherine] Harvard Univ, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Sch Med, Boston, MA 02115 USA. [Lees, Martin; Golombok, Susan] Univ Cambridge, Ctr Family Res, Cambridge CB2 1TN, England. [Trounson, Alan] Calif Inst Regenerat Med, San Francisco, CA USA. [Vincent, Paul] Wrigley Claydon Solicitors, Oldham, Lancs, England. [Barri, Pedro N.] USP Inst Univ Dexeus, Dept Obstet Gynaecol & Reprod, Barcelona, Spain. [Blackwell, Caroline] Duck End Farm, Reprod BioMed Online, Cambridge, England. [Bolton, Virginia N.] Guys Hosp, Assisted Concept Unit, London SE1 9RT, England. [Chaouat, Gerard] EMBIC, Paris, France. [Crosignani, Piergiorgio] Maggiore Policlin Hosp, IRCCS Ca Granda Fdn, Milan, Italy. [Gianaroli, Luca] SIS Me R SrL, ESHRE, Bologna, Italy. [Hamberger, Lars] Gothenburg Univ, Gothenburg, Sweden. [Hartshorne, Geraldine] Warwick Med Sch, Coventry, W Midlands, England. [Howles, Colin] Merck Serono SA, Fertil & Endocrinol Global Business Unit, Reg Med Affairs, Geneva, Switzerland. [Illmensee, Karl] Genesis Fertil Ctr, Patras, Greece. [Jauniaux, Eric] Royal Free & Univ Coll London, UCL EGA Inst Womens Hlth, Acad Dept Obstet & Gynaecol, London, England. [Ockleford, Colin] Univ Lancaster, Clin Anat Learning Ctr, Sch Hlth & Med, Div Med CME, Lancaster LA1 4YW, England. [Palermo, Gianpiero D.] Cornell Inst Reprod Med, New York, NY USA. [Pandiyan, N.] Chettinad Univ, Madras, Tamil Nadu, India. [Pandiyan, N.] Chettinad Hosp & Res Inst, Madras, Tamil Nadu, India. [Rizk, Botros] Univ S Alabama, Dept Obstet & Gynecol, Mobile, AL 36688 USA. [Rosenwaks, Zev] Weill Cornell Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY USA. [Sathananthan, A. Henry] Monash Univ, Clayton, Vic 3800, Australia. [Saunders, Douglas M.] Univ Sydney, Sydney, NSW 2006, Australia. [Simpson, Joe Leigh] Florida Int Univ, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Sunde, Arne] St Olavs Univ Hosp, Fertil Clin, Trondheim, Norway. [Tan, Seang Lin] MUHC, McGill Reprod Ctr, Montreal, PQ, Canada. [Tan, Seang Lin] Montreal Reprod Ctr, Montreal, PQ, Canada. [Tan, Seang Lin] McGill Univ, Montreal, PQ, Canada. [Veiga, Anna] Ctr Regenerat Med, Inst Univ Dexeus, Barcelona, Spain. [Alikani, Mina] Tyho Galileo Res Labs, Livingston, NJ USA. [Beard, Helen K.] ESHRE Journals Editorial Off, Childerley, Cambs, England. [Ben-Shlomo, Izhar] Zefat Acad Coll, Safed, Israel. [De Jonge, Christopher] Univ Minnesota, Reprod Med Ctr, Dept Ob Gyn & Womens Hlth, Minneapolis, MN 55455 USA. [De Jonge, Christopher] Univ Minnesota, Reprod Med Ctr, Lab Operat, Minneapolis, MN 55455 USA. [Eichenlaub-Ritter, Ursula] Univ Bielefeld, D-33615 Bielefeld, Germany. [Gerris, Jan] Univ Hosp Ghent, Ctr Reprod Med, Dept Ob Gyn, Sector Man Woman & Child, Ghent, Belgium. [Nielsen, H. Ingolf] Aarhus Univ, Aalborg Hosp, Dronninglund Fertil Ctr, DK-8000 Aarhus C, Denmark. [Oehninger, Sergio] Eastern Virginia Med Sch, Jones Inst Reprod Med, Norfolk, VA 23501 USA. [Patrizio, Pasquale] Yale Fertil Ctr, New Haven, CT USA. [Paulson, Richard J.] Univ So Calif, Keck Sch Med, Div Reprod Endocrinol & Infertil, Los Angeles, CA 90033 USA. [Polak de Fried, Ester] Univ Buenos Aires, CER Ctr Reprod Hlth, RA-1053 Buenos Aires, DF, Argentina. [Risquez, Francisco] Ctr Med Docente Trinidad, Caracas, Venezuela. [Sauer, Mark V.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Sciarra, John J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Basuray, Rita] Univ Kentucky, Lexington, KY USA. [Boiso, Irene] Clin Sagrada Familia, Ctr Reprod Asistida, Barcelona, Spain. [Bose, Chinmoy K.] Netaji Subhash Chandra Bose Canc Res Inst, Kolkata, India. [Cryan, Bob] Univ Huddersfield, Huddersfield HD1 3DH, W Yorkshire, England. [Falconer, Anthony] Royal Coll Obstet & Gynaecol, London, England. [Hansis, Christoph] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY 10003 USA. [Ko, Minoru S. H.] NIA, Dev Genom & Ageing Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. [Loeffler, Frank] St Marys Hosp, London, England. [Loeffler, Frank] Queen Charlottes Matern Hosp, London, England. [Ludwig, Michael] Endokrinologikum Hamburg, Hamburg, Germany. [Magli, M. Cristina] SISMER, Bologna, Italy. [Robertson, John A.] Univ Texas Austin, Sch Law, Austin, TX 78712 USA. [Thornhill, A.] Bridge Genoma Ltd, London, England. [Wallberg-Henriksson, Harriet] Karolinska Inst, S-10401 Stockholm, Sweden. RI Ockleford, Colin/A-2921-2009; Tan, Seang Lin/I-7710-2012; Ko, Minoru/B-7969-2009; Sauer, Markus/C-4378-2017 OI Ko, Minoru/0000-0002-3530-3015; Sauer, Markus/0000-0002-1692-3219 NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1472-6483 EI 1472-6491 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD JUL PY 2011 VL 23 SU S BP 1 EP 98 PG 98 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 929FY UT WOS:000303047900001 ER PT J AU Konda, K Celentano, D Kegeles, S Coates, T Caceres, C AF Konda, K. Celentano, D. Kegeles, S. Coates, T. Caceres, C. CA NIMHCollaborative HIV STD Preventi TI LATENT CLASS ANALYSIS OF SEXUAL RISK PATTERNS AMONG HETEROSEXUALLY-IDENTIFIED, SOCIALLY MARGINALISED MEN IN URBAN, COASTAL PERU SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Konda, K.; Coates, T.] Univ Calif Los Angeles, Lima, Peru. [Celentano, D.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Kegeles, S.] UCSF, San Francisco, CA USA. [NIMHCollaborative HIV STD Preventi] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2011 VL 87 SU 1 BP A237 EP A237 DI 10.1136/sextrans-2011-050108.321 PG 1 WC Infectious Diseases SC Infectious Diseases GA 926ZQ UT WOS:000302874201216 ER PT J AU Konda, K Lescano, A Celentano, D Maiorana, A Salazar, X Rosasco, AM Montano, S Kochel, T Hall, E Coates, T Caceres, C Kegeles, S AF Konda, K. Lescano, A. Celentano, D. Maiorana, A. Salazar, X. Rosasco, A. M. Montano, S. Kochel, T. Hall, E. Coates, T. Caceres, C. Kegeles, S. CA NIMH Collaborative HIV STD TI IMPACT OF A COMMUNITY LEVEL, DIFFUSION BASED HIV/STI INTERVENTION ON HETEROSEXUALLY-IDENTIFIED, SOCIALLY MARGINALISED MEN IN URBAN, COASTAL PERU SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Meeting Abstract C1 [Konda, K.; Coates, T.] Univ Calif Los Angeles, Lima, Peru. [Lescano, A.; Montano, S.; Kochel, T.; Hall, E.] NAMRU 6, Callao, Peru. [Celentano, D.] Johns Hopkins Univ, Baltimore, MD USA. [Maiorana, A.; Kegeles, S.] UCSF, San Francisco, CA USA. [Salazar, X.; Rosasco, A. M.; Caceres, C.] UPCH, Lima, Peru. [NIMH Collaborative HIV STD] NIMH, Bethesda, MD USA. NR 0 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 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD JUL PY 2011 VL 87 SU 1 BP A214 EP A215 DI 10.1136/sextrans-2011-050108.269 PG 3 WC Infectious Diseases SC Infectious Diseases GA 926ZQ UT WOS:000302874201165 ER PT J AU Fawcett, J AF Fawcett, Jan TI THIS ISSUE: The Conundrum of Bipolar Depression SO PSYCHIATRIC ANNALS LA English DT Editorial Material ID QUETIAPINE MONOTHERAPY; ANTIDEPRESSANT USE; DOUBLE-BLIND; STEP-BD; DISORDER; EFFICACY C1 [Fawcett, Jan] Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. [Fawcett, Jan] Rush Med Coll, Dept Psychiat, Chicago, IL 60612 USA. [Fawcett, Jan] NIMH, Ctr Clin, Rockville, MD USA. [Fawcett, Jan] Amer Psychiat Assoc, Practice Guidelines Comm Assessment & Management, Washington, DC 20005 USA. [Fawcett, Jan] DSM V Mood Disorders Task Force, Arlington, VA USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUL PY 2011 VL 41 IS 7 BP 333 EP 335 DI 10.3928/00485713-20110627-01 PG 3 WC Psychiatry SC Psychiatry GA 885HB UT WOS:000299768500001 ER PT J AU Hopf, FW Seif, T Bonci, A AF Hopf, F. Woodward Seif, Taban Bonci, Antonello TI The SK channel as a novel target for treating alcohol use disorders SO CHANNELS LA English DT Editorial Material DE SK channel; nucleus accumbens; alcohol use disorder; action potential; waveform ID ACTIVATED POTASSIUM CHANNEL; NUCLEUS-ACCUMBENS NEURONS; CA2+-ACTIVATED K+ CHANNELS; COCAINE WITHDRAWAL; IN-VITRO; CONDUCTANCE; PLASTICITY; CURRENTS; REINFORCEMENT; EXCITABILITY AB We recently described the SK-type potassium channel as a novel target for treatment of excessive alcohol intake.(1) SK channel function is reduced in the nucleus accumbens (NAcb) core in rats consuming alcohol under intermittent (IAA) but not continuous (CAA) access, and the FDA-approved SK activator chlorzoxazone reduces the excessive alcohol intake in IAA rats but not the more moderate intake in CAA rats. Here, we discuss the implications of these and related findings for SK as a treatment for alcohol use disorders. In addition, we report that many NAcb core electrophysiological parameters related to action potential waveform or basal parameters were not altered in alcohol-drinking rats. These results are in strong contrast to those reported for cocaine, where several NAcb ion channels show adaptations after cocaine exposure. These results suggest that alcohol intake is associated with only limited ion channel neuro-adaptations in the NAcb relative to cocaine, and support the hypothesis that SK represents a selective and potent intervention to reduce excessive alcohol intake. C1 [Hopf, F. Woodward; Seif, Taban; Bonci, Antonello] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, San Francisco, CA 94143 USA. [Hopf, F. Woodward; Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Bonci, Antonello] NIDA Intramural Program, Bethesda, MD USA. RP Hopf, FW (reprint author), Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, San Francisco, CA 94143 USA. EM woody@gallo.ucsf.edu NR 34 TC 5 Z9 5 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6950 J9 CHANNELS JI Channels PD JUL-AUG PY 2011 VL 5 IS 4 BP 289 EP 292 DI 10.4161/chan.5.4.16577 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 878NA UT WOS:000299262600001 PM 21712648 ER PT J AU Botelho, MC Machado, JC Brindley, PJ da Costa, JMC AF Botelho, Monica Catarina Machado, Jose Carlos Brindley, Paul J. Correia da Costa, Jose Manuel TI Targeting molecular signaling pathways of Schistosoma haematobium infection in bladder cancer SO VIRULENCE LA English DT Review DE Schistosoma haematobium; urinary schistosomiasis; squamous cell carcinoma of the bladder; CHO cells; carcinogenesis-associated phenotypes; animal models; Kras mutations; estrogenic DNA adducts ID ESTROGEN-RECEPTOR-ALPHA; RURAL ZIMBABWEAN WOMEN; NUCLEIC-ACID ADDUCTS; IN-VITRO; FIBROBLAST PROLIFERATION; TRANSCRIPTIONAL ACTIVITY; GENITAL SCHISTOSOMIASIS; URINARY SCHISTOSOMIASIS; MURINE SCHISTOSOMIASIS; MANSONI EGGS AB Since 1911 epidemiological evidence indicates that S. haematobium is associated to squamous cell carcinoma of the bladder. However, the mechanisms of this interaction are not clearly defined. Using normal epithelial cells, S. haematobium parasite extracts were able to induce cancer-like phenotypes such as proliferation, apoptosis, migration, invasion and tumorigenesis. The parasite extracts on normal urothelium also presented carcinogenic and mutagenic ability. To further elucidate the biological effects of this parasite, new estrogenic molecules were identified in its extracts. These estrogens are also present in the sera of Schistosoma-infected patients, and they have the ability to repress ER transcriptional activity both in estrogen responsive MCF7 cells and normal urothelial HCV29 cells. This review will present some of the recent studies of mass spectrometry of S. haematobium extracts and sequence analysis of bladder tissue treated with the same extracts. Finally the molecular and cellular events that might be responsible for schistosomiasis-related bladder cancer will be discussed. C1 [Botelho, Monica Catarina; Correia da Costa, Jose Manuel] Natl Inst Hlth, CIBP, Bethesda, MD 20892 USA. [Botelho, Monica Catarina; Machado, Jose Carlos] Univ Porto, IPATIMUP Inst Pathol & Mol Immunol, P-4100 Oporto, Portugal. [Machado, Jose Carlos] Univ Porto, FMUP Fac Med, P-4100 Oporto, Portugal. [Correia da Costa, Jose Manuel] Univ Porto, CECA Ctr Study Anim Sci, P-4100 Oporto, Portugal. [Brindley, Paul J.] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. RP Botelho, MC (reprint author), Natl Inst Hlth, CIBP, Bethesda, MD 20892 USA. EM monicabotelho@hotmail.com RI Machado, Jose Carlos/C-5907-2009; Botelho, Monica/E-7170-2014 OI Machado, Jose Carlos/0000-0003-4741-8415; Botelho, Monica/0000-0003-0466-8465 NR 94 TC 25 Z9 25 U1 0 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD JUL-AUG PY 2011 VL 2 IS 4 BP 267 EP 279 DI 10.4161/viru.2.4.16734 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 878LB UT WOS:000299257400003 PM 21788729 ER PT J AU Killian, JK Bilke, S Davis, S Walker, RL Jaeger, E Killian, MS Waterfall, JJ Bibikova, M Fan, JB Smith, WI Meltzer, PS AF Killian, J. Keith Bilke, Sven Davis, Sean Walker, Robert L. Jaeger, Erich Killian, M. Scott Waterfall, Joshua J. Bibikova, Marina Fan, Jian-Bing Smith, William I., Jr. Meltzer, Paul S. TI A Methyl-Deviator Epigenotype of Estrogen Receptor-Positive Breast Carcinoma Is Associated with Malignant Biology SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID DNA METHYLATION; CLINICAL-IMPLICATIONS; PROGNOSTIC VALUE; FOLLOW-UP; CANCER; PATTERNS; SUBTYPE; ORIGIN; TAMOXIFEN; PROJECT AB We broadly profiled DNA methylation in breast cancers (n = 351) and benign parenchyma (n = 47) for correspondence with disease phenotype, using FFPE diagnostic surgical pathology specimens. Exploratory analysis revealed a distinctive primary invasive carcinoma subclass featuring extreme global methylation deviation. Subsequently, we tested the correlation between methylation remodeling pervasiveness and malignant biological features. A methyl deviation index (MDI) was calculated for each lesion relative to terminal ductal-lobular unit baseline, and group comparisons revealed that high-grade and short-survival estrogen receptor-positive (ER) cancers manifest a significantly higher MDI than low-grade and long-survival ER(+) cancers. In contrast, ER(-) cancers display a significantly lower MDI, revealing a striking epigenomic distinction between cancer hormone receptor subtypes. Kaplan-Meier survival curves of MDI-based risk classes showed significant divergence between low- and high-risk groups. MDI showed superior prognostic performance to crude methylation levels, and MDI retained prognostic significance (P < 0.01) in Cox multivariate analysis, including clinical stage and pathological grade. Most MDI targets individually are significant markers of ER(+) cancer survival. Lymphoid and mesenchymal indexes were not substantially different between ER(+) and ER(-) groups and do not explain MDI dichotomy. However, the mesenchymal index was associated with ER(+) cancer survival, and a high lymphoid index was associated with medullary carcinoma. Finally, a comparison between metastases and primary tumors suggests methylation patterns are established early and maintained through disease progression for both ER + and ER- tumors. (Am J Pathol 2011, 179:55-65; DOI: 10.1016/j.ajpath.2011.03.022) C1 [Killian, J. Keith; Bilke, Sven; Davis, Sean; Walker, Robert L.; Waterfall, Joshua J.; Meltzer, Paul S.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Jaeger, Erich; Bibikova, Marina; Fan, Jian-Bing] Illumina Inc, San Francisco, CA USA. [Killian, M. Scott] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Smith, William I., Jr.] Suburban Hosp, Dept Pathol, Bethesda, MD USA. RP Meltzer, PS (reprint author), NCI, Genet Branch, 37 Convent Dr,Room 6138, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov OI Davis, Sean/0000-0002-8991-6458 FU NIH FX Supported primarily by NIH intramural funding. NR 34 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2011 VL 179 IS 1 BP 55 EP 65 DI 10.1016/j.ajpath.2011.03.022 PG 11 WC Pathology SC Pathology GA 865JL UT WOS:000298307100007 PM 21641572 ER PT J AU Martin, P Liu, YN Pierce, R Abou-Kheir, W Casey, O Seng, V Camacho, D Simpson, RM Kelly, K AF Martin, Philip Liu, Yen-Nien Pierce, Rachel Abou-Kheir, Wassim Casey, Orla Seng, Victoria Camacho, Daniel Simpson, R. Mark Kelly, Kathleen TI Prostate Epithelial Pten/TP53 Loss Leads to Transformation of Multipotential Progenitors and Epithelial to Mesenchymal Transition SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID INITIATING CELLS; STEM-CELL; IN-VIVO; CANCER; P53; SENESCENCE; DELETION; DIFFERENTIATION; CARCINOMA; PATTERNS AB Loss of PTEN and loss of TP53 are common genetic aberrations occurring in prostate cancer. PTEN and TP53 contribute to the regulation of self-renewal and differentiation in prostate progenitors, presumptive tumor initiating cells for prostate cancer. Here we characterize the transformed phenotypes resulting from deletion of the Pten and TP53 tumor suppressors in prostate epithelium. Using the PB-Cre4(+) Pten(fl/fl) TP53(fl/fl) model of prostate cancer, we describe the histological and metastatic properties of primary tumors, transplanted primary tumor cells, and clonal cell lines established from tumors. Adenocarcinoma was the major primary tumor type that developed, which progressed to lethal sarcomatoid carcinoma at approximately 6 months of age. In addition, basal carcinomas and prostatic urothelial carcinomas were observed. We show that tumor heterogeneity resulted, at least in part, from the transformation of multipotential progenitors. CK8+ luminal epithelial cells were capable of undergoing epithelial to mesenchymal transition in vivo to sarcomatoid carcinomas containing osseous metaplasia. Metastasis rarely was observed from primary tumors, but metastasis to lung and lymph nodes occurred frequently from orthotopic tumors initiated from a biphenotypic clonal cell line. Androgen deprivation influenced the differentiated phenotypes of metastases. These data show that one functional consequence of Pten/TP53 loss in prostate epithelium is lineage plasticity of transformed cells. (Am J Pathol 2011, 179:422-435; DOI: 10.1016/j.ajpath.2011.03.035) C1 [Martin, Philip; Liu, Yen-Nien; Pierce, Rachel; Abou-Kheir, Wassim; Casey, Orla; Seng, Victoria; Camacho, Daniel; Kelly, Kathleen] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Simpson, R. Mark] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Kelly, K (reprint author), Bldg 37,Room 1068, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 30 TC 25 Z9 26 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2011 VL 179 IS 1 BP 422 EP 435 DI 10.1016/j.ajpath.2011.03.035 PG 14 WC Pathology SC Pathology GA 865JL UT WOS:000298307100040 PM 21703421 ER PT J AU Zeng, CY Du, YP Alberico, T Seeberger, J Sun, XP Zou, S AF Zeng, Chaoyang Du, Yanping Alberico, Thomas Seeberger, Jeanne Sun, Xiaoping Zou, Sige TI Gender-specific prandial response to dietary restriction and oxidative stress in Drosophila melanogaster SO FLY LA English DT Article DE food intake; excretion; aging; dietary restriction; oxidative stress ID CALORIC RESTRICTION; LIFE-SPAN; FEEDING-BEHAVIOR; AGE; RADIOPHOSPHORUS; EXPRESSION; LONGEVITY; MORTALITY; INSIGHTS; DAMAGE AB Drosophila melanogaster is ideal for studying lifespan modulated by dietary restriction (DR) and oxidative stress, and also for screening prolongevity compounds. It is critical to measure food intake in the aforementioned studies. Current methods, however, overlook the amount of the food excreted out of the flies as feces or deposited in eggs. Here we describe a feeding method using a radioactive tracer to measure gender-specific food intake, retention and excretion in response to DR and oxidative stress to account for all the ingested food. Flies were fed a full, restricted or paraquat-containing diet. The radioactivity values of the food in fly bodies, feces and eggs were measured separately after a 24-hr feeding. Food intake was calculated as the sum of these measurements. We found that most of the tracer in the ingested food was retained in the fly bodies and <8% of the tracer was excreted out of the flies as feces and eggs in the case of females during a 24-hr feeding. Under a DR condition, flies increased food intake in volume to compensate for the reduction of calorie content in the diet and also slightly increased excretion. Under an oxidative stress condition, flies reduced both food intake and excretion. Under all the tested dietary conditions, males ingested and excreted 3- to 5-fold less food than females. This study describes an accurate method to measure food intake and provides a basis to further investigate prandial response to DR and prolongevity interve ntions in invertebrates. C1 [Alberico, Thomas; Seeberger, Jeanne; Sun, Xiaoping; Zou, Sige] NIA, Funct Genom Unit, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Zeng, Chaoyang; Du, Yanping] Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53201 USA. RP Zou, S (reprint author), NIA, Funct Genom Unit, Lab Expt Gerontol, Baltimore, MD 21224 USA. EM zous@grc.nia.nih.gov FU National Institute on Aging, NIH; Shaw Scientist Foundation of Milwaukee FX We thank Dr. Donald Ingram, Jason Sinclair and Dr. Toshimitsu Komatsu for discussion, Sharron Daly for assistance with the radioactive measurements and Drs. Kevin Pearson and Min Zhu for critical reading of the manuscript. This study was funded by the Intramural Research Program of the National Institute on Aging, NIH, to Sige Zou and the Shaw Scientist Foundation of Milwaukee to Chaoyang Zeng. NR 42 TC 6 Z9 6 U1 1 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6934 J9 FLY JI Fly PD JUL-SEP PY 2011 VL 5 IS 3 BP 174 EP 180 DI 10.4161/fly.5.3.15572 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863QX UT WOS:000298183400002 PM 21471736 ER PT J AU Velayati, A Knight, MA Stubblefield, BK Sidransky, E Tayebi, N AF Velayati, Arash Knight, Melanie A. Stubblefield, Barbara K. Sidransky, Ellen Tayebi, Nahid TI Identification of Recombinant Alleles Using Quantitative Real-Time PCR Implications for Gaucher Disease SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID GLUCOCEREBROSIDASE GENE; PSEUDOGENE; MUTATION; METAXIN; REGION; N370S AB Pseudogenes, resulting from duplications of functional genes, contribute to the functional complexity of their parental genes. The glucocerebrosidase gene (GBA), located in a gene-rich region on chromosome 1q 21, is mutated in Gaucher disease. The presence of contiguous, highly homologous pseudogenes for both GBA and metaxin 1 at this locus increases the likelihood of DNA rearrangement. We describe a facile method to identify and analyze recombinant alleles in patients with Gaucher disease. Genomic DNA from 20 patients with recombinant GBA alleles and five controls was evaluated to identify DNA rearrangements or copy number variation using six probes specific for either the GBA gene or pseudogene. Quantitative real-time PCR was performed on genomic DNA, and Southern blot analyses using HincII together with sequencing confirmed the real-time results. Both GBA fusions and duplications could be detected. Different sites of crossover were identified, and alleles resulting from gene conversion could be distinguished from reciprocal recombinant alleles. Quantitative real-time PCR is a sensitive and rapid method to detect fusions and duplications in patients with recombinant GBA alleles. This technique is more sensitive, faster, and cheaper than Southern blot analysis, and can be used in diagnostic laboratories, and to detect other recombinant alleles within the genome. (J Mol Diagn 2011, 13:401-405; DOI: 10.1016/j.jmoldx.2011.02.005) C1 [Velayati, Arash; Knight, Melanie A.; Stubblefield, Barbara K.; Sidransky, Ellen; Tayebi, Nahid] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Division of Intramural Research of the National Human Genome Research Institute; National Institutes of Health FX Supported by the Division of Intramural Research of the National Human Genome Research Institute, and the National Institutes of Health. NR 13 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2011 VL 13 IS 4 BP 401 EP 405 DI 10.1016/j.jmoldx.2011.02.005 PG 5 WC Pathology SC Pathology GA 865JF UT WOS:000298306500007 PM 21704274 ER PT J AU Hosey, G Ichiho, H Satterfield, D Dankwa-Mullan, I Kuartei, S Rhee, K Belyeu-Camacho, T Debrum, I Demei, Y Lippwe, K Luces, PS Roby, F AF Hosey, Gwen Ichiho, Henry Satterfield, Dawn Dankwa-Mullan, Irene Kuartei, Stevenson Rhee, Kyu Belyeu-Camacho, Tayna deBrum, Ione Demei, Yorah Lippwe, Kipier Luces, Patrick Solidum Roby, Faiese TI Chronic Disease Surveillance Systems Within the US Associated Pacific Island Jurisdictions SO PREVENTING CHRONIC DISEASE LA English DT Article AB In recent years, illness and death due to chronic disease in the US Associated Pacific Islands (USAPI) jurisdictions have dramatically increased. Effective chronic disease surveillance can help monitor disease trends, evaluate public policy, prioritize resource allocation, and guide program planning, evaluation, and research. Although chronic disease surveillance is being conducted in the USAPI, no recently published capacity assessments for chronic disease surveillance are available. The objective of this study was to assess the quality of existing USAPI chronic disease data sources and identify jurisdictional capacity for chronic disease surveillance. The assessment included a chronic disease data source inventory, literature review, and review of surveillance documentation available from the web or through individual jurisdictions. We used the World Health Organization's Health Metric Network Framework to assess data source quality and to identify jurisdictional capacity. Results showed that USAPI data sources are generally aligned with widely accepted chronic disease surveillance indicators and use standardized data collection methodology to measure chronic disease behavioral risks, preventive practices, illness, and death. However, all jurisdictions need to strengthen chronic disease surveillance through continued assessment and expanded support for valid and reliable data collection, analysis and reporting, dissemination, and integration among population-based and institution-based data sources. For sustained improvement, we recommend investment and technical assistance in support of a chronic disease surveillance system that integrates population-based and institution-based data sources. An integrated strategy that bridges and links USAPI data sources can support evidence-based policy and population health interventions. C1 [Ichiho, Henry] Pacific Diabet Educ Program, Honolulu, HI USA. [Satterfield, Dawn] Ctr Dis Control & Prevent, Atlanta, GA USA. [Dankwa-Mullan, Irene] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. [Kuartei, Stevenson] Minist Hlth, Koror, Palau. [Rhee, Kyu] Hlth Resources & Serv Adm, Rockville, MD USA. RP Hosey, G (reprint author), Ctr Dis Control & Prevent, 4150 Technol Way,Ste 210, Carson City, NV 89706 USA. EM ghh0@cdc.gov FU Nia Aitaoto and Dorraine Watts FX We thank the following Pacific Island representatives who contributed to this project: Tuiasina Salamo Laumoli, Dottie Siavii, and Pasa Turituri, American Samoa; Joseph K. Villagomez, Rebecca Ann Covarrubias, Isidro Ogarto, John Tagabuel, Commonwealth of the Northern Mariana Islands; Vita A. Skilling, Marcus Samo, Shra Alik, and Brenda Hadley Eperiam, Federated States of Micronesia; J. Peter Roberto, Roselie Zabala, and Gil S. Suguitan, Guam; Amenta Matthew, Justina Langidrik, Donny Andrike, and Godfrey Waidubu, Republic of the Marshall Islands; Augusta Rengiil, Republic of Palau. We also recognize the contributions of Lawrence Barker, Kaetz Beartusk, Michelle Carlberg, Gloria Colclough, Jack Colbert, Ed Gregg, Ann Goding, Laura Kann, Juliette Lee, Veronica Lea, Kristen McCall, Barbara Park, Karen Siener, Castine Verrill, Charles Warren, and MaryBeth Welton, Centers for Disease Control and Prevention; and Susan Tanner, End-Stage Renal Disease Network 17. Finally, we thank Nia Aitaoto and Dorraine Watts for their support and encouragement during this project. NR 20 TC 3 Z9 3 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2011 VL 8 IS 4 AR A86 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 874OY UT WOS:000298969100016 PM 21672410 ER PT J AU Beare, PA Gilk, SD Larson, CL Hill, J Stead, CM Omsland, A Cockrell, DC Howe, D Voth, DE Heinzen, RA AF Beare, Paul A. Gilk, Stacey D. Larson, Charles L. Hill, Joshua Stead, Christopher M. Omsland, Anders Cockrell, Diane C. Howe, Dale Voth, Daniel E. Heinzen, Robert A. TI Dot/Icm Type IVB Secretion System Requirements for Coxiella burnetii Growth in Human Macrophages SO MBIO LA English DT Article ID LEGIONELLA-PNEUMOPHILA; HOST-CELL; Q-FEVER; PARASITOPHOROUS VACUOLES; THP-1 CELLS; LEISHMANIA; PROTEIN; IDENTIFICATION; PHAGOLYSOSOME; APOPTOSIS AB Central to Q fever pathogenesis is replication of the causative agent, Coxiella burnetii, within a phagolysosome-like parasitophorous vacuole (PV) in mononuclear phagocytes. C. burnetii modulates PV biogenesis and other host cell functions, such as apoptotic signaling, presumably via the activity of proteins delivered to the host cytosol by a Dot/Icm type IVB secretion system (T4BSS). In this study, we utilized a C. burnetii strain carrying IcmD inactivated by the Himar1 transposon to investigate the requirements for Dot/Icm function in C. burnetii parasitism of human THP-1 macrophage-like cells. The icmD::Tn mutant failed to secrete characterized T4BSS substrates, a defect that correlated with deficient replication, PV development, and apoptosis protection. Restoration of type IVB secretion and intracellular growth of the icmD:: Tn mutant required complementation with icmD, -J, and -B, indicating a polar effect of the transposon insertion on downstream dot/icm genes. Induction of icmDJB expression at 1 day postinfection resulted in C. burnetii replication and PV generation. Collectively, these data prove that T4BSS function is required for productive infection of human macrophages by C. burnetii. However, illustrating the metabolic flexibility of C. burnetti, the icmD:: Tn mutant could replicate intracellularly when sequestered in a PV generated by wild-type bacteria, where Dot/Icm function is provided in trans, and within a phenotypically similar PV generated by the protozoan parasite Leishmania amazonensis, where host cells are devoid of Dot/Icm T4BSS effector proteins. IMPORTANCE Coxiella burnetii, the cause of human Q fever, is the only bacterial pathogen known to replicate in a vacuole resembling a phagolysosome. The organism manipulates host macrophages to promote the biogenesis of a vacuolar compartment permissive for growth. By analogy to the well-established cellular microbiology of Legionella pneumophila, the Dot/Icm type IVB secretion system of C. burnetii is implicated as a critical virulence factor in host cell modification that delivers proteins with effector functions directly into the host cell cytosol. Using new genetic tools, we verify that Dot/Icm function is essential for productive infection of human macrophages by C. burnetii. Interestingly, despite the production of homologous secretion systems, L. pneumophila and C. burnetii have strikingly different temporal requirements for Dot/Icm function during their respective infectious cycles. C1 [Beare, Paul A.; Gilk, Stacey D.; Larson, Charles L.; Hill, Joshua; Stead, Christopher M.; Omsland, Anders; Cockrell, Diane C.; Howe, Dale; Heinzen, Robert A.] NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Coxiella Pathogenesis Sect,NIH, Hamilton, MT 59840 USA. [Voth, Daniel E.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. RP Heinzen, RA (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Coxiella Pathogenesis Sect,NIH, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) [R01AI087669] FX This work was supported by funding from the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) grant R01AI087669 (D. E. V.), and the Intramural Research Program of the NIH, NIAID (R.A.H.). NR 50 TC 71 Z9 71 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2011 VL 2 IS 4 AR e00175-11 DI 10.1128/mBio.00175-11 PG 10 WC Microbiology SC Microbiology GA 845SX UT WOS:000296844000021 PM 21862628 ER PT J AU Csiszovszki, Z Krishna, S Orosz, L Adhya, S Semsey, S AF Csiszovszki, Zsolt Krishna, Sandeep Orosz, Laszlo Adhya, Sankar Semsey, Szabolcs TI Structure and Function of the D-Galactose Network in Enterobacteria SO MBIO LA English DT Article ID ESCHERICHIA-COLI; YERSINIA-PESTIS; REGULATORY NETWORKS; GAL TRANSCRIPTION; GENE-EXPRESSION; LIPOPOLYSACCHARIDE; REPRESSOR; PROTEIN; OPERON; DNA AB Galactose is important for the survival and virulence of bacteria. In Escherichia coli, galactose is utilized by the Leloir pathway, which is controlled by a complex network. To shed light on the potential functions the galactose network could perform, we performed bioinformatical analysis of reference genome sequences belonging to the Enterobacteriaceae family. We found that several genomes have reduced numbers of components compared to the E. coli galactose system, suggesting that the network can be optimized for different environments. Typically, genes are removed by deletions; however, in Yersinia pestis, the galactose mutarotase (galM) gene is inactivated by a single-base-pair deletion. Lack of GalM activity indicates that the two anomers of D-galactose are used for different purposes, alpha-D-galactose as a carbon source and beta-D-galactose for induction of UDP-galactose synthesis for biosynthetic glycosylation. We demonstrate that activity of the galM gene can be restored by different single-base-pair insertions. During the evolution of Y. pestis to become a vector-transmitted systemic pathogen, many genes were converted to pseudogenes. It is not clear whether pseudogenes are present to maintain meiotrophism or are in the process of elimination. Our results suggest that the galM pseudogene has not been deleted because its reactivation may be beneficial in certain environments. IMPORTANCE Evolution of bacteria to populate a new environment necessarily involves reengineering of their molecular network. Members of the Enterobacteriaceae family of bacteria have diverse lifestyles and can function in a wide range of environments. In this study we performed bioinformatical analysis of 34 reference genome sequences belonging to the Enterobacteriaceae family to gain insight into the natural diversity of the D-galactose utilization network. Our bioinformatical analysis shows that in several species, some genes of the network are completely missing or are inactivated by large deletions. The only exception is the galactose mutarotase (galM) gene of Yersinia pestis, which is converted to a pseudogene by a single-base-pair deletion. In this paper, we discuss the possible consequences of galM inactivation on network function. We suggest that galM was converted to a pseudogene rather than being deleted in evolution because its reactivation can be beneficial in certain environments. C1 [Orosz, Laszlo; Semsey, Szabolcs] Eotvos Lorand Univ, Dept Genet, Budapest, Hungary. [Csiszovszki, Zsolt; Adhya, Sankar] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Krishna, Sandeep] NCBS, Bangalore, Karnataka, India. [Semsey, Szabolcs] Niels Bohr Inst, DK-2100 Copenhagen, Denmark. RP Semsey, S (reprint author), Eotvos Lorand Univ, Dept Genet, Budapest, Hungary. EM semsey@nbi.dk RI Semsey, Szabolcs/L-6329-2013; OI Semsey, Szabolcs/0000-0002-4522-5495 FU Hungarian Scientific Research Fund (OTKA) [PD75496]; Danish Council for Independent ResearchpipeNatural Sciences; NIH, National Cancer Institute, Center for Cancer Research, United States; Danish National Research Foundation FX This research was supported by the Hungarian Scientific Research Fund (OTKA) grant PD75496 to S. S., by the Danish Council for Independent Research vertical bar Natural Sciences, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, United States, and by the Danish National Research Foundation. NR 43 TC 3 Z9 4 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2011 VL 2 IS 4 AR e00053-11 DI 10.1128/mBio.00053-11 PG 8 WC Microbiology SC Microbiology GA 845SX UT WOS:000296844000003 PM 21712421 ER PT J AU Srikantan, S Gorospe, M AF Srikantan, Subramanya Gorospe, Myriam TI Altered glycobiology of stem cells linked to age-related osteoarthritis SO AGING-US LA English DT Article C1 [Srikantan, Subramanya; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519 NR 5 TC 0 Z9 0 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JUL PY 2011 VL 3 IS 7 BP 663 EP 664 PG 2 WC Cell Biology SC Cell Biology GA 845AU UT WOS:000296796000001 PM 21808096 ER PT J AU Warwick, MT AF Warwick, Margaret Turner TI Clinical leadership and management in the NHS SO JOURNAL OF THE ROYAL SOCIETY OF MEDICINE LA English DT Editorial Material C1 [Warwick, Margaret Turner] Natl Heart & Lung Inst, Bethesda, MD USA. [Warwick, Margaret Turner] Royal Brompton Hosp, Brompton, England. [Warwick, Margaret Turner] Royal Coll Phys, Ottawa, ON, Canada. [Warwick, Margaret Turner] Royal Devon & Exeter Healthcare Trust, Board Governors, Devon, England. RP Warwick, MT (reprint author), Natl Heart & Lung Inst, Bethesda, MD USA. EM m@turnerwarwick.eclipse.co.uk NR 3 TC 1 Z9 1 U1 0 U2 2 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0141-0768 J9 J ROY SOC MED JI J. R. Soc. Med. PD JUL PY 2011 VL 104 IS 7 BP 308 EP 309 DI 10.1258/jrsm.2011.110105 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 839WL UT WOS:000296400100010 ER PT J AU Wickner, RB Edskes, HK Kryndushkin, D McGlinchey, R Bateman, D Kelly, A AF Wickner, Reed B. Edskes, Herman K. Kryndushkin, Dmitry McGlinchey, Ryan Bateman, David Kelly, Amy TI Prion diseases of yeast: Amyloid structure and biology SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Prion ID HET-S PRION; BETA-SHEET STRUCTURE; SOLID-STATE NMR; SACCHAROMYCES-CEREVISIAE; TRANSLATION TERMINATION; IN-VITRO; HETEROKARYON INCOMPATIBILITY; ENVIRONMENTAL-STRESS; PODOSPORA-ANSERINA; POLAR ZIPPERS AB Prion "variants" or "strains" are prions with the identical protein sequence, but different characteristics of the prion infection: e. g. different incubation periods for scrapie strains or different phenotype intensities for yeast prion variants. We have shown that infectious amyloids of the yeast prions [PSI+], [URE3] and [PIN+] each have an in-register parallel beta-sheet architecture. Moreover, we have pointed out that this amyloid architecture can explain how one protein can faithfully transmit any of several conformations to new protein monomers. This explains how proteins can be genes. Published by Elsevier Ltd. C1 [Wickner, Reed B.; Edskes, Herman K.; Kryndushkin, Dmitry; McGlinchey, Ryan; Bateman, David; Kelly, Amy] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU National Institute of Diabetes Digestive and Kidney Diseases FX This work was supported by the Intramural Program of the National Institute of Diabetes Digestive and Kidney Diseases. NR 87 TC 19 Z9 19 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD JUL PY 2011 VL 22 IS 5 BP 469 EP 475 DI 10.1016/j.semcdb.2011.02.021 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 839JF UT WOS:000296360800006 PM 21345375 ER PT J AU Lee, KA Lee, SM Yang, HJ Park, CW Mazaki-Tovi, S Yoon, BH Romero, R AF Lee, Kyung A. Lee, Seung Mi Yang, Hye Jin Park, Chan-Wook Mazaki-Tovi, Shali Yoon, Bo Hyun Romero, Roberto TI The frequency of meconium-stained amniotic fluid increases as a function of the duration of labor SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Fetal bowel function; first stage of labor; pregnancy ID PRETERM PREMATURE RUPTURE; ACID-BASE STATUS; IN-UTERO DEFECATION; INTRAAMNIOTIC INFECTION/INFLAMMATION; ASPIRATION SYNDROME; NEONATAL OUTCOMES; PROLONGED 2ND-STAGE; PRELABOR RUPTURE; GESTATIONAL-AGE; FETAL MEMBRANES AB Methods. aEuro integral The clinical characteristics of women who delivered term singleton live newborns between 2001 and 2006 were examined. The cases involving neonates with major congenital anomalies were excluded. Results. aEuro integral(1) The frequency of MSAF in term pregnancies was 18.4%% (806/4376); (2) MSAF was found in only 2.8%% (28/1008) of women who delivered by elective cesarean, but in 23.1%% (778/3368) of women who delivered after the onset of labor (p aEuroS < aEuroS0.001); (3) The longer the duration of labor (first stage, second stage, or total), the higher the frequency of MSAF (p aEuroS < aEuroS0.001 for each); this remained significant after adjusting for other confounding variables such as parity, duration of rupture of membranes, gestational age at delivery, and mode of delivery (p aEuroS < aEuroS0.001 for each). Conclusion. aEuro integral MSAF was found in only 2.8%% (28/1008) of women who delivered before the onset of labor, but in 23.1%% (778/3368) of women who delivered after the onset of labor. The longer the duration of labor, the higher the risk of MSAF in term singleton gestation. C1 [Lee, Kyung A.; Lee, Seung Mi; Yang, Hye Jin; Park, Chan-Wook; Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul 110744, South Korea. [Mazaki-Tovi, Shali; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Yoon, BH (reprint author), Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul 110744, South Korea. EM yoonbh@snu.ac.kr RI Yoon, Bo Hyun/H-6344-2011; Park, Chan-Wook/J-5498-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 58 TC 11 Z9 13 U1 0 U2 3 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 JUL PY 2011 VL 24 IS 7 BP 880 EP 885 DI 10.3109/14767058.2010.531329 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 772FY UT WOS:000291220900002 PM 21410421 ER PT J AU Schroeder, JL Bakalar, M Pohida, TJ Balaban, RS AF Schroeder, J. L. Bakalar, M. Pohida, T. J. Balaban, R. S. TI Rapid overlapping-volume acquisition and reconstruction (ROVAR): automated 3D tiling for high-resolution, large field-of-view optical microscopy SO JOURNAL OF MICROSCOPY LA English DT Article DE Automation; in vivo; multiphoton; stitching; volume; 3D ID IN-VIVO; MULTIPHOTON AB Micrometer-scale three-dimensional data from fluorescence microscopes oiler unique insight into cellular morphology and function by resolving subcellular locations of fluorescent dyes and proteins. To increase field-of-view size while using a high-resolution multiphoton microscope, we have created an automated system of rapidly acquiring overlapping image stacks from multiple fields-of-view along a nonplanar tissue surface. Each image stack is acquired only between the surface and the maximal penetrating depth. as determined by the image signal-to-background ratio. This results in the acquisition of the volume containing visible tissue along the tissue surface, excluding the empty volume above the tissue and the volume beyond the maximum imaging depth within the tissue. The automated collection of overlapping volumes is Followed by reconstruction that can efficiently generate a single three-dimensional volume of the tissue surface. This approach yields data spanning multiple millimetres at micrometre resolution that is faster while requiring less work from the microscope operator. The advantages of the system are demonstrated by acquisition of data from intact, unfixed organs without a coverglass both in vivo and in situ. C1 [Schroeder, J. L.; Balaban, R. S.] NHLBI, Cardiac Energet Lab, Bethesda, MD USA. [Bakalar, M.; Pohida, T. J.] NIH, CIT, Div Computat Biosci, Bethesda, MD USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, Bethesda, MD USA. EM balabanr@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 12 TC 6 Z9 6 U1 0 U2 0 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 JUL PY 2011 VL 243 IS 1 BP 103 EP 110 DI 10.1111/j.1365-2818.2011.03490.x PG 8 WC Microscopy SC Microscopy GA 788XT UT WOS:000292478400010 PM 21348869 ER PT J AU Graves, RE Freedy, JR Aigbogun, NU Lawson, WB Mellman, TA Alim, TN AF Graves, Ruth Elaine Freedy, John R. Aigbogun, Notalelomwan U. Lawson, William B. Mellman, Thomas A. Alim, Tanya N. TI PTSD Treatment of African American Adults in Primary Care: The Gap Between Current Practice and Evidence-Based Treatment Guidelines SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE posttraumatic stress disorder; African Americans; treatment; primary care; mental health; collaborative care ID POSTTRAUMATIC-STRESS-DISORDER; DISEASE MANAGEMENT PROGRAMS; NATIONAL COMORBIDITY SURVEY; COLLABORATIVE CARE; ANXIETY DISORDERS; PHYSICAL SYMPTOMS; MENTAL-DISORDERS; PANIC DISORDER; DEPRESSION; POPULATION AB Background: Posttraumatic stress disorder (PTSD) is a common, potentially disabling, underdiagnosed, and undertreated illness. Primary care physicians assume a critical role in the diagnosis, treatment, and referral of African Americans with PTSD since mental health access is limited for this population. This study is an examination of PTSD treatment of African Americans in the primary care setting. Actual treatment provision is contrasted with existing evidence-based PTSD treatment guidelines. Method: Researchers screened 738 consenting, mostly African American, adults in 4 academically affiliated primary care offices for both trauma exposure and mental health symptoms, including PTSD. Results: Employing criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV), investigators diagnosed 91 of the participants with current PTSD using the Structured Clinical Interview for DSM and the Clinician-Administered of PTSD Scale for DSM-IV. Treatment statistics include: 69.2% (n = 63) had never received treatment from a mental health provider; 18.6% (n = 17) were currently seeing a mental health practitioner; nearly half (47.9%, n = 24) of a subsample had never discussed traumatic event exposure or mental health symptoms with their primary care doctor; 32% (n = 29) were prescribed psychotropic medication and only 18.6% (n = 171 were participating in any form of psychotherapy. Concurrent psychiatric disorders were found in 46.2% (n = 42) of the participants with PTSD. Conclusion: Most African American adult primary care patients with PTSD were either undiagnosed or undertreated in this inner-city setting. These results demonstrate a clear need to improve screening and treatment services. Both individual (provider and patient) and system-based changes will be required to meet the demonstrated clinical need. C1 [Graves, Ruth Elaine] Howard Univ, Dept Community & Family Med, Washington, DC 20059 USA. [Freedy, John R.] Med Univ S Carolina, Dept Family Med, Charleston, SC USA. [Aigbogun, Notalelomwan U.] NCI, Frederick, MD 21701 USA. RP Graves, RE (reprint author), Howard Univ Hosp, Psychiat Suite 5B,2041 Georgia Ave NW, Washington, DC 20060 USA. EM RevElaineGraves@att.net OI Lawson, William/0000-0002-9324-7090 FU National Institute of Mental Health [01-D1-007]; Howard University; General Clinical Research Center from the National Institutes of Health [2 MO 1 RR1024] FX Funding for this study was made possible by a National Institute of Mental Health contract (01-D1-007), a Howard University New Faculty Research grant, and in part by a General Clinical Research Center grant from the National Institutes of Health (2 MO 1 RR1024). NR 60 TC 5 Z9 5 U1 1 U2 6 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUL PY 2011 VL 103 IS 7 BP 585 EP 593 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 829SY UT WOS:000295605800005 PM 21999033 ER PT J AU Wang, YM Cheng, ZQ ElAlieh, HZ Nakamura, E Nguyen, MT Mackem, S Clemens, TL Bikle, DD Chang, WH AF Wang, Yongmei Cheng, Zhiqiang ElAlieh, Hashem Z. Nakamura, Eiichiro Nguyen, Minh-Thanh Mackem, Susan Clemens, Thomas L. Bikle, Daniel D. Chang, Wenhan TI IGF-1R Signaling in Chondrocytes Modulates Growth Plate Development by Interacting With the PTHrP/Ihh Pathway SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE IGF-1 RECEPTOR; CHONDROCYTE; GROWTH PLATE DEVELOPMENT; IHH; PTHRP ID HORMONE-RELATED PEPTIDE; ENDOCHONDRAL BONE-FORMATION; PTH-RELATED-PROTEIN; INDIAN-HEDGEHOG; FACTOR-I; HYPERTROPHIC CHONDROCYTES; INDEPENDENT REGULATION; EXTRACELLULAR CALCIUM; SKELETAL DEVELOPMENT; POSTNATAL-GROWTH AB Systemic derangements and perinatal death of generalized insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) knockout mice preclude definitive assessment of IGF-1R actions in growth-plate (GP) chondrocytes. We generated cartilage-specific Igf1r knockout ((Cart)Igf1r(-/-)) mice to investigate local control of chondrocyte differentiation in the GP by this receptor. These mice died shortly after birth and showed disorganized chondrocyte columns, delayed ossification and vascular invasion, decreased cell proliferation, increased apoptosis, and increased expression of parathyroid hormone-related protein (Pthrp) RNA and protein in their GPs. The increased Pthrp expression in the knockout GPs likely was due to an increase in gene transcription, as determined by the increased activity of a LacZ reporter that was inserted downstream of the endogenous PTHrP promoter and bred into the knockout mice. To circumvent the early death of (Cart)Igf1r(-/-) mice and investigate the role of IGF-1R during postnatal growth, we made tamoxifen (Tam)-inducible, cartilage-specific Igf1r knockout ((TamCart)Igf1(-/-)) mice. At 2 weeks of age and 7 to 8 days after Tam injection, the (TamCart)Igf1(-/-) mice showed growth retardation with a disorganized GP, reduced chondrocyte proliferation, decreased type 2 collagen and Indian Hedgehog (Ihh) expression, but increased expression of PTHrP. Consistent with in vivo observations, in vitro knockout of the Igf1r gene by adenoviral expression of Cre recombinase suppressed cell proliferation, promoted apoptosis, and increased Pthrp expression. Our data indicate that the IGF-1R in chondrocytes controls cell growth, survival, and differentiation in embryonic and postnatal GPs in part by suppression of Pthrp expression. (C) 2011 American Society for Bone and Mineral Research. C1 [Wang, Yongmei; Cheng, Zhiqiang; ElAlieh, Hashem Z.; Bikle, Daniel D.; Chang, Wenhan] Univ Calif San Francisco, Vet Affairs Med Ctr, Endocrine Unit, San Francisco, CA 94143 USA. [Nakamura, Eiichiro; Nguyen, Minh-Thanh; Mackem, Susan] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Clemens, Thomas L.] Johns Hopkins Univ, Ctr Musculoskeletal Res, Dept Orthoped Surg, Baltimore, MD USA. RP Chang, WH (reprint author), Vet Adm Med Ctr, Endocrine Unit 111N, 4150 Clement St, San Francisco, CA 94121 USA. EM wenhan.chang@ucsf.edu FU NIH [RO1-AG21353, R21-AR50662, RO1-AR050023, RO1 DK 54793]; Department of Veterans Affairs Merit Review; Research Enhancement Award Program in Bone Disease FX This work was supported by NIH RO1-AG21353 (WC), R21-AR50662 (WC), RO1-AR050023 (DB), and RO1 DK 54793 (DB); by the Department of Veterans Affairs Merit Review (DB); and by the Research Enhancement Award Program in Bone Disease (WC and DB). NR 35 TC 34 Z9 36 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2011 VL 26 IS 7 BP 1437 EP 1446 DI 10.1002/jbmr.359 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 783DJ UT WOS:000292061400007 PM 21312270 ER PT J AU Barnett, BP Ruiz-Cabello, J Hota, P Ouwerkerk, R Shamblott, MJ Lauzon, C Walczak, P Gilson, WD Chacko, VP Kraitchman, DL Arepally, A Bulte, JWM AF Barnett, Brad P. Ruiz-Cabello, Jesus Hota, Partha Ouwerkerk, Ronald Shamblott, Michael J. Lauzon, Cal Walczak, Piotr Gilson, Wesley D. Chacko, Vadappuram P. Kraitchman, Dara L. Arepally, Aravind Bulte, Jeff W. M. TI Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE cell tracking; molecular imaging; fluorine MRI; ultrasound imaging; X-ray imaging; islet cell; diabetes ID F-19 MAGNETIC-RESONANCE; STEM-CELLS; TARGETED DELIVERY; 1.5 TESLA; TRANSPLANTATION; MRI; PERFLUOROCTYLBROMIDE; REJECTION; SYSTEM; MODEL AB In vivo imaging of engraftment and immunorejection of transplanted islets is critical for further clinical development, with (1)H MR imaging of superparamagnetic iron oxide-labeled cells being the current premier modality. Using perfluorocarbon nanoparticles, we present here a strategy for non-invasive imaging of cells using other modalities. To this end, human cadaveric islets were labeled with rhodamine-perfluorooctylbromide (PFOB) nanoparticles, rhodamine-perfluoropolyether (PFPE) nanoparticles or Feridex (R) as control and tested in vitro for cell viability and c-peptide secretion for 1 week. (19)F MRI, computed tomography (CT) and ultrasound (US) imaging was performed on labeled cell phantoms and on cells following transplantation beneath the kidney capsule of mice and rabbits. PFOB and PFPE-labeling did not reduce human islet viability or glucose responsiveness as compared with unlabeled cells or SPIO-labeled cells. PFOB-and PFPE-labeled islets were effectively fluorinated for visualization by (19)F MRI. PFOB-labeled islets were acoustically reflective for detection by US imaging and became sufficiently brominated to become radiopaque allowing visualization with CT. Thus, perfluorocarbon nanoparticles are multimodal cellular contrast agents that may find applications in real-time targeted delivery and imaging of transplanted human islets or other cells in a clinically applicablemanner using MRI, US or CT imaging. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Bulte, Jeff W. M.] Johns Hopkins Univ, Sch Med, Dept Radiol, Inst Cell Engn,Cellular Imaging Sect, Baltimore, MD 21205 USA. [Barnett, Brad P.; Ruiz-Cabello, Jesus; Hota, Partha; Walczak, Piotr; Bulte, Jeff W. M.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Biol Program, Baltimore, MD 21205 USA. [Barnett, Brad P.; Ruiz-Cabello, Jesus; Hota, Partha; Lauzon, Cal; Walczak, Piotr; Gilson, Wesley D.; Chacko, Vadappuram P.; Kraitchman, Dara L.; Arepally, Aravind; Bulte, Jeff W. M.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Div MR Res, Baltimore, MD 21205 USA. [Ruiz-Cabello, Jesus] Univ Complutense Madrid, Inst Estudios Biofunc, Madrid, Spain. [Hota, Partha; Bulte, Jeff W. M.] Johns Hopkins Univ, Sch Med, Dept Chem & Biomol Engn, Baltimore, MD 21205 USA. [Ouwerkerk, Ronald] NIDDK, NIH, Bethesda, MD USA. [Shamblott, Michael J.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Shamblott, Michael J.; Lauzon, Cal] Johns Hopkins Univ, Sch Med, Hugo W Moser Kennedy Krieger Inst, Baltimore, MD 21205 USA. RP Bulte, JWM (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, Inst Cell Engn,Cellular Imaging Sect, 217 Traylor,720 Rutland Ave, Baltimore, MD 21205 USA. RI Walczak, Piotr/B-8707-2008; Bulte, Jeff/A-3240-2008; Ruiz-Cabello, Jesus/A-9570-2012; OI Bulte, Jeff/0000-0003-1202-1610; Ruiz-Cabello, Jesus/0000-0001-8681-5056; Walczak, Piotr/0000-0002-3733-3322 FU NIBIB NIH HHS [R01 EB007825-02, R01 EB007825, R01 EB007825-03] NR 42 TC 34 Z9 35 U1 1 U2 20 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1555-4309 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JUL-AUG PY 2011 VL 6 IS 4 BP 251 EP 259 DI 10.1002/cmmi.424 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 825QB UT WOS:000295295100009 PM 21861285 ER PT J AU Minnicozzi, M Sawyer, RT Fenton, MJ AF Minnicozzi, Michael Sawyer, Richard T. Fenton, Matthew J. TI Innate immunity in allergic disease SO IMMUNOLOGICAL REVIEWS LA English DT Review DE innate immunity; allergy; asthma; atopic dermatitis; food allergy; inflammation ID THYMIC STROMAL LYMPHOPOIETIN; INTESTINAL EPITHELIAL-CELLS; TOLL-LIKE RECEPTORS; PULMONARY DENDRITIC CELLS; CD4(+) T-CELLS; ANTIGEN-PRESENTING CELLS; NOD-LIKE RECEPTORS; FC-EPSILON-RI; PATTERN-RECOGNITION RECEPTORS; EPIDERMAL LANGERHANS CELLS AB The innate immune system consists of multiple cell types that express germline-encoded pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Allergens are frequently found in forms and mixtures that contain PAMPs and DAMPs. The innate immune system is interposed between the external environment and the internal acquired immune system. It is also an integral part of the airways, gut, and skin. These tissues face continuous exposure to allergens, PAMPs, and DAMPs. Interaction of allergens with the innate immune system normally results in immune tolerance but, in the case of allergic disease, this interaction induces recurring and/or chronic inflammation as well as the loss of immunologic tolerance. Upon activation by allergens, the innate immune response commits the acquired immune response to a variety of outcomes mediated by distinct T-cell subsets, such as T-helper 2, regulatory T, or T-helper 17 cells. New studies highlighted in this review underscore the close relationship between allergens, the innate immune system, and the acquired immune system that promotes homeostasis versus allergic disease. C1 [Minnicozzi, Michael; Sawyer, Richard T.; Fenton, Matthew J.] NIAID, Asthma Allergy & Inflammat Branch, Div Allergy Immunol & Transplantat, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Fenton, MJ (reprint author), NIAID, Asthma Allergy & Inflammat Branch, Div Allergy Immunol & Transplantat, Dept Hlth & Human Serv,NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM fentonm@niaid.nih.gov NR 274 TC 34 Z9 34 U1 2 U2 20 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2011 VL 242 SI SI BP 106 EP 127 DI 10.1111/j.1600-065X.2011.01025.x PG 22 WC Immunology SC Immunology GA 822AR UT WOS:000295016200007 PM 21682741 ER PT J AU Srivastava, K Srivastava, A Sharma, KL Mittal, B AF Srivastava, Kshitij Srivastava, Anvesha Sharma, Kiran Lata Mittal, Balraj TI Candidate gene studies in gallbladder cancer: A systematic review and meta-analysis SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE Gallbladder cancer; Polymorphism; Review; Cancer; Meta-analysis ID BILIARY-TRACT CANCERS; NORTH INDIAN POPULATION; GALL-BLADDER CANCER; DNA-REPAIR GENES; PRIMARY-CARCINOMA; DISEASE ASSOCIATIONS; REPRODUCTIVE FACTORS; GALLSTONE DISEASE; INCREASED RISK; CHILEAN WOMEN AB Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene-disease association using fixed and random effect models. Meta-regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility except TP53 (rs1042522) polymorphism. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene-gene, gene-environment interactions and high-risk haplotypes. (C) 2011 Elsevier B.V. All rights reserved. C1 [Srivastava, Anvesha; Sharma, Kiran Lata; Mittal, Balraj] Sanjay Gandhi Post Grad Inst Med Sci, Dept Genet, Lucknow 226014, Uttar Pradesh, India. [Srivastava, Kshitij] NHGRI, NIH, Bethesda, MD 20892 USA. RP Mittal, B (reprint author), Sanjay Gandhi Post Grad Inst Med Sci, Dept Genet, Lucknow 226014, Uttar Pradesh, India. EM balraj@sgpgi.ac.in FU National Human Genome Research Institute; National Institutes of Health (USA); Indian council of Medical Research (ICMR); DST; CSIR Government of India FX This research was supported [in part] by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (USA), Indian council of Medical Research (ICMR), DST and CSIR Government of India. NR 108 TC 43 Z9 45 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD JUL-OCT PY 2011 VL 728 IS 1-2 BP 67 EP 79 DI 10.1016/j.mrrev.2011.06.002 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 821MX UT WOS:000294980200006 PM 21708280 ER PT J AU Kamino, H Moore, R Negishi, M AF Kamino, Hiroki Moore, Rick Negishi, Masahiko TI Role of a novel CAR-induced gene, TUBA8, in hepatocellular carcinoma cell lines SO CANCER GENETICS LA English DT Article DE CAR; cell growth; cell migration; liver cancer; nuclear receptor; TUBA8 ID NUCLEAR RECEPTORS; POSTTRANSLATIONAL MODIFICATIONS; RAT HEPATOCARCINOGENESIS; TUMOR PROMOTION; TUBULIN; MICE; PATHOGENESIS; MIGRATION; PROTEIN; STRAIN AB Phenobarbital (PB), a nongenotoxic carcinogen, activates the nuclear constitutive active/androstane receptor (CAR), resulting in the transcriptional induction or repression of various hepatic genes. We previously demonstrated that liver tumors developed after chronic PB treatment only when CAR is present. To understand the molecular mechanism of tumor promotion, cDNA microarray analysis was performed. We identified tubulin alpha 8 (TU8A8) as one of the candidate genes that may be involved in liver tumor promotion. Tuba8 mRNA was induced with PB treatment in mouse livers before tumor development as well as in tumor tissues. Because the functions of TUBA8 are unknown in liver, we investigated the effects of TUBA8 gene expression on cell growth, proliferation, and cell migration. Sense or antisense cDNA for Tuba8 was stably transfected into Huh7 and HepG2 cells. Exogenous overexpression of Tuba8 inhibited cell growth and proliferation in Huh7 but not in HepG2 cells, while cell migration was increased in HepG2 cells but not Huh7 cells. These results indicate that TUBA8 can play a role in the regulation of cell growth, proliferation, and cell migration in a cell-specific manner in vitro, suggesting that TUBA8 may contribute to mouse liver tumorigenesis through these functions. C1 [Kamino, Hiroki; Moore, Rick; Negishi, Masahiko] Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health and National Institute of Environmental Health Sciences [Z01ES1005-01] FX This research was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences (Z01ES1005-01). We acknowledge the efforts the staff of the NIEHS DNA Sequencing Core, Flow Cytometry Center, and Fluorescence Microscopy and Imaging Center. We especially thank all of our laboratory members for valuable discussion. NR 31 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 J9 CANCER GENET-NY JI Cancer Genet. PD JUL PY 2011 VL 204 IS 7 BP 382 EP 391 DI 10.1016/j.cancergen.2011.05.007 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 819NX UT WOS:000294834700004 PM 21872825 ER PT J AU Albrecht, M Mukherjee, AL Tierney, C Morse, GD Dykes, C Klingman, KL Demeter, LM AF Albrecht, Mary Mukherjee, A. Lisa Tierney, Camlin Morse, Gene D. Dykes, Carrie Klingman, Karin L. Demeter, Lisa M. TI A Randomized Clinical Trial Evaluating Therapeutic Drug Monitoring (TDM) for Protease Inhibitor-Based Regimens in Antiretroviral-Experienced HIV-Infected Individuals: Week 48 Results of the A5146 Study SO HIV CLINICAL TRIALS LA English DT Article DE antiretroviral therapy; clinical trials; HIV drug resistance; pharmacokinetics; protease inhibitors; therapeutic drug monitoring ID HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITORS; HEAVILY PRETREATED PATIENTS; VIROLOGICAL RESPONSE; LOPINAVIR-RITONAVIR; HIV-1-INFECTED INDIVIDUALS; DARUNAVIR-RITONAVIR; QUOTIENT; AMPRENAVIR; ATAZANAVIR AB Background: We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (Pis) and dose escalation based upon a normalized inhibitory quotient (NI), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented. Methods: Eligible HIV-infected subjects with a screening viral load of >= 1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ <= 1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation. Results: One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [P = .13, median (25th, 75th percentile log(10) copies/mL change): -0.03 (-0.74, 0.62) with TDM and 0.11 (-2.3, 0.82) with SOC]. In subgroup analysis, patients with 1:169 active PIs benefited from TDM compared to those with <0.69 active PIs (P = .05). Conclusions: While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity. C1 [Albrecht, Mary] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Mukherjee, A. Lisa; Tierney, Camlin] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Morse, Gene D.] SUNY Buffalo, Dept Pharm Practice, Buffalo, NY 14260 USA. [Dykes, Carrie; Demeter, Lisa M.] Univ Rochester, Sch Med & Dent, Div Infect Dis, Rochester, NY USA. [Klingman, Karin L.] NIH, Div Aids, Bethesda, MD 20892 USA. RP Albrecht, M (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, 110 Francis St, Boston, MA 02215 USA. EM malbrech@bidmc.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636, AI-25859, AI-25915, AI-27658, AI-27661, AI-32782, AI-34853, AI-38855, AI-38858-09S1, AI-46370, AI-04637, AI-68634, AI-69415, AI-69418, AI-69419, AI-69423, AI-69424, AI-69428, AI-69432, AI-69434, AI-69439, AI-69447, AI-69450, AI-69452, AI-69467, AI-69470, AI-69471, AI-69472, AI-69474, AI-69477, AI-69484, AI-69494, AI-69495, AI-69501, AI-69502, AI-69511, AI-69513, AI-695332, AI-69556, P30-AI-050409, P30-AI-045008, P30-AI-050410]; National Center for Research Resources [RR-0032, RR-024156, RR 024160, RR-024992, RR-024996, RR-025747, RR-025780]; Virco; General Clinical Research Center Units FX The project described was supported by award U01AI068636 from the National Institute of Allergy and Infectious Diseases (AI-25859, AI-25915, AI-27658, AI-27661, AI-32782, AI-34853, AI-38855, AI-38858-09S1, AI-46370, AI-04637, AI-68634, AI-69415, AI-69418, AI-69419, AI-69423, AI-69424, AI-69428, AI-69432, AI-69434, AI-69439, AI-69447, AI-69450, AI-69452, AI-69467, AI-69470, AI-69471, AI-69472, AI-69474, AI-69477, AI-69484, AI-69494, AI-69495, AI-69501, AI-69502, AI-69511, AI-69513, AI-695332, AI-69556); P30-AI-050409, P30-AI-045008, P30-AI-050410), and supported in part by General Clinical Research Center Units funded by the National Center for Research Resources (RR-0032, RR-024156, RR 024160, RR-024992, RR-024996, RR-025747, RR-025780). Virco performed drug resistance testing and provided partial financial support for drug concentration testing which was performed in Dr. Morse's laboratory at SUNY Buffalo. NR 50 TC 4 Z9 4 U1 0 U2 0 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD JUL-AUG PY 2011 VL 12 IS 4 BP 201 EP 214 DI 10.1310/hct1204-201 PG 14 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 820AU UT WOS:000294878700003 PM 22044856 ER PT J AU Reznick, JS AF Reznick, Jeffrey S. TI Perspectives from the History of Medicine Division of the United States National Library of Medicine, National Institutes of Health SO MEDICAL HISTORY LA English DT Article DE US National Library of Medicine (NLM); IndexCat; Directory of History of Medicine Collections; Images; PubMed Central; Digital Collections; Exhibition Programme; Turning the Pages; Profiles in Science; Medical Heritage Library C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 20894 USA. RP Reznick, JS (reprint author), Natl Lib Med, Hist Med Div, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM jeffrey.reznick@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU PROF SCI PUBL PI LONDON PA TAVISTOCK HOUSE EAST, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0025-7273 J9 MED HIST JI Med. Hist. PD JUL PY 2011 VL 55 IS 3 SI SI BP 413 EP 418 PG 6 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 807XH UT WOS:000293935800024 PM 21792270 ER PT J AU Roney, CA Xu, BY Xie, JW Yuan, SA Wierwille, J Chen, CW Chen, Y Griffiths, GL Summers, RM AF Roney, Celeste A. Xu, Biying Xie, Jianwu Yuan, Shuai Wierwille, Jeremiah Chen, Chao-Wei Chen, Yu Griffiths, Gary L. Summers, Ronald M. TI Rh-I-UEA-1 Polymerized Liposomes Target and Image Adenomatous Polyps in the APC(Min/+) Mouse Using Optical Colonography SO MOLECULAR IMAGING LA English DT Article ID COLORECTAL-CARCINOMA; COHERENCE TOMOGRAPHY; CT COLONOGRAPHY; BINDING SITES; COLON-CANCER; MUCIN; EXPRESSION; MUCOSA; VIVO; MIXTURES AB Mutated adenomatous polyposis coli (APC) genes predispose transformations to neoplasia, progressing to colorectal carcinoma. Early detection facilitates clinical management and therapy. Novel lectin-mediated polymerized targeted liposomes (Rh-I-UEA-1), with polyp specificity and incorporated imaging agents were fabricated to locate and image adenomatous polyps in APC(Min/+) mice. The biomarker alpha-L-fucose covalently joins the liposomal conjugated lectin Ulex europaeus agglutinin (UEA-1), via glycosidic linkage to the polyp mucin layer. Multispectral optical imaging (MSI) corroborated a global perspective of specific binding (rhodamine B 532 nm emission, 590-620 nm excitation) of targeted Rh-I-UEA-1 polymerized liposomes to polyps with 1.4-fold labeling efficiency. High-resolution coregistered optical coherence tomography (OCT) and fluorescence molecular imaging (FMI) reveal the spatial correlation of contrast distribution and tissue morphology. Freshly excised APC(Min) bowels were incubated with targeted liposomes (UEA-1 lectin), control liposomes (no lectin), or iohexol (Omnipaque) and imaged by the three techniques. Computed tomographic quantitative analyses did not confirm that targeted liposomes more strongly bound polyps than nontargeted liposomes or iohexol (Omnipaque) alone. OCT, with anatomic depth capabilities, along with the coregistered FMI, substantiated Rh-I-UEA-1 liposome binding along the mucinous polyp surface. UEA-1 lectin denotes alpha-L-fucose biomarker carbohydrate expression at the mucin glycoprotein layer; Rh-I-UEA-1 polymerized liposomes target and image adenomatous polyps in APC(Min) mice. C1 [Summers, Ronald M.] NHLBI, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci Dept, Ctr Clin,NIH, Bethesda, MD 20892 USA. NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Summers, RM (reprint author), NHLBI, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci Dept, Ctr Clin,NIH, Bldg 10,Room 1C368X,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU National Institutes of Health Clinical Center; National Heart, Lung, and Blood Institute FX Financial dislosure of authors: This research was supported by the Intramural Research Programs of the National Institutes of Health Clinical Center, and National Heart, Lung, and Blood Institute. NR 31 TC 3 Z9 3 U1 3 U2 6 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD JUL-AUG PY 2011 VL 10 IS 4 BP 305 EP 316 DI 10.2310/7290.2010.00054 PG 12 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 815XF UT WOS:000294562600009 PM 21521550 ER PT J AU Chalamalasetty, RB Dunty, WC Biris, KK Ajima, R Iacovino, M Beisaw, A Feigenbaum, L Chapman, DL Yoon, JK Kyba, M Yamaguchi, TP AF Chalamalasetty, Ravindra B. Dunty, William C., Jr. Biris, Kristin K. Ajima, Rieko Iacovino, Michelina Beisaw, Arica Feigenbaum, Lionel Chapman, Deborah L. Yoon, Jeong Kyo Kyba, Michael Yamaguchi, Terry P. TI The Wnt3a/beta-catenin target gene Mesogenin1 controls the segmentation clock by activating a Notch signalling program SO NATURE COMMUNICATIONS LA English DT Article ID LUNATIC-FRINGE EXPRESSION; SOMITE BOUNDARY FORMATION; PARAXIAL MESODERM; PRESOMITIC MESODERM; DYNAMIC EXPRESSION; MOUSE RIPPLY2; WNT; SOMITOGENESIS; CATENIN; EMBRYOS AB Segmentation is an organizing principle of body plans. The segmentation clock, a molecular oscillator best illustrated by the cyclic expression of Notch signalling genes, controls the periodic cleavage of somites from unsegmented presomitic mesoderm during vertebrate segmentation. Wnt3a controls the spatiotemporal expression of cyclic Notch genes; however, the underlying mechanisms remain obscure. Here we show by transcriptional profiling of Wnt3a(-/-) embryos that the bHLH transcription factor, Mesogenin1 (Msgn1), is a direct target gene of Wnt3a. To identify Msgn1 targets, we conducted genome-wide studies of Msgn1 activity in embryonic stem cells. We show that Msgn1 is a major transcriptional activator of a Notch signalling program and synergizes with Notch to trigger clock gene expression. Msgn1 also indirectly regulates cyclic genes in the Fgf and Wnt pathways. Thus, Msgn1 is a central component of a transcriptional cascade that translates a spatial Wnt3a gradient into a temporal pattern of clock gene expression. C1 [Chalamalasetty, Ravindra B.; Dunty, William C., Jr.; Biris, Kristin K.; Ajima, Rieko; Beisaw, Arica; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Iacovino, Michelina; Kyba, Michael] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN 55455 USA. [Iacovino, Michelina; Kyba, Michael] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Frederick, MD 21702 USA. [Chapman, Deborah L.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Yoon, Jeong Kyo] Maine Med Ctr, Ctr Mol Med, Res Inst, Scarborough, ME 04074 USA. RP Yamaguchi, TP (reprint author), NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM yamagute@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Y. Saga, B. Herrmann, and R. Kageyama for providing reagents. We are grateful to S. Mackem, A. Perantoni, M. Lewandoski, M. Anderson, N. Adler, and M. Kennedy for providing comments on versions of this manuscript. We are particularly indebted to J. Greear and R. Wolfe (SAIC-Frederick) for excellent animal husbandry. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 57 TC 25 Z9 25 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2011 VL 2 AR 390 DI 10.1038/ncomms1381 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DJ UT WOS:000294805300017 PM 21750544 ER PT J AU Nery, FC Armata, IA Farley, JE Cho, JA Yaqub, U Chen, P da Hora, CC Wang, QY Tagaya, M Klein, C Tannous, B Caldwell, KA Caldwell, GA Lencer, WI Ye, YH Breakefield, XO AF Nery, Flavia C. Armata, Ioanna A. Farley, Jonathan E. Cho, Jin A. Yaqub, Uzma Chen, Pan da Hora, Cintia Carla Wang, Qiuyan Tagaya, Mitsuo Klein, Christine Tannous, Bakhos Caldwell, Kim A. Caldwell, Guy A. Lencer, Wayne I. Ye, Yihong Breakefield, Xandra O. TI TorsinA participates in endoplasmic reticulum-associated degradation SO NATURE COMMUNICATIONS LA English DT Article ID DYSTONIA-ASSOCIATED PROTEIN; VALOSIN-CONTAINING PROTEIN; ER-ASSOCIATED DEGRADATION; DELTA-E-TORSINA; NUCLEAR-ENVELOPE; DYT1 DYSTONIA; CHOLERA-TOXIN; RETRO-TRANSLOCATION; SECRETORY PATHWAY; MOUSE MODEL AB TorsinA is an AAA+ ATPase located within the lumen of the endoplasmic reticulum and nuclear envelope, with a mutant form causing early onset torsion dystonia (DYT1). Here we report a new function for torsinA in endoplasmic reticulum-associated degradation (ERAD). Retro-translocation and proteosomal degradation of a mutant cystic fibrosis transmembrane conductance regulator (CFTR Delta F508) was inhibited by downregulation of torsinA or overexpression of mutant torsinA, and facilitated by increased torsinA. Retro-translocation of cholera toxin was also decreased by downregulation of torsinA. TorsinA associates with proteins implicated in ERAD, including Derlin-1, VIMP and p97. Further, torsinA reduces endoplasmic reticulum stress in nematodes overexpressing CFTR Delta F508, and fibroblasts from DYT1 dystonia patients are more sensitive than controls to endoplasmic reticulum stress and less able to degrade mutant CFTR. Therefore, compromised ERAD function in the cells of DYT1 patients may increase sensitivity to endoplasmic reticulum stress with consequent alterations in neuronal function contributing to the disease state. C1 [Nery, Flavia C.; Armata, Ioanna A.; Farley, Jonathan E.; Yaqub, Uzma; da Hora, Cintia Carla; Tannous, Bakhos; Breakefield, Xandra O.] Harvard Univ, Sch Med, Ctr Neurosci, Dept Neurol, Boston, MA 02114 USA. [Nery, Flavia C.; Armata, Ioanna A.; Farley, Jonathan E.; Yaqub, Uzma; da Hora, Cintia Carla; Tannous, Bakhos; Breakefield, Xandra O.] Harvard Univ, Sch Med, Ctr Mol Imaging Res, Dept Radiol,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nery, Flavia C.; Armata, Ioanna A.; Farley, Jonathan E.; Yaqub, Uzma; da Hora, Cintia Carla; Tannous, Bakhos; Breakefield, Xandra O.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. [Cho, Jin A.; Lencer, Wayne I.] Harvard Univ, Sch Med, Gastrointestinal Cell Biol & Harvard Digest Dis C, Childrens Hosp, Boston, MA 02115 USA. [Chen, Pan; Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Chen, Pan; Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama, Dept Tuscaloosa, Tuscaloosa, AL 35487 USA. [Chen, Pan; Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama, Ctr Neurodegenerat & Expt Therapeut, Dept Neurol, Tuscaloosa, AL 35487 USA. [Chen, Pan; Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama, Ctr Neurodegenerat & Expt Therapeut, Dept Neurobiol, Tuscaloosa, AL 35487 USA. [Wang, Qiuyan; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Tagaya, Mitsuo] Tokyo Univ Pharm & Life Sci, Sch Sci, Tokyo 1920392, Japan. [Klein, Christine] Med Univ Lubeck, Sect Clin & Mol Neurogenet, D-23538 Lubeck, Germany. RP Breakefield, XO (reprint author), Harvard Univ, Sch Med, Ctr Neurosci, Dept Neurol, Boston, MA 02114 USA. EM breakefield@hms.harvard.edu FU NINDS [NS037409, P30NS045776]; Dystonia Medical Research Foundation; NSF; QRxPharma; Volkswagen Foundation; Hermann and Lilly Schilling Foundation; Crohn's & Colitis Foundation of America [3042]; [HD007466-11]; [DK083894]; [DK48106]; [DK0484424] FX We thank Nathan Roberts (Dystonia Support Group of Alabama), Nathan Spielberg, Igor Bagayev and Xuan Zhang for help with experiments; Suzanne McDavitt for skilled editorial assistance; Trisha Multhaupt-Buell for IRB submissions; Dr Phyllis Hanson (Washington University) for torsinA constructs; Dr Pedro Gonzalez-Allegre (University of Iowa) for torsinA antibodies; Drs Dinah Sah and Pei Ge (Alnylam Pharmaceuticals) for siRNAs for torsinA; and the Imaging Core of the Harvard Digestive Disease Center DK034854 (W.I.L.) for assistance with confocal imaging. Adenovirus vectors were provided by the Vector Core at the University of Pennsylvania School of Medicine; AAV vectors were provided by Dr Miguel Sena-Esteves (UMass Memorial Medical. Center.). This work was supported by: NINDS NS037409 (XOB); the Dystonia Medical Research Foundation (F.N.); NINDS P30NS045776 and NSF CAREER Award (K.A.C.); QRxPharma (K.A.C. and G.A.C.); Volkswagen Foundation. and Hermann and Lilly Schilling Foundation. (C.K.); HD007466-11, DK083894 and Crohn's & Colitis Foundation of America 3042 (J.A.C.); and DK48106 and DK0484424 (W.I.L.). NR 60 TC 44 Z9 44 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2011 VL 2 AR 393 DI 10.1038/ncomms1383 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DJ UT WOS:000294805300020 PM 21750546 ER PT J AU Cuttica, MJ Langenickel, T Noguchi, A Machado, RF Gladwin, MT Boehm, M AF Cuttica, Michael J. Langenickel, Thomas Noguchi, Audrey Machado, Roberto F. Gladwin, Mark T. Boehm, Manfred TI Perivascular T-Cell Infiltration Leads to Sustained Pulmonary Artery Remodeling after Endothelial Cell Damage SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE pulmonary vascular remodeling; inflammation; CD4(+) T cells; Rag1(tm1Mom) mice ID C-REACTIVE PROTEIN; MONOCYTE CHEMOATTRACTANT; VASCULAR-DISEASE; HYPERTENSION; MONOCROTALINE; MICE; RATS; ATHEROSCLEROSIS; FIBROSIS; FIBROBLASTS AB Pulmonary hypertension is a vascular proliferative disease characterized by pulmonary artery remodeling because of dysregulated endothelial and smooth muscle cell proliferation. Although the role of inflammation in the development of the disease is not well-defined, plexogenic lesions in human disease are characterized by perivascular inflammation composed, in part, of T cells. We explored the role of T-cell infiltration on pulmonary vascular remodeling after endothelial cell damage. We induced endothelial cell damage using monocrotaline and isolated the role of T cells by using Rag1(tm1Mom) mice and performing adoptive T-cell transfer. We found that monocrotaline causes pulmonary vascular endothelial cell injury followed by a perivascular inflammatory response. The infiltration of inflammatory cells primarily involves CD4(+) T cells and leads to the progressive muscularization of small (< 30 mu m) arterioles. Pulmonary vascular proliferative changes were accompanied by progressive and persistent elevations in right ventricular pressure and right ventricular hypertrophy. Supporting the central role of CD4(+) T cells in the inflammatory response, Rag1(tm1Mom) (Rag12/2) mice, which are devoid of T and B cells, were protected from the development of vascular injury when exposed to monocrotaline. The introduction of T cells from control mice into Rag1(-/-) mice reproduced the vascular injury phenotype. These data indicate that after endothelial cell damage, CD4(+) T-cell infiltration participates in pulmonary vascular remodeling. This finding suggests that a CD4(+) T-cell immune response may contribute to the pathogenesis of inflammatory vascular lesions seen in some forms of pulmonary hypertension. C1 [Cuttica, Michael J.] Northwestern Univ, Dept Pulm & Crit Care Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Langenickel, Thomas] Bristol Myers Squibb Co, Discovery Med & Clin Pharmacol, Princeton, NJ USA. [Boehm, Manfred] NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. [Machado, Roberto F.] Univ Illinois, Sect Pulm Crit Care Sleep & Allergy, Chicago, IL USA. [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Dept Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RP Boehm, M (reprint author), NHLBI, Translat Med Branch, NIH, 10 Ctr Dr,MSC1454,Bldg 10-CRC,Room 5 East 3132, Bethesda, MD 20892 USA. EM boehmm@nhlbi.nih.gov NR 45 TC 13 Z9 15 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUL PY 2011 VL 45 IS 1 BP 62 EP 71 DI 10.1165/rcmb.2009-0365OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 808BL UT WOS:000293948200007 PM 20813993 ER PT J AU Yang, XB Walton, W Cook, DN Hua, XY Tilley, S Haskell, CA Horuk, R Blackstock, AW Kirby, SL AF Yang, Xuebin Walton, William Cook, Donald N. Hua, Xiaoyang Tilley, Stephen Haskell, Christopher A. Horuk, Richard Blackstock, A. William Kirby, Suzanne L. TI The Chemokine, CCL3, and Its Receptor, CCR1, Mediate Thoracic Radiation-Induced Pulmonary Fibrosis SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE chemokine; fibrosis; radiation; lung; inflammation ID MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; INDUCED LUNG INJURY; RENAL FIBROSIS; MULTIPLE-MYELOMA; HOST-DEFENSE; MICE; ANTAGONIST; DISEASE; RECRUITMENT; MECHANISMS AB Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis. C57BL/6J mice received thoracic radiation, and the interaction of CCL3 with CCR1 or CCR5 was blocked using genetic techniques, or by pharmacologic intervention. Lung inflammation was assessed by histochemical staining of lung tissue and by flow cytometry. Fibrosis was measured by hydroxyproline assays and collagen staining, and lung function was studied by invasive procedures. Irradiated mice lacking CCL3 or its receptor, CCR1, did not develop the lung inflammation, fibrosis, and decline in lung function seen in irradiated wild-type mice. Pharmacologic treatment of wild-type mice with a small molecule inhibitor of CCR1 also prevented lung inflammation and fibrosis. By contrast, mice lacking CCR5 were not protected from radiation-induced injury and fibrosis. The selective interaction of CCL3 with its receptor, CCR1, is critical for radiation-induced lung inflammation and fibrosis, and these conditions can be largely prevented by a small molecule inhibitor of CCR1. C1 [Yang, Xuebin; Walton, William; Kirby, Suzanne L.] Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. [Cook, Donald N.] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Hua, Xiaoyang; Tilley, Stephen] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Haskell, Christopher A.] Bayer Healthcare Pharmaceut, Davis, CA USA. [Horuk, Richard] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Blackstock, A. William] Wake Forest Univ, Dept Radiat Oncol, Winston Salem, NC 27109 USA. RP Kirby, SL (reprint author), Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. EM skirby7001@gmail.com FU National Institutes of Health [5R0 1CA098641-02, 5-U19-AI067798] FX This work was supported by National Institutes of Health grants 5R0 1CA098641-02 and 5-U19-AI067798. NR 46 TC 15 Z9 15 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUL PY 2011 VL 45 IS 1 BP 127 EP 135 DI 10.1165/rcmb.2010-0265OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 808BL UT WOS:000293948200015 PM 20870892 ER PT J AU Russell, RM AF Russell, Robert M. TI A primer on determining the dietary requirements for folate SO BIOFACTORS LA English DT Editorial Material ID FOLIC-ACID; PROSTATE; TRIAL; RISK C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Russell, RM (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0951-6433 J9 BIOFACTORS JI Biofactors PD JUL-AUG PY 2011 VL 37 IS 4 SI SI BP 251 EP 252 DI 10.1002/biof.167 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 816DE UT WOS:000294578100001 PM 21674646 ER PT J AU Yetley, EA AF Yetley, Elizabeth A. TI Monitoring folate status in population-based surveys SO BIOFACTORS LA English DT Review DE folate status; National Health and Nutrition Examination Survey ID SERUM 25-HYDROXYVITAMIN D; FOLIC-ACID; UNITED-STATES; BLOOD FOLATE; VITAMIN-B-12 STATUS; FOOD FORTIFICATION; CANCER-RISK; INDICATORS; SUPPLEMENTS; RADIOASSAY AB Folate status assessments depend primarily on the measurement of biomarkers such as serum and red blood cell folate. Lessons learned from a large national monitoring system such as the National Health and Nutrition Examination Survey and a public health intervention such as the implementation of folic acid fortification in the United States have provided useful insights into the challenges of assessing folate status and possible solutions for addressing these challenges. C1 [Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Yetley, EA (reprint author), 302 King James Ct, Upper Marlboro, MD 20774 USA. EM beth@yetley.com NR 28 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-6433 J9 BIOFACTORS JI Biofactors PD JUL-AUG PY 2011 VL 37 IS 4 SI SI BP 285 EP 289 DI 10.1002/biof.176 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 816DE UT WOS:000294578100007 PM 21809406 ER PT J AU Palini, S Zolla, L De Stefani, S Scala, V D'Alessandro, A Polli, V Rocchi, P Tiezzi, A Pelosi, E Dusi, L Bulletti, C AF Palini, S. Zolla, L. De Stefani, S. Scala, V. D'Alessandro, A. Polli, V. Rocchi, P. Tiezzi, A. Pelosi, E. Dusi, L. Bulletti, C. TI Eomics in blastocoele SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 27th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology CY JUL 03-06, 2011 CL Stockholm, SWEDEN SP European Soc Human Reprod & Embryol C1 [Zolla, L.; D'Alessandro, A.] Univ Tuscia, Viterbo, Italy. [Pelosi, E.] NIA, Baltimore, MD USA. [Dusi, L.] Med Ctr Palladio, Vicenza, Italy. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2011 VL 26 SU 1 BP I170 EP I170 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 814KO UT WOS:000294450500424 ER PT J AU Falik-Zaccai, TC Gunay-Aygun, M Zivony-Elboum, Y Gumruk, F Geiger, D Cetin, M Khayat, M Kleta, R Kfir, N Anikster, Y Arcos-Bugos, M Stanescu, H Arat, M Freiberg, A Maric, I Kehrel, BE Jurk, K Nurden, A White, JG Gahl, WA AF Falik-Zaccai, T. C. Gunay-Aygun, M. Zivony-Elboum, Y. Gumruk, F. Geiger, D. Cetin, M. Khayat, M. Kleta, R. Kfir, N. Anikster, Y. Arcos-Bugos, M. Stanescu, H. Arat, M. Freiberg, A. Maric, I Kehrel, B. E. Jurk, K. Nurden, A. White, J. G. Gahl, W. A. TI Gray platelet syndrome: clinical features and genetic analysis SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Falik-Zaccai, T. C.] Technion Israel Inst Technol, Inst Human Genet, Western Galilee Hosp Nahariya, IL-32000 Haifa, Israel. [Gunay-Aygun, M.; Kleta, R.; Anikster, Y.; Arcos-Bugos, M.; Stanescu, H.; Gahl, W. A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. [Zivony-Elboum, Y.; Khayat, M.; Kfir, N.] Western Galilee Hosp, Inst Human Genet, Nahariyya, Israel. [Gumruk, F.; Cetin, M.] Hacettepe Univ, Childrens Hosp, Pediat Hematol Unit, Ankara, Turkey. [Geiger, D.] Technion Israel Inst Technol, Dept Comp Sci, IL-32000 Haifa, Israel. [Arat, M.] Ankara Univ, Fac Med, Dept Hematol, TR-06100 Ankara, Turkey. [Freiberg, A.] PennState Hershey Childrens Hosp, Div Pediat Hematol Oncol, Hershey, PA USA. [Maric, I] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Kehrel, B. E.; Jurk, K.] Univ Hosp Munster, Dept Anaesthesiol & Intens Care, Munster, Germany. [Nurden, A.] Hop Xavier Arnozan, Ctr Reference Pathol Plaquettaires Plateforme Tec, Pessac, France. [White, J. G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2011 VL 9 SU 2 SI SI BP 8 EP 8 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 800DU UT WOS:000293340800030 ER PT J AU Haberichter, S Schroeder, JA Jacobi, PM Gehrand, AL Friedman, KD DiMichele, D Montgomery, RR AF Haberichter, S. Schroeder, J. A. Jacobi, P. M. Gehrand, A. L. Friedman, K. D. DiMichele, D. Montgomery, R. R. TI An L1278P von Willebrand factor (VWF) mutation identified in a type 1 VWD patient causes reduced VWF secretion and increased VWF clearance SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Haberichter, S.; Schroeder, J. A.; Jacobi, P. M.; Gehrand, A. L.; Friedman, K. D.] BloodCtr Wisconsin, Blood Res Inst, Kenosha, WI USA. [DiMichele, D.] NHLBI, NIH, Bethesda, MD USA. [Montgomery, R. R.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2011 VL 9 SU 2 SI SI BP 55 EP 55 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 800DU UT WOS:000293340800167 ER PT J AU Erten-Lyons, D Wilmot, B Anur, P McWeeney, S Westaway, SK Silbert, L Kramer, P Kaye, J AF Erten-Lyons, Deniz Wilmot, Beth Anur, Pavana McWeeney, Shannon Westaway, Shawn K. Silbert, Lisa Kramer, Patricia Kaye, Jeffrey CA Alzheimer's Dis Neuroimaging TI Microcephaly Genes and Risk of Late-onset Alzheimer Disease SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; microcephaly genes; cognitive reserve ID ONGOING ADAPTIVE EVOLUTION; BRAIN SIZE; MOLECULAR EVOLUTION; HEAD CIRCUMFERENCE; MAJOR DETERMINANT; OLDEST-OLD; ASPM GENE; ASSOCIATION; POPULATION; DEMENTIA AB Brain development in the early stages of life has been suggested to be one of the factors that may influence an individual's risk of Alzheimer disease (AD) later in life. Four microcephaly genes, which regulate brain development in utero and have been suggested to play a role in the evolution of the human brain, were selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms tagging common sequence variations in these genes and risk of AD in two case-control samples. We found that the G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P = 0.01; odds ratio = 3.41; confidence interval, 1.77-6.57). However, this association was not replicated using another case-control sample research participants from the Alzheimer Disease Neuroimaging Initiative. We conclude that the common variations we measured in the 4 microcephaly genes do not affect the risk of AD or that their effect size is small. C1 [Erten-Lyons, Deniz; Kaye, Jeffrey] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. [Erten-Lyons, Deniz; Westaway, Shawn K.; Silbert, Lisa; Kramer, Patricia; Kaye, Jeffrey] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Wilmot, Beth; Anur, Pavana; McWeeney, Shannon] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Ctr, Portland, OR 97201 USA. [Wilmot, Beth; McWeeney, Shannon] Oregon Hlth & Sci Univ, Div Bioinformat & Computat Biol, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [McWeeney, Shannon] Oregon Hlth & Sci Univ, Dept Publ Hlth & Preventat Med, Div Biostat, Portland, OR 97201 USA. RP Erten-Lyons, D (reprint author), NIA, Layton Aging & Alzheimers Dis Ctr, 3181 SW Sam Jackson Pk Rd,CR 131, Portland, OR 97239 USA. EM ertenlyo@ohsu.edu RI Scharre, Douglas/E-4030-2011; OI Kaye, Jeffrey/0000-0002-9971-3478; McWeeney, Shannon/0000-0001-8333-6607; Silbert, Lisa/0000-0002-4525-0068 FU Office of Research and Development, Department of Veterans Affairs, National Institutes of Health [AG08017, MO1 RR000334, UL1 RR024140]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Northern California Institute for Research and Education; NIH [P30 AG010129, K01 AG030514]; Dana Foundation FX Supported by Merit Review Grant and Research Career Development Award, Office of Research and Development, Department of Veterans Affairs, National Institutes of Health (AG08017, MO1 RR000334, UL1 RR024140), Alzheimer Tax Check-off Grant. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation; Genentech; GE Healthcare; GlaxoSmithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co.; Medpace, Inc.; Merck and Co., Inc.; Novartis AG; Pfizer Inc.; F. Hoffman-La Roche; Schering-Plough; Synarc, Inc.; and nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 34 TC 0 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2011 VL 25 IS 3 BP 276 EP 282 DI 10.1097/WAD.0b013e31820a1d32 PG 7 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 811JW UT WOS:000294206600013 PM 21297427 ER PT J AU Cornwell, BR Heller, R Biggs, A Pine, DS Grillon, C AF Cornwell, Brian R. Heller, Randi Biggs, Arter Pine, Daniel S. Grillon, Christian TI Becoming the Center of Attention in Social Anxiety Disorder: Startle Reactivity to a Virtual Audience During Speech Anticipation SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PUBLIC SPEAKING TASK; CEREBRAL BLOOD-FLOW; AMYGDALA ACTIVATION; VIETNAM VETERANS; ACOUSTIC STARTLE; PHOBIA; COMORBIDITY; REALITY; FACES AB Objective: A detailed understanding of how individuals diagnosed with social anxiety disorder (SAD) respond physiologically under social-evaluative threat is lacking. Our aim was to isolate the specific components of public speaking that trigger fear in vulnerable individuals and best discriminate between SAD and healthy individuals. Method: Sixteen individuals diagnosed with SAD (DSM-IV-TR criteria) and 16 healthy individuals were enrolled in the study from December 2005 to March 2008. Subjects were asked to prepare and deliver a short speech in a virtual reality (VR) environment. The VR environment simulated standing center stage before a live audience and allowed us to gradually introduce social cues during speech anticipation. Startle eye-blink responses were elicited periodically by white noise bursts presented during anticipation, speech delivery, and recovery in VR, as well as outside VR during an initial habituation phase, and startle reactivity was measured by electromyography. Subjects rated their distress at 4 time-points in VR using a 0-10 scale, with anchors being "not distressed" to "highly distressed." State anxiety was measured before and after VR with the Spielberger State-Trait Anxiety Inventory. Results: Individuals with SAD reported greater distress and state anxiety than healthy individuals across the entire procedure (P values < .005). Analyses of startle reactivity revealed a robust group difference during speech anticipation in VR, specifically as audience members directed their eye gaze and turned their attention toward participants (P < .05, Bonferroni-corrected). Conclusions: The VR environment is sufficiently realistic to provoke fear and anxiety in individuals highly vulnerable to socially threatening situations. Individuals with SAD showed potentiated startle, indicative of a strong phasic fear response, specifically when they perceived themselves as occupying the focus of others' attention as speech time approached. Potentiated startle under social-evaluative threat indexes SAD-related fear of negative evaluation. J Clin Psychiatry 2011;72(7):942-948 (C) Copyright 2010 Physicians Postgraduate Press, Inc. C1 [Cornwell, Brian R.; Heller, Randi; Biggs, Arter; Pine, Daniel S.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Cornwell, BR (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, I5K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM cornwellb@mail.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 46 TC 17 Z9 18 U1 7 U2 20 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2011 VL 72 IS 7 BP 942 EP 948 DI 10.4088/JCP.09m05731blu PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 804UD UT WOS:000293678600009 PM 21034683 ER PT J AU Lopez, JE McCoy, BN Krajacich, BJ Schwan, TG AF Lopez, Job E. McCoy, Brandi N. Krajacich, Benjamin J. Schwan, Tom G. TI Acquisition and Subsequent Transmission of Borrelia hermsii by the Soft Tick Ornithodoros hermsi SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE relapsing fever spirochetes; Borrelia hermsii; Ornithodoros hermsi; acquisition; transmission ID RELAPSING FEVER; ANTIGENIC VARIATION; BURGDORFERI; ARGASIDAE; INFECTION; DEFENSIN; IMMUNITY; MOUBATA; DISEASE; MIDGUT AB Tick-borne relapsing fever is caused by spirochetes within the genus Borrelia. The hallmark of this disease is recurrent febrile episodes and high spirochete densities in mammalian blood resulting from immune evasion. Between episodes of spirochetemia when bacterial densities are low, it is unknown whether ticks can acquire the spirochetes, become colonized by the bacteria, and subsequently transmit the bacteria once they feed again. We addressed these questions by feeding ticks, Ornithodoros hermsi Wheeler (Acari: Argasidae), daily on an infected mouse during low and high levels of spirochete infections. This study demonstrates that spirochete acquisition by the tick vector can occur during low levels of mammalian infection and that once a spirochetemic threshold is attained within the blood, nearly 100% of ticks become colonized by Borrelia hermsii. C1 [Lopez, Job E.; McCoy, Brandi N.; Krajacich, Benjamin J.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Lopez, JE (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM lopezjob@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank B. Joseph Hinnebusch and Ryan O. Rego for reviewing this manuscript. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 31 TC 7 Z9 7 U1 1 U2 4 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD JUL PY 2011 VL 48 IS 4 BP 891 EP 895 DI 10.1603/ME10283 PG 5 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 810KJ UT WOS:000294123900021 PM 21845950 ER PT J AU Cebrian-Torrejon, G Spelman, K Leblanc, K Munoz-Durango, K Gutierrez, ST Ferreira, ME de Arias, AR Figadere, B Fournet, A Maciuk, A Grellier, P Cech, NB Poupon, E AF Cebrian-Torrejon, Gerardo Spelman, Kevin Leblanc, Karine Munoz-Durango, Katalina Gutierrez, Sandra Torijano Ferreira, Maria Elena de Arias, Antonieta Rojas Figadere, Bruno Fournet, Alain Maciuk, Alexandre Grellier, Philippe Cech, Nadja B. Poupon, Erwan TI The antiplasmodium effects of a traditional South American remedy: Zanthoxylum chiloperone var. angustifolium against chloroquine resistant and chloroquine sensitive strains of Plasmodium falciparum SO REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY LA English DT Article DE alkylamides; avicennol; canthinone alkaloids; Heme-drug adducts; Plasmodium falciparum; Zanthoxylum chiloperone ID HIGH-THROUGHPUT SCREEN; CANTHIN-6-ONE ALKALOIDS; IN-VITRO; ANTIMALARIAL; CONSTITUENTS; MALARIA; ASSAY; HEME; ALKYLAMIDES; ARTEMISININ AB Zanthoxylum chiloperone var. angustifolium Engl., Rutaceae, is used in traditional medicine to treat fungal and protozoal infections in the central area of South America. Considering the increasing resistance of Plasmodium falciparum in malarial ridden areas, we explored the anti-plasmodial effects of three compounds isolated from Z. chiloperone. The pyranocoumarin trans-avicennol and the canthinone alkaloids, canthin-6-one and 5-methoxycanthin-6-one, were found to have IC50 on chloroquine/mefloquine resistant and sensitive strains of P. falciparum of 0.5-2.7, 2.0-5.3 and 5.1-10.4 mu g/mL, respectively. Moreover, the formation of heme adducts by these compounds is described by a novel alternative method based on MS-CID methods. The alkylamide sanshool was also identified, for first time in this plant, in the dichloromethanic and ethanolic extracts and the extracts were found to be notably non-toxic and displayed good anti-plasmodial effects. C1 [Cebrian-Torrejon, Gerardo; Leblanc, Karine; Munoz-Durango, Katalina; Gutierrez, Sandra Torijano; Figadere, Bruno; Fournet, Alain; Maciuk, Alexandre; Poupon, Erwan] Univ Paris Sud, Fac Pharm, Lab Pharmacognosie, CNRS,UMR BioCIS 8076, F-92296 Chatenay Malabry, France. [Spelman, Kevin] NIA, Bioanalyt Chem & Drug Discovery Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. [Ferreira, Maria Elena] Univ Nacl Asuncion, Inst Invest Ciencias Salud Asuncion, Dept Trop Med, San Lorenzo, Paraguay. [de Arias, Antonieta Rojas] Ctr Desarrollo Invest Cient CEDIC FMB Diaz Gill M, Asuncion, Paraguay. [Grellier, Philippe] Museum Natl Hist Nat, CNRS, Dept Reg Dev & Diversite Mol, FRE 3206, Paris, France. [Cech, Nadja B.] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27412 USA. RP Fournet, A (reprint author), Univ Paris Sud, Fac Pharm, Lab Pharmacognosie, CNRS,UMR BioCIS 8076, 5 Rue Jean Baptiste Clement, F-92296 Chatenay Malabry, France. EM alain.fournet@ird.fr OI Munoz-Durango, Katalina/0000-0002-7905-1243 FU European Community FX The authors thank the European Community for the financial support (Marie Curie Early Stage Training Fellowship of the European Community's Sixth Framework Programme: contract BioMedChem (for G. CT., K. S. and K. MD.). Thanks are due to Mrs. A. Solgadi (SAMM) for MS experiments and Dra Nashira Campos Vieira (University of Brasilia) for the portuguese traduction. NR 34 TC 4 Z9 4 U1 0 U2 13 PU SOC BRASILEIRA FARMACOGNOSIA PI JOAO PESSOA PA C/O PROF JOSE MARIA BARBOSA FILHO, UNIV FEDERAL PARAIBA, LAB TECNOLOGIA FARMACEUTICA, JOAO PESSOA, 58051-970PB, BRAZIL SN 0102-695X J9 REV BRAS FARMACOGN JI Rev. Bras. Farmacogn.-Braz. J. Pharmacogn. PD JUL-AUG PY 2011 VL 21 IS 4 BP 652 EP 661 DI 10.1590/S0102-695X2011005000104 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 810KB UT WOS:000294123100014 ER PT J AU Nelson, LM AF Nelson, Lawrence M. TI One World, One Woman: A Kyosei Approach to Primary Ovarian Insufficiency PREFACE SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Editorial Material ID WOMEN C1 NICHHD, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Nelson, LM (reprint author), NICHHD, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM Lawrence_Nelson@nih.gov FU Intramural NIH HHS [Z01 HD000633-17] NR 10 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JUL PY 2011 VL 29 IS 4 BP 279 EP 281 DI 10.1055/s-0031-1280913 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 810PQ UT WOS:000294138600002 PM 21969263 ER PT J AU Sullivan, SD Castrillon, DH AF Sullivan, Shannon D. Castrillon, Diego H. TI Insights into Primary Ovarian Insufficiency through Genetically Engineered Mouse Models SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE Primary ovarian insufficiency; premature ovarian failure; primordial follicle activation; apoptosis; mouse model ID ANTI-MULLERIAN HORMONE; FOLLICLE-STIMULATING-HORMONE; POLYCYCLIC AROMATIC-HYDROCARBONS; GRANULOSA-CELL APOPTOSIS; BAX GENE-EXPRESSION; C-KIT RECEPTOR; PRIMORDIAL FOLLICLES; OOCYTE GROWTH; LIFE-SPAN; TRANSCRIPTION FACTOR AB Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a form of hypergonadotropic hypogonadism that causes infertility in similar to 1% of women <40 years of age. POI has important health consequences for affected patients; however, the mechanisms that cause ovarian dysfunction are poorly understood. Elucidating these mechanisms is paramount to developing better testing and treatment strategies for affected girls and women. For obvious reasons, studies looking directly at the human ovary are extremely limited. Recently, numerous genetically engineered mouse models have been developed to investigate the molecular mechanisms that may be involved in the pathogenesis of POI. Two potential mechanisms may be involved in the development of POI: (1) abnormalities in primordial follicle activation and (2) increased rates of apoptosis of oocytes. Each of these mechanisms may lead to early depletion of ovarian follicular reserve, and thus be a contributing factor in POI. This review addresses current knowledge of molecular mechanisms controlling primordial follicle activation and oocyte apoptosis, as evidenced from various genetic mouse models. Translation of these data into clinically effective treatments or even prevention strategies may improve fertility and quality of life for women with this form of reproductive dysfunction. C1 [Castrillon, Diego H.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Sullivan, Shannon D.] NICHD, NIH, Washington, DC USA. [Sullivan, Shannon D.] Washington Hosp Ctr, Washington, DC 20010 USA. RP Castrillon, DH (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pathol, Room NB6-452,6000 Harry Hines Blvd, Dallas, TX 75390 USA. EM diego.castrillon@utsouthwestern.edu FU National Institutes of Health [R01HD048690]; Eunice Kennedy Shriver National Institute of Child Health & Human Development FX Research in the Castrillon Laboratory was supported by grant No. R01HD048690 from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development or the National Institutes of Health. NR 97 TC 16 Z9 16 U1 1 U2 8 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JUL PY 2011 VL 29 IS 4 BP 283 EP 298 DI 10.1055/s-0031-1280914 PG 16 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 810PQ UT WOS:000294138600003 PM 21972066 ER PT J AU Cheng, MH Nelson, LM AF Cheng, Mickie H. Nelson, Lawrence M. TI Mechanisms and Models of Immune Tolerance Breakdown in the Ovary SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE Primary ovarian insufficiency; ovarian autoimmunity; SCA-POI; APS1; ovarian failure ID IDIOPATHIC ADDISONS-DISEASE; EARLY EMBRYONIC-DEVELOPMENT; AIRE-DEFICIENT MICE; AUTOIMMUNE OOPHORITIS; ZONA-PELLUCIDA; T-CELLS; ADRENAL INSUFFICIENCY; STEROIDOGENIC ENZYMES; THYMECTOMIZED MICE; SELF-TOLERANCE AB Ovarian autoimmunity is increasingly implicated in the etiology of primary ovarian insufficiency (POI), previously termed premature ovarian failure or premature menopause. Links to autoimmunity in human POI have long been noted due to the close association of POI with several autoimmune diseases and syndromes such as Addison's disease and Autoimmune polyglandular syndrome 1. However, diagnosis of autoimmune-mediated POI (aPOI) remains challenging because of the lack of sensitive or specific markers of disease. Autoimmunity can arise from the breakdown of immunological tolerance in several ways. How then may we discern what constitutes a relevant target and what represents a downstream phenomenon? The answer lies in the study of pathogenic mechanisms in translational models of disease. From examples in humans and mice, we see that ovarian autoimmunity likely arises from a limited number of antigens targeted in the ovary that are organ specific. These antigens may be conserved but not limited to those seen in animal models of autoimmune ovarian disease. Recent advances in these areas have begun to define the relevant antigens and mechanisms of immune tolerance breakdown in the ovary. Work in translational models continues to provide insight into mechanisms of disease pathogenesis that will allow more accurate diagnosis and, ultimately, improved interventions for women with aPOI. C1 [Cheng, Mickie H.] Univ Calif San Francisco, Ctr Diabet, Dept Med, Div Endocrinol, San Francisco, CA 94143 USA. [Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Cheng, MH (reprint author), Univ Calif San Francisco, Ctr Diabet, Dept Med, Div Endocrinol, 513 Parnassus Ave,HSW 1102 Box 0540, San Francisco, CA 94143 USA. EM mickie.cheng@ucsf.edu FU National Institute of Child Health and Human Development, National Institutes of Health [K08HD058599] FX Supported in part by the Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health. LMN is a commissioned officer in the U.S. Public Health Service. MHC is supported by the National Institute of Child Health and Human Development, National Institutes of Health (K08HD058599). NR 66 TC 3 Z9 3 U1 0 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JUL PY 2011 VL 29 IS 4 BP 308 EP 316 DI 10.1055/s-0031-1280916 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 810PQ UT WOS:000294138600005 PM 21969265 ER PT J AU Sterling, EW Nelson, LM AF Sterling, Evelina Weidman Nelson, Lawrence M. TI From Victim to Survivor to Thriver: Helping Women with Primary Ovarian Insufficiency Integrate Recovery, Self-Management, and Wellness SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE Primary ovarian insufficiency (POI); premature ovarian failure (POF); integrative care; recovery; self-management ID RANDOMIZED CONTROLLED-TRIAL; VITRO FERTILIZATION PREGNANCIES; UNDERLYING COPING FLEXIBILITY; HORMONE REPLACEMENT THERAPY; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; NATURAL MENOPAUSE; YOUNG-WOMEN; PSYCHOSOCIAL TRANSITION; VENOUS THROMBOEMBOLISM AB Most women discover that they are infertile in a gradual manner after many failed attempts at conception. By contrast, most women with primary ovarian insufficiency (POI) uncover their infertility as part of an evaluation of other presenting complaints, frequently before attempts at conception have even been contemplated. The most common words women use to describe how they feel in the hours after getting the diagnosis of POI are "devastated," "shocked," and "confused." Clearly, the news propels some patients onto a difficult journey. POI is a serious and incurable chronic disease. The diagnosis is more than infertility and affects a woman's physical and emotional well-being. Management of the condition must address both. Patients face the acute shock of the diagnosis, associated stigma of infertility, grief from the death of dreams, anxiety from the disruption of life plans, confusion around the cause, symptoms of estrogen deficiency, worry over the associated potential medical sequelae such as reduced bone density and cardiovascular risk, and the uncertain future that all of these factors create. There is a need for an evidenced-based integrated program to assist women with POI in navigating the transition to acceptance of the diagnosis, ongoing management of the condition, and ongoing maintenance of wellness in the presence of the disorder. A health-centered approach can gradually replace the disease-centered approach and put patients in partnerships with professional health-care providers. Ideally, the journey transitions each patient from seeing herself as a victim, to a survivor, to a woman who is thriving. C1 [Sterling, Evelina Weidman] Rachels Well, Marietta, GA 30068 USA. [Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Sterling, EW (reprint author), Rachels Well, 4880 Lower Roswell Rd,Suite 165,610, Marietta, GA 30068 USA. EM evelina@rachelswell.org FU National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD FX This work was supported in part by the Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. LMN is a commissioned officer in the U.S. Public Health Service. NR 99 TC 3 Z9 3 U1 3 U2 7 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JUL PY 2011 VL 29 IS 4 BP 353 EP 361 DI 10.1055/s-0031-1280920 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 810PQ UT WOS:000294138600009 PM 21969269 ER PT J AU Gordon, J Kopp, JB AF Gordon, Judit Kopp, Jeffrey B. TI Off the Beaten Renin-Angiotensin-Aldosterone System Pathway: New Perspectives on Antiproteinuric Therapy SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Proteinuria; Albuminuria; Podocyte; Glomerulus; Diabetes; Novel therapies ID CHRONIC KIDNEY-DISEASE; IDIOPATHIC MEMBRANOUS NEPHROPATHY; EXPERIMENTAL DIABETIC-NEPHROPATHY; CHILDHOOD IGA NEPHROPATHY; URINE PROTEIN EXCRETION; PKC BETA INHIBITOR; APOPTOSIS IN-VITRO; PODOCYTE INJURY; RENAL-FUNCTION; TGF-BETA AB CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin-angiotensin-aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin-angiotensin-aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. C1 [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Div Nephrol, Baltimore, MD 21205 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM Jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK FX This work was supported by the NIDDK Intramural Research Program. NR 127 TC 7 Z9 7 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JUL PY 2011 VL 18 IS 4 BP 300 EP 311 DI 10.1053/j.ackd.2011.06.002 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 805HK UT WOS:000293717300011 PM 21782136 ER PT J AU Goodman, M Squibb, K Youngstrom, E Anthony, LG Kenworthy, L Lipkin, PH Mattison, DR LaKind, JS AF Goodman, Michael Squibb, Katherine Youngstrom, Eric Anthony, Laura Gutermuth Kenworthy, Lauren Lipkin, Paul H. Mattison, Donald R. LaKind, Judy S. TI Using systematic reviews and meta-analyses to support regulatory decision making for neurotoxicants: lessons learned from a case study of PCBs SO CIENCIA & SAUDE COLETIVA LA English DT Review DE Domain; Function testing; Meta-analysis; Neurodevelopment; Neurotoxicants; PCBs; Risk assessment; Weight of evidence ID POLYCHLORINATED-BIPHENYLS PCBS; PRENATAL EXPOSURE; DICHLORODIPHENYL DICHLOROETHENE; DEVELOPMENTAL NEUROTOXICITY; CHEMICAL-EXPOSURE; MOTOR DEVELOPMENT; PUBLICATION BIAS; CHILDREN; DIOXINS; CONTAMINANTS AB We examined prospective cohort studies evaluating the relation between prenatal and neonatal exposure to polychlorinated biphenyls (PCBs) and neurodevelopment in children to assess the feasibility of conducting a meta-analysis to support decision making. We described studies in terms of exposure and end point categorization, statistical analysis, and reporting of results. We used this evaluation to assess the feasibility of grouping studies into reasonably uniform categories. The most consistently used tests included Brazelton's Neonatal Behavioral Assessment Scale, the neurologic optimality score in the neonatal period, the Bayley Scales of Infant Development at 5-8months of age, and the McCarthy Scales of Children's Abilities in 5-year-olds. Despite administering the same tests at similar ages, the studies were too dissimilar to allow a meaningful quantitative examination of outcomes across cohorts. These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability. C1 [LaKind, Judy S.] LaKind Associates LLC, Catonsville, MD 21228 USA. [Goodman, Michael] Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA. [Squibb, Katherine] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Anthony, Laura Gutermuth; Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. [Youngstrom, Eric] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Youngstrom, Eric] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Anthony, Laura Gutermuth; Kenworthy, Lauren] George Washington Univ, Dept Pediat, Washington, DC 20052 USA. [Anthony, Laura Gutermuth; Kenworthy, Lauren] George Washington Univ, Dept Psychiat, Washington, DC USA. [Kenworthy, Lauren] George Washington Univ, Dept Neurol, Washington, DC USA. [Lipkin, Paul H.] Kennedy Krieger Inst, Ctr Dev & Learning, Baltimore, MD USA. [Lipkin, Paul H.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [LaKind, Judy S.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [LaKind, Judy S.] Penn State Coll Med, Milton S Hershey Med Ctr, Dept Pediat, Hershey, PA USA. RP LaKind, JS (reprint author), LaKind Associates LLC, 106 Oakdale Ave, Catonsville, MD 21228 USA. EM lakindassoc@comcast.net RI Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 44 TC 0 Z9 0 U1 0 U2 4 PU ABRASCO PI RIO DE JANEIRO PA RUA HESPERIA, 16-PARTE MANGUINHOS, RIO DE JANEIRO, 21050-040, BRAZIL SN 1413-8123 J9 CIENC SAUDE COLETIVA JI Cienc. Saude Coletiva PD JUL PY 2011 VL 16 IS 7 BP 3207 EP 3220 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 801LV UT WOS:000293441300020 PM 21808908 ER PT J AU Wing, RR Lang, W Wadden, TA Safford, M Knowler, WC Bertoni, AG Hill, JO Brancati, FL Peters, A Wagenknecht, L AF Wing, Rena R. Lang, Wei Wadden, Thomas A. Safford, Monika Knowler, William C. Bertoni, Alain G. Hill, James O. Brancati, Frederick L. Peters, Anne Wagenknecht, Lynne CA Look AHEAD Res Grp TI Benefits of Modest Weight Loss in Improving Cardiovascular Risk Factors in Overweight and Obese Individuals With Type 2 Diabetes SO DIABETES CARE LA English DT Article ID LIFE-STYLE INTERVENTION; LONG-TERM; LIPOPROTEINS; REDUCTION; DISEASE; PLASMA; MAINTENANCE; MELLITUS; HEALTH; LIPIDS AB OBJECTIVE-Overweight and obese individuals are encouraged to lose 5-10% of their body weight to improve cardiovascular disease (CVD) risk, but data supporting this recommendation are limited, particularly for individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS-We conducted an observational analysis of participants in the Look AHEAD (Action For Health in Diabetes) study (n = 5,145, 40.5% male, 37% from ethnic/racial minorities) and examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with type 2 diabetes. RESULTS-The magnitude of weight loss at 1 year was strongly (P < 0.0001) associated with improvements in glycemia, blood pressure, tryiglycerides, and HDL cholesterol but not with LDL cholesterol (P = 0.79). Compared with weight-stable participants, those who lost 5 to <10% ([means +/- SD] 7.25 +/- 2.1 kg) of their body weight had increased odds of achieving a 0.5% point reduction in HbA(1c) (odds ratio 3.52 [95% CI 2.81-4.40]), a 5-mmHg decrease in diastolic blood pressure (1.48 [1.20-1.82]), a 5-mmHg decrease in systolic blood pressure (1.56 [1.27-1.91]), a 5 mg/dL increase in HDL cholesterol (1.69 [1.37-2.07]), and a 40 mg/dL decrease in triglycerides (2.20 [1.71-2.83]). The odds of clinically significant improvements in most risk factors were even greater in those who lost 10-15% of their body weight. CONCLUSIONS-Modest weight losses of 5 to <10% were associated with significant improvements in CVD risk factors at 1 year, but larger weight losses had greater benefits. C1 [Wing, Rena R.] Miriam Hosp, Dept Psychiat & Human Behav, Brown Med Sch, Providence, RI 02906 USA. [Lang, Wei] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Wadden, Thomas A.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Safford, Monika] Univ Alabama, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Knowler, William C.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Bertoni, Alain G.; Wagenknecht, Lynne] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Hill, James O.] Univ Colorado, Hlth Sci Ctr, Ctr Human Nutr, Denver, CO USA. [Brancati, Frederick L.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Peters, Anne] Roybal Comprehens Hlth Ctr, Los Angeles, CA USA. RP Wing, RR (reprint author), Miriam Hosp, Dept Psychiat & Human Behav, Brown Med Sch, Providence, RI 02906 USA. EM rwing@lifespan.org OI Peters, Anne/0000-0003-0520-0776 FU National Institute of Diabetes and Digestive and Kidney Diseases; NIH; CDC FX This trial was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, with cofunding from other institutes at NIH and from CDC; all institutions were involved in design, conduct, and reporting of results. NR 24 TC 340 Z9 342 U1 2 U2 24 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 JUL PY 2011 VL 34 IS 7 BP 1481 EP 1486 DI 10.2337/dc10-2415 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200007 PM 21593294 ER PT J AU Bainbridge, KE Hoffman, HJ Cowie, CC AF Bainbridge, Kathleen E. Hoffman, Howard J. Cowie, Catherine C. TI Risk Factors for Hearing Impairment Among US Adults With Diabetes National Health and Nutrition Examination Survey 1999-2004 SO DIABETES CARE LA English DT Article ID NOISE EXPOSURE HISTORY; UNITED-STATES; OLDER-ADULTS; MELLITUS; PREVALENCE; NIDDM AB OBJECTIVE-The objective of this study was to examine the risk factors of low/mid-frequency and high-frequency hearing impairment among a nationally representative sample of diabetic adults. RESEARCH DESIGN AND METHODS-Data came from 536 participants, aged 20-69 years, with diagnosed or undiagnosed diabetes who completed audiometric testing during 1999 2004 in the National Health and Nutrition Examination Survey (NHANES). We defined hearing impairment as the pure-tone average >25 dB hearing level of pure-tone thresholds at low/mid-frequencies (500; 1,000; and 2,000 Hz) and high frequencies (3,000; 4,000; 6,000; and 8,000 Hz) and identified independent risk factors using logistic regression. RESULTS-Controlling for age, race/ethnicity, and marital status, odds ratios for associations with low/mid-frequency hearing impairment were 2.20 (95% CI 1.28-3.79) for HDL <40 mg/dL and 3.55 (1.57-8.03) for poor health. Controlling for age, race/ethnicity, sex, and income-to-poverty ratio, odds ratios for associations with high-frequency hearing impairment were 4.39 (1.26-15.26) for history of coronary heart disease and 4.42 (1.26-15.45) for peripheral neuropathy. CONCLUSIONS-Low HDL, coronary heart disease, peripheral neuropathy, and having poor health are potentially preventable correlates of hearing impairment for people with diabetes. Glycemic control, years since diagnosis, and type of glycemic medication were not associated with hearing impairment. C1 [Bainbridge, Kathleen E.; Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, Bethesda, MD 20892 USA. [Cowie, Catherine C.] NIDDKD, Diabet Epidemiol Program, Bethesda, MD 20892 USA. RP Bainbridge, KE (reprint author), Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, Bethesda, MD 20892 USA. EM bainbridgek@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN267200700001G] FX This work was financially supported by the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN267200700001G). NR 25 TC 25 Z9 29 U1 0 U2 4 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 JUL PY 2011 VL 34 IS 7 BP 1540 EP 1545 DI 10.2337/dc10-2161 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200019 PM 21593298 ER PT J AU Bowers, K Yeung, E Williams, MA Qi, L Tobias, DK Hu, FB Zhang, CL AF Bowers, Katherine Yeung, Edwina Williams, Michelle A. Qi, Lu Tobias, Deirdre K. Hu, Frank B. Zhang, Cuilin TI A Prospective Study of Prepregnancy Dietary Iron Intake and Risk for Gestational Diabetes Mellitus SO DIABETES CARE LA English DT Article ID PROSPECTIVE COHORT; PREGNANT-WOMEN; SERUM FERRITIN; DEFICIENCY; ANEMIA; DETERMINANTS; STORES AB OBJECTIVE-It is important to identify modifiable factors that may lower gestational diabetes mellitus (GDM) risk. Dietary iron is of particular interest given that iron is a strong prooxidant, and high body iron levels can damage pancreatic beta-cell function and impair glucose metabolism. The current study is to determine if prepregnancy dietary and supplemental iron intakes are associated with the risk of GDM. RESEARCH DESIGN AND METHODS-A prospective study was conducted among 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses' Health Study II. A total of 867 incident GDM cases were reported. Pooled logistic regression was used to estimate the relative risk (RR) of GDM by quintiles of iron intake controlling for dietary and nondietary risk factors. RESULTS-Dietary heme iron intake was positively and significantly associated with GDM risk. After adjusting for age, BMI, and other risk factors, RRs (95% CIs) across increasing quintiles of heme iron were 1.0 (reference), 1.11 (0.87-1.43), 1.31 (1.03-1.68), 1.51 (1.17-1.93), and 1.58 (1.21-2.08), respectively (P for linear trend 0.0001). The multivariate adjusted RR for GDM associated with every 0.5-mg per day of increase in intake was 1.22 (1.10-1.36). No significant associations were observed between total dietary, nonheme, or supplemental iron intake and GDM risk. CONCLUSIONS-These findings suggest that higher prepregnancy intake of dietary heme iron is associated with an increased GDM risk. C1 [Bowers, Katherine; Yeung, Edwina; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20847 USA. [Williams, Michelle A.] Swedish Med Ctr, Ctr Perinatal Studies, Seattle, WA USA. [Williams, Michelle A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Qi, Lu; Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Hu, Frank B.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Qi, Lu; Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA USA. [Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20847 USA. EM bowerska2@mail.nih.gov; zhangcu@mail.nih.gov RI Yeung, Edwina/F-5992-2015; Bowers, Katherine/N-5226-2015 OI Yeung, Edwina/0000-0002-3851-2613; FU National Institutes of Health (NIH) [CA50385, DK58845]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This study was funded by research grants CA50385 and DK58845 from the National Institutes of Health (NIH). K.B., C.Z., and E.Y. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 26 TC 32 Z9 35 U1 1 U2 10 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 JUL PY 2011 VL 34 IS 7 BP 1557 EP 1563 DI 10.2337/dc11-0134 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200022 PM 21709294 ER PT J AU Qiu, CF Zhang, CL Gelaye, B Enquobahrie, DA Frederick, IO Williams, MA AF Qiu, Chunfang Zhang, Cuilin Gelaye, Bizu Enquobahrie, Daniel A. Frederick, Ihunnaya O. Williams, Michelle A. TI Gestational Diabetes Mellitus in Relation to Maternal Dietary Heme Iron and Nonheme Iron Intake SO DIABETES CARE LA English DT Article ID SERUM FERRITIN; WOMENS HEALTH; RISK; PREGNANCY; STORES AB OBJECTIVE-Higher heme iron intake is associated with increased type 2 diabetes risk. However, no previous study has evaluated gestational diabetes mellitus (GDM) risk in relation to heme iron intake during pregnancy. We investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk. RESEARCH DESIGN AND METHODS-We conducted a prospective cohort study of 3,158 pregnant women. A food frequency questionnaire was used to assess maternal diet. Multivariable generalized linear regression models were used to derive estimates of relative risks (RRs) and 95% CIs. RESULTS-Approximately 5.0% of the cohort developed GDM (n = 158). Heme iron intake was positively and significantly associated with GDM risk (P(trend) = 0.04). After adjusting for confounders, women reporting the highest heme iron intake levels (>= 1.52 vs. <0.48 mg per day) experienced a 3.31-fold increased GDM risk (95% CI 1.02-10.72). In fully adjusted models, we noted that a 1-mg per day increase in heme iron was associated with a 51% increased GDM risk (RR 1.51 [95% CI 0.99-2.36]). Nonheme iron was inversely, though not statistically significantly, associated with GDM risk, and the corresponding RRs were 1.00, 0.83, 0.62, and 0.61 across quartiles of nonheme iron intake (P(trend) = 0.08). CONCLUSIONS-High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk. Associations of GDM risk with dietary nonheme iron intake are less clear. Confirmation of these findings by future studies is warranted. C1 [Qiu, Chunfang; Enquobahrie, Daniel A.; Frederick, Ihunnaya O.; Williams, Michelle A.] Swedish Med Ctr, Ctr Perinatal Studies, Seattle, WA 98107 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Gelaye, Bizu; Enquobahrie, Daniel A.; Williams, Michelle A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Qiu, CF (reprint author), Swedish Med Ctr, Ctr Perinatal Studies, Seattle, WA 98107 USA. EM chun-fang.qiu@swedish.org OI Gelaye, Bizu/0000-0001-7934-548X FU National Institutes of Health [R01-HD-32562]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by an award from the National Institutes of Health (R01-HD-32562). C.Z. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 25 TC 33 Z9 37 U1 3 U2 9 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 JUL PY 2011 VL 34 IS 7 BP 1564 EP 1569 DI 10.2337/dc11-0135 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200023 PM 21709295 ER PT J AU Tobias, DK Hu, FB Forman, JP Chavarro, J Zhang, CL AF Tobias, Deirdre K. Hu, Frank B. Forman, John P. Chavarro, Jorge Zhang, Cuilin TI Increased Risk of Hypertension After Gestational Diabetes Mellitus Findings from a large prospective cohort study SO DIABETES CARE LA English DT Article ID GLUCOSE-INTOLERANCE; CARDIOVASCULAR RISK; YOUNG-WOMEN; PREGNANCY AB OBJECTIVE-Whether a history of gestational diabetes mellitus (GDM) is associated with an increased risk of hypertension after the index pregnancy is not well established. RESEARCH DESIGN AND METHODS-We investigated the association between GDM and subsequent risk of hypertension after the index pregnancy among 25,305 women who reported at least one singleton pregnancy between 1991 and 2007 in the Nurses' Health Study II. RESULTS-During 16 years of follow-up, GDM developed in 1,414 women (5.6%) and hypertension developed in 3,138. A multivariable Cox proportional hazards model showed women with a history of GDM had a 26% increased risk of developing hypertension compared with those without a history of GDM (hazard ratio 1.26 [95% CI 1.11-1.431; P = 0.0004). These results were independent of pregnancy hypertension or subsequent type 2 diabetes. CONCLUSIONS-These results indicate that women with GDM are at a significant increased risk of developing hypertension after the index pregnancy. C1 [Tobias, Deirdre K.; Hu, Frank B.; Chavarro, Jorge] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tobias, Deirdre K.; Hu, Frank B.; Chavarro, Jorge] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.; Forman, John P.; Chavarro, Jorge] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hu, Frank B.; Forman, John P.; Chavarro, Jorge] Harvard Univ, Sch Med, Boston, MA USA. [Forman, John P.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. RP Tobias, DK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM dbanel@hsph.harvard.edu; zhangcu@mail.nih.gov FU Eunice Kennedy Shriver NICHD, National Institutes of Health (NIH); NIH [CA-50385, DK-58845]; Eunice Kennedy Shriver NICHD FX C.Z. was supported by the Intramural Research Program of the Eunice Kennedy Shriver NICHD, National Institutes of Health (NIH). This study was funded by NIH research grants CA-50385 and DK-58845 and the Intramural Research Program of the Eunice Kennedy Shriver NICHD. NR 11 TC 12 Z9 12 U1 0 U2 5 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 JUL PY 2011 VL 34 IS 7 BP 1582 EP 1584 DI 10.2337/dc11-0268 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200027 PM 21593289 ER PT J AU Dabelea, D Pihoker, C Talton, JW D'Agostino, RB Fujimoto, W Klingensmith, GJ Lawrence, JM Linder, B Marcovina, SM Mayer-Davis, EJ Imperatore, G Dolan, LM AF Dabelea, Dana Pihoker, Catherine Talton, Jennifer W. D'Agostino, Ralph B., Jr. Fujimoto, Wilfred Klingensmith, Georgeanna J. Lawrence, Jean M. Linder, Barbara Marcovina, Santica M. Mayer-Davis, Elizabeth J. Imperatore, Giuseppina Dolan, Lawrence M. CA SEARCH Diabet Youth Study TI Etiological Approach to Characterization of Diabetes Type The SEARCH for Diabetes in Youth Study SO DIABETES CARE LA English DT Article ID BETA-CELL FUNCTION; CHILDREN; MELLITUS; DIAGNOSIS; GENOTYPES; CLASSIFICATION; INSULIN; AUTOIMMUNITY; ADOLESCENTS; ADULTS AB OBJECTIVE-To describe an etiologic approach to classification of diabetes types in youth based on the 1997 American Diabetes Association (ADA) framework, using data from the SEARCH for Diabetes in Youth Study. RESEARCH DESIGN AND METHODS-SEARCH conducted a comprehensive assessment of 2,291 subjects aged <20 years with recently diagnosed diabetes. Using autoimmunity (at least one of two diabetes autoantibodies) and insulin sensitivity (equation validated against hyperinsulinemic-euglycemic clamps) as the main etiologic markers, we described four categories along a bidimensional spectrum: autoimmune plus insulin-sensitive (IS), autoimmune plus insulin-resistant (IR), nonautoimmune plus IS, and nonautoimmune plus IR. We then explored how characteristics, including genetic susceptibility to autoimmunity (HLA genotypes), insulin deficiency, and clinical factors varied across these four categories. RESULTS-Most subjects fell into either the autoimmune plus IS (54.5%) or nonautoimmune plus IR categories (15.9%) and had characteristics that align with traditional descriptions of type 1 or type 2 diabetes. The group classified as autoimmune plus IR (19.5%) had similar prevalence and titers of diabetes autoantibodies and similar distribution of HLA risk genotypes to those in the autoimmune plus IS group, suggesting that it includes individuals with type 1 diabetes who are obese. The group classified as nonautoimmune plus IS (10.1%) likely includes individuals with undetected autoimmunity but may also include those with monogenic diabetes and thus requires further testing. CONCLUSIONS-The SEARCH study offers researchers and clinicians a practical application for the etiologic classification of diabetes type and at the same time identifies a group of youths who would benefit from further testing. C1 [Dabelea, Dana] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO 80045 USA. [Pihoker, Catherine] Univ Washington, Dept Washington, Seattle, WA 98195 USA. [Talton, Jennifer W.; D'Agostino, Ralph B., Jr.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Fujimoto, Wilfred] Kuakini Med Ctr, Honolulu, HI USA. [Klingensmith, Georgeanna J.] Univ Colorado Denver, Barbara Davis Ctr, Sch Med, Aurora, CO USA. [Klingensmith, Georgeanna J.] Univ Colorado Denver, Dept Pediat, Sch Med, Aurora, CO USA. [Lawrence, Jean M.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA USA. [Linder, Barbara] NIDDK, NIH, Bethesda, MD USA. [Marcovina, Santica M.] Univ Washington, Dept Med, Seattle, WA USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Imperatore, Giuseppina] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Dolan, Lawrence M.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati Childrens Hosp, Cincinnati, OH USA. RP Dabelea, D (reprint author), Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO 80045 USA. EM dana.dabelea@ucdenver.edu RI Dagostino Jr, Ralph/C-4060-2017 OI Dagostino Jr, Ralph/0000-0002-3550-8395 FU NCRR NIH HHS [UL1 RR025014] NR 25 TC 67 Z9 69 U1 0 U2 5 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 JUL PY 2011 VL 34 IS 7 BP 1628 EP 1633 DI 10.2337/dc10-2324 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200036 PM 21636800 ER PT J AU O'Connor, PJ Bodkin, NL Fradkin, J Glasgow, RE Greenfield, S Gregg, E Kerr, EA Pawlson, LG Selby, JV Sutherland, JE Taylor, ML Wysham, CH AF O'Connor, Patrick J. Bodkin, Noni L. Fradkin, Judith Glasgow, Russell E. Greenfield, Sheldon Gregg, Edward Kerr, Eve A. Pawlson, L. Gregory Selby, Joseph V. Sutherland, John E. Taylor, Michael L. Wysham, Carol H. TI Diabetes Performance Measures: Current Status and Future Directions SO DIABETES CARE LA English DT Article ID QUALITY-OF-CARE; GLYCEMIC CONTROL; CLINICAL-QUALITY; CARDIOTHORACIC SURGEONS; MEDICATION NONADHERENCE; UNINTENDED CONSEQUENCES; INTERMEDIATE OUTCOMES; TRANSLATING RESEARCH; SURGICAL MORTALITY; COST-EFFECTIVENESS C1 [O'Connor, Patrick J.] Hlth Partners Res Fdn, Minneapolis, MN 55440 USA. [Bodkin, Noni L.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Fradkin, Judith] NIDDK, Bethesda, MD USA. [Glasgow, Russell E.] NCI, Rockville, MD USA. [Greenfield, Sheldon] Univ Calif Irvine, Irvine, CA USA. [Gregg, Edward] Ctr Dis Control & Prevent, Atlanta, GA USA. [Kerr, Eve A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Pawlson, L. Gregory] Natl Comm Qual Assurance, Washington, DC USA. [Selby, Joseph V.] Kaiser Permanente No Calif, Oakland, CA USA. [Sutherland, John E.] NE Iowa Med Educ Fdn, Waterloo, IA USA. [Taylor, Michael L.] Caterpillar Inc, Peoria, IL 61629 USA. [Wysham, Carol H.] Univ Washington, Sch Med, Spokane, WA USA. RP O'Connor, PJ (reprint author), Hlth Partners Res Fdn, Minneapolis, MN 55440 USA. EM patrick.j.oconnor@healthpartners.com RI Kerr, Eve/I-3330-2013 FU sanofi-aventis FX The consensus development conference was supported by an unrestricted grant from sanofi-aventis. The company had no input into the content of the report. No other potential conflicts of interest relevant to this article were reported. NR 93 TC 51 Z9 51 U1 3 U2 12 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 JUL PY 2011 VL 34 IS 7 BP 1651 EP 1659 DI 10.2337/dc11-0735 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 799CN UT WOS:000293261200041 PM 21709298 ER PT J AU Aronow, WS Fleg, JL Pepine, CJ Artinian, NT Bakris, G Brown, AS Ferdinand, KC Forciea, MA Frishman, WH Jaigobin, C Kostis, JB Mancia, G Oparil, S Ortiz, E Reisin, E Rich, MW Schocken, DD Weber, MA Wesley, DJ Harrington, RA Bates, ER Bhatt, DL Bridges, CR Eisenberg, MJ Ferrari, VA Fisher, JD Gardner, TJ Gentile, F Gilson, MF Hlatky, MA Jacobs, AK Kaul, S Moliterno, DJ Mukherjee, D Rosenson, RS Stein, JH Weitz, HH Wesley, DJ AF Aronow, Wilbert S. Fleg, Jerome L. Pepine, Carl J. Artinian, Nancy T. Bakris, George Brown, Alan S. Ferdinand, Keith C. Forciea, Mary Ann Frishman, William H. Jaigobin, Cheryl Kostis, John B. Mancia, Giuseppi Oparil, Suzanne Ortiz, Eduardo Reisin, Efrain Rich, Michael W. Schocken, Douglas D. Weber, Michael A. Wesley, Deborah J. Harrington, Robert A. Bates, Eric R. Bhatt, Deepak L. Bridges, Charles R. Eisenberg, Mark J. Ferrari, Victor A. Fisher, John D. Gardner, Timothy J. Gentile, Federico Gilson, Michael F. Hlatky, Mark A. Jacobs, Alice K. Kaul, Sanjay Moliterno, David J. Mukherjee, Debabrata Rosenson, Robert S. Stein, James H. Weitz, Howard H. Wesley, Deborah J. TI ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents Developed in Collaboration With the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE ACCF/AHA Expert Consensus Documents; antihypertensive agents; elderly; risk assessment; hypertension comorbidities; hypertension pathophysiology; hypertension therapy ID ISOLATED SYSTOLIC HYPERTENSION; RENAL-ARTERY STENOSIS; AMBULATORY BLOOD-PRESSURE; LEFT-VENTRICULAR HYPERTROPHY; RANDOMIZED CONTROLLED-TRIAL; CONVERTING-ENZYME-INHIBITORS; CONGESTIVE-HEART-FAILURE; VERAPAMIL SR-TRANDOLAPRIL; RENIN-ANGIOTENSIN SYSTEM; LIPID-LOWERING TREATMENT C1 [Aronow, Wilbert S.; Pepine, Carl J.; Frishman, William H.] Amer Coll Cardiol Fdn, New York, NY 13206 USA. [Fleg, Jerome L.; Ortiz, Eduardo] NHLBI, Bethesda, MD USA. [Artinian, Nancy T.; Brown, Alan S.] Amer Heart Assoc, Dallas, TX USA. [Ferdinand, Keith C.] Assoc Black Cardiologists, Atlanta, GA USA. [Forciea, Mary Ann] Amer Coll Physicians, Philadelphia, PA USA. [Jaigobin, Cheryl] Amer Acad Neurol, St Paul, MN USA. [Mancia, Giuseppi] European Soc Hypertens, Iowa City, IA USA. [Reisin, Efrain] Amer Soc Nephrol, Washington, DC 20005 USA. [Rich, Michael W.] Amer Geriatr Soc, New York, NY USA. [Schocken, Douglas D.] Amer Soc Prevent Cardiol, Jacksonville, FL 32216 USA. [Weber, Michael A.] Amer Soc Hypertens, New York, NY USA. [Wesley, Deborah J.] ACCF Task Force Clin Expert Consensus Documents, Detroit, MI USA. RP Aronow, WS (reprint author), Amer Coll Cardiol Fdn, New York, NY 13206 USA. NR 740 TC 52 Z9 58 U1 3 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD JUL-AUG PY 2011 VL 5 IS 4 BP 259 EP 352 DI 10.1016/j.jash.2011.06.001 PG 94 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 807BF UT WOS:000293866000007 PM 21771565 ER PT J AU D'Adamo, CR Miller, RR Hicks, GE Orwig, DL Hochberg, MC Semba, RD Yu-Yahiro, JA Ferrucci, L Magaziner, J Shardell, MD AF D'Adamo, Christopher R. Miller, Ram R. Hicks, Gregory E. Orwig, Denise L. Hochberg, Marc C. Semba, Richard D. Yu-Yahiro, Janet A. Ferrucci, Luigi Magaziner, Jay Shardell, Michelle D. TI Serum Vitamin E Concentrations and Recovery of Physical Function During the Year After Hip Fracture SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Vitamin E; Physical function; Hip fracture; Nutrition; Micronutrients ID OLDER WOMEN; GAMMA-TOCOPHEROL; CONTROLLED-TRIAL; PERFORMANCE; SUPPLEMENTATION; INTERVENTION; COMMUNITY; INCHIANTI; OUTCOMES; SCALE AB Background. Poor nutritional status after hip fracture is common and may contribute to physical function decline. Low serum concentrations of vitamin E have been associated with decline in physical function among older adults, but the role of vitamin E in physical recovery from hip fracture has never been explored. Methods. Serum concentrations of alpha- and gamma-tocopherol, the two major forms of vitamin E, were measured in female hip fracture patients from the Baltimore Hip Studies cohort 4 at baseline and at 2-, 6-, and 12-month postfracture follow-up visits. Four physical function measures-Six-Minute Walk Distance, Lower Extremity Gain Scale, Short Form-36 Physical Functioning Domain, and Yale Physical Activity Survey-were assessed at 2, 6, and 12 months postfracture. Generalized estimating equations modeled the relationship between baseline and time-varying serum tocopherol concentrations and physical function after hip fracture. Results. A total of 148 women aged 65 years and older were studied. After adjusting for covariates, baseline vitamin E concentrations were positively associated with Six-Minute Walk Distance, Lower Extremity Gain Scale, and Yale Physical Activity Survey scores (p < .1) and faster improvement in Lower Extremity Gain Scale and Yale Physical Activity Survey scores (p < .008). Time-varying vitamin E was also positively associated with Six-Minute Walk Distance, Lower Extremity Gain Scale, Yale Physical Activity Survey, and Short Form-36 Physical Functioning Domain (p < .03) and faster improvement in Six-Minute Walk Distance and Short Form-36 Physical Functioning Domain (p < .07). Conclusions. Serum concentrations of both alpha- and gamma-tocopherol were associated with better physical function after hip fracture. Vitamin E may represent a potentially modifiable factor related to recovery of postfracture physical function. C1 [D'Adamo, Christopher R.; Miller, Ram R.; Orwig, Denise L.; Magaziner, Jay; Shardell, Michelle D.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Hochberg, Marc C.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Yu-Yahiro, Janet A.] Union Mem Hosp, Dept Orthoped Res, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP D'Adamo, CR (reprint author), 520 W Lombard St,E Hall, Baltimore, MD 21201 USA. EM cdadamo@compmed.umm.edu FU National Institute on Aging at the National Institutes of Health [R01 AG018668, R37 AG09901, T32 AG00262, K23 AG027746, P60 AG12583, P30 AG028747] FX This work was supported by the National Institute on Aging at the National Institutes of Health (R01 AG018668, R37 AG09901, T32 AG00262, K23 AG027746, P60 AG12583, and P30 AG028747). NR 40 TC 6 Z9 6 U1 1 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 JUL PY 2011 VL 66 IS 7 BP 784 EP 793 DI 10.1093/gerona/glr057 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 806KZ UT WOS:000293807900007 PM 21486921 ER PT J AU Semba, RD Cappola, AR Sun, K Bandinelli, S Dalal, M Crasto, C Guralnik, JM Ferrucci, L AF Semba, Richard D. Cappola, Anne R. Sun, Kai Bandinelli, Stefania Dalal, Mansi Crasto, Candace Guralnik, Jack M. Ferrucci, Luigi TI Plasma Klotho and Mortality Risk in Older Community-Dwelling Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Klotho; Longevity; Mortality ID CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; BONE-MINERAL DENSITY; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; FUNCTIONAL VARIANT; GENE POLYMORPHISMS; OXIDATIVE STRESS; HORMONE KLOTHO AB Background. The aging-suppressor gene klotho encodes a single-pass transmembrane protein that in mice is known to extend life span when overexpressed and resemble accelerated aging when expression is disrupted. It is not known whether there is a relationship between plasma levels of secreted klotho protein and longevity in humans. Methods. We measured plasma klotho in 804 adults, greater than or equal to 65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Results. During 6 years of follow-up, 194(24.1%) of the participants died. In a multivariate Cox proportional hazards model, adjusting for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases, participants in the lowest tertile of plasma klotho (<575 pg/mL) had an increased risk of death compared with participants in the highest tertile of plasma klotho (>763 pg/mL; hazards ratio 1.78, 95% confidence interval 1.20-2.63). Conclusions. In older community-dwelling adults, plasma klotho is an independent predictor of all-cause mortality. Further studies are needed to elucidate the potential biological mechanisms by which circulating klotho could affect longevity in humans. C1 [Semba, Richard D.; Sun, Kai; Dalal, Mansi; Crasto, Candace] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Bandinelli, Stefania] Azienda Sanit, Florence, Italy. [Guralnik, Jack M.] NIA, Epidemiol & Demog Sect, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Smith Bldg,M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu FU National Institute on Aging (NIA) [R01 AG027012, 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; Italian Ministry of Health [ICS110.1/RF97.71]; NIA, National Institutes of Health, Baltimore, Maryland FX This work was supported by the National Institute on Aging (NIA) (R01 AG027012), the Italian Ministry of Health (ICS110.1/RF97.71), and NIA contracts 263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, and N01-AG-5-0002, the Intramural Research Program of NIA, National Institutes of Health, Baltimore, Maryland. NR 35 TC 51 Z9 52 U1 0 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 JUL PY 2011 VL 66 IS 7 BP 794 EP 800 DI 10.1093/gerona/glr058 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 806KZ UT WOS:000293807900008 PM 21474560 ER PT J AU Rossi, AP Watson, NL Newman, AB Harris, TB Kritchevsky, SB Bauer, DC Satterfield, S Goodpaster, BH Zamboni, M AF Rossi, Andrea P. Watson, Nora L. Newman, Anne B. Harris, Tamara B. Kritchevsky, Stephen B. Bauer, Douglas C. Satterfield, Suzanne Goodpaster, Bret H. Zamboni, Mauro TI Effects of Body Composition and Adipose Tissue Distribution on Respiratory Function in Elderly Men and Women: The Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Lung function; Body composition ID FAT-FREE MASS; X-RAY ABSORPTIOMETRY; SKELETAL-MUSCLE MASS; PULMONARY-FUNCTION; LUNG-FUNCTION; WEIGHT CHANGE; PHYSICAL-DISABILITY; MORTALITY; AGE; OBESITY AB Background. Previous cross-sectional studies demonstrate positive associations of fat-free mass and negative associations of centrally distributed fat deposits with respiratory function in older adults. Few studies have evaluated whether greater losses of muscle and increases in fat are associated with more rapid decline in respiratory function in aging. Methods. Nine hundred and fifty-seven men and 1,024 women aged, respectively. 73.6 +/- 2.8 years and 73.2 +/- 2.8 years at baseline were followed for 5 years. Body weight, waist circumference, bone mineral density, fat-free mass, fat mass and fat mass percentage as measured by DXA, abdominal subcutaneous and visceral adipose tissue, thigh muscle area, thigh intermuscular fat by CT and forced expiratory volume in 1 second (FEV1) and forced vital capacity (PVC) were evaluated at baseline and after 5-years follow-up. Results. Cross-sectional analyses showed that height and thigh muscle area were positively and visceral adipose tissue negatively related to FEV1 and FVC. Increase in fat mass over five years was associated with concurrent FEV1 and FVC decline. In analyses stratified by weight-change categories, men and women who gained weight (vs stable/lost weight) had more rapid declines in FEV1 and PVC. Conclusion. In this well-functioning cohort, less muscle and greater abdominal fat were each associated with poorer lung spirometry cross-sectionally, whereas increase in fat mass over 5 years was associated with concurrent FEV1 and FVC decline. Weight gain and accompanying fat deposition may accelerate age-related declines in respiratory function. C1 [Rossi, Andrea P.; Zamboni, Mauro] Univ Verona, Div Geriatr Med, Dept Med, I-37126 Verona, Italy. [Watson, Nora L.; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Goodpaster, Bret H.] Univ Pittsburgh, Div Endocrinol & Metab, Dept Med, Pittsburgh, PA 15260 USA. RP Rossi, AP (reprint author), Univ Verona, Osped Maggiore, Cattedra Geriatria, Piazzale Stefani 1, I-37126 Verona, Italy. EM andrea.rossi@hotmail.it RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; ZAMBONI, Mauro/0000-0001-6961-9483; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institutes of Health, National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106). NR 30 TC 18 Z9 19 U1 0 U2 4 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 JUL PY 2011 VL 66 IS 7 BP 801 EP 808 DI 10.1093/gerona/glr059 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 806KZ UT WOS:000293807900009 PM 21498841 ER PT J AU Beck, A Crain, AL Solberg, LI Unutzer, J Glasgow, RE Maciosek, MV Whitebird, R AF Beck, Arne Crain, A. Lauren Solberg, Leif I. Unuetzer, Juergen Glasgow, Russell E. Maciosek, Michael V. Whitebird, Robin TI Severity of Depression and Magnitude of Productivity Loss SO ANNALS OF FAMILY MEDICINE LA English DT Article DE Depression, severity; work impairment; primary care; practice-based research ID RANDOMIZED CONTROLLED-TRIAL; WORK PRODUCTIVITY; PRIMARY-CARE; ACTIVITY IMPAIRMENT; VALIDITY; PERFORMANCE; SYMPTOMS; PHQ-9; METAANALYSIS; IMPROVEMENT AB PURPOSE Depression is associated with lowered work functioning, including absences, impaired productivity, and decreased job retention. Few studies have examined depression symptoms across a continuum of severity in relationship to the magnitude of work impairment in a large and heterogeneous patient population, however. We assessed the relationship between depression symptom severity and productivity loss among patients initiating treatment for depression. METHODS Data were obtained from patients participating in the DIAMOND (Depression Improvement Across Minnesota: Offering a New Direction) initiative, a statewide quality improvement collaborative to provide enhanced depression care. Patients newly started on antidepressants were surveyed with the Patient Health Questionnaire 9-item screen (PHQ-9), a measure of depression symptom severity; the Work Productivity and Activity Impairment (WPAI) questionnaire, a measure of loss in productivity; and items on health status and demographics. RESULTS We analyzed data from the 771 patients who reported being currently employed. General linear models adjusting for demographics and health status showed a significant linear, monotonic relationship between depression symptom severity and productivity loss: with every 1-point increase in PHQ-9 score, patients experienced an additional mean productivity loss of 1.65% (P < .001). Even minor levels of depression symptoms were associated with decrements in work function. Full-time vs part-time employment status and self-reported fair or poor health vs excellent, very good, or good health were also associated with a loss of productivity (P < .001 and P = .045, respectively). CONCLUSIONS This study shows a relationship between the severity of depression symptoms and work function, and suggests that even minor levels of depression are associated with a loss of productivity. Employers may find it beneficial to invest in effective treatments for depressed employees across the continuum of depression severity. C1 [Beck, Arne] Kaiser Permanente, Inst Hlth Res, Denver, CO 80237 USA. [Beck, Arne] Univ Colorado, Hlth Sci Ctr, Dept Family Med, Denver, CO USA. [Crain, A. Lauren; Solberg, Leif I.; Maciosek, Michael V.; Whitebird, Robin] HealthPartners Res Fdn, Minneapolis, MN USA. [Unuetzer, Juergen] Univ Washington, Seattle, WA 98195 USA. [Glasgow, Russell E.] NCI, Washington, DC USA. RP Beck, A (reprint author), Kaiser Permanente, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. EM arne.beck@kp.org FU National Institute of Mental Health [5R01MH080692] FX This research was funded by grant 5R01MH080692 from the National Institute of Mental Health. NR 28 TC 44 Z9 44 U1 5 U2 15 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 J9 ANN FAM MED JI Ann. Fam. Med. PD JUL-AUG PY 2011 VL 9 IS 4 BP 305 EP 311 DI 10.1370/afm.1260 PG 7 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 797ED UT WOS:000293106400005 PM 21747101 ER PT J AU Williams, DE Lynch, JE Doshi, V Singh, GD Hargens, AR AF Williams, David E. Lynch, John E. Doshi, Vidhi Singh, G. Dave Hargens, Alan R. TI Bruxism and Temporal Bone Hypermobility in Patients with Multiple Sclerosis SO CRANIO-THE JOURNAL OF CRANIOMANDIBULAR PRACTICE LA English DT Article ID INTRACRANIAL-PRESSURE; CRANIAL BONE; VITAMIN-D; FLEXURE AB In this study, the authors investigated the link between jaw clenching/bruxism and temporal bone movement associated with multiple sclerosis (MS). Twenty-one subjects participated in this study (10 patients with MS and 11 controls). To quantify the change in intracranial dimension between the endocranial surfaces of the temporal bones during jaw clenching, an ultrasonic pulsed phase locked loop (PPLL) device was used. A sustained jaw clenching force of 100 lbs was used to measure the mean change in acoustic pathlength (Delta L) as the measure of intracranial distance. In the control subjects the mean Delta L was 0.27 mm +/- 0.24. In subjects with MS the mean Delta L was 1.71 mm +/- 1.18 (p<0.001). The increase in magnitude of bi-temporal bone intracranial expansion was approximately six times greater in subjects with MS compared to controls. Therefore, jaw clenching/bruxism is associated with more marked displacement of the temporal bones and expansion of the cranial cavity in patients with MS than in control subjects. C1 [Singh, G. Dave] BioModeling Solut LLC, Cornell Oaks Corp Ctr, Beaverton, OR 97006 USA. [Lynch, John E.] Lunas Med Prod Grp, Blacksburg, VA USA. [Singh, G. Dave] NIH Funded Program Craniofacial Res, Bethesda, MD USA. [Hargens, Alan R.] Univ Calif San Diego, Orthopaed Clin Physiol Lab, San Diego, CA 92103 USA. [Hargens, Alan R.] NASA, Washington, DC 20546 USA. [Hargens, Alan R.] Stanford Univ, Stanford, CA 94305 USA. RP Singh, GD (reprint author), BioModeling Solut LLC, Cornell Oaks Corp Ctr, 15455 NW Greenbrier Pkwy,Commons Bldg,Suite 250, Beaverton, OR 97006 USA. EM drsingh@drdavesingh.com FU Stryker Corp., Kalamazoo, MI FX This research was supported by a research grant from Stryker Corp., Kalamazoo, MI. The authors would like to thank G.W. Ellison, UCSD Department of Neurosciences, San Diego, CA, and B.R. Macias, Department of Health and Kinesiology, Texas A&M University, for technical assistance. NR 29 TC 2 Z9 2 U1 1 U2 4 PU CHROMA INC PI CHATTANOOGA PA PO BOX 8887, CHATTANOOGA, TN 37414 USA SN 0886-9634 J9 CRANIO JI Cranio-J. Craniomandib. Pract. PD JUL PY 2011 VL 29 IS 3 BP 178 EP 186 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 803XE UT WOS:000293614800005 PM 22586826 ER PT J AU Sheffield, AM Gubbels, SP Hildebrand, MS Newton, SS Chiorini, JA Di Pasquale, G Smith, RJH AF Sheffield, Abraham M. Gubbels, Samuel P. Hildebrand, Michael S. Newton, Stephen S. Chiorini, John A. Di Pasquale, Giovanni Smith, Richard J. H. TI Viral vector tropism for supporting cells in the developing murine cochlea SO HEARING RESEARCH LA English DT Article ID MEDIATED GENE-TRANSFER; MAMMALIAN INNER-EAR; ADENOASSOCIATED VIRUS TYPE-2; GUINEA-PIG COCHLEA; HEARING-LOSS; IN-VIVO; HAIR-CELLS; CONNEXIN 26; SENSORINEURAL DEAFNESS; TRANSGENE EXPRESSION AB Gene-based therapeutics are being developed as novel treatments for genetic hearing loss. One roadblock to effective gene therapy is the identification of vectors which will safely deliver therapeutics to targeted cells. The cellular heterogeneity that exists within the cochlea makes viral tropism a vital consideration for effective inner ear gene therapy. There are compelling reasons to identify a viral vector with tropism for organ of Corti supporting cells. Supporting cells are the primary expression site of connexin 26 gap junction proteins that are mutated in the most common form of congenital genetic deafness (DFNB1). Supporting cells are also primary targets for inducing hair cell regeneration. Since many genetic forms of deafness are congenital it is necessary to administer gene transfer-based therapeutics prior to the onset of significant hearing loss. We have used transuterine microinjection of the fetal murine otocyst to investigate viral tropism in the developing inner ear. For the first time we have characterized viral tropism for supporting cells following in utero delivery to their progenitors. We report the inner ear tropism and potential ototoxicity of three previously untested vectors: early-generation adenovirus (Ad5.CMV.GFP), advanced-generation adenovirus (Adf.11D) and bovine adeno-associated virus (BAAV.CMV.GFP). Adenovirus showed robust tropism for organ of Corti supporting cells throughout the cochlea but induced increased ABR thresholds indicating ototoxicity. BAAV also showed tropism for organ of Corti supporting cells, with preferential transduction toward the cochlear apex. Additionally, BAAV readily transduced spiral ganglion neurons. Importantly, the BAAV-injected ears exhibited normal hearing at 5 weeks of age when compared to non-injected ears. Our results support the use of BAAV for safe and efficient targeting of supporting cell progenitors in the developing murine inner ear. (C) 2011 Elsevier B.V. All rights reserved. C1 [Sheffield, Abraham M.; Hildebrand, Michael S.; Newton, Stephen S.; Smith, Richard J. H.] Univ Iowa, Dept Otolaryngol, Iowa City, IA 52242 USA. [Gubbels, Samuel P.] Univ Wisconsin, Dept Surg, Div Otolaryngol, Madison, WI USA. [Chiorini, John A.; Di Pasquale, Giovanni] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Smith, RJH (reprint author), Univ Iowa, Dept Otolaryngol, Iowa City, IA 52242 USA. EM richard-smith@uiowa.edu OI Hildebrand, Michael/0000-0003-2739-0515 FU NIH - NIDCD [DC003544]; Royal National Institute for Deaf People (RJHS); NIH-NCRR-CTSA [1UL1RR025011] FX We would like to acknowledge Dr. Douglas Brough (GenVec Inc., Gaithersburg, MD, USA) for providing the Adf.11D vector as well as valuable discussion; The University of Iowa Gene Transfer Vector Core for preparation of Ad5.CMV.GFP; Dr. Marlan Hansen (U. of Iowa, Iowa City, IA, USA) for assistance with images and cochlear dissections; Penny Harding (U. of Iowa, Iowa City, IA, USA) for cryosectioning cochleae. No researchers involved in this study report a conflict of interest. This research was supported in part by grants from the NIH - NIDCD (DC003544) and The Royal National Institute for Deaf People (RJHS). SPG is supported by NIH-NCRR-CTSA 1UL1RR025011 (PI-Marc K. Drezner, MD). NR 61 TC 8 Z9 8 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUL PY 2011 VL 277 IS 1-2 BP 28 EP 36 DI 10.1016/j.heares.2011.03.016 PG 9 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 805KZ UT WOS:000293726600004 PM 21530627 ER PT J AU Olulade, O Hu, S Gonzalez-Castillo, J Tamer, GG Luh, WM Ulmer, JL Talavage, TM AF Olulade, O. Hu, S. Gonzalez-Castillo, J. Tamer, G. G., Jr. Luh, W. -M. Ulmer, J. L. Talavage, T. M. TI Assessment of temporal state-dependent interactions between auditory fMRI responses to desired and undesired acoustic sources SO HEARING RESEARCH LA English DT Article ID EVENT-RELATED FMRI; FUNCTIONAL MRI; HEMODYNAMIC-RESPONSES; BOLD RESPONSE; HUMAN BRAIN; VOLUME MEASUREMENT; CORTICAL AREAS; GRADIENT NOISE; SCANNER NOISE; CORTEX AB A confounding factor in auditory functional magnetic resonance imaging (fMRI) experiments is the presence of the acoustic noise inherently associated with the echo planar imaging acquisition technique. Previous studies have demonstrated that this noise can induce unwanted neuronal responses that can mask stimulus-induced responses. Similarly, activation accumulated over multiple stimuli has been demonstrated to elevate the baseline, thus reducing the dynamic range available for subsequent responses. To best evaluate responses to auditory stimuli, it is necessary to account for the presence of all recent acoustic stimulation, beginning with an understanding of the attenuating effects brought about by interaction between and among induced unwanted neuronal responses, and responses to desired auditory stimuli. This study focuses on the characterization of the duration of this temporal memory and qualitative assessment of the associated response attenuation. Two experimental parameters - inter-stimulus interval (ISI) and repetition time (TR) - were varied during an fMRI experiment in which participants were asked to passively attend to an auditory stimulus. Results present evidence of a state-dependent interaction between induced responses. As expected, attenuating effects of these interactions become less significant as TR and ISI increase and in contrast to previous work, persist up to 18s after a stimulus presentation. (C) 2011 Elsevier B.V. All rights reserved. C1 [Olulade, O.; Talavage, T. M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. [Olulade, O.] Georgetown Univ, Med Ctr, Ctr Study Learning, Washington, DC 20007 USA. [Hu, S.] USA, Res Lab, Adelphi, MD USA. [Gonzalez-Castillo, J.; Tamer, G. G., Jr.; Talavage, T. M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Luh, W. -M.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. [Ulmer, J. L.] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. RP Olulade, O (reprint author), Purdue Univ, Sch Elect & Comp Engn, EE Bldg,465 Northwestern Ave, W Lafayette, IN 47907 USA. EM oao24@georgetown.edu; shuowen.hu@us.army.mil; javier.gonzalez-castillo@nih.gov; gtamer@purdue.edu; luhw@mail.nih.gov; julmer@mcw.edu; tmt@ecn.purdue.edu RI Gonzalez-Castillo, Javier/B-6903-2012; OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU NIH [R01EB003990]; National Institute of Mental Health FX The authors wish to thank Dr. Robert W. Prost and Cathy S. Marszalkowski for their assistance in the execution of this project. This research was supported in part by NIH grant R01EB003990 and the Intramural Research Program of the National Institute of Mental Health. NR 57 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUL PY 2011 VL 277 IS 1-2 BP 67 EP 77 DI 10.1016/j.heares.2011.03.008 PG 11 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 805KZ UT WOS:000293726600009 PM 21426929 ER PT J AU Rahman, MM Antani, SK Thoma, GR AF Rahman, Md Mahmudur Antani, Sameer K. Thoma, George R. TI A Learning-Based Similarity Fusion and Filtering Approach for Biomedical Image Retrieval Using SVM Classification and Relevance Feedback SO IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE LA English DT Article DE Classification; classifier combination; content-based image retrieval (CBIR); medical imaging; relevance feedback (RF); similarity fusion ID MEDICAL APPLICATIONS; CLASSIFIERS AB This paper presents a classification-driven biomedical image retrieval framework based on image filtering and similarity fusion by employing supervised learning techniques. In this framework, the probabilistic outputs of a multiclass support vector machine (SVM) classifier as category prediction of query and database images are exploited at first to filter out irrelevant images, thereby reducing the search space for similarity matching. Images are classified at a global level according to their modalities based on different low-level, concept, and keypoint-based features. It is difficult to find a unique feature to compare images effectively for all types of queries. Hence, a query-specific adaptive linear combination of similarity matching approach is proposed by relying on the image classification and feedback information from users. Based on the prediction of a query image category, individual pre-computed weights of different features are adjusted online. The prediction of the classifier may be inaccurate in some cases and a user might have a different semantic interpretation about retrieved images. Hence, the weights are finally determined by considering both precision and rank order information of each individual feature representation by considering top retrieved relevant images as judged by the users. As a result, the system can adapt itself to individual searches to produce query-specific results. Experiment is performed in a diverse collection of 5 000 biomedical images of different modalities, body parts, and orientations. It demonstrates the efficiency (about half computation time compared to search on entire collection) and effectiveness (about 10%-15% improvement in precision at each recall level) of the retrieval approach. C1 [Rahman, Md Mahmudur; Antani, Sameer K.; Thoma, George R.] NIH, US Natl Lib Med, Bethesda, MD 20892 USA. RP Rahman, MM (reprint author), NIH, US Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM rahmanmm@mail.nih.gov; santani@mail.nih.gov; gthoma@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX Manuscript received August 23, 2010; revised December 23, 2010; accepted March 30, 2011. Date of publication June 16, 2011; date of current version July 15, 2011. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). NR 33 TC 43 Z9 46 U1 0 U2 13 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1089-7771 J9 IEEE T INF TECHNOL B JI IEEE T. Inf. Technol. Biomed. PD JUL PY 2011 VL 15 IS 4 BP 640 EP 646 DI 10.1109/TITB.2011.2151258 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA 804NK UT WOS:000293660300018 PM 21690019 ER PT J AU Ssebugenyi, I Kizza, A Mpoza, B Aluma, G Boaz, I Newell, K Laeyendecker, O Shott, JP Serwadda, D Reynolds, SJ AF Ssebugenyi, I. Kizza, A. Mpoza, B. Aluma, G. Boaz, I. Newell, K. Laeyendecker, O. Shott, J. P. Serwadda, D. Reynolds, S. J. TI Comparison of the Abbott m2000 HIV-1 Real-Time and Roche AMPLICOR Monitor v1.5 HIV-1 assays on plasma specimens from Rakai, Uganda SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV-1; viral load; antiretroviral treatment; monitoring; resource-limited; realtime polymerase chain reaction ID ANTIRETROVIRAL TREATMENT FAILURE; COBAS-TAQMAN; SOUTH-AFRICA; GROUP-O; PERFORMANCE; VIRUS; CRITERIA; SUBTYPES; RNA AB The need for viral load (VL) monitoring of HIV patients receiving antiretroviral therapy (ART) in resource-limited settings (RLS) has become apparent with studies showing the limitations of immunological monitoring. We compared the Abbott m2000 Real-Time (Abbott) HIV-1 assay with the Roche AMPLICOR Monitor v1.5 (Roche) HIV-1 assay over a range of VL concentrations. Three hundred and eleven plasma samples were tested, including 164 samples from patients on ART >= six months and 147 from ART-naive patients. The Roche assay detected >= 400 copies/mL in 158 (50.8%) samples. Of these, Abbott produced 145 (91.8%) detectable results >= 400 copies/mL; 13 (8.2%) samples produced discrepant results. Concordance between the assays for detecting HIV-1 RNA >= 400 copies/mL was 95.8% (298/311). The sensitivity, specificity, positive predictive value and negative predictive value of Abbott to detect HIV-1 RNA >= 400 copies/mL were 91.8%, 100%, 100% and 92.2%, respectively. For the 151 samples with HIV-1 RNA >= 400 copies/mL for both assays, a good linear correlation was found (r = 0.81, P < 0.0001; mean difference, 0.05). The limits of agreement were -0.97 and 1.07 log(10) copies/mL (mean +/- 2 SD). The Abbott assay performed well in our setting, offering an alternative methodology for HIV-1 VL for laboratories with realtime polymerase chain reaction (PCR) capacity. C1 [Ssebugenyi, I.; Kizza, A.; Mpoza, B.; Aluma, G.; Boaz, I.] Rakai Hlth Sci Program, Kalisizo, Rakai, Uganda. [Newell, K.; Shott, J. P.] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Newell, K.; Laeyendecker, O.; Shott, J. P.; Reynolds, S. J.] NIAID, NIH, Bethesda, MD 20892 USA. [Laeyendecker, O.; Reynolds, S. J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Serwadda, D.] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Reynolds, SJ (reprint author), US Embassy Kampala, POB 7007, Kampala, Uganda. EM sjr@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors would like to thank Abbott Molecular Inc for providing the instruments, assay reagents and supplies to support this study. The study was supported through the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 12 TC 6 Z9 6 U1 0 U2 0 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD JUL PY 2011 VL 22 IS 7 BP 373 EP 375 DI 10.1258/ijsa.2009.009526 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 797AX UT WOS:000293095700004 PM 21729954 ER PT J AU Sica, A Melillo, G Varesio, L AF Sica, Antonio Melillo, Giovanni Varesio, Luigi TI Hypoxia: a double-edged sword of immunity SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Review DE Hypoxia; Innate immunity; Adaptive immunity ID NF-KAPPA-B; INDUCIBLE FACTOR-1-ALPHA; TUMOR PROGRESSION; DENDRITIC CELLS; OXYGEN HOMEOSTASIS; ENDOTHELIAL-CELLS; SUPPRESSOR-CELLS; EPITHELIAL-CELLS; GENE-EXPRESSION; INNATE IMMUNITY AB Hypoxia is a condition of low oxygen tension that characterizes virtually every site of inflammation, tissue damage, and neoplasia. Hypoxic environment attracts infiltrating immune cells that move against oxygen gradients and respond to these demanding conditions by switching to anaerobic metabolism to maintain their energy requirements. Several lines of evidence suggest that oxygen deprivation causes opposite effects on the innate or adaptive immune responses. We will review the evidence that the hypoxic environment promotes the recruitment, activation, and survival of innate immune cells while inhibiting the adaptive immunity through downregulation of effector lymphocyte functions. This divergent regulation of the innate and adaptive immunity appears to reflect evolutionary mechanisms aimed to both guarantee tissue homeostasis and provide safeguard mechanisms against autoimmunity. Selective inhibition of hypoxic signaling pathways in myeloid versus lymphoid cells may open new therapeutic opportunities in diseases characterized by low oxygen tension. C1 [Sica, Antonio] IRCCS, Ist Clin Humanitas, I-20089 Milan, Italy. [Sica, Antonio] Univ Piemonte, DISCAFF, I-28100 Novara, Italy. [Melillo, Giovanni] NCI, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Varesio, Luigi] G Gaslini Inst Children, Mol Biol Lab, Genoa, Italy. RP Sica, A (reprint author), IRCCS, Ist Clin Humanitas, Italy Via Manzoni 56, I-20089 Milan, Italy. EM antonio.sica@humanitas.it RI varesio, luigi/J-8261-2016 OI varesio, luigi/0000-0001-5659-2218 FU Associazione Italiana Ricerca sul Cancro (AIRC), Italy; Fondazione Berlucchi, Italy; European Commission; Ministero Universita Ricerca (MUR), Italy; Associazione Italiana Glicogenosi; Fondazione Italiana per la lotta al neuroblastoma; Ministero della Salute; Regione Piemonte [331] FX This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Italy; Fondazione Berlucchi, Italy; European Commission (project Mugen); Ministero Universita Ricerca (MUR), Italy; Associazione Italiana Glicogenosi; Fondazione Italiana per la lotta al neuroblastoma; and Ministero della Salute and by Regione Piemonte (project number 331, August 8th, 2009). NR 97 TC 28 Z9 30 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 J9 J MOL MED JI J. Mol. Med. PD JUL PY 2011 VL 89 IS 7 BP 657 EP 665 DI 10.1007/s00109-011-0724-8 PG 9 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 804FG UT WOS:000293639100004 PM 21336851 ER PT J AU Grefsheim, SF LaBeause, JH Satterthwaite, RK AF Grefsheim, Suzanne F. LaBeause, Jan H. Satterthwaite, Rebecca K. TI Jocelyn Anne Rankin, PhD, FMLA, 1946-2010 OBITUARY SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Biographical-Item C1 [Grefsheim, Suzanne F.] NIH, Div Lib Serv, Off Res Serv, Bethesda, MD 20892 USA. [LaBeause, Jan H.] Mercer Univ, Sch Med, Med Lib, Macon, GA 31207 USA. [LaBeause, Jan H.] Mercer Univ, Sch Med, Peyton T Anderson Learning Resources Ctr, Macon, GA 31207 USA. [Satterthwaite, Rebecca K.] Ctr Dis Control & Prevent, TechSoft Grp, Atlanta, GA 30333 USA. RP Grefsheim, SF (reprint author), NIH, Div Lib Serv, Off Res Serv, 10 Ctr Dr, Bethesda, MD 20892 USA. EM grefshes@mail.nih.gov; labeause_j@mercer.edu; bus8@cdc.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD JUL PY 2011 VL 99 IS 3 BP 183 EP 184 DI 10.3163/1536-5050.99.3.002 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 801ND UT WOS:000293445700002 PM 21874675 ER PT J AU Cooper, ID AF Cooper, I. Diane TI Is the informationist a new role? A logic model analysis SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Editorial Material ID MEDICAL LIBRARIAN C1 NIH, NIH Lib, Bethesda, MD 20892 USA. RP Cooper, ID (reprint author), NIH, NIH Lib, 10 Ctr Dr,Room 1L09H,MSC 1150, Bethesda, MD 20892 USA. EM cooperd@mail.nih.gov RI Cooper, Diane/G-5826-2011 NR 13 TC 2 Z9 3 U1 2 U2 9 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD JUL PY 2011 VL 99 IS 3 BP 189 EP 192 DI 10.3163/1536-5050.99.3.004 PG 4 WC Information Science & Library Science SC Information Science & Library Science GA 801ND UT WOS:000293445700004 PM 21753909 ER PT J AU Ananias, HJK Yu, ZL Dierckx, RA van der Wiele, C Helfrich, W Wang, F Tan, YJ Chen, XY de Jong, IJ Elsinga, PH AF Ananias, Hildo J. K. Yu, Zilin Dierckx, Rudi A. van der Wiele, Christophe Helfrich, Wijnand Wang, Fan Tan, Yongjun Chen, Xiaoyuan de Jong, Igle J. Elsinga, Philip H. TI (99m)Technetium-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) as a Targeted Imaging Agent with MicroSPECT in a PC-3 Prostate Cancer Xenograft Model SO MOLECULAR PHARMACEUTICS LA English DT Article DE bombesin; prostate; cancer; imaging; SPECT; microSPECT; GRPR; GRP ID GASTRIN-RELEASING-PEPTIDE; RADIOLABELED BOMBESIN ANALOGS; PELVIC LYMPH-NODES; RECEPTOR ANTAGONIST; POSITIVE TUMORS; BONE METASTASES; IN-VITRO; GRP; RADIOPHARMACEUTICALS; DIAGNOSIS AB The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical (99m)technetium-HYNIC(tricine/TPPTS)-Aca-BN(7-14) (Tc-99m-HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for human prostate cancer in athymic mice. Tc-99m-HABN was synthesized, and its lipophilicity and stability were investigated. The IC50, internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. Tc-99m-HABN biodistribution and microSPECT imaging were performed in PC-3 tumor-bearing athymic mice. Tc-99m-HABN was prepared with high labeling yield (>90%), hip radiochemical purity (>95%) and a specific activity of similar to 19.8 MBq/nmol. The partition coefficient log D value was -1.60 +/- 0.06. Tc-99m-HABN proved to be stable in human serum for 6 h. The IC50 of HYNIC-Aca-BN(7-14) was 12.81 +/- 0.14 nM. Incubation of PC-3 cells with Tc-99m-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with Tc-99m-HABN, the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24 +/- 0.64% ID/g after 30 min, with a steady decrease during the 4 h study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. Tc-99m-HABN microSPECT imaging resulted in clear delineation of the tumor. Tc-99m-HABN is a novel BN-based radiopharmaceutical that proved to be suitable for targeted imaging of prostate cancer with microSPECT using the human prostate cancer cell line PC-3 in a xenograft mouse model. C1 [Ananias, Hildo J. K.; de Jong, Igle J.] Univ Groningen, Univ Med Ctr Groningen, Dept Urol, NL-9713 AV Groningen, Netherlands. [Yu, Zilin; Dierckx, Rudi A.; Elsinga, Philip H.] Univ Groningen, Univ Med Ctr Groningen, Dept Nucl Med & Mol Imaging, NL-9713 AV Groningen, Netherlands. [van der Wiele, Christophe] Ghent Univ Hosp, Dept Nucl Med, B-9000 Ghent, Belgium. [Helfrich, Wijnand] Univ Groningen, Univ Med Ctr Groningen, Surg Res Lab, NL-9713 AV Groningen, Netherlands. [Wang, Fan] Peking Univ, Med Isotopes Res Ctr, Beijing, Peoples R China. [Tan, Yongjun; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Ananias, HJK (reprint author), Hanzeplein 1, NL-9712 RB Groningen, Netherlands. EM h.j.k.ananias@uro.umcg.nl FU Dutch Cancer Society [KWF 2008-4243]; Dutch Urology Foundation; Jan Kornelis de Cock Stichting [08-02] FX We thank Jurgen Sijbesma for his assistance with the animal experiments and Chao Wu for his assistance with the micro-SPECT imaging and image reconstruction. This work was supported by grants of the Dutch Cancer Society (KWF 2008-4243), the Dutch Urology Foundation 1973 (Stichting Urologie 1973) and the Jan Kornelis de Cock Stichting (J.K. de Cock Stichting 08-02). NR 53 TC 18 Z9 18 U1 0 U2 6 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 JUL-AUG PY 2011 VL 8 IS 4 SI SI BP 1165 EP 1173 DI 10.1021/mp200014h PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 799SW UT WOS:000293307400019 PM 21699202 ER PT J AU Zhou, Y Kim, YS Yan, X Jacobson, O Chen, XY Liu, S AF Zhou, Yang Kim, Young-Seung Yan, Xin Jacobson, Orit Chen, Xiaoyuan Liu, Shuang TI Cu-64-Labeled Lissamine Rhodamine B: A Promising PET Radiotracer Targeting Tumor Mitochondria SO MOLECULAR PHARMACEUTICS LA English DT Article DE Cu-64 PET radiotracers; mitochondrial potential; tumor imaging ID IN-VIVO; IMAGING AGENTS; TRIPHENYLPHOSPHONIUM CATIONS; LIPOPHILIC CATIONS; PEG(4) LINKERS; BRAIN-TUMOR; RGD PEPTIDE; CELLS; PROBE; DERIVATIVES AB Enhanced mitochondrial potential in carcinoma cells is an important characteristic of cancer. It is of great current interest to develop a radiotracer that is sensitive to mitochondrial potential changes at the early stage of tumor growth. In this report, we present the synthesis and evaluation of Cu-64-labeled Lissamine rhodamine B (LRB), Cu-64(DOTA-LRB) (DOTA-LRB = 2-(6-(diethylamino)-3-(diethyliminio)-3H-xanthen-9-yl)-5-(N-(2-(2-(4,7,10-tris(carb oxym ethyl)- 1,4,7,10-tetraazacyclo-dodecan-1-yl)acetamido)ethyl)sulfamoyl)benzenesulfonate) as a new radiotracer for imaging tumors in athymic nude mice bearing U87MG human glioma xenografts by positron emission tomography (PET). We also explored its localization mechanism using Cu(DOTA-LRB) as the fluorescent probe in both the U87MG human glioma cell line and the cultured primary U87MG glioma cells. It was found that Cu-64(DOTA-LRB) had the highest tumor uptake (6.54 +/- 1.50, 6.91 +/- 1.26, 5.68 +/- 1.13, 7.58 +/- 1.96, and 5.14 +/- 1.50%ID/g at 0.5, 1, 2, 4, and 24 h postinjection, respectively) among many Cu-64-labeled organic cations evaluated in the same animal model. The cellular staining study indicated that Cu(DOTA-LRB) was able to localize in mitochondria of U87MG glioma cells due to the enhanced negative rnitochondrial potential. This statement is completely supported by the results from decoupling experiment with carbonylcyanide-m-chlorophenylhydrazone (CCCP). MicroPET data showed that the U87MG glioma tumors were clearly visualized as early as 30 min postinjection with Cu-64 (DOTA-LRB). Cu-64(DOTA-LRB) remained stable during renal excretion, but underwent extensive degradation during hepatobiliary excretion. On the basis of the results from this study, it was concluded that Cu-64(DOTA-LRB) represents a new class of promising PET radiotracers for noninvasive imaging of the MDR-negative tumors. C1 [Zhou, Yang; Kim, Young-Seung; Yan, Xin; Liu, Shuang] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Jacobson, Orit; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD USA. RP Liu, S (reprint author), Purdue Univ, Sch Hlth Sci, 550 Stadium Mall Dr, W Lafayette, IN 47907 USA. EM liu100@purdue.edu FU Purdue University; National Cancer Institute (NCI) [R01 CA115883] FX This work is supported, in part, by Purdue University and Research Grant R01 CA115883 from the National Cancer Institute (NCI). NR 61 TC 13 Z9 13 U1 1 U2 18 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 JUL-AUG PY 2011 VL 8 IS 4 SI SI BP 1198 EP 1208 DI 10.1021/mp200025m PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 799SW UT WOS:000293307400022 PM 21545131 ER PT J AU Navath, RS Menjoge, AR Dai, H Romero, R Kannan, S Kannan, RM AF Navath, Raghavendra S. Menjoge, Anupa R. Dai, Hui Romero, Roberto Kannan, Sujatha Kannan, Rangararnanujam M. TI Injectable PAMAM Dendrimer-PEG Hydrogels for the Treatment of Genital Infections: Formulation and in Vitro and in Vivo Evaluation SO MOLECULAR PHARMACEUTICS LA English DT Article DE injectable hydrogels; biodegradable hydrogel; sustained release of amoxicillin; pregnant guinea pig model; pregnancy; treatment of genital infections; formulation; in vitro and in vivo evaluation ID SEXUALLY-TRANSMITTED INFECTIONS; REPRODUCTIVE-TRACT SECRETIONS; DRUG-DELIVERY APPLICATIONS; GUINEA-PIG MODEL; POLYAMIDOAMINE DENDRIMER; MECHANISTIC INVESTIGATIONS; POLY(ETHYLENE GLYCOL); BACTERIAL VAGINOSIS; CHORIOAMNIONITIS; RELEASE AB Local intravaginal drug therapy is preferred for treatment of ascending genital infections during pregnancy. In the present study, an in situ forming biodegradable hydrogel for sustained release of amoxicillin in the cervicovaginal region is described. A generation 4 poly(amidoamine) [G4-(NH(2))(64)] dendrimer with peripheral thiopyridyl terminations is crosslinked with 8-arm polyethylene glycol (PEG) bearing thiol terminations. The hydrogels were formulated and tested in vivo in a pregnant guinea pig model for volume, retention times, biodegradation, tolerability and transport across fetal membrane. The physicochemical characterization of the hydrogels was carried out using differential calorimetry, SEM, and confocal imaging. The hydrogels offer antibacterial activity arising from sustained release of amoxicillin from gels. The in vivo studies in guinea pig showed that 100-200 mu L, of gel sufficiently covered the cervicovaginal region with a residence time of at least 72 h and gel was primarily retained in the maternal tissues without crossing the fetal membranes into the fetus. The dendrimer gels were stable up to 72 h, and the in vivo biodegradation of gel occurred after 72 h; this correlated well with the in vitro degradation pattern. The pH of the vagina was not altered upon application of the gel, and none of the animals aborted up to 72 h after application of gel. The histological evaluation of the cervical tissues showed absence of edema in the epithelial cell layer, no sloughing of the epithelial or superficial mucous layer, and absence of necrosis and infiltration of inflammatory cells in the submucosal layers, confirming that tissues were tolerant to the gel. The immunohistofluorescence images showed the localization of the gel components on the superficial mucified epithelial layer. The cross-linking density and swelling of hydrogels was impacted by the polymer content, and the 10% hydrogels exhibited the highest cross-link density. The in vitro drug release studies carried out using Franz diffusion cells showed that amoxicillin release from 6 and 10% gels was sustained for 240 h as compared to 3% gels. As the polymer concentration increased to 10%, the release pattern from gels approached diffusion controlled mechanism with diffusional exponent n = 0.49. In conclusion, the biodegradable in situ forming hydrogels of the present study offer a therapeutic option to provide sustained localized delivery of amoxillin intracervically to the pregnant woman for the treatment of ascending genital infections. C1 [Navath, Raghavendra S.; Menjoge, Anupa R.; Kannan, Rangararnanujam M.] Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. [Navath, Raghavendra S.; Menjoge, Anupa R.; Kannan, Rangararnanujam M.] Wayne State Univ, Dept Biomed Engn, Detroit, MI 48202 USA. [Navath, Raghavendra S.; Menjoge, Anupa R.; Dai, Hui; Romero, Roberto; Kannan, Sujatha; Kannan, Rangararnanujam M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI 48201 USA. [Navath, Raghavendra S.; Menjoge, Anupa R.; Dai, Hui; Romero, Roberto; Kannan, Sujatha; Kannan, Rangararnanujam M.] Dept Hlth & Human Serv, Detroit, MI 48201 USA. [Dai, Hui; Kannan, Sujatha] Wayne State Univ, Childrens Hosp Michigan, Dept Pediat Crit Care Med, Detroit, MI 48201 USA. RP Kannan, RM (reprint author), Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. EM rkannan.wsu@gmail.com FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS) FX This research was supported by the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS). We would like to thank Dr. Mihai Manitiu for his help with SEM images, Dr. Bing Wang for help with animal experiments and Dr. C. J. Kim for the histopathological evaluations of the tissues. NR 65 TC 42 Z9 42 U1 2 U2 84 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 JUL-AUG PY 2011 VL 8 IS 4 SI SI BP 1209 EP 1223 DI 10.1021/mp200027z PG 15 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 799SW UT WOS:000293307400023 PM 21615144 ER PT J AU Shukla, S Skoumbourdis, AP Walsh, MJ Hartz, AMS Fung, KL Wu, CP Gottesman, MM Bauer, B Thomas, CJ Ambudkar, SV AF Shukla, Suneet Skoumbourdis, Amanda P. Walsh, Martin J. Hartz, Anika M. S. Fung, King Leung Wu, Chung-Pu Gottesman, Michael M. Bauer, Bjoern Thomas, Craig J. Ambudkar, Suresh V. TI Synthesis and Characterization of a BODIPY Conjugate of the BCR-ABL Kinase Inhibitor Tasigna (Nilotinib): Evidence for Transport of Tasigna and Its Fluorescent Derivative by ABC Drug Transporters SO MOLECULAR PHARMACEUTICS LA English DT Article DE ABC transporter; ABCG2; BCR-ABL kinase; multidrug resistance; P-glycoprotein; Tasigna ID CHRONIC MYELOID-LEUKEMIA; BLOOD-BRAIN-BARRIER; CHRONIC MYELOGENOUS LEUKEMIA; REVERSES MULTIDRUG-RESISTANCE; HIGH-AFFINITY INTERACTION; HEMATOPOIETIC STEM-CELLS; HUMAN P-GLYCOPROTEIN; IMATINIB MESYLATE; TYROSINE KINASE; IN-VIVO AB Tasigna (Nilotinib) is a BCR-ABL kinase inhibitor recently approved by the Food and Drug Administration, which is indicated for the treatment of drug-resistant chronic myelogenous leukemia (CML). The efflux of tyrosine kinase inhibitors by ATP-binding cassette (ABC) drug transporters, which actively pump these drugs out of cells utilizing ATP as an energy source, has been linked to the development of drug resistance in CML patients. We report here the synthesis and characterization of a fluorescent derivative of Tasigna to study its interaction with two major ABC transporters, P-glycoprotein (Pgp) and ABCG2, in in vitro and ex vivo assays. A fluorescent derivative of Tasigna, BODIPY FL Tasigna, inhibited the BCR-ABL kinase activity in K562 cells and was also effluxed by Pgp- and ABCG2-expressing cells in both cultured cells and rat brain capillaries expressing Pgp and ABCG2. In addition, [H-3]-Tasigna was found to be transported by Pgp-expressing polarized LLC-PK1 cells in a transepithelial transport assay. Consistent with these results, both Tasigna and BODIPY FL Tasigna were less effective at inhibiting the phosphorylation of Crkl (a substrate of BCR-ABL kinase) in Pgp- and ABCG2-expressing K562 cells due to their reduced intracellular concentration. Taken together, these data provide evidence that BODIPY FL Tasigna is transported by Pgp and ABCG2, and Tasigna is transported by Pgp. Further, we propose that BODIPY FL Tasigna can potentially be used as a probe for functional analysis of Pgp and ABCG2 in cancer cells and in other preclinical studies. C1 [Shukla, Suneet; Fung, King Leung; Wu, Chung-Pu; Gottesman, Michael M.; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Skoumbourdis, Amanda P.; Walsh, Martin J.; Thomas, Craig J.] NIH, Chem Genom Ctr, Rockville, MD 20850 USA. [Hartz, Anika M. S.] Univ Minnesota, Sch Med, Dept Biochem & Mol Biochem, Duluth, MN 55812 USA. [Hartz, Anika M. S.] Univ Minnesota, Coll Pharm, Dept Pharmaceut Sci, Duluth, MN 55812 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI shukla, suneet/B-4626-2012 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. We thank Dr. Krishnamachary Nandigama for providing Pgp-expressing High-five insect cell crude membranes, Anne Ramsey for help in kinase assays, and George Leiman for editorial assistance. NR 53 TC 20 Z9 20 U1 2 U2 15 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 JUL-AUG PY 2011 VL 8 IS 4 SI SI BP 1292 EP 1302 DI 10.1021/mp2001022 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 799SW UT WOS:000293307400031 PM 21630681 ER PT J AU Djamshidian, A O'Sullivan, SS Wittmann, BC Lees, AJ Averbeck, BB AF Djamshidian, Atbin O'Sullivan, Sean S. Wittmann, Bianca C. Lees, Andrew J. Averbeck, Bruno B. TI Novelty seeking behaviour in Parkinson's disease SO NEUROPSYCHOLOGIA LA English DT Article DE Impulsive compulsive behaviour; Parkinson's disease; Novelty seeking; Learning; Dopamine ID STRIATAL DOPAMINE RELEASE; IMPULSE-CONTROL; COMPULSIVE BEHAVIORS; DRUG-USE; MECHANISMS; DISORDERS; COCAINE; HUMANS; MEMORY; RISK AB Novelty seeking can be a positive trait leading to creativity and innovation, but it is also related to increased risk of damaging addictive behaviour. We have assessed novelty seeking with a three armed bandit task, in which novel stimuli were occasionally introduced, replacing choice options from which the participants had been choosing. This allowed us to assess whether or not they would be prone to selecting novel stimuli. We tested 25 non impulsive patients with Parkinson's disease (PD) and 27 PD patients with impulsive compulsive behaviours (ICBs). Both patient groups were examined "on" and "off" dopaminergic medication in a counterbalanced order and their behaviour was compared with 24 healthy controls. We found that PD patients with ICBs were significantly more prone to choose novel options than either non impulsive PD patients or controls, regardless of medication status. Our findings suggest that attraction to novelty is a personality trait in all PD patients with ICBs which is independent of medication status. Published by Elsevier Ltd. C1 [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Djamshidian, Atbin; O'Sullivan, Sean S.; Lees, Andrew J.] Univ London, Dept Mol Neurosci, London, England. [Djamshidian, Atbin; O'Sullivan, Sean S.; Lees, Andrew J.] Univ London, Reta Lila Weston Inst Neurol Studies, London, England. [Wittmann, Bianca C.] Univ Giessen, Dept Psychol, Giessen, Germany. [Averbeck, Bruno B.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov RI O'Sullivan, Sean/C-9333-2012; Lees, Andrew/A-6605-2009; OI O'Sullivan, Sean/0000-0002-0583-7956; Djamshidian, Atbin/0000-0001-7174-6000; Wittmann, Bianca/0000-0002-2583-3311 FU NIH, NIMH FX The authors wish to thank the patients and families who participated in the study. This research was supported in part by the Intramural Research Program of the NIH, NIMH. NR 42 TC 25 Z9 25 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUL PY 2011 VL 49 IS 9 BP 2483 EP 2488 DI 10.1016/j.neuropsychologia.2011.04.026 PG 6 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 803WA UT WOS:000293611600022 PM 21565210 ER PT J AU McCann, TE Kosaka, N Turkbey, B Mitsunaga, M Choyke, PL Kobayashi, H AF McCann, Thomas E. Kosaka, Nobuyuki Turkbey, Baris Mitsunaga, Makoto Choyke, Peter L. Kobayashi, Hisataka TI Molecular imaging of tumor invasion and metastases: the role of MRI SO NMR IN BIOMEDICINE LA English DT Review DE cancer; invasion; metastasis; molecular imaging; MRI; PET; optical imaging ID SUPERPARAMAGNETIC IRON-OXIDE; CELL-PENETRATING PEPTIDES; MAGNETIC RESONANCE LYMPHANGIOGRAPHY; MATRIX-METALLOPROTEINASE ACTIVITY; OPTICAL PROTEOLYTIC BEACONS; LYMPH-NODE METASTASES; WHOLE-BODY MRI; IN-VIVO; CONTRAST AGENT; BONE METASTASES AB The processes of tumor invasion and metastasis have been well characterized at the molecular level, and numerous biomarkers of tumor aggressiveness have been discovered. Molecular imaging offers the opportunity to depict specific cell markers relevant to tumor aggressiveness. Here, we describe the role of MRI in identifying tumor invasiveness and metastasis with reference to other methods. Target-specific molecular imaging probes for tumor invasiveness have been developed for positron emission tomography and optical imaging, but progress in MRI has been slower. For example, proteases associated with tumor invasion, such as specific matrix metalloproteinases or cathepsins, can be targeted in vivo using optical and positron emission tomography methods, but have not yet been successful with MRI. In addition, we describe the use of MRI to detect metastases. Novel MR contrast agents based on iron oxide and dendrimer nanomaterials allow for better characterization of tumor metastases. Organ-specific MR contrast agents are used to identify metastatic disease in the liver. Finally, diffusion-weighted whole-body MRI is discussed as an alternative offered by MRI that does not require the use of molecular probes to screen distant metastases. Published in 2010 by John Wiley & Sons, Ltd. C1 [McCann, Thomas E.; Kosaka, Nobuyuki; Turkbey, Baris; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. FU National Institutes of Health (NIH); Pfizer Inc.; Center for Cancer Research, NCI/NIH FX This research year was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI/NIH. NR 52 TC 13 Z9 13 U1 1 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD JUL PY 2011 VL 24 IS 6 SI SI BP 561 EP 568 DI 10.1002/nbm.1590 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 806LE UT WOS:000293808500002 PM 21793070 ER PT J AU Ching, W Luhmann, M AF Ching, Willie Luhmann, Melissa TI Neuro-Oncologic Physical Therapy for the Older Person SO TOPICS IN GERIATRIC REHABILITATION LA English DT Article DE brain metastases; brain tumor; neuro-oncology; physical therapy; rehabilitation; spinal cord tumor ID SPINAL-CORD COMPRESSION; BRAIN METASTASES; RADIATION-THERAPY; CANCER-PATIENTS; REHABILITATION; TUMORS; FATIGUE; GLIOBLASTOMA; INSTRUMENT; GUIDELINES AB Because of the uncertainty of the course of diagnoses, patients with neuro-oncological malignancies present challenges to the physical therapist. At times, the presentation of impairments and disabilities of these patients with neuro-oncological diagnoses do not necessarily coincide with the involved area of the brain or spinal cord. It is our intention to provide guidance to the physical therapist who will be working with these patients with neuro-oncological diagnoses, in hopes that their encounters will be more productive and meaningful. This article describes a brief overview of common central nervous system malignancies, its medical treatment, as well as possible complications and adverse effects that would need to be considered in rehabilitating these patients. Special consideration is given to the elderly patients with neuro-oncological diagnoses. Pertinent physical therapy assessments and interventions are discussed. C1 [Ching, Willie; Luhmann, Melissa] NIH, Dept Hlth & Human Serv, Mark O Hatfield Clin Res Ctr, Rehabil Med Dept,Phys Therapy Sect, Bethesda, MD 20892 USA. RP Ching, W (reprint author), NIH, Dept Hlth & Human Serv, Mark O Hatfield Clin Res Ctr, Rehabil Med Dept,Phys Therapy Sect, Bethesda, MD 20892 USA. EM chingw@mail.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 56 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0882-7524 EI 1550-2414 J9 TOP GERIATR REHABIL JI Top. Geriatr. Rehabil. PD JUL-SEP PY 2011 VL 27 IS 3 BP 184 EP 192 DI 10.1097/TGR.0b013e3182198f25 PG 9 WC Gerontology; Rehabilitation SC Geriatrics & Gerontology; Rehabilitation GA 802IQ UT WOS:000293503600005 PM 22049262 ER PT J AU Stout, NL Levy, E Pfalzer, L AF Stout, Nicole L. Levy, Ellen Pfalzer, Lucinda TI Upper Quadrant Impairments Associated With Cancer Treatment SO TOPICS IN GERIATRIC REHABILITATION LA English DT Article DE cancer rehabilitation; upper quadrant dysfunction ID LYMPH-NODE BIOPSY; QUALITY-OF-LIFE; MODIFIED RADICAL-MASTECTOMY; ACCESSORY NERVE PALSY; PRIMARY BREAST-CANCER; AXILLARY WEB SYNDROME; SHOULDER COMPLAINTS; NECK DISSECTIONS; EARLY-DIAGNOSIS; ARM MORBIDITY AB Cancer treatments commonly compromise a patient's functional mobility. Cancers of the upper body affect use of the upper extremities and incite many impairments of the upper quadrant. Cancer treatments including surgery, chemotherapy, and radiation each have unique side effects and adverse effects that directly and indirectly impact the upper quadrant. Impairments can occur early, during, or immediately after cancer treatment; or late, long after the patient has completed treatment. It is imperative in physical therapy practice that clinicians are knowledgeable about the cancer disease process, cancer treatment, and its short- and long-term effects. This article highlights cancer treatment modalities and their side effects, summarizes the presenting signs and symptoms of upper extremity impairments that the physical therapist should recognize as cancer-related in the Review of Systems, and highlights many upper extremity impairments commonly associated with cancer treatment. C1 [Stout, Nicole L.] Natl Naval Med Ctr, Breast Care Ctr, Bethesda, MD 20889 USA. [Levy, Ellen] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Pfalzer, Lucinda] Univ Michigan, Dept Phys Therapy, Flint, MI 48503 USA. RP Stout, NL (reprint author), Natl Naval Med Ctr, Breast Care Ctr, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM nicole.stout@med.navy.mil NR 93 TC 0 Z9 0 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0882-7524 J9 TOP GERIATR REHABIL JI Top. Geriatr. Rehabil. PD JUL-SEP PY 2011 VL 27 IS 3 BP 222 EP 233 DI 10.1097/TGR.0b013e31821990fb PG 12 WC Gerontology; Rehabilitation SC Geriatrics & Gerontology; Rehabilitation GA 802IQ UT WOS:000293503600009 ER PT J AU Croarkin, E Huang, MH AF Croarkin, Earllaine Huang, Min-Hui TI Screening Balance Deficits in Older Individuals Diagnosed With Cancer SO TOPICS IN GERIATRIC REHABILITATION LA English DT Article DE balance; cancer; falls ID ANDROGEN-DEPRIVATION THERAPY; PARANEOPLASTIC CEREBELLAR DEGENERATION; RECEIVING RADIATION-THERAPY; BODY-COMPOSITION CHANGES; DWELLING ELDERLY-PEOPLE; CENTRAL-NERVOUS-SYSTEM; BREAST-CANCER; PROSTATE-CANCER; RISK-FACTORS; FALL RISK AB Nearly one-third of older adults experience a fall every year. Balance and gait deficits are among the most important risk factors of falls. Cancer and associated interventions used to cure it challenge systems responsible for maintaining balance control. Older individuals diagnosed with cancer are more likely to develop impairments and disability and are at a slightly higher risk of falls. An improved understanding of age-related changes in balance control and increased knowledge of screening tools that identify those at risk for falls can help lower fall risk. C1 [Croarkin, Earllaine] NIH, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20896 USA. [Huang, Min-Hui] Univ Michigan, Phys Therapy Dept, Sch Hlth Profess & Studies, Flint, MI 48503 USA. RP Croarkin, E (reprint author), NIH, Mark O Hatfield Clin Res Ctr, 10 Ctr Dr MSC 1604, Bethesda, MD 20896 USA. EM earllaine_croarkin@nih.gov NR 104 TC 0 Z9 0 U1 6 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0882-7524 J9 TOP GERIATR REHABIL JI Top. Geriatr. Rehabil. PD JUL-SEP PY 2011 VL 27 IS 3 BP 244 EP 251 DI 10.1097/TGR.0b013e318219915a PG 8 WC Gerontology; Rehabilitation SC Geriatrics & Gerontology; Rehabilitation GA 802IQ UT WOS:000293503600011 ER PT J AU Gaitan, MI Shea, CD Evangelou, IE Stone, RD Fenton, KM Bielekova, B Massacesi, L Reich, DS AF Gaitan, Maria I. Shea, Colin D. Evangelou, Iordanis E. Stone, Roger D. Fenton, Kaylan M. Bielekova, Bibiana Massacesi, Luca Reich, Daniel S. TI Evolution of the Blood-Brain Barrier in Newly Forming Multiple Sclerosis Lesions SO ANNALS OF NEUROLOGY LA English DT Article ID GADOLINIUM-ENHANCING LESIONS; MRI; PERFUSION; RING; DTPA; DEMYELINATION; PERMEABILITY; INFLAMMATION; ENHANCEMENT; PATHOLOGY AB Objective: Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood-brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability. Methods: We performed dynamic contrast-enhanced (DCE) MRI in relapsing-remitting MS. We obtained data over 65 minutes, during and after gadolinium injection. We labeled spatiotemporal enhancement dynamics as centrifugal when initially central enhancement expanded outward and centripetal when initially peripheral enhancement gradually filled the center. Results: We detected 34 enhancing lesions in 200 DCE-MRI scans. In 65%, enhancement first appeared as a closed ring; in 18%, as a nodule; and in 18%, as an open ring. Lesions with initially nodular enhancement were smaller than those initially enhancing as rings (p < 0.0001). All initially nodular lesions enhanced centrifugally, whereas initially ringlike lesions enhanced centripetally, becoming nodular if small (82%) or nearly nodular if larger (18%). Open-ring lesions were periventricular or juxtacortical and enhanced centripetally. Centrifugally enhancing lesions evolved into centripetally enhancing lesions over several days. Interpretation: The rapid change of enhancement dynamics from centrifugal to centripetal reflects the outward growth of MS lesions around their central vein and suggests that factors mediating lesion growth and tissue repair derive from different locations at different times. We propose a model of new lesion growth that unites our imaging observations with existing pathology data. ANN NEUROL 2011;70:22-29 C1 [Gaitan, Maria I.; Shea, Colin D.; Evangelou, Iordanis E.; Stone, Roger D.; Fenton, Kaylan M.; Bielekova, Bibiana; Massacesi, Luca; Reich, Daniel S.] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Massacesi, Luca] Univ Florence, Dept Neurol & Psychiat Sci, Florence, Italy. RP Reich, DS (reprint author), 10 Ctr Dr MSC 1400,Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Massacesi, Luca/0000-0001-5083-372X FU National Institute of Neurological Disorders and Stroke FX The Intramural Research Program of the National Institute of Neurological Disorders and Stroke supported this work. NR 40 TC 61 Z9 62 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2011 VL 70 IS 1 BP 22 EP 29 DI 10.1002/ana.22472 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 800CN UT WOS:000293336600006 PM 21710622 ER PT J AU Hottinger, AF Iwamoto, FM Karimi, S Riedel, E Dantis, J Park, J Panageas, KS Lassman, AB Abrey, LE Fleisher, M Holland, EC DeAngelis, LM Hormigo, A AF Hottinger, Andreas F. Iwamoto, Fabio M. Karimi, Sasan Riedel, Elyn Dantis, Jocelynn Park, Joseph Panageas, Katherine S. Lassman, Andrew B. Abrey, Lauren E. Fleisher, Martin Holland, Eric C. DeAngelis, Lisa M. Hormigo, Adilia TI YKL-40 and MMP-9 as Serum Markers for Patients with Primary Central Nervous System Lymphoma SO ANNALS OF NEUROLOGY LA English DT Article ID CHITINASE PROTEIN FAMILY; HUMAN CARTILAGE GP-39; PRIMARY CNS LYMPHOMA; MATRIX METALLOPROTEINASES; GENE-EXPRESSION; SURVIVAL; MATRIX-METALLOPROTEINASE-9; BIOMARKER; ADHESION; GLIOMAS AB Objective: To evaluate YKL-40 and MMP-9 proteins as tumor biomarkers in serum samples from patients with primary central nervous system lymphoma (PCNSL). Methods: In this prospective longitudinal study, serum samples from consecutive patients with histologically confirmed PCNSL were collected concurrently with magnetic resonance imaging (MRI) scans at multiple time points and were analyzed for levels of YKL-40 and MMP-9 by enzyme-linked immunosorbent assay. Marker levels were correlated to disease status and survival. Results: Forty-five patients with PCNSL were accrued. Median follow-up for survivors was 25 months, and 21 (47%) died during the study. A total of 230 serum samples were collected, and 93% had corresponding MRI scans. PCNSL patients without evidence of radiographic disease (29 patients, 131 samples) had significantly lower levels of serum YKL-40 and MMP-9 than patients with active tumor (n = 34 patients, 84 samples; p = 0.03 and 0.01, respectively). There was a significant inverse correlation between survival and doubling of the YKL-40 level (hazard ratio, 1.7; p = 0.01). Interpretation: In patients with PCNSL, serum levels of YKL-40 and MMP-9 are associated with radiographic disease status. Longitudinal increase in serum levels of YKL-40, but not MMP-9, predicts survival in patients with PCNSL. ANN NEUROL 2011;70:163-169 C1 [Hottinger, Andreas F.; Iwamoto, Fabio M.; Dantis, Jocelynn; Park, Joseph; Lassman, Andrew B.; Abrey, Lauren E.; Holland, Eric C.; DeAngelis, Lisa M.; Hormigo, Adilia] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Hottinger, Andreas F.; Iwamoto, Fabio M.; Karimi, Sasan; Lassman, Andrew B.; Abrey, Lauren E.; Holland, Eric C.; DeAngelis, Lisa M.; Hormigo, Adilia] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA. [Hottinger, Andreas F.] Univ Hosp Geneva, Dept Oncol, Geneva, Switzerland. [Iwamoto, Fabio M.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Karimi, Sasan] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Riedel, Elyn; Panageas, Katherine S.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol Biostat, New York, NY 10021 USA. [Fleisher, Martin] Mem Sloan Kettering Canc Ctr, Dept Clin Labs, New York, NY 10021 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10021 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10021 USA. RP Hormigo, A (reprint author), Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA. EM hormigoa@mskcc.org FU Society for Memorial Sloan-Kettering Cancer Center FX Supported by the Society for Memorial Sloan-Kettering Cancer Center (A.H.). NR 39 TC 17 Z9 17 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2011 VL 70 IS 1 BP 163 EP 169 DI 10.1002/ana.22360 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 800CN UT WOS:000293336600020 PM 21391238 ER PT J AU Pratt, MM John, K MacLean, AB Afework, S Phillips, DH Poirier, MC AF Pratt, M. Margaret John, Kaarthik MacLean, Allan B. Afework, Senait Phillips, David H. Poirier, Miriam C. TI Polycyclic Aromatic Hydrocarbon (PAH) Exposure and DNA Adduct Semi-Quantitation in Archived Human Tissues SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE DNA damage; human tissues; immunohistochemistry; immunoassay; PAH-DNA adducts; semi-quantitation; molecular epidemiology ID WHITE BLOOD-CELLS; SISTER-CHROMATID EXCHANGE; CELLULAR IMAGING-SYSTEM; HUMAN CANCER-RISK; BREAST-CANCER; IMMUNOHISTOCHEMICAL DETECTION; COLORECTAL ADENOMA; UROTHELIAL CELLS; ANIMAL-MODELS; BIOMARKERS AB Polycyclic aromatic hydrocarbons (PAHs) are combustion products of organic materials, mixtures of which contain multiple known and probable human carcinogens. PAHs occur in indoor and outdoor air, as well as in char-broiled meats and fish. Human exposure to PAHs occurs by inhalation, ingestion and topical absorption, and subsequently formed metabolites are either rendered hydrophilic and excreted, or bioactivated and bound to cellular macromolecules. The formation of PAH-DNA adducts (DNA binding products), considered a necessary step in PAH-initiated carcinogenesis, has been widely studied in experimental models and has been documented in human tissues. This review describes immunohistochemistry (IHC) studies, which reveal localization of PAH-DNA adducts in human tissues, and semi-quantify PAH-DNA adduct levels using the Automated Cellular Imaging System (ACIS). These studies have shown that PAH-DNA adducts concentrate in: basal and supra-basal epithelium of the esophagus, cervix and vulva; glandular epithelium of the prostate; and cytotrophoblast cells and syncitiotrophoblast knots of the placenta. The IHC photomicrographs reveal the ubiquitous nature of PAH-DNA adduct formation in human tissues as well as PAH-DNA adduct accumulation in specific, vulnerable, cell types. This semi-quantative method for PAH-DNA adduct measurement could potentially see widespread use in molecular epidemiology studies. C1 [Pratt, M. Margaret; John, Kaarthik; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Bethesda, MD 20892 USA. [MacLean, Allan B.; Afework, Senait] Royal Free Hosp Hampstead, Dept Obstet & Gynaecol, London NW3 2QG, England. [Phillips, David H.] Inst Canc Res, Sect Mol Carcinogenesis, Sutton SM2 5NG, Surrey, England. RP Pratt, MM (reprint author), NCI, Carcinogen DNA Interact Sect, Bldg 37,Rm 4032 NIH,37 Convent Dr, Bethesda, MD 20892 USA. EM m2pratt@yahoo.com; kaarthikj@gmail.com; a.maclean@ucl.ac.uk; senuch@yahoo.com; d.phillips@qub.ac.uk; poirierm@exchange.nih.gov OI Phillips, David/0000-0001-8509-3485 FU Center for Cancer Research, National Cancer Institute, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. We wish to thank all of our colleagues who contributed to these studies, including: Hilde E. Van Gijssel, Philip R. Taylor, Sanford M. Dawsey, Philip E. Castle, Francis L. Martin, David M. DeMarini, Radim J. Sram, David K. Manchester, Paul Sirajuddin, Ofelia A. Olivero, Rao L. Divi, Laura J. Schild-Hay, Mark J. Roth, and Steven Hewitt. NR 49 TC 31 Z9 33 U1 1 U2 44 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2011 VL 8 IS 7 BP 2675 EP 2691 DI 10.3390/ijerph8072675 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 796QS UT WOS:000293067300007 PM 21845152 ER PT J AU Kraft, AD Harry, GJ AF Kraft, Andrew D. Harry, G. Jean TI Features of Microglia and Neuroinflammation Relevant to Environmental Exposure and Neurotoxicity SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE neuroinflammation; microglia; neurotoxicity; neurodegeneration; cytokines; environmental exposure ID CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; DIESEL EXHAUST PARTICLES; TOLL-LIKE RECEPTORS; NITRIC-OXIDE SYNTHASE; MANGANESE-INDUCED PARKINSONISM; FOCAL CEREBRAL-ISCHEMIA; NECROSIS-FACTOR-ALPHA; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; OXIDATIVE STRESS CONTRIBUTES AB Microglia are resident cells of the brain involved in regulatory processes critical for development, maintenance of the neural environment, injury and repair. They belong to the monocytic-macrophage lineage and serve as brain immune cells to orchestrate innate immune responses; however, they are distinct from other tissue macrophages due to their relatively quiescent phenotype and tight regulation by the CNS microenvironment. Microglia actively survey the surrounding parenchyma and respond rapidly to changes such that any disruption to neural architecture or function can contribute to the loss in regulation of the microglia phenotype. In many models of neurodegeneration and neurotoxicity, early events of synaptic degeneration and neuronal loss are accompanied by an inflammatory response including activation of microglia, perivascular monocytes, and recruitment of leukocytes. In culture, microglia have been shown to be capable of releasing several potentially cytotoxic substances, such as reactive oxygen intermediates, nitric oxide, proteases, arachidonic acid derivatives, excitatory amino acids, and cytokines; however, they also produce various neurotrophic factors and quench damage from free radicals and excitotoxins. As the primary source for pro-inflammatory cytokines, microglia are implicated as pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Neuroinflammation should be considered as a balanced network of processes whereby subtle modifications can shift the cells toward disparate outcomes. For any evaluation of neuroinflammation and microglial responses, within the framework of neurotoxicity or degeneration, one key question in determining the consequence of neuroinflammation is whether the response is an initiating event or the consequence of tissue damage. As examples of environmental exposure-related neuroinflammation in the literature, we provide an evaluation of data on manganese and diesel exhaust particles. C1 [Harry, G. Jean] NIEHS, Neurotoxicol Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Kraft, Andrew D.] US EPA, Oak Ridge Inst Sci & Educ Res Participant, Natl Ctr Environm Assessment, Off Res & Dev, Arlington, VA 22202 USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. EM kraft.andrew@epamail.epa.gov; harry@niehs.nih.gov FU Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [1Z01ES101623 and ES021164]; U.S. Department of Energy; EPA FX This research was supported by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services #1Z01ES101623 and ES021164, and in part by an appointment to the Research Participation Program for the U. S. Environmental Protection Agency, Office of Research and Development, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and EPA. The views expressed in this article are those of the authors and they do not represent the NIH or U. S. EPA policy and guidance. NR 282 TC 76 Z9 80 U1 3 U2 24 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2011 VL 8 IS 7 BP 2980 EP 3018 DI 10.3390/ijerph8072980 PG 39 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 796QS UT WOS:000293067300025 PM 21845170 ER PT J AU Klein, AP Duggal, P Lee, KE Cheng, CY Klein, R Bailey-Wilson, JE Klein, BEK AF Klein, Alison P. Duggal, Priya Lee, Kristine E. Cheng, Ching-Yu Klein, Ronald Bailey-Wilson, Joan E. Klein, Barbara E. K. TI Linkage Analysis of Quantitative Refraction and Refractive Errors in the Beaver Dam Eye Study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID HIGH MYOPIA MAPS; GENOME-WIDE ASSOCIATION; HIGH-GRADE MYOPIA; OCULAR REFRACTION; SUSCEPTIBILITY LOCUS; SCAN; POPULATION; FAMILIES; TRAITS; IDENTIFICATION AB PURPOSE. Refraction, as measured by spherical equivalent, is the need for an external lens to focus images on the retina. While genetic factors play an important role in the development of refractive errors, few susceptibility genes have been identified. However, several regions of linkage have been reported for myopia (2q, 4q, 7q, 12q, 17q, 18p, 22q, and Xq) and for quantitative refraction (1p, 3q, 4q, 7p, 8p, and 11p). To replicate previously identified linkage peaks and to identify novel loci that influence quantitative refraction and refractive errors, linkage analysis of spherical equivalent, myopia, and hyperopia in the Beaver Dam Eye Study was performed. METHODS. Nonparametric, sibling-pair, genome-wide linkage analyses of refraction (spherical equivalent adjusted for age, education, and nuclear sclerosis), myopia and hyperopia in 834 sibling pairs within 486 extended pedigrees were performed. RESULTS. Suggestive evidence of linkage was found for hyperopia on chromosome 3, region q26 (empiric P = 5.34 X 10(-4)), a region that had shown significant genome-wide evidence of linkage to refraction and some evidence of linkage to hyperopia. In addition, the analysis replicated previously reported genome-wide significant linkages to 22q11 of adjusted refraction and myopia (empiric P = 4.43 X 10(-3) and 1.48 X 10(-3), respectively) and to 7p15 of refraction (empiric P = 9.43 X 10(-4)). Evidence was also found of linkage to refraction on 7q36 (empiric P = 2.32 X 10-3), a region previously linked to high myopia. CONCLUSIONS. The findings provide further evidence that genes controlling refractive errors are located on 3q26, 7p15, 7p36, and 22q11. (Invest Ophthalmol Vis Sci. 2011; 52:5220-5225) DOI: 10.1167/iovs.10-7096 C1 [Klein, Alison P.] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD USA. [Klein, Alison P.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Klein, Alison P.; Duggal, Priya] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lee, Kristine E.; Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Cheng, Ching-Yu; Bailey-Wilson, Joan E.] NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Klein, AP (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 1550 Orleans St, Baltimore, MD 21231 USA. EM aklein1@jhmi.edu RI Cheng, Ching-Yu/K-7017-2013; OI Cheng, Ching-Yu/0000-0003-0655-885X; Bailey-Wilson, Joan/0000-0002-9153-2920; Klein, Ronald/0000-0002-4428-6237 FU National Eye Institute [EY06594, EY015286]; Research to Prevent Blindness; National Human Genome Research Institute; National Center for Research Resources [RR03655]; National Institutes of Health [HHSN268200782096C] FX Supported by National Eye Institute Grants EY06594 (RK, BEKK) and EY015286 (BEKK) from the National Eye Institute; grants from Research to Prevent Blindness (RK, BEKK); and the Intramural Research Program of the National Human Genome Research Institute. Some of the results of this paper were obtained by using the software program S. A. G. E., which is supported by U.S. Public Health Service Resource Grant RR03655 from the National Center for Research Resources. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract HHSN268200782096C. APK has full access to the data and takes responsibility for the integrity of the data and the data analysis NR 41 TC 4 Z9 4 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2011 VL 52 IS 8 BP 5220 EP 5225 DI 10.1167/iovs.10-7096 PG 6 WC Ophthalmology SC Ophthalmology GA 800QC UT WOS:000293377400028 PM 21571680 ER PT J AU Chen, JJ Smaoui, N Hammer, MBH Jiao, XD Riazuddin, SA Harper, S Katsanis, N Riazuddin, S Chaabouni, H Berson, EL Hejtmancik, JF AF Chen, Jianjun Smaoui, Nizar Hammer, Monia Ben Hamed Jiao, Xiaodong Riazuddin, S. Amer Harper, Shyana Katsanis, Nicholas Riazuddin, Sheikh Chaabouni, Habiba Berson, Eliot L. Hejtmancik, J. Fielding TI Molecular Analysis of Bardet-Biedl Syndrome Families: Report of 21 Novel Mutations in 10 Genes SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BBS GENES; POPULATION; DISEASE; IDENTIFICATION; COMPLEX; LOCUS; INHERITANCE; PROTEINS; OBESITY AB PURPOSE. Bardet-Biedl syndrome (BBS) is genetically heterogeneous with 15 BBS genes currently identified, accounting for approximately 70% of cases. The aim of our study was to define further the spectrum of BBS mutations in a cohort of 44 European-derived American, 8 Tunisian, 1 Arabic, and 2 Pakistani families (55 families in total) with BBS. METHODS. A total of 142 exons of the first 12 BBS-causing genes were screened by dideoxy sequencing. Cases in which no mutations were found were then screened for BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, and INPP5E. RESULTS. Forty-three mutations, including 8 frameshift mutations, 10 nonsense mutations, 4 splice site mutations, 1 deletion, and 20 potentially or probably pathogenic missense variations, were identified in 46 of the 55 families studied (84%). Of these, 21 (2 frameshift mutations, 4 nonsense mutations, 4 splice site mutations, 1 deletion, and 10 missense variations) were novel. The molecular genetic findings raised the possibility of triallelic inheritance in 7 Caucasian families, 1 Arabian family, and 1 Tunisian patient. No mutations were detected for BBS4, BBS11, BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, or INPP5E. CONCLUSIONS. This mutational analysis extends the spectrum of known BBS mutations. Identification of 21 novel mutations highlights the genetic heterogeneity of this disorder. Differences in European and Tunisian patients, including the high frequency of the M390R mutation in Europeans, emphasize the population specificity of BBS mutations with potential diagnostic implications. The existence of some BBS cases without mutations in any currently identified BBS genes suggests further genetic heterogeneity. (Invest Ophthalmol Vis Sci. 2011; 52:5317-5324) DOI: 10.1167/iovs.11-7554 C1 [Chen, Jianjun; Jiao, Xiaodong; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Rockville, MD 20852 USA. [Smaoui, Nizar; Hammer, Monia Ben Hamed] NEI, DNA Diagnost Lab, NIH, Rockville, MD 20852 USA. [Riazuddin, S. Amer; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Harper, Shyana; Berson, Eliot L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA USA. [Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA. [Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Durham, NC USA. [Riazuddin, Sheikh] Allama Iqbal Med Coll, Allama Iqbal Med Res Ctr, Lahore, Pakistan. [Chaabouni, Habiba] Hop Charles Nicolle, Serv Malad Congenitales & Hereditaires, Tunis, Tunisia. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 5635 Fishers Lane, Rockville, MD 20852 USA. EM f3h@helix.nih.gov RI Katsanis, Nicholas/E-1837-2012; OI Katsanis, Nicholas/0000-0002-2480-0171 FU Foundation Fighting Blindness FX Supported in part by a Center Grant from the Foundation Fighting Blindness (ELB). NR 42 TC 17 Z9 18 U1 1 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2011 VL 52 IS 8 BP 5317 EP 5324 DI 10.1167/iovs.11-7554 PG 8 WC Ophthalmology SC Ophthalmology GA 800QC UT WOS:000293377400041 PM 21642631 ER PT J AU Ma, ZW Yao, WL Theendakara, V Chan, CC Wawrousek, E Hejtmancik, JF AF Ma, Zhiwei Yao, Wenliang Theendakara, Veena Chan, Chi-Chao Wawrousek, Eric Hejtmancik, J. Fielding TI Overexpression of Human gamma C-crystallin 5 bp Duplication Disrupts Lens Morphology in Transgenic Mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BETA-B1-CRYSTALLIN PROMOTER; CATARACT; MOUSE; MUTATIONS; GENE; SUPERFAMILY; PROTEINS; CHICKEN; MUTANT AB PURPOSE. To delineate the molecular mechanisms underlying autosomal dominant congenital cataracts caused by a 5 bp duplication in human CRYGC. METHODS. c. 119_123dup (CRYGC5bpd) and wild-type human gamma C-crystallin (CRYGC) were expressed in transgenic mouse lenses by the chicken beta B1-crystallin promoter. Lenses were characterized histologically, by real-time PCR, SDS-PAGE, and Western blot. pET and Tet-on expression systems were used to express human CRYGC and CRYGC5bpd proteins in Escherichia coliand HeLa cells, respectively. RESULTS. Transgenic expression of CRYGC5bpd mutant gamma C-crystallin results in nuclear cataracts in which lens fiber cells begin to show variable degrees of degeneration and vacuolization by postnatal day 21. By 6 weeks of age all CRYGC5bpd lenses exhibit abnormalities of varying severity, comprising large vacuoles in cortical fiber cells, swelling and disorganization of fiber cells, and defective fiber cell migration and elongation. Levels of CRYGC5bpd mRNA are 3.7- and 14.1-fold higher than endogenous Crygc mRNA in postnatal day 1 and 6-week CRYGC5bpd mice lens, respectively. Crygc, Crygb, Crybb2, and Crybb3 mRNA levels are decreased in CRYGC5bpd mice compared with wild-type and CRYGC mice. Both wild-type and mutant human gamma C crystallin are uniformly distributed in the cytosol of HeLa cells, but CRYGC5bpd is degraded when expressed in E. coli BL21(DE3). CONCLUSIONS. Transgenic expression of mutant CRYGC5bpd gamma-crystallin at near-physiological levels causes lens opacities and fiber cell defects, confirming the pathogenicity of this mutation. These results further suggest that HCG5pbd gamma-crystallin causes cataracts through a direct toxic or developmental effect on lens cells causing damaged microstructure rather than through formation of HMW aggregates with resultant light scattering. (Invest Ophthalmol Vis Sci. 2011; 52:5369-5375) DOI: 10.1167/iovs.11-7168 C1 [Ma, Zhiwei; Yao, Wenliang; Theendakara, Veena; Hejtmancik, J. Fielding] NEI, OGVFB, NIH, Rockville, MD 20852 USA. [Wawrousek, Eric] NEI, Lab Mol & Dev Biol, NIH, Rockville, MD 20852 USA. [Yao, Wenliang] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Theendakara, Veena] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. RP Hejtmancik, JF (reprint author), NEI, OGVFB, NIH, 5635 Fishers Lane,Room 1127, Rockville, MD 20852 USA. EM f3h@helix.nih.gov FU National Eye Institute FX Supported by the National Eye Institute Intramural Program. NR 20 TC 4 Z9 5 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2011 VL 52 IS 8 BP 5369 EP 5375 DI 10.1167/iovs.11-7168 PG 7 WC Ophthalmology SC Ophthalmology GA 800QC UT WOS:000293377400047 PM 21436266 ER PT J AU West, SK Stare, D Mkocha, H Munoz, B Gaydos, C Quinn, TC AF West, Sheila K. Stare, Dianne Mkocha, Harran Munoz, Beatriz Gaydos, Charlotte Quinn, Thomas C. TI Do Infants Increase the Risk of Re-emergent Infection in Households after Mass Drug Administration for Trachoma? SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID AZITHROMYCIN AB PURPOSE. Mass treatment with azithromycin for trachoma endemic communities typically excludes infants under age 6 months, whose parents are provided with tubes of tetracycline to administer daily over 4 to 6 weeks. The authors sought to determine whether infants aged < 6 months are a source of re-emergent infection in their families after mass treatment in trachoma-endemic communities. METHODS. In a longitudinal study of all children aged less than 10 years in four communities, the authors identified 91 infants aged < 6 months living in 86 of 1241 households. All children aged < ten years in all households were examined for trachoma and ocular infection with C. trachomatis at baseline, and 6 months after mass drug administration. RESULTS. The prevalence of infection at baseline in the infants was 5.9%. At 6 months post mass drug administration, the rate of infection among children older than 6 months and less than 10 years who resided in households with infants was 6.0% compared with 11.1% in children in households without infants (P = 0.18). After adjustment for age, sex, baseline infection status, and treatment, residing in a household with an infant was not associated with infection at 6 months (odds ratio [95% confidence interval] 0.50 [0.20-1.22]). CONCLUSIONS. This prospective study did not find evidence that living in a household with an infant increased the risk of infection 6 months post mass drug administration in other children residing in the household. (Invest Ophthalmol Vis Sci. 2011;52:6040-6042) DOI:10.1167/iovs.11-7372 C1 [West, Sheila K.; Stare, Dianne; Munoz, Beatriz] Johns Hopkins Univ, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21287 USA. [Gaydos, Charlotte; Quinn, Thomas C.] Johns Hopkins Univ, Dept Infect Dis, Baltimore, MD 21287 USA. [Mkocha, Harran] Kongwa Trachoma Project, Kongwa, Tanzania. [Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP West, SK (reprint author), Johns Hopkins Univ, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, 600 N Wolfe St,Wilmer Room 129, Baltimore, MD 21287 USA. EM shwest@jhmi.edu FU Bill and Melinda Gates Foundation; Research to Prevent Blindness; Division of Intramural Research, NIAID FX Supported by the Bill and Melinda Gates Foundation. Pfizer provided azithromycin to Tanzania as part of their donation program. SKW received a Senior Scientific Investigator award from Research to Prevent Blindness. TCQ was supported by the Division of Intramural Research, NIAID. NR 7 TC 4 Z9 4 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2011 VL 52 IS 8 BP 6040 EP 6042 DI 10.1167/iovs.11-7372 PG 3 WC Ophthalmology SC Ophthalmology GA 800QC UT WOS:000293377400132 PM 21680866 ER PT J AU Waryah, AM Ahmed, ZM Binder, MA Choo, DI Sisk, RA Shahzad, M Khan, SN Friedman, TB Riazuddin, S Riazuddin, S AF Waryah, Ali M. Ahmed, Zubair M. Binder, Munir A. Choo, Daniel I. Sisk, Robert A. Shahzad, Mohsin Khan, Shaheen N. Friedman, Thomas B. Riazuddin, Sheikh Riazuddin, Saima TI Molecular and clinical studies of X-linked deafness among Pakistani families SO JOURNAL OF HUMAN GENETICS LA English DT Article DE DFN3; gushers; hearing loss; NDP; Norrie disease; POU3F4 ID NORRIE-DISEASE GENE; EXUDATIVE VITREORETINOPATHY; HEARING-LOSS; PRENATAL-DIAGNOSIS; MISSENSE MUTATIONS; POU3F4 MUTATIONS; CHINESE FAMILY; DFN3 PATIENTS; CHROMOSOME; PHENOTYPE AB There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p. Q136X and p. W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM# 310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c. 49delG causing a frameshift and premature truncation (p. V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis. Journal of Human Genetics (2011) 56, 534-540; doi: 10.1038/jhg.2011.55; published online 2 June 2011 C1 [Waryah, Ali M.; Binder, Munir A.; Shahzad, Mohsin; Khan, Shaheen N.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Ahmed, Zubair M.; Choo, Daniel I.; Riazuddin, Saima] Cincinnati Children Hosp Res Fdn, Mol Genet Lab, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH USA. [Ahmed, Zubair M.; Choo, Daniel I.; Riazuddin, Saima] Univ Cincinnati, Coll Med, Dept Otolaryngol, Cincinnati, OH USA. [Ahmed, Zubair M.; Sisk, Robert A.; Riazuddin, Saima] Cincinnati Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH USA. [Ahmed, Zubair M.; Sisk, Robert A.; Riazuddin, Saima] Univ Cincinnati, Coll Med, Dept Ophthalmol, Cincinnati, OH USA. [Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD USA. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. RP Riazuddin, S (reprint author), Cincinnati Childrens Hosp Med Ctr, Mol Genet Lab, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. EM saima.riazuddin@cchmc.org; saima.riazuddin@cchmc.org RI Nasim Khan, Shaheen/F-2135-2015 FU Cincinnati Children's Hospital Research Foundation (CCHMC); National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) [R00-DC009287-03, Z01-DC00039-14]; RPB; Higher Education Commission; EMRO/WHO-COMSTECH; Ministry of Science and Technology (MoST); International Center for Genetic Engineering and Biotechnology, Trieste, Italy [CRP/PAK08-01, 08/009] FX We are grateful to the families who made this research possible. This work was supported by Cincinnati Children's Hospital Research Foundation (CCHMC) intramural research funds to Sheikh Riazuddin and ZMA, the National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research Grant R00-DC009287-03, a Career Development Award from RPB to ZMA. Work in Pakistan was supported by the Higher Education Commission to Sheikh Riazuddin, Islamabad; EMRO/WHO-COMSTECH and Ministry of Science and Technology (MoST) to Sheikh Riazuddin, Islamabad; the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 Contract no. 08/009 to Sheikh Riazuddin. Part of this study carried out in the USA was supported by intramural funds from the NIDCD/NIH (Z01-DC00039-14) to TBF. NR 42 TC 3 Z9 4 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 J9 J HUM GENET JI J. Hum. Genet. PD JUL PY 2011 VL 56 IS 7 BP 534 EP 540 DI 10.1038/jhg.2011.55 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 796PE UT WOS:000293063200011 PM 21633365 ER PT J AU Chimowitz, MI Lynn, MJ Turan, TN Fiorella, D Lane, BF Janis, S Derdeyn, CP AF Chimowitz, Marc I. Lynn, Michael J. Turan, Tanya N. Fiorella, David Lane, Bethany F. Janis, Scott Derdeyn, Colin P. CA SAMMPRIS Investigators TI Design of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Atherosclerosis; intracranial; stenosis; stroke ID TRANSIENT ISCHEMIC ATTACK; CORONARY-ARTERY-DISEASE; ATHEROSCLEROTIC DISEASE; CARDIOVASCULAR-DISEASE; RANDOMIZED-TRIAL; CLINICAL-TRIALS; WINGSPAN STENT; CT ANGIOGRAPHY; BLOOD-PRESSURE; DOUBLE-BLIND AB Background: Patients with recent transient ischemic attack (TIA) or stroke caused by 70% to 99% stenosis of a major intracranial artery are at high risk of recurrent stroke on usual medical management, suggesting the need for alternative therapies for this disease. Methods: The Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial is an ongoing, randomized, multicenter, 2-arm trial that will determine whether intracranial angioplasty and stenting adds benefit to aggressive medical management alone for preventing the primary endpoint (any stroke or death within 30 days after enrollment or after any revascularization procedure of the qualifying lesion during follow-up, or stroke in the territory of the symptomatic intracranial artery beyond 30 days) during a mean follow-up of 2 years in patients with recent TIA or stroke caused by 70% to 99% stenosis of a major intracranial artery. Aggressive medical management in both arms consists of aspirin 325 mg per day, clopidogrel 75 mg per day for 90 days after enrollment, intensive risk factor management primarily targeting systolic blood pressure <140 mm Hg (<130 mm Hg in diabetics) and low density cholesterol <70 mg/dL, and a lifetsyle modification program. The sample size required to detect a 35% reduction in the rate of the primary endpoint from angioplasty and stenting based on the log-rank test with an alpha of 0.05, 80% power, and adjusting for a 2% loss to follow-up and 5% crossover from the medical to the stenting arm is 382 patients per group. Results: Enrollment began in November 2008 and 451 patients have been enrolled as of March 31, 2011. Conclusions: This is the first randomized stroke prevention trial to compare angioplasty and stenting with medical therapy in patients with intracranial arterial stenosis and to incorporate intensive management of multiple risk factors and a lifestyle modification program in the study design. Hopefully, the results of the trial will lead to more effective therapy for this high-risk disease. C1 [Chimowitz, Marc I.] Med Univ S Carolina, Stroke Program, Dept Neurosci, Stroke Ctr, Charleston, SC 29425 USA. [Lynn, Michael J.; Lane, Bethany F.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Cerebrovasc Ctr, Stony Brook, NY 11794 USA. [Janis, Scott] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurosurg, St Louis, MO USA. RP Chimowitz, MI (reprint author), Med Univ S Carolina, Stroke Program, Dept Neurosci, Stroke Ctr, 19 Hagood Ave,Harborview Off Tower,Ste 501, Charleston, SC 29425 USA. EM mchimow@musc.edu OI Turan, Tanya/0000-0001-5399-8845; Derdeyn, Colin/0000-0002-5932-2683 FU US Public Health Service National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058728] FX Funded by a research grant (U01 NS058728) from the US Public Health Service National Institute of Neurological Disorders and Stroke (NINDS). Other support is provided in the acknowledgment section. NR 40 TC 59 Z9 62 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD JUL-AUG PY 2011 VL 20 IS 4 BP 357 EP 368 DI 10.1016/j.jstrokecerebrovasdis.2011.05.001 PG 12 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 803TD UT WOS:000293603300013 PM 21729789 ER PT J AU Forger, DB Paydarfar, D Clay, JR AF Forger, Daniel B. Paydarfar, David Clay, John R. TI Optimal Stimulus Shapes for Neuronal Excitation SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID DEEP BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS; COMPUTATIONAL MODEL; INPUTS AB An important problem in neuronal computation is to discern how features of stimuli control the timing of action potentials. One aspect of this problem is to determine how an action potential, or spike, can be elicited with the least energy cost, e. g., a minimal amount of applied current. Here we show in the Hodgkin & Huxley model of the action potential and in experiments on squid giant axons that: 1) spike generation in a neuron can be highly discriminatory for stimulus shape and 2) the optimal stimulus shape is dependent upon inputs to the neuron. We show how polarity and time course of postsynaptic currents determine which of these optimal stimulus shapes best excites the neuron. These results are obtained mathematically using the calculus of variations and experimentally using a stochastic search methodology. Our findings reveal a surprising complexity of computation at the single cell level that may be relevant for understanding optimization of signaling in neurons and neuronal networks. C1 [Forger, Daniel B.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Forger, Daniel B.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Forger, Daniel B.; Paydarfar, David; Clay, John R.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Paydarfar, David] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Paydarfar, David] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Paydarfar, David] Univ Massachusetts, Sch Med, Dept Physiol, Worcester, MA USA. [Clay, John R.] NINDS, NIH, Bethesda, MD 20892 USA. RP Forger, DB (reprint author), Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. EM forger@umich.edu RI Forger, Daniel/C-5552-2015 OI Forger, Daniel/0000-0001-7581-4031 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD [20892]; NIH [R01 HL718884] FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 and NIH grant R01 HL718884 to DP. DBF is an AFOSR Young Investigator (FA 9550-08-01-0076). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 10 Z9 10 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2011 VL 7 IS 7 AR e1002089 DI 10.1371/journal.pcbi.1002089 PG 9 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 800BS UT WOS:000293333200004 PM 21760759 ER PT J AU Lemaitre, RN Tanaka, T Tang, WH Manichaikul, A Foy, M Kabagambe, EK Nettleton, JA King, IB Weng, LC Bhattacharya, S Bandinelli, S Bis, JC Rich, SS Jacobs, DR Cherubini, A McKnight, B Liang, S Gu, XJ Rice, K Laurie, CC Lumley, T Browning, BL Psaty, BM Chen, YDI Friedlander, Y Djousse, L Wu, JHY Siscovick, DS Uitterlinden, AG Arnett, DK Ferrucci, L Fornage, M Tsai, MY Mozaffarian, D Steffen, LM AF Lemaitre, Rozenn N. Tanaka, Toshiko Tang, Weihong Manichaikul, Ani Foy, Millennia Kabagambe, Edmond K. Nettleton, Jennifer A. King, Irena B. Weng, Lu-Chen Bhattacharya, Sayanti Bandinelli, Stefania Bis, Joshua C. Rich, Stephen S. Jacobs, David R., Jr. Cherubini, Antonio McKnight, Barbara Liang, Shuang Gu, Xiangjun Rice, Kenneth Laurie, Cathy C. Lumley, Thomas Browning, Brian L. Psaty, Bruce M. Chen, Yii-Der I. Friedlander, Yechiel Djousse, Luc Wu, Jason H. Y. Siscovick, David S. Uitterlinden, Andre G. Arnett, Donna K. Ferrucci, Luigi Fornage, Myriam Tsai, Michael Y. Mozaffarian, Dariush Steffen, Lyn M. TI Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-Wide Association Studies from the CHARGE Consortium SO PLOS GENETICS LA English DT Article ID ALPHA-LINOLENIC ACID; ISCHEMIC-HEART-DISEASE; DOCOSAHEXAENOIC ACID; EICOSAPENTAENOIC ACID; DEPRESSIVE SYMPTOMATOLOGY; MYOCARDIAL-INFARCTION; DIETARY-INTAKE; RISK-FACTOR; FISH-OIL; VARIANTS AB Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from a-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p=3x10(-64)) and lower levels of eicosapentaenoic acid (EPA, p=5x10(-58)) and docosapentaenoic acid (DPA, p=4x10(-154)). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p=2x10(-12)) and DPA (p=1x10(-43)) and lower docosahexaenoic acid (DHA, p=1x10(-15)). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p=1x10(-8)). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries. C1 [Lemaitre, Rozenn N.; Bis, Joshua C.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Tang, Weihong; Weng, Lu-Chen; Jacobs, David R., Jr.; Steffen, Lyn M.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Genom, Div Biostat & Epidemiol, Charlottesville, VA USA. [Foy, Millennia; Gu, Xiangjun; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Kabagambe, Edmond K.; Arnett, Donna K.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Nettleton, Jennifer A.; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [King, Irena B.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Bhattacharya, Sayanti] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Cherubini, Antonio] Univ Perugia, Inst Gerontol & Geriatr, Dept Clin & Expt Med, I-06100 Perugia, Italy. [McKnight, Barbara; Rice, Kenneth; Laurie, Cathy C.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Liang, Shuang; Tsai, Michael Y.] Univ Minnesota, Lab Med & Pathol, Minneapolis, MN USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Browning, Brian L.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Chen, Yii-Der I.] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Friedlander, Yechiel] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Sch Publ Hlth, Epidemiol Unit, Jerusalem, Israel. [Djousse, Luc] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging,Dept Med, Boston, MA 02115 USA. [Djousse, Luc] Boston VA Healthcare Syst, Boston, MA USA. [Wu, Jason H. Y.; Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Nutr, Boston, MA 02115 USA. [Wu, Jason H. Y.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Siscovick, David S.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Mozaffarian, Dariush] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. RP Lemaitre, RN (reprint author), Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. EM rozenl@u.washington.edu RI Manichaikul, Ani/B-7726-2009; Browning, Brian/A-1178-2010; Rice, Kenneth/A-4150-2013; Djousse, Luc/F-5033-2017; OI Browning, Brian/0000-0001-6454-6633; Rice, Kenneth/0000-0001-5779-4495; Djousse, Luc/0000-0002-9902-3047; Kabagambe, Edmond/0000-0002-8993-3186; Manichaikul, Ani/0000-0002-5998-795X; Cherubini, Antonio/0000-0003-0261-9897 FU National Heart, Lung, and Blood Institute (NHLBI); National Human Genome Research Institute [HSN268200625226C, U01-HG-004729, U01-HG-004446, U01-HG-004424]; National Institutes of Health; NIH Roadmap for Medical Research; National Institute of Neurological Disorders and Stroke [HL075366, HL080295, HL087652, HL105756, HL085251]; National Institute on Aging [AG-023269, AG-15928, AG-20098, AG-027058]; National Center for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; National Institute on Aging, National Institutes of Health, Baltimore, Maryland; MESA; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [5K01DK082729-02]; [UL1RR025005]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071252]; [R01HL071258]; [R01HL071259] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Cardiovascular Health Study research reported in this article was supported by the National Heart, Lung, and Blood Institute contract N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and grants HL075366, HL080295, HL087652, HL105756, and HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support from the National Institute on Aging was provided through AG-023269, AG-15928, AG-20098, and AG-027058. DNA handling and genotyping was supported in part by the National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Coronary Artery Risk Development in Young Adults (CARDIA) study is funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from the National Heart, Lung, and Blood Institute to the CARDIA investigators. Genotyping of the CARDIA participants was supported by grants U01-HG-004729, U01-HG-004446, and U01-HG-004424 from the National Human Genome Research Institute and R01-HL-084099 from the National Heart, Lung, and Blood Institute to MF. The InCHIANTI Study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336) and was supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SHARe were supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung, and Blood Institute. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02HL64278. MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. JA Nettleton is supported by a K01 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (5K01DK082729-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 105 Z9 107 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2011 VL 7 IS 7 AR e1002193 DI 10.1371/journal.pgen.1002193 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 800DB UT WOS:000293338600041 PM 21829377 ER PT J AU Meyer, KB Maia, AT O'Reilly, M Ghoussaini, M Prathalingam, R Porter-Gill, P Ambs, S Prokunina-Olsson, L Carroll, J Ponder, BAJ AF Meyer, Kerstin B. Maia, Ana-Teresa O'Reilly, Martin Ghoussaini, Maya Prathalingam, Radhika Porter-Gill, Patricia Ambs, Stefan Prokunina-Olsson, Ludmila Carroll, Jason Ponder, Bruce A. J. TI A Functional Variant at a Prostate Cancer Predisposition Locus at 8q24 Is Associated with PVT1 Expression SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TRANSCRIPTION FACTOR YY1; LONG-RANGE INTERACTION; BREAST-CANCER; C-MYC; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; CHROMOSOME 8Q24; SNP RS6983267; MULTIPLE LOCI AB Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream. C1 [Meyer, Kerstin B.; Maia, Ana-Teresa; O'Reilly, Martin; Prathalingam, Radhika; Carroll, Jason; Ponder, Bruce A. J.] Canc Res UK Cambridge Res Inst, Cambridge, England. [Maia, Ana-Teresa; Ghoussaini, Maya; Carroll, Jason; Ponder, Bruce A. J.] Univ Cambridge, Dept Oncol, Cambridge, England. [Porter-Gill, Patricia; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Meyer, KB (reprint author), Canc Res UK Cambridge Res Inst, Cambridge, England. EM kerstin.meyer@cancer.org.uk RI Maia, Ana-Teresa/F-4404-2012; OI Maia, Ana-Teresa/0000-0002-0454-9207; Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU Cancer Research UK; Division of Cancer Epidemiology and Genetics and Centre for Cancer Research, National Cancer Institute, National Institutes of Health, United States of America FX This work was funded by Cancer Research UK (http://www.cancerresearchuk.org/) and by the Intramural Research Program, Division of Cancer Epidemiology and Genetics and Centre for Cancer Research, National Cancer Institute, National Institutes of Health, United States of America (http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 56 Z9 61 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2011 VL 7 IS 7 AR e1002165 DI 10.1371/journal.pgen.1002165 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 800DB UT WOS:000293338600015 PM 21814516 ER PT J AU Sanna, S Li, BS Mulas, A Sidore, C Kang, HM Jackson, AU Piras, MG Usala, G Maninchedda, G Sassu, A Serra, F Palmas, MA Wood, WH Njolstad, I Laakso, M Hveem, K Tuomilehto, J Lakka, TA Rauramaa, R Boehnke, M Cucca, F Uda, M Schlessinger, D Nagaraja, R Abecasis, GR AF Sanna, Serena Li, Bingshan Mulas, Antonella Sidore, Carlo Kang, Hyun M. Jackson, Anne U. Piras, Maria Grazia Usala, Gianluca Maninchedda, Giuseppe Sassu, Alessandro Serra, Fabrizio Palmas, Maria Antonietta Wood, William H., III Njolstad, Inger Laakso, Markku Hveem, Kristian Tuomilehto, Jaakko Lakka, Timo A. Rauramaa, Rainer Boehnke, Michael Cucca, Francesco Uda, Manuela Schlessinger, David Nagaraja, Ramaiah Abecasis, Goncalo R. TI Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-E POLYMORPHISM; CORONARY-ARTERY-DISEASE; SEQUENCE VARIATIONS; RARE VARIANTS; HEART-DISEASE; RISK; GENE; POPULATION; PCSK9 AB Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of similar to 10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. C1 [Sanna, Serena; Mulas, Antonella; Sidore, Carlo; Piras, Maria Grazia; Usala, Gianluca; Cucca, Francesco; Uda, Manuela] CNR, Ist Ric Genet & Biomed, Monserrato, Italy. [Li, Bingshan; Sidore, Carlo; Kang, Hyun M.; Jackson, Anne U.; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Sidore, Carlo; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Maninchedda, Giuseppe; Sassu, Alessandro; Serra, Fabrizio; Palmas, Maria Antonietta] Shardna Life Sci, Pula, Italy. [Wood, William H., III] NIA, Gene Express & Genom Unit, Res Resources Branch, Baltimore, MD 21224 USA. [Njolstad, Inger] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Hveem, Kristian] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland. [Lakka, Timo A.; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Kuopio, Finland. [Schlessinger, David; Nagaraja, Ramaiah] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Sanna, S (reprint author), CNR, Ist Ric Genet & Biomed, Monserrato, Italy. EM serena.sanna@inn.cnr.it; goncalo@umich.edu RI Li, Bingshan/H-1944-2011; Abecasis, Goncalo/B-7840-2010; OI Mulas, Antonella/0000-0002-6856-1483; Sidore, Carlo/0000-0001-7504-7477; piras, maria grazia/0000-0001-9004-0900; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Lakka, Timo/0000-0002-9199-2871 FU NIA [NO1-AG-1-2109]; National Institute on Aging [263-MA-410953]; National Institutes of Health [HG002651, HG005581, HL084729]; Fondazione San Raffaele del Monte Tabor; municipal administrations; [DK062370] FX This work was supported by contract NO1-AG-1-2109, from the NIA, to the SardiNIA ("ProgeNIA") team and the Intramural Research Program of the National Institute on Aging (263-MA-410953), and by the National Institutes of Health (HG002651, HG005581, HL084729). The efforts of MB, JT, and AUJ were supported in part by research grant DK062370. SharDNA was supported by the Fondazione San Raffaele del Monte Tabor. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We are grateful to all the volunteers who generously participated in this study; Monsignore Piseddu, Bishop of Ogliastra, and the mayors and citizens of the Sardinian towns of Lanusei, Ilbono, Arzana, and Elini for their continuous support. We also thank Debbie Nickerson and the University of Washington Genome Sequencing Center, for providing sequencing data, and Francis S. Collins and Karen L. Mohlke, for sharing the Finnish and Norwegian results. The SharDNA investigators are thankful to the populations of the ten Ogliastra villages for their volunteerism, the municipal administrations for their support, and Raffaela Lener, Massimiliano Cosso and Ignazio Piras for their collaboration. NR 37 TC 88 Z9 88 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2011 VL 7 IS 7 AR e1002198 DI 10.1371/journal.pgen.1002198 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 800DB UT WOS:000293338600045 PM 21829380 ER PT J AU Macon, MB Villanueva, LR Tatum-Gibbs, K Zehr, RD Strynar, MJ Stanko, JP White, SS Helfant, L Fenton, SE AF Macon, Madisa B. Villanueva, LaTonya R. Tatum-Gibbs, Katoria Zehr, Robert D. Strynar, Mark J. Stanko, Jason P. White, Sally S. Helfant, Laurence Fenton, Suzanne E. TI Prenatal Perfluorooctanoic Acid Exposure in CD-1 Mice: Low-Dose Developmental Effects and Internal Dosimetry SO TOXICOLOGICAL SCIENCES LA English DT Article DE perfluorooctanoic acid; mammary gland; development; prenatal; dosimetry ID MAMMARY-GLAND DEVELOPMENT; NATIONAL BIRTH COHORT; SULFONATE PFOS; PERFLUORINATED CHEMICALS; PEROXISOME PROLIFERATOR; PERFLUOROALKYL ACIDS; SERUM CONCENTRATIONS; NEONATAL EXPOSURE; LACTATING MICE; COMPOUNDS PFCS AB Perfluorooctanoic acid (PFOA) is an environmental contaminant that causes adverse developmental effects in laboratory animals. To investigate the low-dose effects of PFOA on offspring, timed-pregnant CD-1 mice were gavage dosed with PFOA for all or half of gestation. In the full-gestation study, mice were administered 0, 0.3, 1.0, and 3.0 mg PFOA/kg body weight (BW)/day from gestation days (GD) 1-17. In the late-gestation study, mice were administered 0, 0.01, 0.1, and 1.0 mg PFOA/kg BW/day from GD 10-17. Exposure to PFOA significantly (p < 0.05) increased offspring relative liver weights in all treatment groups in the full-gestation study and in the 1.0 mg PFOA/kg group in the late-gestation study. In both studies, the offspring of all PFOA-treated dams exhibited significantly stunted mammary epithelial growth as assessed by developmental scoring. At postnatal day 21, mammary glands from the 1.0 mg/kg GD 10-17 group had significantly less longitudinal epithelial growth and fewer terminal end buds compared with controls (p < 0.05). Evaluation of internal dosimetry in offspring revealed that PFOA concentrations remained elevated in liver and serum for up to 6 weeks and that brain concentrations were low and undetectable after 4 weeks. These data indicate that PFOA-induced effects on mammary tissue (1) occur at lower doses than effects on liver weight in CD-1 mice, an observation that may be strain specific, and (2) persist until 12 weeks of age following full-gestational exposure. Due to the low-dose sensitivity of mammary glands to PFOA in CD-1 mice, a no observable adverse effect level for mammary developmental delays was not identified in these studies. C1 [Macon, Madisa B.; Tatum-Gibbs, Katoria] Univ N Carolina, Sch Med, Curriculum Toxicol, Chapel Hill, NC 27599 USA. [Macon, Madisa B.; Stanko, Jason P.; White, Sally S.; Fenton, Suzanne E.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27711 USA. [Villanueva, LaTonya R.] N Carolina Cent Univ, Dept Chem, Durham, NC 27709 USA. [Villanueva, LaTonya R.; Tatum-Gibbs, Katoria] US EPA, Dev Toxicol Branch, Tox Assessment Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Zehr, Robert D.; Strynar, Mark J.; Helfant, Laurence] US EPA, Methods Dev & Applicat Branch, Human Exposure & Atmospher Sci Div, Natl Exposure Res Lab,Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Fenton, SE (reprint author), POB 12233,Bldg 101,Mail Drop E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU U.S. Environmental Protection Agency; National Institute of Environmental Health Sciences; University of North Carolina Curriculum in Toxicology [5-T32 ES07126-26] FX U.S. Environmental Protection Agency; National Institute of Environmental Health Sciences; University of North Carolina Curriculum in Toxicology Training Grant (5-T32 ES07126-26) to M.B.M. NR 58 TC 30 Z9 30 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2011 VL 122 IS 1 BP 134 EP 145 DI 10.1093/toxsci/kfr076 PG 12 WC Toxicology SC Toxicology GA 800CT UT WOS:000293337500014 PM 21482639 ER PT J AU Lacerda, SHD Semberova, J Holada, K Simakova, O Hudson, SD Simak, J AF Lacerda, Silvia H. De Paoli Semberova, Jana Holada, Karel Simakova, Olga Hudson, Steven D. Simak, Jan TI Carbon Nanotubes Activate Store-Operated Calcium Entry in Human Blood Platelets SO ACS NANO LA English DT Article DE platelet activation; intracellular calcium; carbon nanotubes; fullerene; nanotoxicity; thrombosis ID MEMBRANES; AGGREGATION; CHOLESTEROL; SIMULATION; THROMBOSIS; BILAYER; SURFACE; LENGTH AB Carbon nanotubes (CNTs) are known to potentiate arterial thrombosis in animal models, which raises serious safety Issues concerning environmental or occupational exposure to CNTs and their use in various biomedical applications. We have shown previously that different CNTs, but not fullerene (nC60), induce the aggregation of human blood platelets. To date, however, a mechanism of potentially thrombogenic CNT-induced platelet activation has not been elucidated. Here we show that pristine multiwalled CNTs (MWCNTs) penetrate platelet plasma membrane without any discernible damage but interact with the dense tubular system (DTS) causing depletion of platelet intracellular Ca(2+) stores. This process is accompanied by the clustering of stromal interaction molecule 1 (STIM1) colocalized with Orai1, indicating the activation of store-operated Ca(2+) entry (SOCE). Our findings reveal the molecular mechanism of CNT-induced platelet activation which is critical in the evaluation of the biocompatibility of carbon nanomaterials with blood. C1 [Lacerda, Silvia H. De Paoli; Semberova, Jana; Simak, Jan] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Holada, Karel] Charles Univ Prague, Fac Med 1, Prague, Czech Republic. [Semberova, Jana] Charles Univ Prague, Fac Med 3, Prague, Czech Republic. [Simakova, Olga] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hudson, Steven D.] NIST, Gaithersburg, MD 20899 USA. RP Simak, J (reprint author), US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. EM jan.simak@fda.hhs.gov FU Ministry of Education, Youth and Sport of the Czech Republic [MSM 0021620806] FX We thank G. Sando, Malvern Instruments, Columbia, MD, for the flow particle image analysis of nanomaterial suspensions, M. Krumwiede, University of Minnesota, Minneapolis, MN, for the valuable consultations on the DAB-osmium labeling, and L. Diduch, National Institute of Standards and Technology, Gaithersburg, MD, for image processing. K. Holada was supported by Grant MSM 0021620806 of the Ministry of Education, Youth and Sport of the Czech Republic. NR 32 TC 25 Z9 26 U1 0 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUL PY 2011 VL 5 IS 7 BP 5808 EP 5813 DI 10.1021/nn2015369 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 796ES UT WOS:000293035200059 PM 21639133 ER PT J AU Courtney, PK AF Courtney, Paul K. TI Data Liquidity in Health Information Systems SO CANCER JOURNAL LA English DT Review DE Medical informatics; knowledge management; electronic health records; personal health record AB In 2001, the Institute of Medicine report Crossing the Quality Chasm and the National Committee on Vital and Health Statistics report Information for Health were released, and they provided the context for the development of information systems used to support health-supporting processes. Both had as their goals, implicit or explicit, to ensure the right data are provided to the right person at the right time, which is one definition of "data liquidity.'' This concept has had some traction in recent years as a shorthand way to express a system property for health information technology, but there is not a well-defined characterization of what properties of a system or of its components give it better or worse data liquidity. This article looks at some recent work that help to identify those properties and perhaps can help to ground the concept with metrics that are assessable. C1 [Courtney, Paul K.] NCI, Clin Res Directorate, CMRP, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Courtney, PK (reprint author), NCI, 6116 Execut Blvd,MSC 8317, Rockville, MD 20852 USA. EM paul.courtney@nih.gov RI Courtney, Paul/C-9906-2009; OI Courtney, Paul/0000-0001-6377-6103 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 12 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2011 VL 17 IS 4 BP 219 EP 221 DI 10.1097/PPO.0b013e3182270c83 PG 3 WC Oncology SC Oncology GA 799DZ UT WOS:000293265100005 PM 21799328 ER PT J AU Hesse, BW Suls, JM AF Hesse, Bradford W. Suls, Jerry M. TI Informatics-Enabled Behavioral Medicine in Oncology SO CANCER JOURNAL LA English DT Review DE Behavioral medicine; biomedical informatics; health communication ID QUALITY CANCER CARE; HEALTH INFORMATION; MEANINGFUL-USE; RANDOMIZED-TRIAL; DECISION-MAKING; PALLIATIVE CARE; SPECIALTY CARE; BREAST-CANCER; TECHNOLOGY; SURVIVORS AB For the practicing physician, the behavioral implications of preventing, diagnosing, and treating cancer are many and varied. Fortunately, an enhanced capacity in informatics may help create a redesigned ecosystem in which applying evidence-based principles from behavioral medicine will become a routine part of care. Innovation to support this evolution will be spurred by the "meaningful use'' criteria stipulated by the Health Information Technology for Economic and Clinical Health Act of 2009 and by focused research and development efforts within the broader health information ecosystem. The implications for how to better integrate evidence-based principles in behavioral medicine into oncology care through both spheres of development are discussed within the framework of the cancer control continuum. The promise of using the data collected through these tools to accelerate discovery in psycho-oncology is also discussed. If nurtured appropriately, these developments should help accelerate successes against cancer by altering the behavioral milieu. C1 [Hesse, Bradford W.] NCI, NIH, Bethesda, MD 20892 USA. [Suls, Jerry M.] Univ Iowa, Iowa City, IA USA. RP Hesse, BW (reprint author), NCI, NIH, 6130 Execut Blvd,MSC 7365, Bethesda, MD 20892 USA. EM hesseb@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU Intramural NIH HHS [Z99 CA999999] NR 106 TC 1 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2011 VL 17 IS 4 BP 222 EP 230 DI 10.1097/PPO.0b013e318227c811 PG 9 WC Oncology SC Oncology GA 799DZ UT WOS:000293265100006 PM 21799329 ER PT J AU Basch, EM Reeve, BB Mitchell, SA Clauser, SB Minasian, L Sit, L Chilukuri, R Baumgartner, P Rogak, L Blauel, E Abernethy, AP Bruner, D AF Basch, Ethan M. Reeve, Bryce B. Mitchell, Sandra A. Clauser, Stephen B. Minasian, Lori Sit, Laura Chilukuri, Ram Baumgartner, Paul Rogak, Lauren Blauel, Emily Abernethy, Amy P. Bruner, Deborah TI Electronic Toxicity Monitoring and Patient-Reported Outcomes SO CANCER JOURNAL LA English DT Review DE symptom; adverse event; patient-reported outcome; PRO; toxicity; tolerability; CTCAE; PRO-CTCAE ID SYMPTOMS AB Understanding the potential profile of adverse events associated with cancer treatment is essential in balancing safety versus benefits. Multiple stakeholders make use of this information for decision making, including patients, clinicians, researchers, regulators, and payors. Currently, adverse events are reported by clinical research staff, yet evidence suggests that this may contribute to underreporting of symptom events. Direct patient reporting via electronic interfaces offers a promising mechanism to enhance the efficiency and precision of our current approach and may complement clinician reports of adverse events. The National Cancer Institute has contracted to develop and test an item bank and software system for directly eliciting adverse symptom event information from patients in cancer clinical research, called the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. The validity, usability, and scalability of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events prototype are currently being examined in academic and community-based settings. C1 [Basch, Ethan M.; Sit, Laura; Rogak, Lauren; Blauel, Emily] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Reeve, Bryce B.] Univ N Carolina, Chapel Hill, NC USA. [Mitchell, Sandra A.; Clauser, Stephen B.; Minasian, Lori] NCI, Bethesda, MD 20892 USA. [Chilukuri, Ram; Baumgartner, Paul] SemanticBits LLC, Reston, VA USA. [Abernethy, Amy P.] Duke Univ, Ctr Canc, Durham, NC USA. [Bruner, Deborah] Univ Penn, Philadelphia, PA 19104 USA. RP Basch, EM (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. EM basche@mskcc.org FU National Cancer Institute [HHSN261201000043C, HHSN261201000063C]; Pfizer; Lilly; BMS; Helsinn; Amgen; Kanglaite; Alexion; Biovex FX Development of the PRO-CTCAE was supported by the National Cancer Institute (HHSN261201000043C and HHSN261201000063C). P.B. and R.C. are employed by SemanticBits LLC. A.P.A's institution has received grants from the following: Pfizer, Lilly, BMS, Helsinn, Amgen, Kanglaite, Alexion, Biovex, and A.P.A. has also received honorarium from Heisinn, Proventys, and Amgen. NR 16 TC 25 Z9 25 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2011 VL 17 IS 4 BP 231 EP 234 DI 10.1097/PPO.0b013e31822c28b3 PG 4 WC Oncology SC Oncology GA 799DZ UT WOS:000293265100007 PM 21799330 ER PT J AU Polkampally, PR Matta, JR McAreavey, D Bakalov, V Bondy, CA Gharib, AM AF Polkampally, Pritam R. Matta, Jatin R. McAreavey, Dorothea Bakalov, Vladimir Bondy, Carolyn A. Gharib, Ahmed M. TI Aneurysmal Dilatation of Medium Caliber Arteries in Turner Syndrome SO CONGENITAL HEART DISEASE LA English DT Editorial Material DE Aneurysm; Coronary Artery; Turners Syndrome; CT Angiogram ID MORTALITY AB Turner syndrome is the most common chromosomal abnormality in female subjects, affecting 1 in 2000 live births. The condition is associated with a generalized vasculopathy as well as congenital cardiac and other defects. We report aneurysmal dilation of medium caliber arteries involving the celiac axis and coronary vessels in two women with Turner syndrome. C1 [Polkampally, Pritam R.; Matta, Jatin R.; Gharib, Ahmed M.] NIDDK, Bethesda, MD USA. [McAreavey, Dorothea] Ctr Clin, Bethesda, MD USA. [Bakalov, Vladimir; Bondy, Carolyn A.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Gharib, AM (reprint author), 10 Ctr Dr,CRC Room 3-5340, Bethesda, MD 20892 USA. EM agharib@niddk.nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU Intramural NIH HHS [Z99 DK999999] NR 5 TC 4 Z9 4 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1747-079X J9 CONGENIT HEART DIS JI Congenit. Heart Dis. PD JUL-AUG PY 2011 VL 6 IS 4 BP 382 EP 383 DI 10.1111/j.1747-0803.2011.00485.x PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 795NW UT WOS:000292981900014 PM 21463486 ER PT J AU Hamano, R Huang, JQ Yoshimura, T Oppenheim, JJ Chen, X AF Hamano, Ryoko Huang, Jiaqiang Yoshimura, Teizo Oppenheim, Joost J. Chen, Xin TI TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Co-stimulation; Immune regulation; TNF; Tregs ID DENDRITIC CELLS; CUTTING EDGE; EXPANSION; SUPPRESSION; LOCALIZATION; CHEMOTHERAPY; MECHANISMS; EXPRESSION; INDUCTION; TOLERANCE AB TNF is a pleiotropic cytokine with intriguing biphasic pro-inflammatory and anti-inflammatory effects. Our previous studies demonstrated that TNF up-regulated FoxP3 expression and activated and expanded CD4(+)FoxP3(+) regulatory T cells (Tregs) via TNFR2. Furthermore, TNFR2-expressing Tregs exhibited maximal suppressive activity. In this study, we show that TNF, in concert with IL-2, preferentially up-regulated mRNA and surface expression of TNFR2, 4-1BB and OX40 on Tregs. Agonistic antibodies against 4-1BB and OX40 also induced the proliferation of suppressive Tregs. Thus, TNF amplifies its stimulatory effect on Tregs by inducing TNF receptor superfamily (TNFRSF) members. In addition, administration of neutralizing anti-TNF Ab blocked LPS-induced expansion of splenic Tregs and up-regulation of TNFR2, OX40 and 4-1BB receptors on Tregs in vivo, indicating that the expansion of Tregs expressing these co-stimulatory TNFRSF members in response to LPS is mediated by TNF. Altogether, our novel data indicate that TNF preferentially up-regulates TNFR2 on Tregs, and this is amplified by the stimulation of 4-1BB and OX40, resulting in the optimal activation of Tregs and augmented attenuation of excessive inflammatory responses. C1 [Chen, Xin] SAIC Frederick Inc, BSP, Mol Immunoregulat Lab, CIP,NCI Frederick,Ctr Canc Res, Frederick, MD 21702 USA. [Huang, Jiaqiang] QIAGEN Co, SABiosci Corp, Frederick, MD USA. [Chen, Xin] SAIC Frederick Inc, NCI Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Hamano, Ryoko] Kanazawa Univ, Grad Sch Med, Dept Internal Med, Div Rheumatol, Kanazawa, Ishikawa, Japan. RP Chen, X (reprint author), SAIC Frederick Inc, BSP, Mol Immunoregulat Lab, CIP,NCI Frederick,Ctr Canc Res, POB B,Bldg 560,Rm 31-19, Frederick, MD 21702 USA. EM chenxin@mail.nih.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Japan Society for the Promotion of Science FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This Research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. R. H. is supported by International Training Program of Japan Society for the Promotion of Science. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors thank Dr. Teresa Born and Dr. John E Sims at Amgen Inc. for providing anti-mouse TNF antibody and isotype control Mu IgG, and Dr O. M. Zack Howard, Dr. Hong Lou, Dr Hongchuan Li and Dr Gonzalo M. de la Rosa for help in this study. NR 32 TC 26 Z9 26 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2011 VL 41 IS 7 BP 2010 EP 2020 DI 10.1002/eji.201041205 PG 11 WC Immunology SC Immunology GA 797ME UT WOS:000293131200022 PM 21491419 ER PT J AU Largent, EA Joffe, S Miller, FG AF Largent, Emily A. Joffe, Steven Miller, Franklin G. TI Can RESEARCH and CARE Be Ethically Integrated? SO HASTINGS CENTER REPORT LA English DT Article ID CLINICAL-TRIALS C1 [Largent, Emily A.] Harvard Univ, PhD Program Hlth Policy, Cambridge, MA 02138 USA. [Joffe, Steven] Childrens Hosp Boston, Dana Farber Canc Inst, Boston, MA USA. [Miller, Franklin G.] Natl Inst Hlth, Dept Bioeth, Bethesda, MD 20892 USA. [Joffe, Steven] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Largent, EA (reprint author), Harvard Univ, PhD Program Hlth Policy, Cambridge, MA 02138 USA. OI Joffe, Steven/0000-0002-0667-7384 FU Greenwall Foundation FX Steven Joffe's work was supported by a faculty scholar award from the Greenwall Foundation. NR 25 TC 37 Z9 37 U1 0 U2 3 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD JUL-AUG PY 2011 VL 41 IS 4 BP 37 EP 46 PG 10 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 797WB UT WOS:000293159700019 PM 21845922 ER PT J AU McDermott, MM Liu, K Carroll, TJ Tian, L Ferrucci, L Li, DB Carr, J Guralnik, JM Kibbe, M Pearce, WH Yuan, C McCarthy, W Kramer, CM Tao, HM Liao, YH Clark, ET Xu, DX Berry, J Orozco, J Sharma, L Criqui, MH AF McDermott, Mary M. Liu, Kiang Carroll, Timothy J. Tian, Lu Ferrucci, Luigi Li, Debiao Carr, James Guralnik, Jack M. Kibbe, Melina Pearce, William H. Yuan, Chun McCarthy, Walter Kramer, Christopher M. Tao, Huimin Liao, Yihua Clark, Elizabeth Talley Xu, Dongxiang Berry, Jarett Orozco, Jennifer Sharma, Leena Criqui, Michael H. TI Superficial Femoral Artery Plaque and Functional Performance in Peripheral Arterial Disease Walking and Leg Circulation Study (WALCS III) SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE atherosclerotic plaque intermittent claudication; peripheral arterial disease; physical functioning ID ANKLE-BRACHIAL INDEX; INTERMITTENT CLAUDICATION; MAGNETIC-RESONANCE; MORTALITY; CLASSIFICATION; OSTEOARTHRITIS; ASSOCIATION; CRITERIA AB OBJECTIVES We studied associations of magnetic resonance imaging measurements of plaque area and relative percent lumen reduction in the proximal superficial femoral artery with functional performance among participants with peripheral arterial disease. BACKGROUND The clinical significance of directly imaged plaque characteristics in lower extremity arteries is not well established. METHODS A total of 454 participants with an ankle brachial index <1.00 underwent magnetic resonance cross-sectional imaging of the proximal superficial femoral artery and completed a 6-min walk test, measurement of 4-m walking velocity at usual and fastest pace, and measurement of physical activity with a vertical accelerometer. RESULTS Adjusting for age, sex, race, body mass index, smoking, statin use, comorbidities, and other covariates, higher mean plaque area (1st quintile [least plaque]: 394 m, 2nd quintile: 360 m, 3rd quintile: 359 m, 4th quintile: 329 m, 5th quintile [greatest plaque]: 311 m; p trend <0.001) and smaller mean percent lumen area (1st quintile [greatest plaque]: 319 m, 2nd quintile: 330 m, 3rd quintile: 364 m, 4th quintile: 350 m, 5th quintile: 390 m; p trend <0.001) were associated with shorter distance achieved in the 6-min walk test. Greater mean plaque area was also associated with slower usual-paced walking velocity (p trend = 0.006) and slower fastest-paced 4-m walking velocity (p trend = 0.003). Associations of mean plaque area and mean lumen area with 6-min walk distance remained statistically significant even after additional adjustment for the ankle brachial index and leg symptoms. CONCLUSIONS Among participants with peripheral arterial disease, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated independently with poorer functional performance, even after adjusting for the ankle brachial index and leg symptoms. (J Am Coll Cardiol Img 2011;4:730-9) (C) 2011 by the American College of Cardiology Foundation C1 [McDermott, Mary M.; Sharma, Leena] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Tao, Huimin; Liao, Yihua] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Li, Debiao; Carr, James] Northwestern Univ, Dept Radiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Kibbe, Melina] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Pearce, William H.] Northwestern Univ, Div Vasc Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Kibbe, Melina; Pearce, William H.] Jesse Brown Vet Affairs Med Ctr, Surg Serv, Chicago, IL USA. [McCarthy, Walter] Rush Univ, Med Ctr, Univ Cardiovasc Surg, Chicago, IL 60612 USA. [Orozco, Jennifer] Rush Univ, Med Ctr, Dept Vasc Surg, Chicago, IL 60612 USA. [Clark, Elizabeth Talley] Mt Sinai Hosp, Dept Surg, Chicago, IL USA. [Carroll, Timothy J.] Northwestern Univ, Dept Biomed Engn & Radiol, Evanston, IL USA. [Tian, Lu] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Bethesda, MD 20892 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Yuan, Chun] Univ Washington, Dept Radiol Elect Engn & Bioengn, Seattle, WA 98195 USA. [Xu, Dongxiang] Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. [Kramer, Christopher M.] Univ Virginia Hlth Syst, Dept Radiol & Med, Charlottesville, VA USA. [Berry, Jarett] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. RP McDermott, MM (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu RI Li, Debiao/B-7622-2009; Carroll, Timothy/B-6934-2009 FU National Heart, Lung, and Blood Institute [R01-HL083064]; National Institute on Aging; Jesse Brown VA Medical Center; VP Diagnostics; Philips Healthcare; Siemens Healthcare FX From the *Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; dagger Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; double dagger Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; parallel to Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Surgical Services, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; #University Cardiovascular Surgeons, Rush University Medical Center, Chicago, Illinois; **Department of Vascular Surgery, Rush University Medical Center, Chicago, Illinois; dagger dagger Department of Surgery, Mount Sinai Hospital, Chicago, Illinois; double dagger double dagger Department of Biomedical Engineering and Radiology, Northwestern University, Evanston, Illinois; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; parallel to parallel to Department of Family and Preventive Medicine, University of California at San Diego, San Diego, California; Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Bethesda, Maryland; ##Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland; ***Department of Radiology, Electrical Engineering, and Bioengineering, University of Washington, Seattle, Washington; dagger dagger dagger Department of Radiology, University of Washington School of Medicine, Seattle, Washington; double dagger double dagger double dagger Department of Radiology and Medicine, University of Virginia Health System, Charlottesville, Virginia; and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Dr. Li is currently affiliated with the Department of Radiology and Bioengineering, Cedars Sinai Medical Center, Los Angeles, California. Supported by funding from the National Heart, Lung, and Blood Institute (R01-HL083064), by the Intramural Research Program of the National Institute on Aging, and by the Jesse Brown VA Medical Center. Dr. Yuan receives research support from VP Diagnostics and from Philips Healthcare. Dr. Kramer receives research support from Siemens Healthcare. Dr. Xu is a technical consultant for VP Diagnostics and owner of Imaging Biomarker Solutions. All other authors have reported that they have no relationships to disclose. Eike Nagel, MD, PhD, served as Guest Editor for this article. NR 22 TC 8 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUL PY 2011 VL 4 IS 7 BP 730 EP 739 DI 10.1016/j.jcmg.2011.04.009 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 798CQ UT WOS:000293180100007 PM 21757163 ER PT J AU Thorgeirsson, S AF Thorgeirsson, S. TI Genomic Decoding of Liver Cancer: Mechanistic and Clinical Implications SO JOURNAL OF PATHOLOGY LA English DT Meeting Abstract CT 6th Joint Meeting of the British Division of the International-Academy-of-Pathology-and-the-Pathological-Society-of-Great -Britain-and-Ireland CY MAY 10-13, 2011 CL Univ Ghent, Dept Pathol, Onderbergen, BELGIUM SP Int Acad Pathol, Pathol Soc Great Britain & Ireland HO Univ Ghent, Dept Pathol C1 [Thorgeirsson, S.] NCI, Bethesda, MD 20892 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 0022-3417 J9 J PATHOL JI J. Pathol. PD JUL PY 2011 VL 224 SU 2 BP S14 EP S14 PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 799GZ UT WOS:000293275800049 ER PT J AU O'Seaghdha, CM Fox, CS AF O'Seaghdha, Conall M. Fox, Caroline S. TI The Fourth Dimension: Associations of Change in Albuminuria over Time SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID RECLASSIFICATION; MICROALBUMINURIA; MARKER C1 [O'Seaghdha, Conall M.; Fox, Caroline S.] NHLBI, Framingham Offspring Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Seaghdha, Conall M.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [O'Seaghdha, Conall M.] Harvard Univ, Sch Med, Div Renal, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Div Endocrinol, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov NR 11 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2011 VL 22 IS 7 BP 1186 EP 1188 DI 10.1681/ASN.2011050488 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 798KA UT WOS:000293203400005 PM 21680650 ER PT J AU Matsusaka, T Sandgren, E Shintani, A Kon, V Pastan, I Fogo, AB Ichikawa, I AF Matsusaka, Taiji Sandgren, Eric Shintani, Ayumi Kon, Valentina Pastan, Ira Fogo, Agnes B. Ichikawa, Iekuni TI Podocyte Injury Damages Other Podocytes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GLOMERULAR SCLEROSIS; RENAL-DISEASE; EXTREME ABLATION; NEPHROTIC RATS; KIDNEY-DISEASE; PROTEINURIA; HYPERTROPHY; CELL; PODOCYTOPATHIES AB Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis. C1 [Kon, Valentina; Fogo, Agnes B.; Ichikawa, Iekuni] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Matsusaka, Taiji] Tokai Univ, Sch Med, Dept Internal Med, Kanagawa 2591100, Japan. [Ichikawa, Iekuni] Tokai Univ, Sch Med, Dept Bioeth, Kanagawa 2591100, Japan. [Matsusaka, Taiji] Tokai Univ, Sch Med, Inst Med Sci, Kanagawa 2591100, Japan. [Sandgren, Eric] Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. [Shintani, Ayumi] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37232 USA. [Fogo, Agnes B.; Ichikawa, Iekuni] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Fogo, Agnes B.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ichikawa, I (reprint author), Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. EM iekuni.ichikawa@gmail.com FU National Institutes of Health [DK37868, DK44757]; Japan Society for the Promotion of Science; MEXT; HAITEKU; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Daiichi Sankyo Co., Ltd.; Chugai Pharmaceutical Co., Ltd. FX This study was supported by National Institutes of Health grants DK37868 and DK44757, the Research for the Future Program and Grant-in-Aid for Scientific Research of Japan Society for the Promotion of Science, MEXT, HAITEKU, and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Parts of this study were presented in abstract form at the annual meetings of the American Society of Nephrology in 2003 and 2004. We thank Mr. Yutaka Ishikawa, Mr. Akira Akatsuka, Ms. Shiho Imai, Ms. Naoko Sasaoka, Ms. Suguri Niwa, and Ms. Chic Sakurai for technical assistance, and Dr. Hidetake Kurihara for providing anti-podocalyxin antibody and rat podocyte cell line.; Iekuni Ichikawa received research funds from Daiichi Sankyo Co., Ltd. Taiji Matsusaka received a research fund from Chugai Pharmaceutical Co., Ltd. NR 47 TC 39 Z9 42 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2011 VL 22 IS 7 BP 1275 EP 1285 DI 10.1681/ASN.2010090963 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 798KA UT WOS:000293203400015 PM 21719786 ER PT J AU McCaskill-Stevens, W Abrams, JS AF McCaskill-Stevens, Worta Abrams, Jeffrey S. TI Comorbidities in the Aging Breast Cancer Population: Are Current Assessments Leading to Improved Outcomes? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID COMPREHENSIVE GERIATRIC ASSESSMENT C1 [McCaskill-Stevens, Worta] NCI, Canc Prevent Div, EPN, Bethesda, MD 20892 USA. [Abrams, Jeffrey S.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP McCaskill-Stevens, W (reprint author), NCI, Canc Prevent Div, EPN, Rm 2017,6130 Execut Blvd,MSC-7340, Bethesda, MD 20892 USA. EM wm57h@nih.gov NR 6 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 14 BP 1072 EP 1073 DI 10.1093/jnci/djr239 PG 2 WC Oncology SC Oncology GA 796BB UT WOS:000293024100001 PM 21719778 ER PT J AU Rubinstein, L LeBlanc, M Smith, MA AF Rubinstein, Lawrence LeBlanc, Michael Smith, Malcolm A. TI More Randomization in Phase II Trials: Necessary but not Sufficient SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID RENAL-CELL CARCINOMA; ACUTE PROMYELOCYTIC LEUKEMIA; METASTATIC BREAST-CANCER; SURROGATE END-POINTS; COLORECTAL-CANCER; CHEMOTHERAPY PLUS; CLINICAL-TRIALS; PROGRESSION-FREE; BEVACIZUMAB; SURVIVAL C1 [Rubinstein, Lawrence] NCI, NIH, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Rubinstein, L (reprint author), NCI, NIH, Biometr Res Branch, Div Canc Treatment & Diag, Execut Plaza N,Rm 8130,MSC-7434, Bethesda, MD 20892 USA. EM rubinsteinl@ctep.nci.nih.gov FU NCI NIH HHS [R01 CA090998] NR 41 TC 7 Z9 7 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 14 BP 1075 EP 1077 DI 10.1093/jnci/djr238 PG 3 WC Oncology SC Oncology GA 796BB UT WOS:000293024100003 PM 21709273 ER PT J AU Freedman, LS Schatzkin, A Midthune, D Kipnis, V AF Freedman, Laurence S. Schatzkin, Arthur Midthune, Douglas Kipnis, Victor TI Dealing With Dietary Measurement Error in Nutritional Cohort Studies SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID DOUBLY LABELED WATER; BREAST-CANCER; NATIONAL-INSTITUTES; POOLED ANALYSIS; 24-HOUR RECALL; RELATIVE RISK; FAT; HEALTH; BIOMARKER; QUESTIONNAIRE AB Dietary measurement error creates serious challenges to reliably discovering new diet-disease associations in nutritional cohort studies. Such error causes substantial underestimation of relative risks and reduction of statistical power for detecting associations. On the basis of data from the Observing Protein and Energy Nutrition Study, we recommend the following approaches to deal with these problems. Regarding data analysis of cohort studies using food-frequency questionnaires, we recommend 1) using energy adjustment for relative risk estimation; 2) reporting estimates adjusted for measurement error along with the usual relative risk estimates, whenever possible (this requires data from a relevant, preferably internal, validation study in which participants report intakes using both the main instrument and a more detailed reference instrument such as a 24-hour recall or multiple-day food record); 3) performing statistical adjustment of relative risks, based on such validation data, if they exist, using univariate (only for energy-adjusted intakes such as densities or residuals) or multivariate regression calibration. We note that whereas unadjusted relative risk estimates are biased toward the null value, statistical significance tests of unadjusted relative risk estimates are approximately valid. Regarding study design, we recommend increasing the sample size to remedy loss of power; however, it is important to understand that this will often be an incomplete solution because the attenuated signal may be too small to distinguish from unmeasured confounding in the model relating disease to reported intake. Future work should be devoted to alleviating the problem of signal attenuation, possibly through the use of improved self-report instruments or by combining dietary biomarkers with self-report instruments. C1 [Midthune, Douglas; Kipnis, Victor] US Natl Canc Inst, Biometry Res Grp, Canc Prevent Div, Bethesda, MD USA. [Schatzkin, Arthur] US Natl Canc Inst, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Freedman, Laurence S.] Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, Biostat Unit, Tel Hashomer, Israel. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, 6130 Execut Blvd,EPN-3131,MSC 7354, Bethesda, MD 20892 USA. EM kipnisv@mail.nih.gov NR 37 TC 118 Z9 118 U1 1 U2 30 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 14 BP 1086 EP 1092 DI 10.1093/jnci/djr189 PG 7 WC Oncology SC Oncology GA 796BB UT WOS:000293024100007 PM 21653922 ER PT J AU Pine, SR Mechanic, LE Enewold, L Chaturvedi, AK Katki, HA Zheng, YL Bowman, ED Engels, EA Caporaso, NE Harris, CC AF Pine, Sharon R. Mechanic, Leah E. Enewold, Lindsey Chaturvedi, Anil K. Katki, Hormuzd A. Zheng, Yun-Ling Bowman, Elise D. Engels, Eric A. Caporaso, Neil E. Harris, Curtis C. TI Increased Levels of Circulating Interleukin 6, Interleukin 8, C-Reactive Protein, and Risk of Lung Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SERUM-LEVELS; AFRICAN-AMERICANS; CARCINOMA-CELLS; SURVIVAL; INFLAMMATION; PROGRESSION; EXPRESSION; POPULATION; SENESCENCE; PROGNOSIS AB Background Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking. Methods Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case-control study. Results were validated in 532 case patients and 595 control subjects in a nested case-control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model. Results Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%). Conclusions Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer. J Natl Cancer Inst 2011;103:1112-1122 C1 [Pine, Sharon R.; Mechanic, Leah E.; Bowman, Elise D.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Pine, Sharon R.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Div Med Oncol,Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Mechanic, Leah E.] NCI, Epidemiol & Genet Res Program, Host Susceptibil Factors Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Enewold, Lindsey] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Enewold, Lindsey] Walter Reed Army Med Ctr, US Mil Canc Inst, Washington, DC 20307 USA. [Chaturvedi, Anil K.; Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Rockville, MD USA. [Katki, Hormuzd A.] NCI, Biostat Branch, Rockville, MD USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Rockville, MD USA. [Chaturvedi, Anil K.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Zheng, Yun-Ling] Georgetown Univ, Lombardi Comprehens Canc Ctr, Biomarkers Epidemiol Program, Washington, DC USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, 37 Convent Dr,Rm 3068A,MSC 4258, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov RI Katki, Hormuzd/B-4003-2015; Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 42 TC 120 Z9 123 U1 2 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 14 BP 1112 EP 1122 DI 10.1093/jnci/djr216 PG 11 WC Oncology SC Oncology GA 796BB UT WOS:000293024100010 PM 21685357 ER PT J AU Murphy, G Kamangar, F Dawsey, SM Stanczyk, FZ Weinstein, SJ Taylor, PR Virtamo, J Abnet, CC Albanes, D Freedman, ND AF Murphy, Gwen Kamangar, Farin Dawsey, Sanford M. Stanczyk, Frank Z. Weinstein, Stephanie J. Taylor, Philip R. Virtamo, Jarmo Abnet, Christian C. Albanes, Demetrius Freedman, Neal D. TI The Relationship Between Serum Ghrelin and the Risk of Gastric and Esophagogastric Junctional Adenocarcinomas SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; DIETARY ASSESSMENT INSTRUMENTS; PEPSINOGEN-I; PROSTATE-CANCER; STOMACH-CANCER; CELL-LINES; EXPRESSION; REPRODUCIBILITY; CARCINOGENESIS; QUESTIONNAIRE AB Background Cancers of the upper gastrointestinal tract remain a substantial cause of morbidity and mortality worldwide. Ghrelin is a hormone produced in the oxyntic glands of the stomach, and under conditions of chronic inflammation and atrophy, serum ghrelin concentrations decrease. However, the relationship between ghrelin and the risk of gastric and esophagogastric junctional cancers has not been investigated. Methods We conducted a nested case-control study within the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine the relationship between serum ghrelin concentration and the risk of gastric non cardia adenocarcinoma (GNCA) and esophagogastric junctional adenocarcinoma (EGJA). Data from 261 GNCA patients, 98 EGJA patients, and 441 control subjects were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for potential confounders. Lag analysis was also performed to investigate the temporal nature of the associations between baseline serum pepsinogen I and ghrelin in GNCA and EGJA patients. All statistical tests were two-sided. Results Lower concentrations of serum ghrelin were statistically significantly associated with an increased risk of both GNCA (adjusted OR = 1.75, 95% CI = 1.49 to 2.04; P < .001) and EGJA (adjusted OR = 1.56, 95% CI = 1.28 to 1.89, P < .001). A multivariable model found that the risk of both GNCA and EGJA were statistically significantly increased for those individuals in the lowest quartile of serum ghrelin levels compared with those in the highest quartile (OR of GNCA = 5.63, 95% CI = 3.16 to 10.03; OR of EGJA = 4.90, 95% CI = 2.11 to 11.35). The statistical significance of these associations remained even after restricting the analysis to those patients who developed cancer more than 10 years after baseline serum ghrelin measurements. Conclusion Low baseline concentrations of serum ghrelin were associated with a statistically significant increase in the risk of GNCA and EGJA, suggesting a potential role for gastric hormones in carcinogenesis. J Natl Cancer Inst 2011;103:1123-1129 C1 [Murphy, Gwen] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Stanczyk, Frank Z.] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Stanczyk, Frank Z.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Murphy, G (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 3034, Rockville, MD 20892 USA. EM murphygw@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Abnet, Christian/C-4111-2015; Murphy, Gwen/G-7443-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; National Cancer Institute; US Public Health Service contracts [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX This work was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was supported by funding provided by the Intramural Research Program of the National Cancer Institute and US Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004). NR 39 TC 25 Z9 26 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 14 BP 1123 EP 1129 DI 10.1093/jnci/djr194 PG 7 WC Oncology SC Oncology GA 796BB UT WOS:000293024100011 PM 21693726 ER PT J AU Di Michele, DM AF Di Michele, D. M. TI Immune tolerance induction in haemophilia: evidence and the way forward SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Review DE gene transfer; haemophilia A; haemophilia B; immune modulation; immune tolerance; inhibitors ID RECOMBINANT FACTOR-VIII; HIGH-RESPONDING INHIBITORS; VON-WILLEBRAND-FACTOR; HIGH-TITER INHIBITORS; FACTOR-IX INHIBITORS; REGULATORY T-CELLS; PREVIOUSLY UNTREATED PATIENTS; A PATIENTS; GENE-TRANSFER; SINGLE INSTITUTION AB Given the inhibitor-associated morbidity resulting from limited effective treatment options, antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). First reported over 30 years ago, much of our current knowledge about ITI in haemophilia A and B was derived from small cohort studies and retrospective national and international ITI registries. More recently, prospective randomised ITI trials have been designed and initiated to answer outstanding questions related to the optimisation of current therapeutic strategy in haemophilia A. However, due to the low incidence of inhibitor development in haemophilia B compared to haemophilia A, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of FIX inhibitors. The lack of an effective strategy is particularly problematic given the even greater morbidity associated with the almost unique occurrence of allergic and anaphylactic reactions that often herald FIX antibody development, and further complicates attempts to eradicate FIX inhibitors. Ultimately, successful inhibitor prevention and eradication strategies for both diseases will emerge from the clinical translation of our evolving knowledge of immune stimulation and tolerance. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; it will also review the current consensus recommendations for ITI, as well as the emerging scientific body of immunological knowledge that may significantly impact the therapeutic and preventative strategies of the future. C1 NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. RP Di Michele, DM (reprint author), NHLBI, Div Blood Dis & Resources, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM dimicheledm@nhlbi.nih.gov NR 98 TC 25 Z9 25 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2011 VL 9 SU 1 SI SI BP 216 EP 225 DI 10.1111/j.1538-7836.2011.04349.x PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 796BG UT WOS:000293024600024 PM 21781258 ER PT J AU Johnson, AD AF Johnson, A. D. TI The genetics of common variation affecting platelet development, function and pharmaceutical targeting SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Review DE aggregation; genome; GWAS; platelet; polymorphism; SNP ID QUANTITATIVE TRAIT LOCI; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SINGLE NUCLEOTIDE POLYMORPHISMS; MYOCARDIAL-INFARCTION; DEPENDENT INHIBITION; RECEPTOR EXPRESSION; ISOLATED POPULATION; INHERITED TRAITS; CYP2C19 GENOTYPE AB Common variant effects on human platelet function and response to anti-platelet treatment have traditionally been studied using candidate gene approaches involving a limited number of variants and genes. These studies have often been undertaken in clinically defined cohorts. More recently, studies have applied genome-wide scans in larger population samples than prior candidate studies, in some cases scanning relatively healthy individuals. These studies demonstrate synergy with some prior candidate gene findings (e. g., GP6, ADRA2A) but also uncover novel loci involved in platelet function. Here, I summarise findings on common genetic variation influencing platelet development, function and therapeutics. Taken together, candidate gene and genome-wide studies begin to account for common variation in platelet function and provide information that may ultimately be useful in pharmacogenetic applications in the clinic. More than 50 loci have been identified with consistent associations with platelet phenotypes in >= 2 populations. Several variants are under further study in clinical trials relating to anti-platelet therapies. In order to have useful clinical applications, variants must have large effects on a modifiable outcome. Regardless of clinical applications, studies of common genetic influences, even of small effect, offer additional insights into platelet biology including the importance of intracellular signalling and novel receptors. Understanding of common platelet-related genetics remains behind parallel fields (e. g., lipids, blood pressure) due to challenges in phenotype ascertainment. Further work is necessary to discover and characterise loci for platelet function, and to assess whether these loci contribute to disease aetiologies or response to therapeutics. C1 [Johnson, A. D.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. RP Johnson, AD (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU National Institutes of Health FX A. Johnson was supported by a National Institutes of Health Intramural Research Training Fellowship. NR 116 TC 14 Z9 14 U1 1 U2 4 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 JUL PY 2011 VL 9 SU 1 SI SI BP 246 EP 257 DI 10.1111/j.1538-7836.2011.04359.x PG 12 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 796BG UT WOS:000293024600027 PM 21781261 ER PT J AU Kapogiannis, D Mooshagian, E Campion, P Grafman, J Zimmermann, TJ Ladt, KC Wassermann, EM AF Kapogiannis, Dimitrios Mooshagian, Eric Campion, Paul Grafman, Jordan Zimmermann, Trelawny J. Ladt, Kelsey C. Wassermann, Eric M. TI Reward Processing Abnormalities in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE transcranial magnetic stimulation; dopamine; gambling; motor cortex ID HUMAN MOTOR CORTEX; IMPULSE CONTROL DISORDERS; SOMATIC MARKER HYPOTHESIS; PREFRONTAL CORTEX; INTRACORTICAL INHIBITION; TOURETTE-SYNDROME; DOPAMINE; EXCITABILITY; ASSOCIATION; AGONIST AB The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward. Pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A-mediated inhibition in the motor cortex, measured by paired transcranial magnetic stimulation, changes with expectation and uncertainty of money rewards generated by a slot machine simulation. We examined the role of dopamine in this phenomenon by testing 13 mildly affected patients with Parkinson's disease, off and on dopaminergic medications, and 13 healthy, age-matched controls. Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired transcranial magnetic stimulation in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired transcranial magnetic stimulation response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk-taking behavior on the Iowa Gambling Task. However, pramipexole increased risk-taking behavior more in patients showing lower paired transcranial magnetic stimulation response amplitude during low expectation. These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that the physiological state of the motor cortex changes with risk-taking tendency in patients on pramipexole. The cortical response to reward expectation may represent an endo-phenotype for risk-taking behavior in patients on agonist treatment. (C) 2011 Movement Disorder Society C1 [Kapogiannis, Dimitrios; Mooshagian, Eric; Campion, Paul; Zimmermann, Trelawny J.; Ladt, Kelsey C.; Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Kapogiannis, Dimitrios] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Mooshagian, Eric] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Henry M Jackson Fdn, Rockville, MD USA. [Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM wassermanne@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Campion, Paul/0000-0002-9569-5321 FU National Institute of Neurological Disorders and Stroke; National Institute on Aging, National Institutes of Health; Center for Neuroscience and Regenerative Medicine at the Uniformed Service University of the Health Sciences, via the Henry Jackson foundation FX Nothing to report. Funding for this work came exclusively from the Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke and the Intramural Research Program of the National Institute on Aging (to Dr. Kapogiannis), National Institutes of Health, and the Center for Neuroscience and Regenerative Medicine at the Uniformed Service University of the Health Sciences, via the Henry Jackson foundation (to Dr. Mooshagian). NR 40 TC 18 Z9 20 U1 3 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2011 VL 26 IS 8 BP 1451 EP 1457 DI 10.1002/mds.23701 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 800CB UT WOS:000293334800015 PM 21538525 ER PT J AU Yeh, SH Yang, WB Gean, PW Hsu, CY Tseng, JT Su, TP Chang, W Hung, JJ AF Yeh, Shiu Hwa Yang, Wen Bin Gean, Po Wu Hsu, Chung Yi Tseng, Joseph T. Su, Tsung Ping Chang, Wen Hung, Jan Jong TI Translational and transcriptional control of Sp1 against ischaemia through a hydrogen peroxide-activated internal ribosomal entry site pathway SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; GENE-TRANSCRIPTION; SP-FAMILY; HYPOXIA; PROMOTER; DISEASE; STRESS; PROTECTION; INDUCTION; NEURONS AB The exact mechanism underlying increases in Sp1 and the physiological consequences thereafter remains unknown. In rat primary cortical neurons, oxygen-glucose deprivation (OGD) causes an increase in H(2)O(2) as well as Sp1 in early ischaemia but apparently does not change mRNA level or Sp1 stability. We hereby identified a longer 5'-UTR in Sp1 mRNA that contains an internal ribosome entry site (IRES) that regulates rapid and efficient translation of existing mRNAs. By using polysomal fragmentation and bicistronic luciferase assays, we found that H(2)O(2) activates IRES-dependent translation. Thus, H(2)O(2) or tempol, a superoxide dismutase-mimetic, increases Sp1 levels in OGD-treated neurons. Further, early-expressed Sp1 binds to Sp1 promoter to cause a late rise in Sp1 in a feed-forward manner. Short hairpin RNA against Sp1 exacerbates OGD-induced apoptosis in primary neurons. While Sp1 levels increase in the cortex in a rat model of stroke, inhibition of Sp1 binding leads to enhanced apoptosis and cortical injury. These results demonstrate that neurons can use H(2)O(2) as a signalling molecule to quickly induce Sp1 translation through an IRES-dependent translation pathway that, in cooperation with a late rise in Sp1 via feed-forward transcriptional activation, protects neurons against ischaemic damage. C1 [Yeh, Shiu Hwa; Gean, Po Wu; Chang, Wen; Hung, Jan Jong] Natl Cheng Kung Univ, Dept Pharmacol, Coll Biosci & Biotechnol, Tainan 701, Taiwan. [Yang, Wen Bin; Hsu, Chung Yi; Tseng, Joseph T.; Chang, Wen; Hung, Jan Jong] Natl Cheng Kung Univ, Inst Bioinformat & Biosignal Transduct, Coll Biosci & Biotechnol, Tainan 701, Taiwan. [Gean, Po Wu; Tseng, Joseph T.; Chang, Wen; Hung, Jan Jong] Natl Cheng Kung Univ, Ctr Gene Regulat & Signal Transduct, Tainan 701, Taiwan. [Su, Tsung Ping] Natl Inst Drug Abuse, Dept Hlth & Human Serv, NIH, Baltimore, MD USA. RP Chang, W (reprint author), Natl Cheng Kung Univ, Dept Pharmacol, Coll Biosci & Biotechnol, Tainan 701, Taiwan. EM wcchang@mail.ncku.edu.tw; petehung@mail.ncku.edu.tw RI HUNG, Jan-Jong/G-7872-2011 OI Yang, Wen-Bin/0000-0002-6497-4176; FU National Cheng-Kung University, National Science Council, Taiwan [NSC 97-2320-B-006-016-MY3, NSC 97-2311-B-006-002-MY3]; National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, USA; NSC, Taiwan FX The National Cheng-Kung University project of the Program for Promoting Academic Excellence and Developing World Class Research Centers, National Science Council, Taiwan (NSC 97-2320-B-006-016-MY3 and NSC 97-2311-B-006-002-MY3); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, USA. Funding for open access charge: NSC, Taiwan. NR 36 TC 18 Z9 18 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2011 VL 39 IS 13 BP 5412 EP 5423 DI 10.1093/nar/gkr161 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 795ZV UT WOS:000293020000016 PM 21441538 ER PT J AU Hardin, AH Sarkar, SK Seol, Y Liou, GF Osheroff, N Neuman, KC AF Hardin, Ashley H. Sarkar, Susanta K. Seol, Yeonee Liou, Grace F. Osheroff, Neil Neuman, Keir C. TI Direct measurement of DNA bending by type IIA topoisomerases: implications for non-equilibrium topology simplification SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SCANNING FORCE MICROSCOPY; LOCAL JUXTAPOSITION GEOMETRY; ESCHERICHIA-COLI; STRUCTURAL BASIS; CONFORMATIONAL-ANALYSIS; PLASMID PBR322; MECHANISM; IV; SPECIFICITY; CLEAVAGE AB Type IIA topoisomerases modify DNA topology by passing one segment of duplex DNA (transfer or T-segment) through a transient double-strand break in a second segment of DNA (gate or G-segment) in an ATP-dependent reaction. Type IIA topoisomerases decatenate, unknot and relax supercoiled DNA to levels below equilibrium, resulting in global topology simplification. The mechanism underlying this non-equilibrium topology simplification remains speculative. The bend angle model postulates that non-equilibrium topology simplification scales with the bend angle imposed on the G-segment DNA by the binding of a type IIA topoisomerase. To test this bend angle model, we used atomic force microscopy and single-molecule Forster resonance energy transfer to measure the extent of bending imposed on DNA by three type IIA topoisomerases that span the range of topology simplification activity. We found that Escherichia coli topoisomerase IV, yeast topoisomerase II and human topoisomerase II alpha each bend DNA to a similar degree. These data suggest that DNA bending is not the sole determinant of non-equilibrium topology simplification. Rather, they suggest a fundamental and conserved role for DNA bending in the enzymatic cycle of type IIA topoisomerases. C1 [Hardin, Ashley H.; Sarkar, Susanta K.; Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Hardin, Ashley H.] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Liou, Grace F.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. RP Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health; National Institutes of Health [GM033944] FX This research was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health and by a National Institutes of Health extramural grant (GM033944 to N.O.). NR 65 TC 31 Z9 31 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2011 VL 39 IS 13 BP 5729 EP 5743 DI 10.1093/nar/gkr109 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 795ZV UT WOS:000293020000041 PM 21421557 ER PT J AU Lu, J Kerns, RT Peddada, SD Bushel, PR AF Lu, Jun Kerns, Robnet T. Peddada, Shyamal D. Bushel, Pierre R. TI Principal component analysis-based filtering improves detection for Affymetrix gene expression arrays SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PREFERRED ANALYSIS-METHODS; MICROARRAY DATA-ANALYSIS; FALSE DISCOVERY RATE; PROBE LEVEL DATA; SIGNATURES; DATASET; POWER AB Gene expression array technology has reached the stage of being routinely used to study clinical samples in search of diagnostic and prognostic biomarkers. Due to the nature of array experiments, which examine the expression of tens of thousands of genes simultaneously, the number of null hypotheses is large. Hence, multiple testing correction is often necessary to control the number of false positives. However, multiple testing correction can lead to low statistical power in detecting genes that are truly differentially expressed. Filtering out non-informative genes allows for reduction in the number of null hypotheses. While several filtering methods have been suggested, the appropriate way to perform filtering is still debatable. We propose a new filtering strategy for Affymetrix GeneChips (R), based on principal component analysis of probe-level gene expression data. Using a wholly defined spike-in data set and one from a diabetes study, we show that filtering by the proportion of variation accounted for by the first principal component (PVAC) provides increased sensitivity in detecting truly differentially expressed genes while controlling false discoveries. We demonstrate that PVAC exhibits equal or better performance than several widely used filtering methods. Furthermore, a data-driven approach that guides the selection of the filtering threshold value is also proposed. C1 [Lu, Jun; Kerns, Robnet T.; Bushel, Pierre R.] NIEHS, Microarray & Genome Informat Grp, Res Triangle Pk, NC 27709 USA. [Lu, Jun; Kerns, Robnet T.] SRA Int Inc, Res Triangle Pk, NC 27709 USA. [Peddada, Shyamal D.; Bushel, Pierre R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Bushel, PR (reprint author), NIEHS, Microarray & Genome Informat Grp, POB 12233, Res Triangle Pk, NC 27709 USA. EM bushel@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 FU National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) [Z01 ES102345-04, Z01 ES101744-04]; NIEHS-NIH FX This research was supported, in part by, the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Environmental Health Sciences (NIEHS) (Z01 ES102345-04 and Z01 ES101744-04). Funding for open access charge: NIEHS-NIH. NR 32 TC 4 Z9 4 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2011 VL 39 IS 13 AR e86 DI 10.1093/nar/gkr241 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 795ZV UT WOS:000293020000003 PM 21525126 ER PT J AU Guigon, CJ Kim, DW Willingham, MC Cheng, SY AF Guigon, C. J. Kim, D. W. Willingham, M. C. Cheng, S-y TI Mutation of thyroid hormone receptor-beta in mice predisposes to the development of mammary tumors SO ONCOGENE LA English DT Article DE thyroid hormone receptor; breast cancer; mammary tumors; Pten; mouse models ID BREAST-CANCER RISK; C-ERBA-BETA; TRANSGENIC MICE; HEPATOCELLULAR-CARCINOMA; POSTMENOPAUSAL WOMEN; NUCLEAR RECEPTORS; LIGAND-BINDING; MOUSE MODEL; V-ERBA; GENE AB Correlative data suggest that thyroid hormone receptor-beta (TR beta) mutations could increase the risk of mammary tumor development, but unequivocal evidence is still lacking. To explore the role of TR beta mutants in vivo in breast tumor development and progression, we took advantage of a knock-in mouse model harboring a mutation in the Thrb gene encoding TR beta (Thrb(PV) mouse). Although in adult nulliparous females, a single ThrbPV allele did not contribute to mammary gland abnormalities, the presence of two ThrbPV alleles led to mammary hyperplasia in similar to 36% Thrb(PV/PV) mice. The ThrbPV mutation further markedly augmented the risk of mammary hyperplasia in a mouse model with high susceptibility to mammary tumors (Pten(+/-) mouse), as demonstrated by the occurrence of mammary hyperplasia in similar to 60% of Thrb(PV/+) Pten(+/-) and similar to 77% of Thrb(PV/PV) Pten(+/-) mice versus similar to 33% of Thrb(+/+) Pten(+/-) mice. The Thrb(PV) mutation increased the activity of signal transducer and activator of transcription (STAT5) to increase cell proliferation and the expression of the STAT5 target gene encoding beta-casein in the mammary gland. We next sought to understand the molecular mechanism underlying STAT5 overactivation by TR beta PV. Cell-based studies with a breast cancer cell line (T47D cells) showed that thyroid hormone (T3) repressed STAT5 signaling in TR beta-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TR beta PV-expressing cells. Collectively, these findings show for the first time that a TR beta mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5, thereby conferring a fertile genetic ground for tumorigenesis. Oncogene (2011) 30, 3381-3390; doi:10.1038/onc.2011.50; published online 14 March 2011 C1 [Guigon, C. J.; Kim, D. W.; Cheng, S-y] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Willingham, M. C.] Wake Forest Univ, Dept Pathol, Winston Salem, NC 27109 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank Dr L Fozzatti for her help in mouse dissection, Dr C Lu for taking mouse body pictures, and Drs B Vonderhaar and E Ginsburg for providing T47D cells and helpful technical advice. This research was supported by the Intramural Research Program of Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 65 TC 18 Z9 19 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUL PY 2011 VL 30 IS 30 BP 3381 EP 3390 DI 10.1038/onc.2011.50 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 798NO UT WOS:000293215700008 PM 21399657 ER PT J AU Church, DM Schneider, VA Graves, T Auger, K Cunningham, F Bouk, N Chen, HC Agarwala, R McLaren, WM Ritchie, GRS Albracht, D Kremitzki, M Rock, S Kotkiewicz, H Kremitzki, C Wollam, A Trani, L Fulton, L Fulton, R Matthews, L Whitehead, S Chow, W Torrance, J Dunn, M Harden, G Threadgold, G Wood, J Collins, J Heath, P Griffiths, G Pelan, S Grafham, D Eichler, EE Weinstock, G Mardis, ER Wilson, RK Howe, K Flicek, P Hubbard, T AF Church, Deanna M. Schneider, Valerie A. Graves, Tina Auger, Katherine Cunningham, Fiona Bouk, Nathan Chen, Hsiu-Chuan Agarwala, Richa McLaren, William M. Ritchie, Graham R. S. Albracht, Derek Kremitzki, Milinn Rock, Susan Kotkiewicz, Holland Kremitzki, Colin Wollam, Aye Trani, Lee Fulton, Lucinda Fulton, Robert Matthews, Lucy Whitehead, Siobhan Chow, Will Torrance, James Dunn, Matthew Harden, Glenn Threadgold, Glen Wood, Jonathan Collins, Joanna Heath, Paul Griffiths, Guy Pelan, Sarah Grafham, Darren Eichler, Evan E. Weinstock, George Mardis, Elaine R. Wilson, Richard K. Howe, Kerstin Flicek, Paul Hubbard, Tim TI Modernizing Reference Genome Assemblies SO PLOS BIOLOGY LA English DT Editorial Material ID COPY-NUMBER VARIATION; STRUCTURAL VARIATION; SEQUENCE; DRAFT; MAP C1 [Church, Deanna M.; Schneider, Valerie A.; Bouk, Nathan; Chen, Hsiu-Chuan; Agarwala, Richa] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Graves, Tina; Albracht, Derek; Kremitzki, Milinn; Rock, Susan; Kotkiewicz, Holland; Kremitzki, Colin; Wollam, Aye; Trani, Lee; Fulton, Lucinda; Fulton, Robert; Weinstock, George; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Genome Inst, St Louis, MO USA. [Auger, Katherine; Matthews, Lucy; Whitehead, Siobhan; Chow, Will; Torrance, James; Dunn, Matthew; Harden, Glenn; Threadgold, Glen; Wood, Jonathan; Collins, Joanna; Heath, Paul; Griffiths, Guy; Pelan, Sarah; Grafham, Darren; Howe, Kerstin; Hubbard, Tim] Wellcome Trust Sanger Inst, Cambridge, England. [Cunningham, Fiona; McLaren, William M.; Ritchie, Graham R. S.; Flicek, Paul] European Bioinformat Inst, Cambridge, England. [Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Eichler, Evan E.] Howard Hughes Med Inst, Seattle, WA USA. RP Church, DM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM church@ncbi.nlm.nih.gov RI Hubbard, Tim/C-2567-2008; OI Hubbard, Tim/0000-0002-1767-9318; Ritchie, Graham/0000-0002-6456-9736; Cunningham, Fiona/0000-0002-7445-2419; Howe, Kerstin/0000-0003-2237-513X; Chow, William/0000-0002-9056-201X; Flicek, Paul/0000-0002-3897-7955; McLaren, William/0000-0001-6218-1116 FU Wellcome Trust [095908, 077198] NR 23 TC 94 Z9 94 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD JUL PY 2011 VL 9 IS 7 AR e1001091 DI 10.1371/journal.pbio.1001091 PG 5 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 798OQ UT WOS:000293219800002 PM 21750661 ER PT J AU Zhang, H Zhang, G Gonzalez, FJ Park, SM Cai, DS AF Zhang, Hai Zhang, Guo Gonzalez, Frank J. Park, Sung-min Cai, Dongsheng TI Hypoxia-Inducible Factor Directs POMC Gene to Mediate Hypothalamic Glucose Sensing and Energy Balance Regulation SO PLOS BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; TERMINAL TRANSACTIVATION DOMAIN; MITOCHONDRIAL COMPLEX-III; NERVOUS-SYSTEM CONTROL; BETA/NF-KAPPA-B; FOOD-INTAKE; BODY-WEIGHT; LEPTIN RESISTANCE; MAMMALIAN TARGET; HOMEOSTASIS AB Hypoxia-inducible factor (HIF) is a nuclear transcription factor that responds to environmental and pathological hypoxia to induce metabolic adaptation, vascular growth, and cell survival. Here we found that HIF subunits and HIF2 alpha in particular were normally expressed in the mediobasal hypothalamus of mice. Hypothalamic HIF was up-regulated by glucose to mediate the feeding control of hypothalamic glucose sensing. Two underlying molecular pathways were identified, including suppression of PHDs by glucose metabolites to prevent HIF2 alpha degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2 alpha protein synthesis. HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF inhibition in POMC neurons, revealing that HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing and caused energy imbalance to promote obesity development. The metabolic effects of HIF in hypothalamic POMC neurons were independent of leptin signaling or pituitary ACTH pathway. Hypothalamic gene delivery of HIF counteracted overeating and obesity under conditions of nutritional excess. In conclusion, HIF controls hypothalamic POMC gene to direct the central nutrient sensing in regulation of energy and body weight balance. C1 [Zhang, Hai; Zhang, Guo; Cai, Dongsheng] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10467 USA. [Zhang, Hai; Cai, Dongsheng] Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA. [Zhang, Hai] Univ Wisconsin, Cellular & Mol Biol Program, Madison, WI USA. [Gonzalez, Frank J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Park, Sung-min] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10467 USA. [Cai, Dongsheng] Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10467 USA. RP Zhang, H (reprint author), Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10467 USA. EM dongsheng.cai@einstein.yu.edu RI Zhang, Guo/C-8005-2013; Zhang, Guo/Q-8513-2016 OI Zhang, Guo/0000-0002-3880-6996 FU US National Institutes of Health [RO1 DK078750, RO1 AG 031774] FX This study was supported by US National Institutes of Health grants RO1 DK078750 and RO1 AG 031774. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 39 Z9 42 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD JUL PY 2011 VL 9 IS 7 AR e1001112 DI 10.1371/journal.pbio.1001112 PG 16 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 798OQ UT WOS:000293219800016 PM 21814490 ER PT J AU Goldstein, E Cobey, S Takahashi, S Miller, JC Lipsitch, M AF Goldstein, Edward Cobey, Sarah Takahashi, Saki Miller, Joel C. Lipsitch, Marc TI Predicting the Epidemic Sizes of Influenza A/H1N1, A/H3N2, and B: A Statistical Method SO PLOS MEDICINE LA English DT Article ID VIRUS; VACCINATION; INFECTION; EVOLUTION AB Background: The epidemic sizes of influenza A/H3N2, A/H1N1, and B infections vary from year to year in the United States. We use publicly available US Centers for Disease Control (CDC) influenza surveillance data between 1997 and 2009 to study the temporal dynamics of influenza over this period. Methods and Findings: Regional outpatient surveillance data on influenza-like illness (ILI) and virologic surveillance data were combined to define a weekly proxy for the incidence of each strain in the United States. All strains exhibited a negative association between their cumulative incidence proxy (CIP) for the whole season (from calendar week 40 of each year to calendar week 20 of the next year) and the CIP of the other two strains (the complementary CIP) from the start of the season up to calendar week 2 (or 3, 4, or 5) of the next year. We introduce a method to predict a particular strain's CIP for the whole season by following the incidence of each strain from the start of the season until either the CIP of the chosen strain or its complementary CIP exceed certain thresholds. The method yielded accurate predictions, which generally occurred within a few weeks of the peak of incidence of the chosen strain, sometimes after that peak. For the largest seasons in the data, which were dominated by A/H3N2, prediction of A/H3N2 incidence always occurred at least several weeks in advance of the peak. Conclusion: Early circulation of one influenza strain is associated with a reduced total incidence of the other strains, consistent with the presence of interference between subtypes. Routine ILI and virologic surveillance data can be combined using this new method to predict the relative size of each influenza strain's epidemic by following the change in incidence of a given strain in the context of the incidence of cocirculating strains. C1 [Goldstein, Edward; Cobey, Sarah; Miller, Joel C.; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Takahashi, Saki] Harvard Univ, Dept Appl Math, Cambridge, MA 02138 USA. [Miller, Joel C.] US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Goldstein, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. EM egoldste@hsph.harvard.edu RI Miller, Joel/C-4229-2015; OI Miller, Joel/0000-0003-4426-0405; Lipsitch, Marc/0000-0003-1504-9213 FU US National Institutes of Health [1 U54 GM088558]; Science & Technology Directorate; Department of Homeland Security; Fogarty International Center, US National Institutes of Health; Harvard College; Avian/Pandemic Flu Registry; Roche; Pfizer/Wyeth; Novartis Vaccines and Diagnostics FX This work was supported in part by the US National Institutes of Health Models of Infectious Disease Agent Study program through cooperative agreement 1 U54 GM088558 (ML, EG, SC); by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, US National Institutes of Health (JCM); and by the Harvard College Research Program (ST). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Marc Lipsitch is on the PLoS Medicine Editorial Board. ML discloses consulting income from the Avian/Pandemic Flu Registry (Outcome Sciences, funded in part by Roche) and from Pfizer/Wyeth and from Novartis Vaccines and Diagnostics. The other authors declare no competing interests. NR 13 TC 49 Z9 49 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUL PY 2011 VL 8 IS 7 AR e1001051 DI 10.1371/journal.pmed.1001051 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 797ZQ UT WOS:000293169700002 PM 21750666 ER PT J AU Schowalter, RM Pastrana, DV Buck, CB AF Schowalter, Rachel M. Pastrana, Diana V. Buck, Christopher B. TI Glycosaminoglycans and Sialylated Glycans Sequentially Facilitate Merkel Cell Polyomavirus Infectious Entry SO PLOS PATHOGENS LA English DT Article ID HEPARAN-SULFATE; BK-VIRUS; PAPILLOMAVIRUS CAPSIDS; SIALIC ACIDS; GANGLIOSIDES; BINDING; RECEPTORS; CARCINOMA; HEMAGGLUTINATION; BIOSYNTHESIS AB Merkel cell polyomavirus (MCV or MCPyV) appears to be a causal factor in the development of Merkel cell carcinoma, a rare but highly lethal form of skin cancer. Although recent reports indicate that MCV virions are commonly shed from apparently healthy human skin, the precise cellular tropism of the virus in healthy subjects remains unclear. To begin to explore this question, we set out to identify the cellular receptors or co-receptors required for the infectious entry of MCV. Although several previously studied polyomavirus species have been shown to bind to cell surface sialic acid residues associated with glycolipids or glycoproteins, we found that sialylated glycans are not required for initial attachment of MCV virions to cultured human cell lines. Instead, glycosaminoglycans (GAGs), such as heparan sulfate (HS) and chondroitin sulfate (CS), serve as initial attachment receptors during the MCV infectious entry process. Using cell lines deficient in GAG biosynthesis, we found that N-sulfated and/or 6-O-sulfated forms of HS mediate infectious entry of MCV reporter vectors, while CS appears to be dispensable. Intriguingly, although cell lines deficient in sialylated glycans readily bind MCV capsids, the cells are highly resistant to MCV reporter vector-mediated gene transduction. This suggests that sialylated glycans play a post-attachment role in the infectious entry process. Results observed using MCV reporter vectors were confirmed using a novel system for infectious propagation of native MCV virions. Taken together, the findings suggest a model in which MCV infectious entry occurs via initial cell binding mediated primarily by HS, followed by secondary interactions with a sialylated entry co-factor. The study should facilitate the development of inhibitors of MCV infection and help shed light on the infectious entry pathways and cellular tropism of the virus. C1 [Schowalter, Rachel M.; Pastrana, Diana V.; Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Schowalter, RM (reprint author), NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU NIH; Center for Cancer Research, NCI FX This research was funded by the Intramural Research Program of the NIH, with support from the Center for Cancer Research, NCI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 49 Z9 49 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2011 VL 7 IS 7 AR e1002161 DI 10.1371/journal.ppat.1002161 PG 18 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 800DG UT WOS:000293339300044 PM 21829355 ER PT J AU Cooney, MA Louis, GMB Hediger, ML Vexler, A Kostyniak, PJ AF Cooney, Maureen A. Louis, Germaine M. Buck Hediger, Mary L. Vexler, Albert Kostyniak, Paul J. TI Organochlorine pesticides and endometriosis (vol 30, pg 365, 2010) SO REPRODUCTIVE TOXICOLOGY LA English DT Correction C1 [Cooney, Maureen A.; Louis, Germaine M. Buck; Hediger, Mary L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Vexler, Albert] SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. [Kostyniak, Paul J.] SUNY Buffalo, Dept Pharmacol & Toxicol, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. RP Cooney, MA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Rm 7B05, Rockville, MD 20852 USA. EM cooneyma@mail.nih.gov; louisf@mail.nih.gov; hedigerm@mail.nih.gov; avexler@buffalo.edu; pjkost@buffalo.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2011 VL 32 IS 1 BP 145 EP 145 DI 10.1016/j.reprotox.2011.03.006 PG 1 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 799YO UT WOS:000293323200021 ER PT J AU Stanko, JP Enoch, RR Rayner, JL Davis, CC Wolf, DC Malarkey, DE Fenton, SE AF Stanko, Jason P. Enoch, Rolondo R. Rayner, Jennifer L. Davis, Christine C. Wolf, Douglas C. Malarkey, David E. Fenton, Suzanne E. TI Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats (vol 30, pg 540, 2010) SO REPRODUCTIVE TOXICOLOGY LA English DT Correction C1 [Stanko, Jason P.; Fenton, Suzanne E.] US EPA, Reprod Toxicol Div, ORD NHEERL, Res Triangle Pk, NC 27711 USA. [Davis, Christine C.] US EPA, Hlth & Environm Impacts Div, OAR OAQPS, Res Triangle Pk, NC 27711 USA. [Wolf, Douglas C.] US EPA, ORD, Res Triangle Pk, NC 27711 USA. [Enoch, Rolondo R.] N Carolina Cent Univ, Dept Biol, Durham, NC 27707 USA. [Rayner, Jennifer L.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Malarkey, David E.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Fenton, SE (reprint author), NIEHS, NIH, NTP, CMPB, 111 TW Alexander Dr,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2011 VL 32 IS 1 BP 146 EP 147 DI 10.1016/j.reprotox.2011.03.007 PG 2 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 799YO UT WOS:000293323200022 ER PT J AU Weniger, MA Wiestner, A AF Weniger, Marc A. Wiestner, Adrian TI Molecular Targeted Approaches in Mantle Cell Lymphoma SO SEMINARS IN HEMATOLOGY LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; HISTONE DEACETYLASE INHIBITORS; CHRONIC LYMPHOCYTIC-LEUKEMIA; DEPENDENT KINASE INHIBITOR; SINGLE-AGENT TEMSIROLIMUS; PHASE-1 DOSE-ESCALATION; MULTIPLE-MYELOMA CELLS; CANCER-CELLS; CYCLIN D1; CLINICAL-TRIALS AB Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good, but most patients relapse, resulting in a median survival of 5 to 7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second-generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress. Semin Hematol 48:214-226. Published by Elsevier Inc. C1 [Weniger, Marc A.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Weniger, MA (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL005076-05] NR 100 TC 12 Z9 12 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2011 VL 48 IS 3 BP 214 EP 226 DI 10.1053/j.seminhematol.2011.05.001 PG 13 WC Hematology SC Hematology GA 799YI UT WOS:000293322400010 PM 21782064 ER PT J AU Lee, NR Fidler, DJ Blakeley-Smith, A Daunhauer, L Robinson, C Hepburn, SL AF Lee, Nancy Raitano Fidler, Deborah J. Blakeley-Smith, Audrey Daunhauer, Lisa Robinson, Cordelia Hepburn, Susan L. TI Caregiver Report of Executive Functioning in a Population-Based Sample of Young Children With Down Syndrome SO AJIDD-AMERICAN JOURNAL ON INTELLECTUAL AND DEVELOPMENTAL DISABILITIES LA English DT Article ID AUTISM SPECTRUM DISORDERS; WORKING-MEMORY DEFICITS; PREFRONTAL CORTEX; ADOLESCENTS; DISSOCIATION; DISABILITIES; INDIVIDUALS; BEHAVIOR; RATINGS; DISEASE AB The current study describes everyday executive function (EF) profiles in young children with Down syndrome. Caregivers of children with Down syndrome (n = 26; chronological ages = 4-10 years; mental ages = 2-4 years) completed the Behavior Rating Inventory of Executive Function Preschool (BRIEF-P; G. A. Gioia, K. A. Espy, & P. K. Isquith, 2003), a caregiver report measure of everyday/functional EF skills in multiple domains. On the BRIEF-P, elevations were noted on a global EF composite as well as the Working Memory and Plan/Organize scales in particular (relative to norms developed for typically developing children of a similar mental age). These results suggest a specific pattern of EF weaknesses in young children with Down syndrome, consistent with the extant literature that has focused primarily on older individuals who have been tested using laboratory EF tasks. C1 [Lee, Nancy Raitano; Blakeley-Smith, Audrey; Robinson, Cordelia] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Fidler, Deborah J.; Daunhauer, Lisa] Colorado State Univ, Ft Collins, CO 80523 USA. [Hepburn, Susan L.] Univ Colorado, Hlth Sci Ctr, Boulder, CO 80309 USA. RP Lee, NR (reprint author), NIMH, NIH, Unit Brain Imaging, Child Psychiat Branch, Bldg 10,Room 4C110 MSC 1367,10 Ctr Dr, Bethesda, MD 20892 USA. EM lnancy@mail.nih.gov RI Lee, Nancy Raitano/F-2565-2011; Lee, Nancy/M-7492-2016; OI Lee, Nancy/0000-0002-6663-0713; Hepburn, Susan/0000-0002-8545-3804 FU NICHD NIH HHS [L30 HD048361, U19 HD035468] NR 49 TC 20 Z9 20 U1 2 U2 19 PU AMER ASSOC INTELLECTUAL DEVELOPMENTAL DISABILITIES PI WASHINGTON PA 444 N CAPITOL ST, NW STE 846, WASHINGTON, DC 20001-1512 USA SN 1944-7515 J9 AJIDD-AM J INTELLECT JI AJIDD-Am. J. Intellect. Dev. Disabil. PD JUL PY 2011 VL 116 IS 4 BP 290 EP 304 DI 10.1352/1944-7558-116.4.290 PG 15 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 794ZO UT WOS:000292941500004 PM 21740257 ER PT J AU Andreeva, VA Cockburn, MG Yaroch, AL Unger, JB Rueda, R Reynolds, KD AF Andreeva, Valentina A. Cockburn, Myles G. Yaroch, Amy L. Unger, Jennifer B. Rueda, Robert Reynolds, Kim D. TI Preliminary Evidence for Mediation of the Association Between Acculturation and Sun-Safe Behaviors SO ARCHIVES OF DERMATOLOGY LA English DT Article ID NATIONAL TRENDS SURVEY; SKIN-CANCER; UNITED-STATES; RISK BEHAVIORS; US POPULATION; HEALTH; PROTECTION; MELANOMA; ADULTS; PREVENTION AB Objectives: To identify and test mediators of the relationship between acculturation and sun-safe behaviors among Latinos in the United States. We hypothesized that the effect of acculturation on use of sunscreen, shade, and sun-protective clothing would be mediated by perceived health status, educational level, access to health care, and contact with social networks regarding health matters. Design: The 2005 Health Information National Trends Survey, implemented by the National Cancer Institute. Setting: Nationwide survey. Participants: A probability-based sample of the US civilian, noninstitutionalized adult population, comprising 496 Latino respondents. Main Outcome Measures: Use of sunscreen, shade, and sun-protective clothing when outdoors on sunny days, assessed by self-report on frequency scales. Results: The positive association between acculturation and sunscreen use and the negative association between acculturation and use of sun-protective clothing were mediated by educational level (P <.05 for both). Perceived health status and contact with social networks regarding health matters were supported as mediators for sunscreen use only (P <.05). Health care access was not supported as a mediator for any of the outcomes. Conclusions: Structural equation models revealed distinct direct and indirect paths between acculturation and each sun-safe practice. Our findings emphasize behavior-specific mediated associations and could inform sun safety programming for Latinos with low and high levels of acculturation. The models support educational level, contact with social networks regarding health matters, and perceived health status as mediators primarily for sunscreen use. Future research should test different mediators for use of shade or sun-protective clothing. C1 [Andreeva, Valentina A.] Univ Paris 08, Nutr Epidemiol Res Unit, F-93017 Bobigny, France. [Andreeva, Valentina A.; Cockburn, Myles G.; Unger, Jennifer B.; Reynolds, Kim D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Rueda, Robert] Univ So Calif, Rossier Sch Educ, Dept Educ Psychol, Los Angeles, CA USA. [Yaroch, Amy L.] NCI, Hlth Promot Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Yaroch, Amy L.] Gretchen Swanson Ctr Nutr, Omaha, NE USA. [Reynolds, Kim D.] Claremont Grad Univ, Sch Community & Global Hlth, San Dimas, CA USA. RP Andreeva, VA (reprint author), Univ Paris 08, Nutr Epidemiol Res Unit, 74 Rue Marcel Cachin, F-93017 Bobigny, France. EM v.andreeva@uren.smbh.univ-paris13.fr FU Department of Preventive Medicine, Keck School of Medicine, University of Southern California; Centers for Disease Control and Prevention [U55/CCU921930-02]; National Institute of Environmental Health Sciences [5P30 ES07048]; National Cancer Institute [R01 CA121052, CA100285] FX Dr Andreeva was supported by a doctoral dissertation fellowship at the Department of Preventive Medicine, Keck School of Medicine, University of Southern California. Dr Cockburn was supported in part by grant U55/CCU921930-02 from the Centers for Disease Control and Prevention, grant 5P30 ES07048 from the National Institute of Environmental Health Sciences, and grant R01 CA121052 from the National Cancer Institute. Dr Reynolds was supported by grant CA100285 from the National Cancer Institute. NR 55 TC 7 Z9 7 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUL PY 2011 VL 147 IS 7 BP 814 EP 819 PG 6 WC Dermatology SC Dermatology GA 793RL UT WOS:000292840700007 PM 21768480 ER PT J AU Szentpetery, Z Szakacs, G Bojjireddy, N Tai, AW Balla, T AF Szentpetery, Zsofia Szakacs, Gergely Bojjireddy, Naveen Tai, Andrew W. Balla, Tamas TI Genetic and functional studies of phosphatidyl-inositol 4-kinase type III alpha SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE Phosphoinositide; PI 4-kinase; Chromosome 22; K562 leukemia cells; Golgi; Endoplasmic reticulum ID 22Q11 DELETION SYNDROME; SACCHAROMYCES-CEREVISIAE; PLASMA-MEMBRANE; GOLGI-COMPLEX; CLONING; YEAST; LEUKEMIA; REVEALS; FAMILY; STT4 AB Phosphatidylinositol 4-kinase type IIIa (PI4KIII alpha) is one of four mammalian PI 4-kinases that catalyzes the first committed step in polyphosphoinositide synthesis. PI4KIII alpha has been linked to regulation of ER exit sites and to the synthesis of plasma membrane phosphoinositides and recent studies have also revealed its importance in replication of the Hepatitis C virus in liver. Two isoforms of the mammalian PI4KIII alpha have been described and annotated in GenBank: a larger, similar to 230 kDa (isoform 2) and a shorter splice variant containing only the similar to 97 kDa C-terminus that includes the catalytic domain (isoform 1). However, Northern analysis of human tissues and cancer cells showed only a single transcript of similar to 7.5 kb with the exception of the proerythroleukemia line K562, which contained significantly higher level of the 7.5 kb transcript along with smaller ones of 2.4, 3.5 and 4.2 kb size. Bioinformatic analysis also confirmed the high copy number of PI4KIII alpha transcript in K562 cells along with several genes located in the same region in Chr22, including two pseudogenes that cover most exons coding for isoform 1, consistent with chromosome amplification. A panel of polyclonal antibodies raised against peptides within the C-terminal half of PI4KIII alpha failed to detect the shorter isoform 1 either in COS-7 cells or K562 cells. Moreover, expression of a cDNA encoding isoform 1 yielded a protein of similar to 97 kDa that showed no catalytic activity and failed to rescue hepatitis C virus replication. These data draw attention to PI4KIII alpha as one of the genes found in Chr22q11, a region affected by chromosomal instability, but do not substantiate the existence of a functionally relevant short form of PI4KIII alpha. Published by Elsevier B.V. C1 [Szentpetery, Zsofia; Bojjireddy, Naveen; Balla, Tamas] NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Szakacs, Gergely] Hungarian Acad Sci, Inst Enzymol, Budapest, Hungary. [Tai, Andrew W.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Tai, Andrew W.] Ann Arbor Vet Adm Hlth Syst, Ann Arbor, MI USA. RP Balla, T (reprint author), NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov RI Szakacs, Gergely/A-2580-2009; OI Szakacs, Gergely/0000-0002-9311-7827; Balla, Tamas/0000-0002-9077-3335 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [AI083785]; American Gastroenterological Association Foundation FX This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to T.B.) and grant AI083785 (to A.W.T.) of the National Institutes of Health (T.B.) as well as by the American Gastroenterological Association Foundation (to A.W.T.). NR 44 TC 11 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD JUL-AUG PY 2011 VL 1811 IS 7-8 BP 476 EP 483 DI 10.1016/j.bbalip.2011.04.013 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 794ZM UT WOS:000292941300007 PM 21601653 ER PT J AU Gao, F Kim, HW Igarashi, M Kiesewetter, D Chang, L Ma, KZ Rapoport, SI AF Gao, Fei Kim, Hyung-Wook Igarashi, Miki Kiesewetter, Dale Chang, Lisa Ma, Kaizong Rapoport, Stanley I. TI Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but alpha-LNA-containing n-3 PUFA adequate diet (Retracted article. See vol. 1851, pg. 238, 2015) SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article; Retracted Publication DE Conversion; Arachidonic; Docosahexaenoic; Diet; Liver; Turnover ID POLYUNSATURATED FATTY-ACIDS; LINOLENIC ACID; BRAIN PHOSPHOLIPIDS; ADULT-RATS; IN-VIVO; METABOLISM; DEPRIVATION; DESATURATION; VEGETARIANS; DEFICIENT AB The long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA. 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6), are critical for health. These PUFAs can be synthesized in liver from their plant-derived precursors, a-linolenic acid (alpha-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6). Vegetarians and vegans may have suboptimal long-chain n-3 PUFA status, and the extent of the conversion of alpha-LNA to EPA and DHA by the liver is debatable. We quantified liver conversion of DHA and other n-3 PUFAs from alpha-LNA in rats fed a DHA-free but alpha-LNA (n-3 PUFA) adequate diet, and compared results to conversion of LA to AA. [U-C-13]LA or [U-13C] alpha-LNA was infused intravenously for 2 h at a constant rate into unanesthetized rats fed a DHA-free alpha-LNA adequate diet, and published equations were used to calculate kinetic parameters. The conversion coefficient k* of DHA from alpha-LNA was much higher than for AA from LA (97.2 x 10(-3) vs. 10.6 x 10(-3) min(-1)), suggesting that liver elongation-desaturation is more selective for n-3 PUFA biosynthesis on a per molecule basis. The net daily secretion rate of DHA, 20.3 mu mol/day, exceeded the reported brain DHA consumption rate by 50-fold, suggesting that the liver can maintain brain DHA metabolism with an adequate dietary supply solely of alpha-LNA. This infusion method could be used in vegetarians or vegans to determine minimal daily requirements of EPA and DHA in humans. Published by Elsevier B.V. C1 [Gao, Fei; Kim, Hyung-Wook; Igarashi, Miki; Chang, Lisa; Ma, Kaizong; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Kiesewetter, Dale] Natl Inst Biomed Imaging & Bioengn, Positron Emiss Tomog Radiochem Grp, NIH, Bethesda, MD 20892 USA. RP Gao, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM gaof@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The authors thank Dr. Ameer Taha for the comments on the manuscript and the National Institutes of Health Fellows Editorial Board for editorial assistance. NR 48 TC 12 Z9 12 U1 2 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD JUL-AUG PY 2011 VL 1811 IS 7-8 BP 484 EP 489 DI 10.1016/j.bbalip.2011.05.008 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 794ZM UT WOS:000292941300008 PM 21651989 ER PT J AU Kitamura, A Matsushita, K Takiguchi, Y Shimada, H Tada, Y Yamanaka, M Hiroshima, K Tagawa, M Tomonaga, T Matsubara, H Inoue, M Hasegawa, M Sato, Y Levens, D Tatsumi, K Nomura, F AF Kitamura, Atsushi Matsushita, Kazuyuki Takiguchi, Yuichi Shimada, Hideaki Tada, Yuji Yamanaka, Makako Hiroshima, Kenzo Tagawa, Masatoshi Tomonaga, Takeshi Matsubara, Hisahiro Inoue, Makoto Hasegawa, Mamoru Sato, Yasunori Levens, David Tatsumi, Koichiro Nomura, Fumio TI Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma SO CANCER SCIENCE LA English DT Article ID GENE-THERAPY; PHOSPHORYLATION; TRANSCRIPTION; EFFICACY; SYSTEM; CANCER; REPAIR; CELLS; TFIIH AB Human malignant pleural mesothelioma (HMPM) is highly resistant to conventional therapy, and therefore novel therapies are required. We previously reported that overexpression of the FUSE-binding protein-interacting repressor (FIR), a c-myc transcriptional repressor, induces apoptosis via c-Myc suppression, and is thus a suitable cancer therapy. In the current preclinical trial, a fusion gene deleted non-transmissible Sendai virus vector encoding FIR (SeV/Delta F/FIR) was prepared and its cytotoxic activity against an orthotopic xenograft model of HMPM, in combination with cisplatin, was assessed. SeV/Delta F/FIR and a fusion gene deleted non-transmissible Sendai virus vector encoding green fluorescent protein (SeV/Delta F/GFP) were prepared. The transduction efficiency of these agents in terms of dose-dependent cytotoxicity and/or apoptosis induction was then assessed in a few HMPM cells. Combination therapy with SeV/Delta F/FIR plus cisplatin was evaluated in vitro and in a mouse model. SeV/Delta F/FIR significantly reduced cell viability in three HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells. SeV/Delta F/FIR cytotoxicity was partly due to apoptosis induction via c-Myc suppression. In addition, SeV/Delta F/FIR showed synergistic antitumor effects in combination with cisplatin, as was revealed by isobologram analysis in MSTO-211H. Moreover, combination therapy with SeV/Delta F/FIR plus cisplatin demonstrated significant tumor reduction and improvement in survival rate in an animal model. Combination therapy with SeV/Delta F/FIR plus cisplatin has therapeutic potential against HMPM. SeV/Delta F/FIR plus cisplatin will be an attractive modality against HMPM in the future. (Cancer Sci 2011; 102: 1366-1373) C1 [Kitamura, Atsushi; Matsushita, Kazuyuki; Nomura, Fumio] Chiba Univ, Dept Mol Diag, Grad Sch Med, Chiba, Japan. [Kitamura, Atsushi; Tada, Yuji; Yamanaka, Makako; Tatsumi, Koichiro] Chiba Univ, Dept Respirol, Grad Sch Med, Chiba, Japan. [Takiguchi, Yuichi] Chiba Univ, Dept Chemotherapy, Grad Sch Med, Chiba, Japan. [Shimada, Hideaki] Toho Univ, Dept Surg, Sch Med, Tokyo, Japan. [Hiroshima, Kenzo] Tokyo Womens Med Univ, Yachiyo Med Ctr, Dept Pathol, Yachiyo, Japan. [Tagawa, Masatoshi] Chiba Canc Ctr, Div Pathol & Cell Therapy, Chiba 2608717, Japan. [Tomonaga, Takeshi] Natl Inst Biomed Innovat, Proteome Res Ctr, Proteome Res Project, Ibaraki, Japan. [Matsubara, Hisahiro] Chiba Univ, Dept Frontier Surg, Grad Sch Med, Chiba, Japan. [Inoue, Makoto; Hasegawa, Mamoru] DNAVEC Corp, Tsukuba, Ibaraki, Japan. [Sato, Yasunori] Chiba Univ Hosp, Clin Res Ctr, Chiba, Japan. [Levens, David] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Matsushita, K (reprint author), Chiba Univ, Dept Mol Diag, Grad Sch Med, Chiba, Japan. EM kmatsu@faculty.chiba-u.jp RI Levens, David/C-9216-2009; OI Levens, David/0000-0002-7616-922X; Matsushita, Kazuyuki/0000-0001-6742-0761 NR 29 TC 9 Z9 9 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD JUL PY 2011 VL 102 IS 7 BP 1366 EP 1373 DI 10.1111/j.1349-7006.2011.01931.x PG 8 WC Oncology SC Oncology GA 793ZN UT WOS:000292863100018 PM 21435101 ER PT J AU Aletras, AH Tilak, GS Hsu, LY Arai, AE AF Aletras, Anthony H. Tilak, Gauri S. Hsu, Li-Yueh Arai, Andrew E. TI Heterogeneity of Intramural Function in Hypertrophic Cardiomyopathy Mechanistic Insights From MRI Late Gadolinium Enhancement and High-Resolution Displacement Encoding With Stimulated Echoes Strain Maps SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE hypertrophic cardiomyopathy; MRI; DENSE; displacement encoding with stimulated echoes; myocardial function; strain; late gadolinium enhancement ID CARDIOVASCULAR MAGNETIC-RESONANCE; DELAYED CONTRAST ENHANCEMENT; MYOCARDIAL FIBROSIS; REGIONAL HETEROGENEITY; QUANTITATIVE-ANALYSIS; CONTRACTILE FUNCTION; SYMPTOMATIC PATIENTS; HYPERTENSIVE HEARTS; VENTRICULAR SEPTUM; SUDDEN-DEATH AB Background-In hypertrophic cardiomyopathy (HCM), myocardial abnormalities are commonly heterogeneous. Two patterns of late gadolinium enhancement (LGE) have been reported: a bright "confluent" and an intermediate intensity abnormality termed "diffuse," each representing different degrees of myocardial scarring. We used MRI to study the relation between intramural cardiac function and the extent of fibrosis in HCM. The aim of this study was to determine whether excess collagen or myocardial scarring, as determined by LGE MRI, are the primary mechanisms leading to heterogeneous regional contractile function in patients with HCM. Methods and Results-Intramural left ventricular strain, transmural left ventricular function, and regions of myocardial fibrosis/scarring were imaged in 22 patients with HCM, using displacement encoding with stimulated echoes (DENSE), cine MRI, and LGE. DENSE systolic strain maps were qualitatively and quantitatively compared with LGE images. Intramural systolic strain by DENSE was significantly depressed within areas of confluent and diffuse LGE but also in the core of the most hypertrophic nonenhanced segment (all P<0.001 versus nonhypertrophied segments). DENSE demonstrated an unexpected inner rim of largely preserved contractile function and a noncontracting outer wall within hypertrophic segments in 91% of patients. Conclusions-LGE predicted some but not all of the heterogeneity of intramural contractile abnormalities. This indicates that myocardial scarring or excess interstitial collagen deposition does not fully explain the observed contractile heterogeneity in HCM. Thus, myofibril disarray or other nonfibrotic processes affect systolic function in a large number of patients with HCM. (Circ Cardiovasc Imaging. 2011;4:425-434.) C1 [Aletras, Anthony H.; Tilak, Gauri S.; Hsu, Li-Yueh; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Aletras, Anthony H.] Univ Cent Greece, Dept Comp Sci & Biomed Informat, Lamia, Greece. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bldg 10,B1D-461,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM AraiA@nhlbi.nih.gov OI Aletras, Anthony/0000-0002-3786-3817 FU National Heart, Lung and Blood Institute [Z01 HL004607-08 CE] FX This work was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, Z01 HL004607-08 CE. NR 48 TC 15 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JUL PY 2011 VL 4 IS 4 BP 425 EP 434 DI 10.1161/CIRCIMAGING.110.958751 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 794BV UT WOS:000292871000012 PM 21576279 ER PT J AU Freiberg, MS Chang, CCH Skanderson, M McGinnis, K Kuller, LH Kraemer, KL Rimland, D Goetz, MB Butt, AA Barradas, MCR Gibert, C Leaf, D Brown, ST Samet, J Kazis, L Bryant, K Justice, AC AF Freiberg, Matthew S. Chang, Chung-Chou H. Skanderson, Melissa McGinnis, Kathleen Kuller, Lewis H. Kraemer, Kevin L. Rimland, David Goetz, Matthew B. Butt, Adeel A. Barradas, Maria C. Rodriguez Gibert, Cynthia Leaf, David Brown, Sheldon T. Samet, Jeffrey Kazis, Lewis Bryant, Kendall Justice, Amy C. CA Vet Aging Cohort Study TI The Risk of Incident Coronary Heart Disease Among Veterans With and Without HIV and Hepatitis C SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE viruses; coronary disease; mortality; comorbidity ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACUTE MYOCARDIAL-INFARCTION; MICROBIAL TRANSLOCATION; CARDIOVASCULAR-DISEASE; INFECTED INDIVIDUALS; ARTERY-DISEASE; ASSOCIATION; SEROPOSITIVITY; ATHEROSCLEROSIS; PREVALENCE AB Background-Whether hepatitis C virus (HCV) confers additional coronary heart disease (CHD) risk among human immunodeficiency virus (HIV) infected individuals is unclear. Without appropriate adjustment for antiretroviral therapy, CD4 count, and HIV-1 RNA and substantially different mortality rates among those with and without HIV and HCV infection, the association between HIV, HCV, and CHD may be obscured. Methods and Results-We analyzed data on 8579 participants (28% HIV+, 9% HIV + HCV+) from the Veterans Aging Cohort Study Virtual Cohort who participated in the 1999 Large Health Study of Veteran Enrollees. We analyzed data collected on HIV and HCV status, risk factors for and the incidence of CHD, and mortality from January 2000 to July 2007. We compared models to assess CHD risk when death was treated as a censoring event and as a competing risk. During the median 7.3 years of follow-up, there were 194 CHD events and 1186 deaths. Compared with HIV - HCV - Veterans, HIV + HCV + Veterans had a significantly higher risk of CHD regardless of whether death was adjusted for as a censoring event (adjusted hazard ratio, 2.03; 95% confidence interval, 1.28 to 3.21) or a competing risk (adjusted HR, 2.45; 95% confidence interval, 1.83 to 3.27 respectively). Compared with HIV - HCV - Veterans, HIV + HCV + Veterans also had a significantly higher adjusted risk of CHD regardless of whether death was treated as a censored event (adjusted hazard ratio, 1.93; 95% confidence interval, 1.02 to 3.62) or a competing risk (adjusted hazard ratio, 1.46; 95% confidence interval, 1.03 to 2.07). Conclusions-HIV + HCV + Veterans have an increased risk of CHD compared with HIV + HCV - and HIV - HCV - Veterans. (Circ Cardiovasc Qual Outcomes. 2011;4:425-432.) C1 [Freiberg, Matthew S.; Chang, Chung-Chou H.; Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Freiberg, Matthew S.; Chang, Chung-Chou H.; Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Skanderson, Melissa; McGinnis, Kathleen; Justice, Amy C.] W Haven Vet Adm Med Ctr, VA Connecticut Hlth Care Syst, West Haven, CT USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Rimland, David] Atlanta Vet Adm Med Ctr, Atlanta, GA USA. [Goetz, Matthew B.; Leaf, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Goetz, Matthew B.; Leaf, David] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90095 USA. [Butt, Adeel A.] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Barradas, Maria C. Rodriguez] Baylor Coll Med, Houston, TX 77030 USA. [Barradas, Maria C. Rodriguez] Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Gibert, Cynthia] George Washington Univ, Sch Med, Washington, DC USA. [Gibert, Cynthia] Washington DC Vet Adm Med Ctr, Washington, DC USA. [Brown, Sheldon T.] James J Peters VA Bronx, New York, NY USA. [Brown, Sheldon T.] Mt Sinai Sch Med, New York, NY USA. [Samet, Jeffrey] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kazis, Lewis] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Bryant, Kendall] NIAAA, Bethesda, MD USA. [Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. RP Freiberg, MS (reprint author), Univ Pittsburgh, Sch Med, 230 McKee Pl, Pittsburgh, PA 15213 USA. EM freibergms@upmc.edu OI Kazis, Lewis/0000-0003-1800-5849; Samet, Jeffrey/0000-0002-0897-3400; Goetz, Matthew/0000-0003-4542-992X FU National Institute on Alcohol Abuse and Alcoholism [2U10 AA 13566, K23 AA015914]; National Heart, Lung, and Blood Institute [1RO1HL095136-03] FX This study was supported by the National Institute on Alcohol Abuse and Alcoholism (2U10 AA 13566 and K23 AA015914) and the National Heart, Lung, and Blood Institute (1RO1HL095136-03). NR 33 TC 54 Z9 56 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2011 VL 4 IS 4 BP 425 EP 432 DI 10.1161/CIRCOUTCOMES.110.957415 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 794CH UT WOS:000292872500009 PM 21712519 ER PT J AU Gadgeel, SM Ivy, P Chen, W Mauer, J Smith, D LoRusso, P AF Gadgeel, Shirish M. Ivy, Percy Chen, Wei Mauer, Joan Smith, Daryn LoRusso, Patricia TI Analysis of Lung Cancer Patients Enrolled in CTEP (Cancer Therapy Evaluation Program)-Sponsored Phase I Trials SO CLINICAL LUNG CANCER LA English DT Article DE Clinical Trials; CTEP; Non small-cell; Phase I; Small-cell ID III TRIAL; ONCOLOGY TRIALS; CLINICAL-TRIALS; CHEMOTHERAPY; DOCETAXEL; TOPOTECAN; BENEFITS; RISKS; PARTICIPANTS; PERCEPTIONS AB Introduction: A recent review of phase I trials suggests that participation in these trials can be associated with clinical benefit and the rate of drug-related deaths is low. We conducted an analysis of the Cancer Therapy Evaluation Program (CTEP)-sponsored phase I trials to assess the outcomes of lung cancer patients enrolled in phase I trials. Materials and Methods: Data from all CTEP-sponsored adult phase I trials conducted between 1997 and 2008 were analyzed. An analysis of demographics, rates of toxicities, and clinical benefit rate among patients with non small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and other cancers was conducted. Results: Of the 3560 patients enrolled in 136 phase I trials, 301 (8.5%) had NSCLC and 40 (1.1%) had SCLC. The median age of lung cancer patients, at 60 years, was significantly higher than patients with other cancers. The rest of the demographics were similar among the groups. The rate of Grade 3-5 toxicities was higher among NSCLC patients (54% versus 46%). The toxicity-related death rate was <= 1% among all groups. The clinical benefit rate and median duration in study of approximately 2 months were similar among all groups of patients. Conclusion: An analysis of the CTEP-sponsored phase I trials shows that lung cancer patients enrolled in these trials have a similar incidence of toxicity-related deaths and a similar probability of clinical benefit as patients with other cancers. These data suggest that patients with progressive lung cancer following approved therapies should be considered for phase I trials. C1 [Gadgeel, Shirish M.] Wayne State Univ, Karmanos Canc Ctr, Karmanos Canc Inst, Detroit, MI 48201 USA. [Ivy, Percy; Mauer, Joan] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Gadgeel, SM (reprint author), Wayne State Univ, Karmanos Canc Ctr, Karmanos Canc Inst, 4100 John R St,4 HWCRC, Detroit, MI 48201 USA. EM gadgeels@karmanos.org NR 24 TC 3 Z9 3 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1525-7304 J9 CLIN LUNG CANCER JI Clin. Lung Cancer PD JUL PY 2011 VL 12 IS 4 BP 218 EP 223 DI 10.1016/j.cllc.2011.03.022 PG 6 WC Oncology SC Oncology GA 795PJ UT WOS:000292985800003 PM 21726820 ER PT J AU Kristinsson, SY Minter, AR Korde, N Tan, E Landgren, O AF Kristinsson, Sigurdur Y. Minter, Alex R. Korde, Neha Tan, Esther Landgren, Ola TI Bone disease in multiple myeloma and precursor disease: novel diagnostic approaches and implications on clinical management SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE bisphosphonates; bone disease; fractures; MGUS; multiple myeloma; radiology; smoldering multiple myeloma ID CARBOXY-TERMINAL TELOPEPTIDE; UNDETERMINED SIGNIFICANCE MGUS; REDUCES SKELETAL EVENTS; B LIGAND RANKL; MONOCLONAL GAMMOPATHY; ZOLEDRONIC ACID; RECEPTOR ACTIVATOR; RANDOMIZED-TRIAL; FRACTURE RISK; WORKING GROUP AB The manifestations of bone involvement in patients with multiple myeloma (MM) can have devastating clinical effects and increase mortality. Recent studies demonstrate that patients with the precursor conditions smoldering MM (SMM) and monoclonal gammopathy of undetermined significance (MGUS) show evidence of bone disease and increased risk of fractures. The understanding of the pathogenesis of bone disease in MM has expanded in recent years. The traditional skeletal survey will probably be replaced by newer and more sensitive imaging techniques, which may have a prognostic impact and change our definition of MGUS and SMM. Bisphosphonates are recommended to prevent skeletal events in patients with MM, and have also been studied in SMM and MGUS. This article summarizes the current knowledge of bone disease in plasma cell disorders, and discusses the current standard and future role of novel imaging techniques, as well as the evidence and current guidelines for bisphosphonates in MM, SMM and MGUS. C1 [Kristinsson, Sigurdur Y.] Karolinska Univ, Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. [Minter, Alex R.; Korde, Neha; Tan, Esther; Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Korde, Neha] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Karolinska Univ, Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU National Cancer Institute, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 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 101 TC 8 Z9 12 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2011 VL 11 IS 6 BP 593 EP 603 DI 10.1586/ERM.11.44 PG 11 WC Pathology SC Pathology GA 794PH UT WOS:000292912200010 PM 21745013 ER PT J AU Carson, V Iannotti, RJ Pickett, W Janssen, I AF Carson, Valerie Iannotti, Ronald J. Pickett, William Janssen, Ian TI Urban and rural differences in sedentary behavior among American and Canadian youth SO HEALTH & PLACE LA English DT Article DE Urban-rural health; Sedentary behavior; Youth; Mediation ID PHYSICAL-ACTIVITY; SCHOOL-CHILDREN; UNITED-STATES; SCREEN TIME; ADOLESCENTS; HEALTH; ENVIRONMENT; PERCEPTION; MEDIATION; PATTERNS AB We examined relationships between urban-rural status and three screen time behaviors (television, computer, video games), and the potential mediating effect of parent and peer support on these relationships. Findings are based on American (n=8563) and Canadian (n=8990) youth in grades 6-10 from the 2005/06 Health Behavior in School-Aged Children Survey. Weekly hours of individual screen time behaviors were calculated. Urban-rural status was defined using the Beale coding system. Parent and peer support variables were derived from principal component analysis. In comparison to the referent group (non-metro adjacent), American youth in the most rural areas were more likely to be high television users and less likely to be high computer users. Conversely, Canadian youth in medium and large metropolitan areas were less likely to be high television users and more likely to be high computer users. Parent and peer support did not strongly mediate the relationships between urban-rural status and screen time. These findings suggest that interventions aiming to reduce screen time may be most effective if they consider residential location and the specific screen time behavior. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Carson, Valerie; Janssen, Ian] Queens Univ, Sch Kinesiol & Hlth Studies, Kingston, ON K7L 3N6, Canada. [Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Bethesda, MD 20892 USA. [Pickett, William; Janssen, Ian] Queens Univ, Dept Community Hlth & Epidemiol, Kingston, ON K7L 3N6, Canada. [Pickett, William] Kingston Gen Hosp, Dept Emergency Med, Kingston, ON K7L 3N6, Canada. RP Janssen, I (reprint author), Queens Univ, Sch Kinesiol & Hlth Studies, 28 Div St, Kingston, ON K7L 3N6, Canada. EM ian.janssen@queensu.ca RI Janssen, Ian/B-7700-2009 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Canadian Institutes of Health Research [2004MOP 84478, 2004MOP-CHI-128223-C]; Heart and Stroke Foundation of Canada; Public Health Agency of Canada [HT089-05205/001/SS]; CIHR-Frederick Banting and Charles Best Doctoral Award; Canada Research Chair; Ontario Ministry of Research and Innovation FX The American study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Canadian study was supported by research agreements with the Canadian Institutes of Health Research (operating Grants: 2004MOP 84478 and 2004MOP-CHI-128223-C), the Heart and Stroke Foundation of Canada, and the Public Health Agency of Canada (Contract: HT089-05205/001/SS), the latter of which funds the Canadian version of the World Health Organization Health Behaviour in School-Aged Children Survey (WHO-HBSC). The WHO-HBSC is a WHO/Euro collaborative study. International Coordinator of the 2005-2006 study: Candace Currie, University of Edinburgh, Scotland: Data Bank Manager: Oddrun Samdal, University of Bergen. Norway. VC was supported by a CIHR-Frederick Banting and Charles Best Doctoral Award. IJ was supported by a Canada Research Chair and an Early Research Award from the Ontario Ministry of Research and Innovation. NR 47 TC 5 Z9 5 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 J9 HEALTH PLACE JI Health Place PD JUL PY 2011 VL 17 IS 4 BP 920 EP 928 DI 10.1016/j.healthplace.2011.04.007 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 792ZH UT WOS:000292788400008 PM 21565545 ER PT J AU Tanpure, RP Nguyen, BL Strecker, TE Aguirre, S Sharma, S Chaplin, DJ Siim, BG Hamel, E Lippert, JW Pettit, GR Trawick, ML Pinney, KG AF Tanpure, Rajendra P. Nguyen, Benson L. Strecker, Tracy E. Aguirre, Savannah Sharma, Suman Chaplin, David J. Siim, Bronwyn G. Hamel, Ernest Lippert, John W., III Pettit, George R. Trawick, Mary Lynn Pinney, Kevin G. TI Regioselective Synthesis of Water-Soluble Monophosphate Derivatives of Combretastatin A-1 SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID VASCULAR DISRUPTING AGENTS; ANTINEOPLASTIC AGENTS; PHOSPHATE PRODRUG; A4 PHOSPHATE; CELL-GROWTH; TUMOR; TUBULIN; POTENT; INHIBITORS; THERAPY AB The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents and inhibitors of tubulin assembly (IC50 = 1-2 mu M). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regio chemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (Ic(50) > 40 mu M), as anticipated in this pure protein assay. C1 [Tanpure, Rajendra P.; Nguyen, Benson L.; Strecker, Tracy E.; Aguirre, Savannah; Trawick, Mary Lynn; Pinney, Kevin G.] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA. [Sharma, Suman; Chaplin, David J.; Siim, Bronwyn G.] OXiGENE Inc, San Francisco, CA 94080 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Pettit, George R.] Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. [Pettit, George R.] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 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; Sharma, Sanjeev Kumar/0000-0002-3273-0708 FU OXiGENE, Inc.; Welch Foundation [AA-1278]; Division of Cancer Treatment Diagnosis, NCI, DHHS [R01 CA90441-01, SR01 CA090441-07-08]; NSF [CHE-0420802]; National Cancer Institute [5R01CA140674] FX The authors are grateful to OXiGENE, Inc. (grants to K.G.P. and M.L.T.), and the Welch Foundation (grant no. AA-1278 to K.G.P.), and one of us (G.R.P.) is grateful for grants R01 CA90441-01 and SR01 CA090441-07-08 from The Division of Cancer Treatment Diagnosis, NCI, DHHS, for their financial support of this project, and to the NSF for funding the Varian 500 MHz NMR spectrometer (grant no. CHE-0420802). In addition, portions of this project were partially supported by Award Number 5R01CA140674 (to K.G.P. and M.L.T.) from the National Cancer Institute. 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. A. Ramirez (Mass Spectrometry Core Facility, Baylor University) for mass spectroscopic analysis, Dr. C. Moehnke for assistance with NMR studies, and Dr. J. Karban and Dr. M. Nemec (Director) for use of the shared Molecular Biosciences Center at Baylor University. NR 39 TC 7 Z9 8 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD JUL PY 2011 VL 74 IS 7 BP 1568 EP 1574 DI 10.1021/np200104t PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 796FB UT WOS:000293036100003 PM 21718055 ER PT J AU Zuck, KM Shipley, S Newman, DJ AF Zuck, Karina M. Shipley, Suzanne Newman, David J. TI Induced Production of N-Formyl Alkaloids from Aspergillus fumigatus by Co-culture with Streptomyces peucetius SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID EUPENICILLIUM-SHEARII; MELANOCIN-C; XANTHOCILLIN; FUNGUS; METABOLITES; FERMENTATION AB Co-culture of the fungus Aspergillus fumigatus with the bacteria Streptomyces peucetius led to the induction of production of formyl xanthocillin analogues. This mixed fermentation yielded two new metabolites, fumiformamide (1) and N,N'-((1Z,3Z)-1,4-bis(4-methoxyphenyl)buta-1,3-diene-2,3-diyl)diformamide (2), together with two known N-formyl derivatives and the xanthocillin analogue BU-4704. The structures were determined by spectroscopic methods and by comparison with literature. Cytotoxic activity of all the analogues was tested on the NCI-60 cell line screen, and compound 2 exhibited significant activity against several cell lines. The analogues did not show antimicrobial activity. C1 [Zuck, Karina M.; Shipley, Suzanne] SAIC Frederick Inc, Frederick, MD 21702 USA. [Newman, David J.] NCI, Nat Prod Branch, Frederick, MD 21702 USA. RP Zuck, KM (reprint author), SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. EM zuckk@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. We gratefully acknowledge S. Staffone, C. Manning, and K. Santullo for help with extraction and fractionation of the extracts, Q Van and K. Gustafson for running NMR experiments, L. Cartner and C. Saucedo for assistance with the IR and UV-vis spectrophotometers, and J. Whitt, J. Britt, and L. Bowles for the 60-cell-line NCI screening. NR 25 TC 31 Z9 31 U1 3 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUL PY 2011 VL 74 IS 7 BP 1653 EP 1657 DI 10.1021/np200255f PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 796FB UT WOS:000293036100016 PM 21667925 ER PT J AU Morley, JE Abbatecola, AM Argiles, JM Baracos, V Bauer, J Bhasin, S Cederholm, T Coats, AJS Cummings, SR Evans, WJ Fearon, K Ferrucci, L Fielding, RA Guralnik, JM Harris, TB Inui, A Kalantar-Zadeh, K Kirwan, BA Mantovani, G Muscaritoli, M Newman, AB Rossi-Fanelli, F Rosano, GMC Roubenoff, R Schambelan, M Sokol, GH Storer, TW Vellas, B von Haehling, S Yeh, SS Anker, SD AF Morley, John E. Abbatecola, Angela Marie Argiles, Josep M. Baracos, Vickie Bauer, Juergen Bhasin, Shalender Cederholm, Tommy Coats, Andrew J. Stewart Cummings, Steven R. Evans, William J. Fearon, Kenneth Ferrucci, Luigi Fielding, Roger A. Guralnik, Jack M. Harris, Tamara B. Inui, Akio Kalantar-Zadeh, Kamyar Kirwan, Bridget-Anne Mantovani, Giovanni Muscaritoli, Maurizio Newman, Anne B. Rossi-Fanelli, Filippo Rosano, Giuseppe M. C. Roubenoff, Ronenn Schambelan, Morris Sokol, Gerald H. Storer, Thomas W. Vellas, Bruno von Haehling, Stephan Yeh, Shing-Shing Anker, Stefan D. CA Soc Sarcopenia Cachexia Wasting TI Sarcopenia With Limited Mobility: An International Consensus SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article ID 6-MINUTE WALK DISTANCE; SKELETAL-MUSCLE STRENGTH; CROSS-SECTIONAL AREA; IANA TASK-FORCE; OLDER-ADULTS; BODY-COMPOSITION; PHYSICAL FUNCTION; GAIT SPEED; NEUROMUSCULAR ACTIVATION; PULMONARY-HYPERTENSION AB A consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders has concluded that "Sarcopenia, le, reduced muscle mass, with limited mobility" should be considered an important clinical entity and that most older persons should be screened for this condition. "Sarcopenia with limited mobility" is defined as a person with muscle loss whose walking speed is equal to or less than 1 m/s or who walks less than 400 m during a 6-minute walk, and who has a lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean of healthy persons between 20 and 30 years of age of the same ethnic group. The limitation in mobility should not clearly be a result of otherwise defined specific diseases of muscle, peripheral vascular disease with intermittent claudication, central and peripheral nervous system disorders, or cachexia. Clinically significant interventions are defined as an increase in the 6-minute walk of at least 50 meters or an increase of walking speed of at least 0.1 m/s. (J Am Med Dir Assoc 2011; 12: 403-409) C1 [Morley, John E.] St Louis Univ, Sch Med, Div Geriatr Med, St Louis, MO 63104 USA. [Morley, John E.] VA Med Ctr, GRECC, St Louis, MO USA. [Abbatecola, Angela Marie] INRCA, Sci Direct, Ancona, Italy. [Argiles, Josep M.] Univ Barcelona, Dept Biochem, Barcelona, Spain. [Baracos, Vickie] Univ Alberta, Dept Oncol, Edmonton, AB T6G 2M7, Canada. [Bauer, Juergen] Geriatr Ctr Oldenberg, Oldenburg, Germany. [Bauer, Juergen] Univ Erlangen Nurnberg, Dept Geriatr Med, Nurnberg, Germany. [Bhasin, Shalender; Storer, Thomas W.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Cederholm, Tommy] Univ Uppsala Hosp, Uppsala, Sweden. [Coats, Andrew J. Stewart] Univ E Anglia, Norwich NR4 7TJ, Norfolk, England. [Cummings, Steven R.] Univ Calif San Francisco, San Francisco Coordinating Ctr, San Francisco, CA 94143 USA. [Cummings, Steven R.; Schambelan, Morris] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Cummings, Steven R.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Evans, William J.] GlaxoSmithKline Inc, Muscle Metab Discovery Performance Unit, Durham, NC USA. [Evans, William J.] Duke Univ, Dept Med, Durham, NC USA. [Evans, William J.] Duke Univ, Dept Geriatr, Durham, NC USA. [Fearon, Kenneth] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fearon, Kenneth] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. [Ferrucci, Luigi; Guralnik, Jack M.; Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Fielding, Roger A.] Tufts Univ, Sch Med, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Exercise Physiol & Sarcopenia Lab, Boston, MA 02111 USA. [Inui, Akio] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Psychosomat Internal Med, Kagoshima 890, Japan. [Kalantar-Zadeh, Kamyar] David Geffen UCLA Sch Med, Harold Simmons Ctr, Div Nephrol, Torrance, CA USA. [Kalantar-Zadeh, Kamyar] David Geffen UCLA Sch Med, Harold Simmons Ctr, Div Nephrol, Los Angeles, CA USA. [Kalantar-Zadeh, Kamyar] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Kalantar-Zadeh, Kamyar] Harbor UCLA Med Ctr, Los Angeles, CA USA. [Kirwan, Bridget-Anne] SOCAR Res, Nyon, Switzerland. [Mantovani, Giovanni] Univ Cagliari, Sch Med, Dept Med Oncol, Cagliari, Italy. [Muscaritoli, Maurizio] Univ Roma La Sapienza, Internal Med & Clin Nutr Management Unit, Rome, Italy. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Pittsburgh, PA USA. [Rossi-Fanelli, Filippo] Univ Rome, Rome, Italy. [Rosano, Giuseppe M. C.] IRCCS, Med Sci Ctr Clin & Expt Med, San Raffael, Italy. [Roubenoff, Ronenn] Novartis Inst Biomed Res, Boston, MA USA. [Roubenoff, Ronenn] Tufts Med Ctr, Dept Med, Boston, MA USA. [Schambelan, Morris] Univ Calif San Francisco, Div Endocrinol, San Francisco, CA 94143 USA. [Sokol, Gerald H.] Tampa Gen Hosp, Moffitt Canc Ctr, Tampa, FL 33606 USA. [Sokol, Gerald H.] US FDA, Tampa, FL USA. [Vellas, Bruno] Toulouse Univ Hosp, Toulouse, France. [von Haehling, Stephan] Charite, Dept Cardiol, Berlin, Germany. [Yeh, Shing-Shing] Stony Brook Univ Hosp, Northport VAMC & Med, Stony Brook, NY USA. [Anker, Stefan D.] Charite Campus Virchow Klinikum, Dept Cardiol, Berlin, Germany. RP Morley, JE (reprint author), St Louis Univ, Sch Med, Div Geriatr Med, 1402 S Grand Blvd,M238, St Louis, MO 63104 USA. EM morley@slu.edu RI morley, john/F-9177-2011; Newman, Anne/C-6408-2013; Rossi Fanelli, Filippo/E-9587-2011; OI morley, john/0000-0001-6444-2965; Newman, Anne/0000-0002-0106-1150; Rossi Fanelli, Filippo/0000-0002-8674-1672; Kirwan, Bridget-Anne/0000-0002-3814-3598; Baracos, Vickie/0000-0002-9609-1001; Kalantar-Zadeh, Kamyar/0000-0002-8666-0725 FU Intramural NIH HHS [Z01 AG000015-49] NR 93 TC 263 Z9 266 U1 14 U2 47 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD JUL PY 2011 VL 12 IS 6 BP 403 EP 409 DI 10.1016/j.jamda.2011.04.014 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 795SS UT WOS:000292996700005 PM 21640657 ER PT J AU McGowan, PM Simedrea, C Ribot, EJ Foster, PJ Palmieri, D Steeg, PS Allan, AL Chambers, AF AF McGowan, Patricia M. Simedrea, Carmen Ribot, Emeline J. Foster, Paula J. Palmieri, Diane Steeg, Patricia S. Allan, Alison L. Chambers, Ann F. TI Notch1 Inhibition Alters the CD44(hi)/CD24(lo) Population and Reduces the Formation of Brain Metastases from Breast Cancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID ALDEHYDE DEHYDROGENASE-ACTIVITY; MAMMARY STEM-CELLS; INITIATING CELLS; OVARIAN-CANCER; IN-VITRO; EXPRESSION; ACTIVATION; SURVIVAL; GENES; MODEL AB Brain metastasis from breast cancer is an increasingly important clinical problem. Here we assessed the role of CD44(hi)/CD24(lo) cells and pathways that regulate them, in an experimental model of brain metastasis. Notch signaling (mediated by gamma-secretase) has been shown to contribute to maintenance of the cancer stem cell (CSC) phenotype. Cells sorted for a reduced stem-like phenotype had a reduced ability to form brain metastases compared with unsorted or CD44(hi)/CD24(lo) cells (P < 0.05; Kruskal-Wallis). To assess the effect of gamma-secretase inhibition, cells were cultured with DAPT and the CD44/CD24 phenotypes quantified. 231-BR cells with a CD44(hi)/CD24(lo) phenotype was reduced by about 15% in cells treated with DAPT compared with DMSO-treated or untreated cells (P = 0.001, ANOVA). In vivo, mice treated with DAPT developed significantly fewer micro- and macrometastases compared with vehicle treated or untreated mice (P = 0.011, Kruskal-Wallis). Notch1 knockdown reduced the expression of CD44(hi)/CD24(lo) phenotype by about 20%. In vitro, Notch1 shRNA resulted in a reduction in cellular growth at 24, 48, and 72 hours time points (P = 0.033, P = 0.002, and P = 0.009, ANOVA) and about 60% reduction in Matrigel invasion was observed (P < 0.001, ANOVA). Cells transfected with shNotch1 formed significantly fewer macrometastases and micrometastases compared with scrambled shRNA or untransfected cells (P < 0.001; Kruskal-Wallis). These data suggest that the CSC phenotype contributes to the development of brain metastases from breast cancer, and this may arise in part from increased Notch activity. Mol Cancer Res; 9(7); 834-44. (C)2011 AACR. C1 [McGowan, Patricia M.; Simedrea, Carmen; Foster, Paula J.; Chambers, Ann F.] Univ Western Ontario, Dept Med Biophys, London, ON, Canada. [Allan, Alison L.; Chambers, Ann F.] Univ Western Ontario, Dept Oncol, London, ON, Canada. [Allan, Alison L.] Univ Western Ontario, Dept Anat & Cell Biol, London, ON, Canada. [Ribot, Emeline J.; Foster, Paula J.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada. [Palmieri, Diane; Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP McGowan, PM (reprint author), St Vincents Univ Hosp, Educ & Res Ctr, Elm Pk, Dublin 4, Ireland. EM patricia.mcgowan@ucd.ie RI Foster, Paula/M-2201-2013; Palmieri, Diane/B-4258-2015; Chambers, Ann/L-6285-2015; OI Foster, Paula/0000-0002-4868-3395; Chambers, Ann/0000-0002-9509-5123; McGowan, Patricia/0000-0003-3936-2503 FU US Department of Defense [W81XWH-06-2-0033]; Translational Breast Cancer Research Training Program at the London Regional Cancer Program; Ontario Institute of Cancer Research [08NOV-230]; Canadian Institutes of Health Research; Canada Research Chairs Program FX This research was supported by grant #W81XWH-06-2-0033 US Department of Defense Breast Cancer Research Program (A.F. Chambers, P.J. Foster, and P.S. Steeg). P.M. McGowan was the recipient of a Postdoctoral Fellowship from the Translational Breast Cancer Research Training Program at the London Regional Cancer Program. A.L. Allan is supported by research funding from the Ontario Institute of Cancer Research (#08NOV-230) and a Canadian Institutes of Health Research New Investigator Award. A.F. Chambers is Canada Research Chair in Oncology, supported by the Canada Research Chairs Program. NR 58 TC 56 Z9 58 U1 0 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUL PY 2011 VL 9 IS 7 BP 834 EP 844 DI 10.1158/1541-7786.MCR-10-0457 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 794DG UT WOS:000292875000003 PM 21665937 ER PT J AU Putney, JW AF Putney, James W. TI The Physiological Function of Store-operated Calcium Entry SO NEUROCHEMICAL RESEARCH LA English DT Article DE Calcium channels; Store-operated channels; Calcium signaling; Ion channels; Orai; STIM; Calcium oscillations ID INTRACELLULAR CA2+ STORES; PAROTID ACINAR-CELLS; SMOOTH-MUSCLE-CELLS; RECEPTOR POTENTIAL CHANNELS; ACTIVATES CRAC CHANNELS; EMBRYONIC KIDNEY-CELLS; TYROSINE KINASE SYK; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; CATION CHANNELS AB Store-operated Ca(2+) entry is a process whereby the depletion of intracellular Ca(2+) stores signals the opening of plasma membrane Ca(2+) channels. It has long been thought that the main function of store-operated Ca(2+) entry was the replenishment of intracellular Ca(2+) stores following their discharge during intracellular Ca(2+) signaling. Recent results, however, suggest that the primary function of these channels may be to provide direct Ca(2+) signals to recipients localized to spatially restricted areas close to the sites of Ca(2+) entry in order to initiate specific signaling pathways. C1 Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov FU National Institutes of Health, NIEHS FX Drs. Stephen Shears and David Armstrong read the manuscript and provided helpful comments. Work from the author's laboratory discussed in this review was supported by the Intramural Program of the National Institutes of Health, NIEHS. NR 114 TC 36 Z9 37 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUL PY 2011 VL 36 IS 7 SI SI BP 1157 EP 1165 DI 10.1007/s11064-010-0383-0 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 794NU UT WOS:000292907700003 PM 21234676 ER PT J AU Yang, DK Shcheynikov, N Muallem, S AF Yang, Dongki Shcheynikov, Nikolay Muallem, Shmuel TI IRBIT: It Is Everywhere SO NEUROCHEMICAL RESEARCH LA English DT Article DE IRBIT; IP3 receptors; NBCe1-B; CFTR; NHE3; Fip1 ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; TRANSMEMBRANE CONDUCTANCE REGULATOR; HCO3-SALVAGE MECHANISMS; NA+/H+ EXCHANGER NHE3; BINDING PROTEIN; IP3 RECEPTOR; PANCREATIC-DUCT; MEMBRANE LOCALIZATION; NA+-HCO3-COTRANSPORT; FUNCTIONAL EXPRESSION AB IRBIT (IP(3)Rs binding protein released with IP3) is a protein originally identified by the Mikoshiba group as an inhibitor of IP3 receptors function. Subsequently it was found to have multiple functions and regulate the activity of diverse proteins, including regulation of HCO3- transporters to coordinate epithelial HCO3- secretion and to determine localization of the Fip1 subunit of the CPSF complex to regulate mRNA processing. This review highlights the remarkably divers functions of IRBIT that are likely only a fraction of all the potential functions of this protein. C1 [Yang, Dongki; Shcheynikov, Nikolay; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Muallem, S (reprint author), NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1N-113, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov FU NIDCR NIH HHS [R01 DE012309, R01 DE012309-14] NR 64 TC 13 Z9 13 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUL PY 2011 VL 36 IS 7 SI SI BP 1166 EP 1174 DI 10.1007/s11064-010-0353-6 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 794NU UT WOS:000292907700004 PM 21152975 ER PT J AU Ambudkar, IS AF Ambudkar, Indu S. TI Dissection of Calcium Signaling Events in Exocrine Secretion SO NEUROCHEMICAL RESEARCH LA English DT Article DE Calcium homeostasis; Calcium influx; Ion channels; Fluid secretion; Salivary gland cells; Physiology; Knockout-mouse models ID PROTEIN-COUPLED-RECEPTORS; STORE-OPERATED CHANNELS; SALIVARY-GLAND CELLS; PAROTID ACINAR-CELLS; TRPC CHANNELS; MOLECULAR-BASIS; CRAC CHANNEL; CA2+ INFLUX; ORAI1; STIM1 AB The secretion of fluid and electrolytes by salivary gland acinar cells requires the coordinated regulation of multiple ion channel and transporter proteins, signaling components, and water transport. Importantly, neurotransmitter stimulated increase in the cytosolic free [Ca(2+)] ([Ca(2+)](i)) is critical for the regulation of salivary gland secretion as it regulates several major ion fluxes that together establish the sustained osmotic gradient to drive fluid secretion. The mechanisms that act to modulate these increases in [Ca(2+)] i are therefore central to the process of salivary fluid secretion. Such modulation involves membrane receptors for neurotransmitters, as well as mechanisms that mediate intracellular Ca(2+) release, and Ca(2+) entry, as well as those that maintain cellular Ca(2+) homeostasis. Together, these mechanisms determine the spatial and temporal aspects of the [Ca(2+)] i signals that regulate fluid secretion. Molecular cloning of these transporters and channels as well as development of mice lacking these proteins has established the physiological significance of key components that are involved in regulating [Ca(2+)] i in salivary glands. This review will discuss these important studies and the findings which have led to resolution of the Ca(2+) signaling mechanisms that determine salivary gland fluid secretion. C1 Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Room 1N 113, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov FU Intramural NIH HHS [ZIA DE000438-26] NR 51 TC 22 Z9 22 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUL PY 2011 VL 36 IS 7 SI SI BP 1212 EP 1221 DI 10.1007/s11064-011-0465-7 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 794NU UT WOS:000292907700008 PM 21534000 ER PT J AU He, XJ Takahashi, S Suzuki, H Hashikawa, T Kulkarni, AB Mikoshiba, K Ohshima, T AF He, Xiaojuan Takahashi, Satoru Suzuki, Hiromi Hashikawa, Tsutomu Kulkarni, Ashok B. Mikoshiba, Katsuhiko Ohshima, Toshio TI Hypomyelination Phenotype Caused by Impaired Differentiation of Oligodendrocytes in Emx1-cre Mediated Cdk5 Conditional Knockout Mice SO NEUROCHEMICAL RESEARCH LA English DT Article DE Cyclin-dependent kinase 5; Oligodendrocyte differentiation; Hypomyelination; Conditional knockout mice ID CYCLIN-DEPENDENT KINASE-5; CENTRAL-NERVOUS-SYSTEM; SHAKING RAT KAWASAKI; TRANSCRIPTIONAL CONTROL; NEURONAL MIGRATION; CEREBRAL-CORTEX; P35; EXPRESSION; DISRUPTION; PATTERNS AB Cyclin-dependent kinase 5 (Cdk5) plays a pivotal role in neuronal migration and differentiation, and in axonal elongation. Although many studies have been conducted to analyze neuronal functions of Cdk5, its kinase activity has also been reported during oligodendrocyte differentiation, which suggests Cdk5 may play an important role in oligodendrocytes. Here, we describe a hypomyelination phenotype observed in Emx1-cre mediated Cdk5 conditional knockout (cKO) mice (Emx1-cKO), in which the Cdk5 gene was deleted in neurons, astrocytes and oligodendrocyte -lineage cells. In contrast, the Cdk5 gene in CaMKII cKO mice was deleted only in neurons. Because the development of mature oligodendrocytes from oligodendrocyte precursor cells is a complex process, we performed in situ hybridization using markers for the oligodendrocyte precursor cell and for the differentiated oligodendrocyte. Our results indicate that hypomyelination in Emx1-cKO is due to the impaired differentiation of oligodendrocytes, rather than to the proliferation or migration of their precursors. The present study confirmed the in vivo role of Cdk5 in oligodendrocyte differentiation. C1 [He, Xiaojuan; Ohshima, Toshio] Waseda Univ, Dept Life Sci & Med Biosci, Shinjuku Ku, Tokyo 1628480, Japan. [Takahashi, Satoru] Asahikawa Med Coll, Dept Pediat, Asahikawa, Hokkaido 0788510, Japan. [Suzuki, Hiromi; Mikoshiba, Katsuhiko] RIKEN, Brain Sci Inst, Dev Neurobiol Lab, Wako, Saitama 3510198, Japan. [Hashikawa, Tsutomu] RIKEN, Brain Sci Inst, Support Unit Neuromorphol Anal, Wako, Saitama 3510198, Japan. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Ohshima, T (reprint author), Waseda Univ, Dept Life Sci & Med Biosci, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan. EM ohshima@waseda.jp RI Mikoshiba, Katsuhiko/N-7943-2015 FU Intramural NIH HHS [Z01 DE000664-12] NR 41 TC 7 Z9 9 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUL PY 2011 VL 36 IS 7 SI SI BP 1293 EP 1303 DI 10.1007/s11064-010-0391-0 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 794NU UT WOS:000292907700017 PM 21210220 ER PT J AU Gan, CP Zain, RB Abraham, MT Patel, V Gutkind, JS Cheong, SC Chong, CE Hamid, S Teo, SH AF Gan, C. P. Zain, R. Binti Abraham, M. T. Patel, V. Gutkind, J. S. Cheong, S. C. Chong, Chan Eng Hamid, Sharifah Teo, Soo Hwang TI Expression of GNA12 and its role in oral cancer SO ORAL ONCOLOGY LA English DT Meeting Abstract CT 3rd World Congress of the International-Academy-of-Oral-Oncology CY JUL 14-17, 2011 CL Singapore, SINGAPORE SP Int Acad Oral Oncol C1 [Gan, C. P.; Cheong, S. C.; Chong, Chan Eng; Hamid, Sharifah; Teo, Soo Hwang] Canc Res Initiat Fdn CARIF, Oral Canc Res Team, Subang Jaya, Selangor, Malaysia. [Gan, C. P.; Zain, R. Binti] Univ Malaya, Fac Dent, Dept Oral Pathol Oral Med & Periodontol, Kuala Lumpur, Malaysia. [Zain, R. Binti] Univ Malaya, Oral Canc Res & Coordinating Ctr OCRCC, Kuala Lumpur, Malaysia. [Abraham, M. T.] Tengku Ampuan Rahimah Hosp, Dept Oral & Maxillofacial Surg, Klang, Selangor, Malaysia. [Patel, V.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Cheong, S. C.] Univ Malaya, Dept Oral & Maxillofacial Surg, Fac Dent, Kuala Lumpur, Malaysia. RI Zain, Rosnah/B-8054-2010; Gutkind, J. Silvio/A-1053-2009; Management Center, Dental Research/C-2478-2013 NR 0 TC 2 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2011 VL 47 SU 1 BP S114 EP S115 DI 10.1016/j.oraloncology.2011.06.369 PG 2 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 793IX UT WOS:000292815100335 ER PT J AU Gutkind, JS AF Gutkind, J. Silvio TI Emerging animal models for the functional genomics analysis of the oral cancer oncogenome SO ORAL ONCOLOGY LA English DT Meeting Abstract CT 3rd World Congress of the International-Academy-of-Oral-Oncology CY JUL 14-17, 2011 CL Singapore, SINGAPORE SP Int Acad Oral Oncol C1 [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RI Gutkind, J. Silvio/A-1053-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2011 VL 47 SU 1 BP S13 EP S14 DI 10.1016/j.oraloncology.2011.06.061 PG 2 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 793IX UT WOS:000292815100035 ER PT J AU Spelman, K Depoix, D McCray, M Mouray, E Grellier, P AF Spelman, Kevin Depoix, Delphine McCray, Megan Mouray, Elisabeth Grellier, Philippe TI The Traditional Medicine Spilanthes acmella, and the Alkylamides Spilanthol and Undeca-2E-ene-8,10-diynoic Acid Isobutylamide, Demonstrate In Vitro and In Vivo Antimalarial Activity SO PHYTOTHERAPY RESEARCH LA English DT Article DE Plasmodium falciparum; alkylamides; deca-2E,6Z,8E-trienoic acid isobutylamide; malaria; traditional medicine; phytotherapy AB Spilanthes spp. are used as traditional herbal medicines in Africa and India to treat malaria. Yet, to date, there are no data on the active constituents or the most effective extraction methods for this indication. The isolated alkylamides, spilanthol and undeca-2E-ene-8,10-diynoic acid isobutylamide, found in S. acmella Murr., were shown to have IC(50)s of 16.5 mu g/mL and 41.4 mu g/mL on Plasmodium falciparum strain PFB and IC(50)s of 5.8 mu g/mL and 16.3 mu g/mL for the chloroquine resistant P. falciparum K1 strain, respectively. Further investigations revealed that at relatively low concentrations, spilanthol and the water extract of S. acmella reduced the parasitemia 59% and 53% in mice infected with P. yoelii yoelii 17XNL at 5 mg/kg and 50 mg/kg, respectively. Unexpectedly, the 95% ethanol extract of S. acmella was less effective (36% reduction in parasitemia) at 50 mg/kg. These results provide the first evidence supporting S. acmella against malaria and demonstrating active constituents in S. acmella against P. falciparum. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Spelman, Kevin] NIA, NIH, Clin Invest Lab, Baltimore, MD 21224 USA. [McCray, Megan] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27412 USA. [Depoix, Delphine; Mouray, Elisabeth; Grellier, Philippe] Museum Natl Hist Nat, CNRS, FRE 3206, Dept Regulat Dev & Divers Mol, Paris, France. RP Spelman, K (reprint author), NIA, NIH, Clin Invest Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM phytochemks@gmail.com FU National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health [1R15AT001466-01]; Marie Curie Foundation at the Museum National d'Histoire Naturelle, Paris; Laboratoire of Pharmacognosy, Universite Paris [11]; National Science Foundation [0420292] FX This publication was made possible by grant number 1R15AT001466-01 from the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health and the Marie Curie Foundation which provided an early stage training fellowship for KS at the Museum National d'Histoire Naturelle, Paris and the Laboratoire of Pharmacognosy, Universite Paris 11. Additional support was provided by the National Science Foundation under grant number 0420292. Special thanks to Nadja Cech for providing the spilanthol and S. acmella extracts. NR 11 TC 11 Z9 11 U1 3 U2 40 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0951-418X J9 PHYTOTHER RES JI Phytother. Res. PD JUL PY 2011 VL 25 IS 7 BP 1098 EP 1101 DI 10.1002/ptr.3395 PG 4 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 796DW UT WOS:000293031400021 PM 22692989 ER PT J AU Silvera, SAN Mayne, ST Risch, HA Gammon, MD Vaughan, T Chow, WH Dubin, JA Dubrow, R Schoenberg, J Stanford, JL West, AB Rotterdam, H Blot, WJ AF Silvera, Stephanie A. Navarro Mayne, Susan T. Risch, Harvey A. Gammon, Marilie D. Vaughan, Thomas Chow, Wong-Ho Dubin, Joel A. Dubrow, Robert Schoenberg, Janet Stanford, Janet L. West, A. Brian Rotterdam, Heidrun Blot, William J. TI Principal Component Analysis of Dietary and Lifestyle Patterns in Relation to Risk of Subtypes of Esophageal and Gastric Cancer SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Esophageal Adenocarcinoma; Gastric Cardia Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Diet; Principal Components ID BODY-MASS INDEX; SQUAMOUS-CELL CARCINOMA; GASTROESOPHAGEAL-REFLUX DISEASE; GUIDELINES-FOR-AMERICANS; MAJOR CHRONIC DISEASE; BARRETTS-ESOPHAGUS; RISING INCIDENCE; NUTRIENT INTAKE; ADENOCARCINOMA; CARDIA AB PURPOSE: To carry out pattern analyses of dietary and lifestyle factors in relation to risk of esophageal and gastric cancers. METHODS: We evaluated risk factors for esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GC:A), and other gastric cancers (OGA) using data from a population-based case-control study conducted in Connecticut, New Jersey, and western Washington state. Dietary/lifestyle patterns were created using principal component analysis (PCA). Impact of the resultant scores on cancer risk was estimated through logistic regression. RESULTS: PCA identified six patterns: meat/nitrite, fruit/vegetable, smoking/alcohol, legume/meat alternate, GERD/BMI, and fish/vitamin C. Risk of each cancer under study increased with rising meat/nitrite score. Risk of EA increased with increasing GERD/BMI score, and risk of ESCC rose with increasing smoking/alcohol score and decreasing gastroesophageal reflux disease (GERD)/body mass index (BMI) score. Fruit/vegetable scores were inversely associated with EA, ESCC, and GCA. CONCLUSIONS: PCA may provide a useful approach for summarizing extensive dietary/lifestyle data into fewer interpretable combinations that discriminate between cancer cases and controls. The analyses suggest that meat/nitrite intake is associated with elevated risk of each cancer under study, whereas fruit/vegetable intake reduces risk of EA, ESCC, and GCA. GERD/obesity were confirmed as risk factors for EA and smoking/alcohol as risk factors for ESCC. Ann Epidemiol 2011;21:543-550. (C) 2011 Elsevier Inc. All rights reserved. C1 [Silvera, Stephanie A. Navarro] Montclair State Univ, Dept Hlth & Nutr Sci, Montclair, NJ 07043 USA. [Mayne, Susan T.; Risch, Harvey A.; Dubrow, Robert] Yale Univ, Sch Publ Hlth, Div Chron Dis Epidemiol, New Haven, CT USA. [West, A. Brian] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Vaughan, Thomas; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Vaughan, Thomas; Stanford, Janet L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Schoenberg, Janet] New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ USA. [Rotterdam, Heidrun] Columbia Univ, Dept Pathol, New York, NY USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.] Vanderbilt Univ, Nashville, TN USA. [Dubin, Joel A.] Univ Waterloo, Dept Stat & Actuarial Sci, Waterloo, ON N2L 3G1, Canada. [Dubin, Joel A.] Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. RP Silvera, SAN (reprint author), Montclair State Univ, Dept Hlth & Nutr Sci, 1 Normal Ave, Montclair, NJ 07043 USA. EM silveras@mail.montclair.edu FU United States Public Health Service [U01-CA57983, U01-CA57949, U01-CA57923, P30ES10126]; National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Institutes of Health; Department of Health and Human Services [N02-CP40501, N01-CN05230] FX We thank the following: study managers Ms. Sarah Greene and Ms. Linda Lannom (Westat), data management Ms. Shelley Niwa (Westar), and field supervisors Mrs. Patricia Owen (Connecticut), Mr. Tom English (New Jersey), and Ms. Berta Nicol-Blades (Washington) for data collection and processing; Dr. Alan Kristal for assistance in designing and processing the dietary questionnaires; the Yale Cancer Center Rapid Case Ascertainment Shared Resource, the 178 hospitals in Connecticut, New Jersey, and Washington for their participation in the study; and the study participants. This research was supported [in part] by United States Public Health Service (U01-CA57983, U01-CA57949, U01-CA57923, P30ES10126), the National Cancer Institute, Division of Cancer Epidemiology and Genetics, the Intramural Research Program of the National Institutes of Health, and the Department of Health and Human Services (N02-CP40501, N01-CN05230). NR 53 TC 30 Z9 31 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUL PY 2011 VL 21 IS 7 BP 543 EP 550 DI 10.1016/j.annepidem.2010.11.019 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 779GW UT WOS:000291767100009 ER PT J AU Soderholm, JF Bird, SL Kalab, P Sampathkumar, Y Hasegawa, K Uehara-Bingen, M Weis, K Heald, R AF Soderholm, Jonathan F. Bird, Stephen L. Kalab, Petr Sampathkumar, Yasaswini Hasegawa, Keisuke Uehara-Bingen, Michael Weis, Karsten Heald, Rebecca TI Importazole, a Small Molecule Inhibitor of the Transport Receptor Importin-beta SO ACS CHEMICAL BIOLOGY LA English DT Article ID NUCLEAR-PROTEIN IMPORT; DIFFERENTIAL SCANNING FLUOROMETRY; RAN-GTP; EGG EXTRACTS; IN-VITRO; COMPLEX; EXPORT; MOTOR; CRM1; IDENTIFICATION AB During interphase, the transport receptor importin-beta carries cargoes into the nucleus, where,RanGTP releases them. A similar mechanism operates in mitosis to generate a gradient of active spindle assembly factors around mitotic chromosomes. Importin-beta and RanGTP have been implicated in additional cellular processes, but the precise, roles of the Ran/importin-beta pathway throughout the cell cycle remain poorly understood. We implemented a FRET-based, high-throughput small molecule screen for compounds that interfere with the interaction between RanGTP and importin-beta and identified importazole, a 2,4-diaminoquinazoline. Importazole specifically blocks importin-beta-mediated nuclear import both in-Xenopus egg extracts and cultured cells, without disrupting transportin-mediated nuclear import or CRM1-mediated nuclear export. When added during mitosis, importazole impairs the release of an importin-beta cargo FRET probe and causes both predicted and novel defects in spindle assembly. Together, these results indicate that importazole specifically inhibits the function of importin-beta, likely by altering its interaction with RanGTP. Importazole is a valuable tool to evaluate the function of the importin-beta/RanGTP pathway at specific stages during the cell cycle. C1 [Soderholm, Jonathan F.; Bird, Stephen L.; Kalab, Petr; Sampathkumar, Yasaswini; Weis, Karsten; Heald, Rebecca] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Kalab, Petr; Hasegawa, Keisuke] NCI, NIH, Bethesda, MD 20892 USA. [Uehara-Bingen, Michael] Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94158 USA. RP Weis, K (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, MC 3200 LSA, Berkeley, CA 94720 USA. EM kweis@berkeley.edu; bheald@berkeley.edu RI Weis, Karsten/F-5719-2011; Kalab, Petr/B-2478-2009 OI Weis, Karsten/0000-0001-7224-925X; FU National Institutes of Health [R01 GM065232, R21 NS53592]; Cancer Research Coordinating Committee; Center for Cancer Research, NCI, National Institutes of Health FX The authors thank Brian Wolff Janice Williams, Brian Feng, and James Wells at the Small Molecule Discovery Center at UCSF for help with the screen, Elisa Dultz for live cell imaging of imporatzole effects, Karin Reif for NFAT cDNA, David Halpin for biotin-labeled RCC1, and Lili Wang at the Broad Institute for developing the thermal shift assay to probe binding of importazole to importin-beta. This work was supported by the National Institutes of Health (R01 GM065232 and R21 NS53592, K.W. and RH.), the Cancer Research Coordinating Committee (S.L.B.), and the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health (P.K. and K.H.). NR 43 TC 56 Z9 58 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUL PY 2011 VL 6 IS 7 BP 700 EP 708 DI 10.1021/cb2000296 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 793VB UT WOS:000292850900005 PM 21469738 ER PT J AU Ruder, EH Laiyemo, AO Graubard, BI Hollenbeck, AR Schatzkin, A Cross, AJ AF Ruder, Elizabeth H. Laiyemo, Adeyinka O. Graubard, Barry I. Hollenbeck, Albert R. Schatzkin, Arthur Cross, Amanda J. TI Non-Steroidal Anti-Inflammatory Drugs and Colorectal Cancer Risk in a Large, Prospective Cohort SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID LOW-DOSE ASPIRIN; FAMILIAL ADENOMATOUS POLYPOSIS; SERVICES-TASK-FORCE; PRIMARY PREVENTION; WOMENS HEALTH; FOLLOW-UP; COLON; INFLAMMATION; EXPRESSION; PARADIGM AB OBJECTIVES: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been inversely associated with colorectal cancer; however, the association within colorectal subsites or among higher risk individuals is understudied. We investigated NSAID use and colorectal adenocarcinoma by subsite, and among individuals with a family history of colon cancer in the National Institutes of Health-AARP Diet and Health Study. METHODS: Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer incidence among 301,240 men and women (mean age 62.8 years); including 26,994 individuals with a first-degree relative with a history of colon cancer. We accrued 3,894 colorectal cancer cases during 10 years of follow-up; 372 cases had a first-degree relative with colon cancer. RESULTS: Both aspirin and non-aspirin NSAID use reduced colorectal cancer risk (HR for users compared with non-users = 0.91, 95% CI: 0.85, 0.98; HR = 0.82, 95% CI: 0.77, 0.87, respectively). Daily aspirin use reduced the risk of cancer in the distal colon (HR = 0.84, 95% CI: 0.71, 0.99) and rectum (HR = 0.76, 95% CI: 0.64, 0.90); daily non-aspirin NSAID use reduced the risk of both proximal (HR = 0.65, 95% CI: 0.54, 0.78) and distal colon cancer (HR = 0.69, 95% CI: 0.55, 0.87), but not rectal cancer. Among participants with a first-degree relative with colon cancer, daily use of aspirin was associated with a decreased risk of rectal cancer (HR = 0.38, 95% CI: 0.19, 0.78), and daily use of non-aspirin NSAIDs was associated with a decreased risk of colon cancer (HR = 0.49, 95% CI: 0.29, 0.82). No protective benefit for daily aspirin use and colon cancer or daily non-aspirin NSAID use and rectal cancer was observed in this higher risk subgroup, although power was limited by small case numbers. CONCLUSIONS: NSAID use was associated with a reduced colorectal cancer risk; the magnitude of this association differed between aspirin and non-aspirin NSAIDs. Daily aspirin and non-aspirin NSAID use by individuals with a family history of colon cancer significantly reduced the risk of rectal and colon cancer, respectively. C1 [Ruder, Elizabeth H.; Graubard, Barry I.; Schatzkin, Arthur; Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20852 USA. [Ruder, Elizabeth H.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, NIH,US Dept HHS, Rockville, MD 20852 USA. [Laiyemo, Adeyinka O.] Howard Univ, Dept Med, Washington, DC 20059 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Ruder, EH (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Executive Blvd, Rockville, MD 20852 USA. EM rudereh@mail.nih.gov FU National Institutes of Health, National Cancer Institute; Florida Department of Health (FDOH) FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University; those from California by the California Department of Health Services, Cancer Surveillance Section; and those from the Detroit metropolitan area by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans; those from New Jersey by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services; and those from North Carolina by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services, and those from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. We are indebted to the participants in the National Institutes of Health-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. NR 43 TC 59 Z9 60 U1 4 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUL PY 2011 VL 106 IS 7 BP 1340 EP 1350 DI 10.1038/ajg.2011.38 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 789JG UT WOS:000292511100020 PM 21407185 ER PT J AU Kalisch, BJ Tschannen, D Lee, H Friese, CR AF Kalisch, Beatrice J. Tschannen, Dana Lee, Hyunhwa Friese, Christopher R. TI Hospital Variation in Missed Nursing Care SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE nursing; safety; quality; errors of omission ID EARLY MOBILIZATION; PATIENT OUTCOMES; STAFFING LEVELS; ERRORS; MEDICATION; AMBULATION; MORTALITY; WORKLOAD; QUALITY; NURSES AB Quality of nursing care across hospitals is variable, and this variation can result in poor patient outcomes. One aspect of quality nursing care is the amount of necessary care that is omitted. This article reports on the extent and type of nursing care missed and the reasons for missed care. The MISSCARE Survey was administered to nursing staff (n = 4086) who provide direct patient care in 10 acute care hospitals. Missed nursing care patterns as well as reasons for missing care (labor resources, material resources, and communication) were common across all hospitals. Job title (ie, registered nurse vs nursing assistant), shift worked, absenteeism, perceived staffing adequacy, and patient work loads were significantly associated with missed care. The data from this study can inform quality improvement efforts to reduce missed nursing care and promote favorable patient outcomes. C1 [Kalisch, Beatrice J.; Tschannen, Dana; Friese, Christopher R.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Lee, Hyunhwa] NINR, NIH, Bethesda, MD 20892 USA. RP Kalisch, BJ (reprint author), Univ Michigan, Sch Nursing, 400 N Ingalls 4170, Ann Arbor, MI 48109 USA. EM bkalisch@umich.edu RI Friese, Christopher/D-2097-2013 OI Friese, Christopher/0000-0002-2281-2056 FU Blue Cross Blue Shield Foundation of Michigan; R00 Pathway to Independence award [NR010750] FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: This research was supported by a research grant from the Blue Cross Blue Shield Foundation of Michigan. In addition, Dr Friese is supported by a R00 Pathway to Independence award NR010750. NR 37 TC 45 Z9 48 U1 1 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 J9 AM J MED QUAL JI Am. J. Med. Qual. PD JUL-AUG PY 2011 VL 26 IS 4 BP 291 EP 299 DI 10.1177/1062860610395929 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 792ME UT WOS:000292748900006 PM 21642601 ER PT J AU Neubauer, B Machura, K Schnermann, J Wagner, C AF Neubauer, Bjoern Machura, Katharina Schnermann, Juergen Wagner, Charlotte TI Renin expression in large renal vessels during fetal development depends on functional beta(1)/beta(2)-adrenergic receptors SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE sympathetic nervous system; renal development; cAMP signaling; ACE inhibition ID RAT JUXTAGLOMERULAR CELLS; MESSENGER-RNA EXPRESSION; BETA-2-ADRENERGIC RECEPTORS; GENE-EXPRESSION; ACE-INHIBITION; KIDNEY CORTEX; MICE; INNERVATION; MOUSE; APPARATUS AB Neubauer B, Machura K, Schnermann J, Wagner C. Renin expression in large renal vessels during fetal development depends on functional beta(1)/beta(2)-adrenergic receptors. Am J Physiol Renal Physiol 301: F71-F77, 2011. First published March 9, 2011; doi: 10.1152/ajprenal.00443.2010.-During nephrogenesis, renin expression shifts from large renal arteries toward smaller vessels in a defined spatiotemporal pattern, finally becoming restricted to the juxtaglomerular position. Chronic stimulation in adult kidneys leads to a recruitment of renin expression in the upstream vasculature. The mechanisms that control this characteristic switch-on and switch-off in the immature and adult kidney are not well-understood. Previous studies in mice with juxtaglomerular cell-specific deletion of the adenylyl cyclase-stimulatory G protein Gs alpha suggested that signaling along the cAMP pathway plays an essential role for renin expression during nephrogenesis and in the adult kidney. To identify the Gs alpha-dependent receptor that might be involved in activating this pathway, the present studies were performed to compare renin expression in wild types with that in mice with targeted deletions of beta(1) and beta(2)-adrenoceptors. The sympathetic nervous system is an important regulator of the renin system in the adult kidney so that activation of beta-adrenenoceptors may also participate in the activation of renin expression along the developing arterial tree and in upstream vasculature in adulthood. Compared with wild-types, renin expression was found to be significantly lower at all developmental stages in the kidneys of beta(1)/beta(2)Adr(-/-) mice. Three-dimensional analysis showed reduced renin expression in all segments of the vascular tree in mutants and a virtual absence of renin expression in the large arcuate arteries. Adult mutant kidneys showed the typical upstream renin expression after chronic stimulation. Tyrosine hydroxylase staining in fetal and postnatal kidneys revealed that sympathetic innervation of renin-producing cells occurs early in fetal development. Our data indicate that genetic disruption of beta-adrenergic receptors reduces basal renin expression along the developing preglomerular tree and in adult kidneys. Furthermore, beta-adrenergic receptor input is critical for the expression of renin in large renal vessels during early fetal development. C1 [Neubauer, Bjoern; Machura, Katharina; Wagner, Charlotte] Univ Regensburg, Inst Physiol, D-93040 Regensburg, Germany. [Schnermann, Juergen] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. RP Wagner, C (reprint author), Univ Regensburg, Inst Physiol, D-93040 Regensburg, Germany. EM charlotte.schmid@vkl.uni-regensburg.de FU Deutsche Forschungsgemeinschaft [SFB 699, WA 2-1] FX This study was financially supported by the Deutsche Forschungsgemeinschaft (SFB 699, WA 2-1). NR 37 TC 9 Z9 9 U1 1 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2011 VL 301 IS 1 BP F71 EP F77 DI 10.1152/ajprenal.00443.2010 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 791CY UT WOS:000292641000013 PM 21389089 ER PT J AU Stodkilde, L Norregaard, R Fenton, RA Wang, GX Knepper, MA Frokiaer, J AF Stodkilde, Lene Norregaard, Rikke Fenton, Robert A. Wang, Guixian Knepper, Mark A. Frokiaer, Jorgen TI Bilateral ureteral obstruction induces early downregulation and redistribution of AQP2 and phosphorylated AQP2 SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE water transport; membrane protein; degradation; urine-concentrating capacity ID AQUAPORIN-2 WATER CHANNEL; COLLECTING DUCT; PLASMA-MEMBRANE; VASOPRESSIN TREATMENT; EPITHELIAL-CELLS; V2 RECEPTOR; ENDOCYTOSIS; KIDNEY; UBIQUITINATION; ACCUMULATION AB Stodkilde L, Norregaard R, Fenton RA, Wang G, Knepper MA, Frokiaer J. Bilateral ureteral obstruction induces early downregulation and redistribution of AQP2 and phosphorylated AQP2. Am J Physiol Renal Physiol 301: F226-F235, 2011. First published April 27, 2011; doi:10.1152/ajprenal.00664.2010.-Bilateral ureteral obstruction (BUO) is characterized by impairment of urine flow from the kidneys and altered expression of specific membrane proteins in the kidney involved in regulation of renal water and salt transport. Importantly, 24-h BUO reduces the abundance of the collecting duct water channel aquaporin-2 (AQP2) and AQP2 phosphorylated at serine 256 (AQP2pS256). To investigate the mechanism behind downregulation of AQP2 in BUO, rats were subjected to BUO and examined after 2, 6, 12, and 24 h. Q-PCR and immunoblotting showed significantly decreased AQP2 mRNA expression after 2-h BUO and decreased abundance of total AQP2 after 12 and 24 h. In parallel, immunohistochemistry showed weaker labeling of AQP2 at the apical surface of inner medullary collecting ducts (IMCD) compared with controls. The abundance of AQP2pS256 was significantly reduced from 6-h BUO and was confirmed by immunohistochemistry. Importantly, immunoblotting showed reduced abundance of AQP2pS261 after 12- and 24-h BUO mimicking total AQP2. Immunohistochemistry demonstrated early changed intracellular localization of AQP2pS261 in BUO, and colocalization studies showed redistribution from the apical membrane to early endosomes and lysosomes. In conclusion, BUO induces a very early regulation of AQP2 both at the level of abundance and on cellular localization. AQP2 and AQP2 phosphorylated at ser261 redistribute to more intracellular localizations and colocalize with the early endosomal marker EEA1 and the lysosomal marker cathepsin D, suggesting that early downregulation of AQP2 could in part be caused by degradation of AQP2 through a lysosomal degradation pathway. C1 [Stodkilde, Lene; Norregaard, Rikke; Fenton, Robert A.; Wang, Guixian; Frokiaer, Jorgen] Univ Aarhus, Water & Salt Res Ctr, Aarhus, Denmark. [Stodkilde, Lene; Norregaard, Rikke; Wang, Guixian; Frokiaer, Jorgen] Univ Aarhus, Inst Clin Med, Aarhus, Denmark. [Fenton, Robert A.] Univ Aarhus, Inst Anat, Aarhus, Denmark. [Knepper, Mark A.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Aarhus Univ, Hosp Skejby, Water & Salt Res Ctr, Inst Clin Med, DK-8200 Aarhus, Denmark. EM JF@KI.AU.DK OI Frokiaer, Jorgen/0000-0002-6206-8065 FU Danish National Research Foundation (Danmarks Grundforskningsfond); Faculty of Health Sciences, University of Aarhus; Marie Curie Intra-European Fellowship; A. P. Moller Foundation for the Advancement of Medical Science; Aase and Ejnar Danielsen Foundation; Beckett Foundation; National Heart, Lung, and Blood Institute (National Institutes of Health) [ZO1-HL-001285] FX The Water and Salt Research Center at the University of Aarhus is established and supported by the Danish National Research Foundation (Danmarks Grundforskningsfond). L. Stodkilde is partly supported by the Faculty of Health Sciences, University of Aarhus. R. A. Fenton is supported by a Marie Curie Intra-European Fellowship. Additional funding was provided by the A. P. Moller Foundation for the Advancement of Medical Science, Aase and Ejnar Danielsen Foundation, and the Beckett Foundation. Funding to M. A. Knepper was provided by the Intramural Budget of the National Heart, Lung, and Blood Institute (National Institutes of Health Project ZO1-HL-001285). NR 43 TC 6 Z9 7 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2011 VL 301 IS 1 BP F226 EP F235 DI 10.1152/ajprenal.00664.2010 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 791CY UT WOS:000292641000030 PM 21525134 ER PT J AU Li, H Bradbury, JA Dackor, RT Edin, ML Graves, JP DeGraff, LM Wang, PM Bortner, CD Maruoka, S Lih, FB Cook, DN Tomer, KB Jetten, AM Zeldin, DC AF Li, Hong Bradbury, J. Alyce Dackor, Ryan T. Edin, Matthew L. Graves, Joan P. DeGraff, Laura M. Wang, Ping Ming Bortner, Carl D. Maruoka, Shuichiro Lih, Fred B. Cook, Donald N. Tomer, Kenneth B. Jetten, Anton M. Zeldin, Darryl C. TI Cyclooxygenase-2 Regulates Th17 Cell Differentiation during Allergic Lung Inflammation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE Th17 cell; COX-2; asthma; prostaglandins; IL-17 ID PROSTAGLANDIN E-2 PRODUCTION; RAT ALVEOLAR MACROPHAGES; HUMAN SYNOVIAL-CELLS; ROR-GAMMA-T; INDUCIBLE CYCLOOXYGENASE; STIMULATES COLLAGENASE; PROSTACYCLIN RECEPTOR; ASTHMATIC AIRWAYS; DENDRITIC CELLS; T-H-17 CELLS AB Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation. Objectives: To determine the role of COX metabolites in regulating Th17 cell differentiation and function during allergic lung inflammation. Methods: COX-1(-/-), COX-2(-/-), and wild-type mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th17 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time polymerase chain reaction, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. Measurements and Main Results: Th17 cell differentiation in lung, lymph nodes, and bronchoalveolar lavage fluid was significantly lower in COX-2(-/-) mice after ovalbumin sensitization and exposure in vivo. In vitro studies revealed significantly impaired Th17 cell differentiation of COX-2(-/-) naive CD4(+) T cells with decreased Stat3 phosphorylation and ROR gamma t expression. Synthetic PGF(2 alpha) and PGI(2) enhanced Th17 cell differentiation of COX-2(-/-) CD4(+) T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF(2 alpha) receptor and PGI(2) receptor siRNA knockdown significantly decreased Th17 cell differentiation in vitro. Administration of synthetic PGs restored accumulation of Th17 cells in lungs of allergic COX-2(-/-) mice in vivo. Conclusions: COX-2 is a critical regulator of Th17 cell differentiation during allergic lung inflammation via autocrine signaling of PGI(2) and PGF(2 alpha) through their respective cell surface receptors. C1 [Zeldin, Darryl C.] NIEHS, Div Intramural Res, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Bortner, Carl D.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Lih, Fred B.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, Lab Resp Biol, NIH, 111 TW Alexander Dr,Bldg 101,Room A222, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013; OI Jetten, Anton/0000-0003-0954-4445; Edin, Matthew/0000-0002-7042-500X FU Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences [Z01 ES025043, Z01 ES050167] FX Supported by the Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences (Z01 ES025043 and Z01 ES050167). NR 49 TC 24 Z9 29 U1 0 U2 11 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 JUL 1 PY 2011 VL 184 IS 1 BP 37 EP 49 PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 792RL UT WOS:000292766700009 PM 21474648 ER PT J AU Senbagavalli, P Anuradha, R Ramanathan, VD Kumaraswami, V Nutman, TB Babu, S AF Senbagavalli, Prakash Anuradha, Rajamanickam Ramanathan, Vadakkuppattu D. Kumaraswami, Vasanthapuram Nutman, Thomas B. Babu, Subash TI Heightened Measures of Immune Complex and Complement Function and Immune Complex-Mediated Granulocyte Activation in Human Lymphatic Filariasis SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID BLOOD MONONUCLEAR-CELLS; FC-GAMMA-RIIA; BANCROFTIAN FILARIASIS; WUCHERERIA-BANCROFTI; CYTOKINE PRODUCTION; BRUGIA-MALAYI; SOUTH-INDIA; INFECTION; ANTIGEN; MICROFILARIAE AB The presence of circulating immune complexes (CICs) is a characteristic feature of human lymphatic filariasis. However, the role of CICs in modulating granulocyte function and complement functional activity in filarial infection is unknown. The levels of CICs in association with complement activation in clinically asymptomatic, filarial-infected patients (INF); filarial-infected patients with overt lymphatic pathologic changes (CPDT); and uninfected controls (EN) were examined. Significantly increased levels of CICs and enhanced functional efficiency of the classical and mannose-binding lectin pathways of the complement system was observed in INF compared with CPDT and EN. Polyethylene glycol precipitated CICs from INF and CPDT induced significantly increased granulocyte activation compared with those from EN, determined by the increased production of neutrophil granular proteins and a variety of pro-inflammatory cytokines. Thus, CIC-mediated enhanced granulocyte activation and modulation of complement function are important features of filarial infection and disease. C1 NIH, Int Ctr Excellence Res, Madras, Tamil Nadu, India. NIH, Parasit Dis Lab, NIAID, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI, Frederick, MD USA. RP Babu, S (reprint author), SAIC Frederick Inc, NIAID, Clin Monitoring Res Program, Int Ctr Excellence Res,TB Res Ctr, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 43 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2011 VL 85 IS 1 BP 89 EP 96 DI 10.4269/ajtmh.2011.11-0086 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 788GK UT WOS:000292433200017 PM 21734131 ER PT J AU Karamchandani-Patel, G Hanson, EP Saltzman, R Kimball, CE Sorensen, RU Orange, JS AF Karamchandani-Patel, Gital Hanson, Eric P. Saltzman, Rushani Kimball, C. Eve Sorensen, Ricardo U. Orange, Jordan S. TI Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID KAPPA-B; MUTATIONS AB Background: Hypomorphic mutations in the nuclear factor-kappa B (NF-kappa B) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. Objective: To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. Methods: Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. Results: Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. Conclusions: Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production. C1 [Saltzman, Rushani] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Karamchandani-Patel, Gital; Sorensen, Ricardo U.; Orange, Jordan S.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Hanson, Eric P.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD USA. [Kimball, C. Eve] All Children Pediat Partners, Reading, PA USA. [Orange, Jordan S.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Orange, JS (reprint author), Childrens Hosp Philadelphia, 3615 Civ Ctr Blvd ARC 907A, Philadelphia, PA 19104 USA. EM Orange@mail.med.upenn.edu OI orange, jordan/0000-0001-7117-7725 FU National Institutes of Health [NIH-AI-079731]; Jeffrey Modell Foundation FX This work was supported by National Institutes of Health grant NIH-AI-079731 to Dr Orange and the Jeffrey Modell Foundation (Dr Orange and Dr Sorensen). NR 10 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD JUL PY 2011 VL 107 IS 1 BP 50 EP 56 DI 10.1016/j.anai.2011.03.009 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 792AG UT WOS:000292712300009 PM 21704885 ER PT J AU Deshpande, N Metter, EJ Ferrucci, L AF Deshpande, Nandini Metter, E. Jeffrey Ferrucci, Luigi TI Sensorimotor and Psychosocial Correlates of Adaptive Locomotor Performance in Older Adults SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Adaptive behavior; Gait; Locomotion; Rehabilitation; Walking ID WALKING INCHIANTI TOOLKIT; COMMUNITY MOBILITY; GAIT PATTERNS; AGE; DISABILITY; PREDICTOR; STRENGTH; BALANCE AB Deshpande N, Metter EJ, Ferrucci L. Sensorimotor and psychosocial correlates of adaptive locomotor performance in older adults. Arch Phys Med Rehabil 2011;92: 1074-9. Objective: To identify sensorimotor and psychosocial factors independently associated with an inability to perform adaptive walking tasks in older adults. Design: Cross-sectional cohort study. Setting: Population-based older cohort. Participants: Community-living elderly (N=720; age >= 65y) who could walk 7m at self-selected normal speed. Interventions: Not applicable. Main Outcome Measures: Walking performance was assessed in 4 walking tests: fast walking, obstacle crossing, narrow-based walking, and walking while talking. Possible correlates of the inability to perform the walking test included knee extensor strength, lower limb coordination, Cumulative Somatosensory Impairment Index (CSII), visual acuity and contrast sensitivity, cognition, depression, personal mastery, social support, and years of education. Results: The results of binary logistic regression analyses, adjusted for demographics and self-selected normal speed, demonstrated that poor knee extensor strength was associated with an inability to perform tasks demanding an increase in walking speed (fast walking and obstacle crossing). Both poor lower limb coordination and higher CSII were significantly associated with failure in tests that demanded precise control over foot placement (obstacle crossing and narrow-based walking). Higher CSII was associated with failure in all tests except in the walking while talking. In contrast, poor cognition was associated with an inability to perform walking while talking. Poor personal mastery was the only variable that was associated with failure in all walking tests. Conclusions: The results demonstrated a systematic and coherent pattern in these associations and indicated possible sensorimotor and psychological parameters that should be specifically investigated and should be intervened if a patient reports a difficulty/inability in walking in certain situations. C1 [Deshpande, Nandini] Queens Univ, Sch Rehabil Therapy, Kingston, ON K7L 3N6, Canada. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Deshpande, N (reprint author), Queens Univ, Sch Rehabil Therapy, 31 George St, Kingston, ON K7L 3N6, Canada. EM nandinijd@yahoo.com FU Italian Ministry of Health [ICS 110.1\RS97.71]; National Institute on Aging [N01-AG-916413, N01-AG-821336, N01-AG-5-0002, R01 AG027012]; National Institute on Aging, National Institutes of Health FX The InCHIANTI study was supported as a "targeted project" (ICS 110.1\RS97.71) by the Italian Ministry of Health and in part, by the National Institute on Aging (contract nos. N01-AG-916413, N01-AG-821336, N01-AG-5-0002; grant no. R01 AG027012) and the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 34 TC 4 Z9 4 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUL PY 2011 VL 92 IS 7 BP 1074 EP 1079 DI 10.1016/j.apmr.2011.02.006 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 790UU UT WOS:000292615900008 PM 21704787 ER PT J AU Rodriguez-Canales, J Eberle, FC Jaffe, ES Emmert-Buck, MR AF Rodriguez-Canales, Jaime Eberle, Franziska C. Jaffe, Elaine S. Emmert-Buck, Michael R. TI Why is it crucial to reintegrate pathology into cancer research? SO BIOESSAYS LA English DT Article DE cancer research; molecular biology; pathology; systems biology; translational research ID LASER CAPTURE MICRODISSECTION; GENE-EXPRESSION; HODGKINS LYMPHOMA; TISSUE SPECIMENS; TUMOR MICROENVIRONMENT; LUNG ADENOCARCINOMA; SYSTEMS PATHOLOGY; PROSTATE-CANCER; MEDICINE; REDUCTIONISM AB The integration of pathology with molecular biology is vital if we are to enhance the translational value of cancer research. Pathology represents a bridge between medicine and basic biology, it remains the gold standard for cancer diagnosis, and it plays an important role in discovery studies. In the past, pathology and cancer research were closely associated; however, the molecular biology revolution has shifted the focus of investigators toward the molecular alterations of tumors. The reductionist approach taken in molecular studies is producing great insight into the inner workings of neoplasia, but it can also minimize the importance of histopathology and of understanding the disease as a whole. In turn, pathologists can underestimate the role of molecular studies in developing new ancillary techniques for clinical diagnosis. A multidisciplinary approach that integrates pathology and molecular biology within a translational research system is needed. This process will require overcoming cultural barriers and can be achieved through education, a more effective incorporation of pathology into biological research, and conversely an integration of biological research into the pathology laboratory. C1 [Rodriguez-Canales, Jaime; Emmert-Buck, Michael R.] NCI, Laser Capture Microdissect Core & Pathogenet Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Eberle, Franziska C.; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Eberle, Franziska C.] Univ Tubingen, Dept Dermatol, Tubingen, Germany. RP Rodriguez-Canales, J (reprint author), NCI, Laser Capture Microdissect Core & Pathogenet Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM rodrigja@mail.nih.gov; buckm@mail.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377; Jaffe, Elaine/0000-0003-4632-0301 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH) FX We thank Kamran Ghoreschi for his assistance with Fig. 2, and Jodie M. Fleming for providing the histological slide of a xenograft from human breast ductal carcinoma (Fig. 1B). This work was supported in part by the intramural program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH). M. R. E.-B. is an inventor on all NIH patents covering laser-capture microdissection technology and receives royalty payments through the NIH technology transfer program. NR 68 TC 7 Z9 7 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD JUL PY 2011 VL 33 IS 7 BP 490 EP 498 DI 10.1002/bies.201100017 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 791ZO UT WOS:000292710500003 PM 21590787 ER PT J AU Rosenberg, PS Anderson, WF AF Rosenberg, Philip S. Anderson, William F. TI Age-Period-Cohort Models in Cancer Surveillance Research: Ready for Prime Time? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID CHRONIC DISEASE RATES; FEMALE BREAST-CANCER; UNITED-STATES; ETIOLOGIC HETEROGENEITY; INTERPRETING TRENDS; EUROPEAN COUNTRIES; TEMPORAL VARIATION; TESTICULAR CANCER; MORTALITY-RATES; LEXIS DIAGRAM AB Standard descriptive methods for the analysis of cancer surveillance data include canonical plots based on the lexis diagram, directly age-standardized rates (ASR), estimated annual percentage change (EAPC), and joinpoint regression. The age-period-cohort (APC) model has been used less often. Here, we argue that it merits much broader use. First, we describe close connections between estimable functions of the model parameters and standard quantities such as the ASR, EAPC, and joinpoints. Estimable functions have the added value of being fully adjusted for period and cohort effects, and generally more precise. Second, the APC model provides the descriptive epidemiologist with powerful new tools, including rigorous statistical methods for comparative analyses, and the ability to project the future burden of cancer. We illustrate these principles by using invasive female breast cancer incidence in the United States, but these concepts apply equally well to other cancer sites for incidence or mortality. Cancer Epidemiol Biomarkers Prev; 20(7); 1263-8. (C)2011 AACR. C1 [Rosenberg, Philip S.; Anderson, William F.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Rockville, MD 20852 USA. EM wanderso@mail.nih.gov FU Intramural NIH HHS [ZIA CP010183-08, Z01 CP010183-05] NR 58 TC 29 Z9 29 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2011 VL 20 IS 7 BP 1263 EP 1268 DI 10.1158/1055-9965.EPI-11-0421 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 789FK UT WOS:000292499700001 PM 21610223 ER PT J AU Breen, EC Hussain, SK Magpantay, L Jacobson, LP Detels, R Rabkin, CS Kaslow, RA Variakojis, D Bream, JH Rinaldo, CR Ambinder, RF Martinez-Maza, O AF Breen, Elizabeth Crabb Hussain, Shehnaz K. Magpantay, Larry Jacobson, Lisa P. Detels, Roger Rabkin, Charles S. Kaslow, Richard A. Variakojis, Daina Bream, Jay H. Rinaldo, Charles R. Ambinder, Richard F. Martinez-Maza, Otoniel TI B-Cell Stimulatory Cytokines and Markers of Immune Activation Are Elevated Several Years Prior to the Diagnosis of Systemic AIDS-Associated Non-Hodgkin B-Cell Lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; ACTIVE ANTIRETROVIRAL THERAPY; EPSTEIN-BARR-VIRUS; INDUCED CYTIDINE DEAMINASE; HIV-1 INFECTION; SOMATIC HYPERMUTATION; SOLUBLE CD30; SERUM-LEVELS; MOLECULAR PATHOGENESIS; INTERLEUKIN-6 AB Background: The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine whether elevated serum levels of molecules associated with B-cell activation precede the diagnosis of AIDS-associated NHL (AIDS-NHL). Methods: Serum levels of B-cell activation-associated molecules, interleukin (IL)6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C-reactive protein (CRP), and immunoglobulin E were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to 3 time points per subject, 0 to 5 years prior to AIDS-NHL diagnosis. Results: Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared with HIV+ controls or with AIDS controls, after adjusting for CD4 T-cell number. Elevated serum levels of B-cell activation-associated molecules were seen to be associated with the development of systemic [non-CNS (central nervous system)] NHL, but not with the development of primary CNS lymphoma. Conclusions: Levels of certain B-cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B-cell activation contributes to the development of these hematologic malignancies. Impact: Marked differences in serum levels of several molecules are seen for several years prediagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL. Cancer Epidemiol Biomarkers Prev; 20(7); 1303-14. (C)2011 AACR. C1 [Breen, Elizabeth Crabb] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Breen, Elizabeth Crabb; Magpantay, Larry; Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, Los Angeles, CA 90095 USA. [Hussain, Shehnaz K.; Magpantay, Larry; Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Magpantay, Larry; Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Magpantay, Larry; Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Hussain, Shehnaz K.; Detels, Roger; Martinez-Maza, Otoniel] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. [Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Bream, Jay H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Ambinder, Richard F.] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD USA. [Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kaslow, Richard A.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Kaslow, Richard A.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Kaslow, Richard A.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Kaslow, Richard A.] Univ Alabama, Dept Genet, Birmingham, AL USA. [Variakojis, Daina] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Rinaldo, Charles R.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Breen, EC (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, 300 Med Plaza,Room 3160A,Box 957076, Los Angeles, CA 90095 USA. EM ebreen@mednet.ucla.edu RI Martinez-Maza, Otoniel/B-2667-2009; Ambinder, Richard/G-1607-2011 OI Martinez-Maza, Otoniel/0000-0003-1364-0675; FU Leukemia and Lymphoma Society [6155-03]; National Institutes of Health [R01-CA57152, R01-CA73475, K07-CA140360]; Specialized Program of Research Excellence (SPORE) in Lymphoma [P50-CA96888]; UCLA Older Americans Independence Center (OAIC); OAIC Inflammatory Biology Core [P30-AG028748]; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Cancer Institute [UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041] FX This work was supported by grants from the Leukemia and Lymphoma Society (6155-03) and the National Institutes of Health (R01-CA57152, R01-CA73475, and K07-CA140360), including the Specialized Program of Research Excellence (SPORE) in Lymphoma (P50-CA96888), the UCLA Older Americans Independence Center (OAIC) and the OAIC Inflammatory Biology Core (P30-AG028748), and the Intramural Research Program, National Cancer Institute. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute [UO1-AI-35042, UL1-RR025005 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041]. Some of 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. NR 81 TC 53 Z9 54 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2011 VL 20 IS 7 BP 1303 EP 1314 DI 10.1158/1055-9965.EPI-11-0037 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 789FK UT WOS:000292499700006 PM 21527584 ER PT J AU Schiffman, M Glass, AG Wentzensen, N Rush, BB Castle, PE Scott, DR Buckland, J Sherman, ME Rydzak, G Kirk, P Lorincz, AT Wacholder, S Burk, RD AF Schiffman, Mark Glass, Andrew G. Wentzensen, Nicolas Rush, Brenda B. Castle, Philip E. Scott, David R. Buckland, Julie Sherman, Mark E. Rydzak, Greg Kirk, Peter Lorincz, Attila T. Wacholder, Sholom Burk, Robert D. TI A Long-term Prospective Study of Type-Specific Human Papillomavirus Infection and Risk of Cervical Neoplasia Among 20,000 Women in the Portland Kaiser Cohort Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CYTOLOGICALLY NORMAL WOMEN; INTRAEPITHELIAL NEOPLASIA; FOLLOW-UP; ABSOLUTE RISK; CANCER; HPV; DNA; ABNORMALITIES; PERSISTENCE AB Background: Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 3 and cancer (>= CIN3). Adding HPV testing to cytology is recommended for women >= 30 but long-term prospective studies of HPV testing are rare. Methods: Beginning in 1989-1990, similar to 20,000 women in a prepaid health maintenance organization (median age 34) were followed passively by recommended annual cytology. We tested archived cervicovaginal lavage specimens collected at enrollment, primarily by MY09-MY11 PCR-based methods, for carcinogenic HPV types. We calculated positive and negative predictive values for the entire study period, and Kaplan-Meier estimates of cumulative probability for >= CIN3, up to 18 years of follow-up. Results: We observed 47 cases of invasive cervical cancer during the study period, and 156 cases of CIN3. Predictive values and Kaplan-Meier analyses yielded the same conclusions. In women 30 and older, the reassurance against >= CIN3 following a single negative HPV test was long-lasting (cumulative probability = 0.7% during follow-up). In this age group, a single HPV test (positive vs. negative, hazard ratio of 8.5, 95% CI = 4.8-15.1) provided greater long-term risk stratification than a single cytologic result (abnormal vs. normal, HR = 2.9, 95% CI = 1.2-6.6). The risk for >= CIN3 was higher for HPV16 than for the average of the other carcinogenic types (hazard ratio = 2.7). Conclusion and Impact: The data from this cohort study show the long-term predictive value of HPV testing, particularly in women >= 30, and a possible role for distinguishing particularly carcinogenic types like HPV16. Cancer Epidemiol Biomarkers Prev; 20(7); 1398-409. (C)2011 AACR. C1 [Schiffman, Mark; Wentzensen, Nicolas; Castle, Philip E.; Sherman, Mark E.; Kirk, Peter; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Glass, Andrew G.; Rush, Brenda B.; Scott, David R.] Kaiser Permanente, Portland, OR USA. [Buckland, Julie; Rydzak, Greg] Informat Management Serv Inc, Silver Spring, MD USA. [Lorincz, Attila T.] Wolfson Inst Prevent Med, London, England. [Burk, Robert D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. FU National Institutes of Health; National Cancer Institute [CA78527] FX The Portland Cohort Study and NCI investigators were funded by the Intramural Research Program of the National Institutes of Health. HPV DNA testing by Dr. Burk was supported by National Cancer Institute grant CA78527 and used the facilities available through the Einstein Cancer Research Center. The earliest rounds of HPV PCR testing at Cetus (now Roche) and the Hybrid Capture testing at Digene Corporation (now Qiagen) were donated by these companies, representing a very small percentage (<<1%) of the total project costs. NR 38 TC 51 Z9 52 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2011 VL 20 IS 7 BP 1398 EP 1409 DI 10.1158/1055-9965.EPI-11-0206 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 789FK UT WOS:000292499700016 PM 21602310 ER PT J AU Jiao, L Taylor, PR Weinstein, SJ Graubard, BI Virtamo, J Albanes, D Stolzenberg-Solomon, RZ AF Jiao, Li Taylor, Philip R. Weinstein, Stephanie J. Graubard, Barry I. Virtamo, Jarmo Albanes, Demetrius Stolzenberg-Solomon, Rachael Z. TI Advanced Glycation End Products, Soluble Receptor for Advanced Glycation End Products, and Risk of Colorectal Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CORONARY-ARTERY-DISEASE; SERUM-LEVELS; DIABETIC-PATIENTS; FORM SRAGE; RAGE; ENDPRODUCTS; INFLAMMATION; ACTIVATION; PROTEIN; AGE AB Background: Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement. Methods: We examined the association between N(epsilon)-(carboxymethyl) lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI. Results: Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend =) 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26). Conclusions: Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers. Impact: This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development. Cancer Epidemiol Biomarkers Prev; 20(7); 1430-8. (C)2011 AACR. C1 [Jiao, Li; Taylor, Philip R.; Weinstein, Stephanie J.; Graubard, Barry I.; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Jiao, L (reprint author), Baylor Coll Med, Dept Med, Sect Gastroenterol & Hepatol, 2002 Holcombe Blvd,MS 152, Houston, TX 77030 USA. EM jiao@bcm.edu RI Albanes, Demetrius/B-9749-2015 FU National Cancer Institute; Division of Cancer Epidemiology and Genetics of the National Cancer Institute at the NIH; U.S. Public Health Service from the National Cancer Institute, U.S. Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HSN261201000006C] FX This work was supported by funding from the Intramural Research Program of the National Cancer Institute (P. R. Taylor, S.J. Weinstein, B. I. Graubard, D. Albanes, R.Z. Stolzenberg-Solomon) and an Intramural Research Award (L. Jiao) in the Division of Cancer Epidemiology and Genetics of the National Cancer Institute at the NIH. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HSN261201000006C) from the National Cancer Institute, U.S. Department of Health and Human Services. NR 46 TC 34 Z9 35 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2011 VL 20 IS 7 BP 1430 EP 1438 DI 10.1158/1055-9965.EPI-11-0066 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 789FK UT WOS:000292499700019 PM 21527578 ER PT J AU Yuan, P Liang, KW Ma, BY Zheng, N Nussinov, R Huang, J AF Yuan, Peng Liang, Kaiwei Ma, Buyong Zheng, Nan Nussinov, Ruth Huang, Jian TI Multiple-Targeting and Conformational Selection in the Estrogen Receptor: Computation and Experiment SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE conformational ensemble; conformational selection; docking; phytoestrogen; SERMs; two-state theory ID LIGAND-BINDING DOMAIN; ER-BETA LIGANDS; BREAST-CANCER CELLS; PROTEIN DOCKING; ALPHA; PHYTOESTROGENS; SUBTYPE; DESIGN; ANTAGONISM; PREDICTION AB Conformational selection is a primary mechanism in biomolecular recognition. The conformational ensemble may determine the ability of a drug to compete with a native ligand for a receptor target. Traditional docking procedures which use one or few protein structures are limited and may not be able to represent a complex competition among closely related protein receptors in agonist and antagonist ensembles. Here, we test a protocol aimed at selecting a drug candidate based on its ability to synergistically bind to distinct conformational states. We demonstrate, for the case of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta), that the functional outcome of ligand binding can be inferred from its ability to simultaneously bind both ER alpha and ER beta in agonist and antagonist conformations as calculated docking scores. Combining a conformational selection method with an experimental reporter gene system in yeast, we propose that several phytoestrogens can be novel estrogen receptor beta selective agonists. Our work proposes a computational protocol to select estrogen receptor subtype selective agonists. Compared with other models, present method gives the best prediction in ligands' function. C1 [Yuan, Peng; Liang, Kaiwei; Zheng, Nan; Huang, Jian] Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Hubei, Peoples R China. [Ma, Buyong; Nussinov, Ruth] NCI, SAIC Frederick, Ctr Canc Res Nanobiol Program, Ft Detrick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Huang, J (reprint author), Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Hubei, Peoples R China. EM jianhuang@whu.edu.cn RI Ma, Buyong/F-9491-2011; Yuan, Peng/P-3244-2016 OI Ma, Buyong/0000-0002-7383-719X; Yuan, Peng/0000-0003-4051-4447 FU National Basic Science Foundation for Talent Education [J0630648]; National Natural Science Foundation of China [30670647, 30970914]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX We are grateful to Dr Dan Noonan for generously providing yeast strains and plasmids. This work was supported by the National Basic Science Foundation for Talent Education (J0630648) and National Natural Science Foundation of China (30670647 and 30970914). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 69 TC 9 Z9 9 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1747-0277 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD JUL PY 2011 VL 78 IS 1 BP 137 EP 149 DI 10.1111/j.1747-0285.2011.01119.x PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 791VR UT WOS:000292695900014 PM 21443691 ER PT J AU Uchida, N Bonifacino, A Krouse, AE Metzger, ME Csako, G Lee-Stroka, A Fasano, RM Leitman, SF Mattapallil, JJ Hsieh, MM Tisdale, JF Donahue, RE AF Uchida, Naoya Bonifacino, Aylin Krouse, Allen E. Metzger, Mark E. Csako, Gyorgy Lee-Stroka, Agnes Fasano, Ross M. Leitman, Susan F. Mattapallil, Joseph J. Hsieh, Matthew M. Tisdale, John F. Donahue, Robert E. TI Accelerated lymphocyte reconstitution and long-term recovery after transplantation of lentiviral-transduced rhesus CD34(+) cells mobilized by G-CSF and plerixafor SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SIMIAN IMMUNODEFICIENCY VIRUS; CD4 T-CELLS; NONHUMAN-PRIMATES; BONE-MARROW; PERIPHERAL-BLOOD; VECTOR; EXPRESSION; INFECTION; GENE AB Objective. Granulocyte colony-stimulating factor (G-CSF) in combination with plerixafor produces significant mobilization of CD34(+) cells in rhesus macaques. We sought to evaluate whether these CD34(+) cells can stably reconstitute blood cells with lentiviral gene marking. Materials and Methods. We performed hematopoietic stem cell transplantation using G-CSF and plerixafor-mobilized rhesus CD34(+) cells transduced with a lentiviral vector, and these data were compared with those of G-CSF and stem cell factor mobilization. Results. G-CSF and plerixafor mobilization resulted in CD34(+) cell yields that were twofold higher than yields with G-CSF and stem cell factor. CD123 (interleukin-3 receptor) expression was greater in G-CSF and plerixafor-mobilized CD34(+) cells when compared to G-CSF alone. Animals transplanted with G-CSF and plerixafor-mobilized cells showed engraftment of all lineages, similar to animals who received G-CSF and stem cell factor mobilized grafts. Lymphocyte engraftment was accelerated in animals receiving the G-CSF and plerixaformobilized CD34(+) cells. One animal in the G-CSF and plerixafor group developed cold agglutinin-associated skin rash during the first 3 months of rapid lymphocyte recovery. One year after transplantation, all animals had 2% to 10% transgene expression in all blood cell lineages. Conclusions. G-CSF and plerixafor-mobilized CD34(+) cells accelerate lymphocyte engraftment and contain hematopoietic stein cell capable of reconstituting multilineage blood cells. These findings indicate important differences to consider in plerixafor-based hematopoietic stem cell mobilization protocols in rhesus macaques. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Bonifacino, Aylin; Krouse, Allen E.; Metzger, Mark E.; Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Rockville, MD 20892 USA. [Uchida, Naoya; Hsieh, Matthew M.; Tisdale, John F.] NIDDKD, Mol & Clin Hematol Branch, NHLBI, NIH, Rockville, MD USA. [Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Lee-Stroka, Agnes; Fasano, Ross M.; Leitman, Susan F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. RP Donahue, RE (reprint author), NHLBI, Hematol Branch, NIH, 5 Res Court,Bldg 5RC,1B06,MSC 3315, Rockville, MD 20892 USA. EM donahuer@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases; Clinical Center at the National Institutes of Health; National Institutes of Allergy and Infectious Diseases [AI07812]; National Institute of Dental and Craniofacial Research [DE018339, DE019397] FX This work was supported by the intramural research programs of the National Heart, Lung, and Blood Institute, the National Institute of Diabetes, Digestive, and Kidney Diseases, and the Clinical Center at the National Institutes of Health, and in part by grants, AI07812 from National Institutes of Allergy and Infectious Diseases and DE018339 and DE019397 from the National Institute of Dental and Craniofacial Research to J.J.M. We thank the staff at 5 Research Court for their excellent care and handling of the rhesus macaques. We particularly would like to thank Earl West for being the first to identify the development of the cold agglutinin in RQ7375 and Dr. Chyi-Chia Richard Lee of the Dermatopathology & Surgical Pathology of the National Cancer Institute for interpreting the skin biopsy. We would also like to thank William DeGraff and Dr. Jim Mitchell of the Radiation Biology Branch, NCI for the use of the Eldorado Cobalt-60 irradiator, and Dr. Derek Persons of the St Jude Children's Research Hospital for providing us viral vectors and sharing data. NR 24 TC 14 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2011 VL 39 IS 7 BP 795 EP 805 DI 10.1016/j.exphem.2011.04.002 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 790WZ UT WOS:000292622800008 PM 21549175 ER PT J AU Wiench, M Miranda, TB Hager, GL AF Wiench, Malgorzata Miranda, Tina B. Hager, Gordon L. TI Control of nuclear receptor function by local chromatin structure SO FEBS JOURNAL LA English DT Review DE chromatin remodeling; DNA methylation; DNase I hypersensitivity; enhancer; histone modifications; nuclear receptors; nucleosome positioning; promoter ID MAMMARY-TUMOR VIRUS; DNASEI HYPERSENSITIVE SITES; TRANSCRIPTION FACTOR ACCESS; STEROID-HORMONE RECEPTORS; NUCLEOSOME CORE PARTICLE; LIGAND-SPECIFIC DYNAMICS; LONG TERMINAL REPEAT; GLUCOCORTICOID-RECEPTOR; ESTROGEN-RECEPTOR; HUMAN GENOME AB Steroid hormone receptors regulate gene transcription in a highly tissue-specific manner. The local chromatin structure underlying promoters and hormone response elements is a major component involved in controlling these highly restricted expression patterns. Chromatin remodeling complexes, as well as histone and DNA modifying enzymes, are directed to gene-specific regions and create permissive or repressive chromatin environments. These structures further enable proper communication between transcription factors, co-regulators and basic transcription machinery. The regulatory elements active at target genes can be either constitutively accessible to receptors or subject to rapid receptor-dependent modification. The chromatin states responsible for these processes are in turn determined during development and differentiation. Thus access of regulatory factors to elements in chromatin provides a major level of cell selective regulation. C1 [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Lib Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIGMS FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. T.B. Miranda is funded in part by the NIGMS Pharmacology Research Associate Fellowship. NR 188 TC 21 Z9 21 U1 2 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUL PY 2011 VL 278 IS 13 BP 2211 EP 2230 DI 10.1111/j.1742-4658.2011.08126.x PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 789PJ UT WOS:000292527500003 PM 21501385 ER PT J AU Cardesa-Salzmann, TM Colomo, L Gutierrez, G Chan, WC Weisenburger, D Climent, F Gonzalez-Barca, E Mercadal, S Arenillas, L Serrano, S Tubbs, R Delabie, J Gascoyne, RD Connors, JM Mate, JL Rimsza, L Braziel, R Rosenwald, A Lenz, G Wright, G Jaffe, ES Staudt, L Jares, P Lopez-Guillermo, A Campo, E AF Cardesa-Salzmann, Teresa M. Colomo, Luis Gutierrez, Gonzalo Chan, Wing C. Weisenburger, Dennis Climent, Fina Gonzalez-Barca, Eva Mercadal, Santiago Arenillas, Leonor Serrano, Sergio Tubbs, Ray Delabie, Jan Gascoyne, Randy D. Connors, Joseph M. Mate, Jose L. Rimsza, Lisa Braziel, Rita Rosenwald, Andreas Lenz, Georg Wright, George Jaffe, Elaine S. Staudt, Louis Jares, Pedro Lopez-Guillermo, Armando Campo, Elias TI High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE rituximab; aggressive non-Hodgkin's lymphoma; kidney; central nervous system ID NF-KAPPA-B; PROGNOSTIC-SIGNIFICANCE; FOLLICULAR LYMPHOMA; GENE SIGNATURES; VEGF-A; SURVIVAL; ANGIOGENESIS; EXPRESSION; IMMUNOCHEMOTHERAPY; MUTATIONS AB Background Diffuse large B-cell lymphoma is a clinically and molecularly heterogeneous disease. Gene expression profiling studies have shown that the tumor microenvironment affects survival and that the angiogenesis-related signature is prognostically unfavorable. The contribution of histopathological microvessel density to survival in diffuse large B-cell lymphomas treated with immunochemotherapy remains unknown. The purpose of this study is to assess the prognostic impact of histopathological microvessel density in two independent series of patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Design and Methods One hundred and forty-seven patients from the Leukemia Lymphoma Molecular Profiling Project (training series) and 118 patients from the Catalan Lymphoma-Study group-GELCAB (validation cohort) were included in the study. Microvessels were immunostained with CD31 and quantified with a computerized image analysis system. The stromal scores previously defined in 110 Leukemia Lymphoma Molecular Profiling Project cases were used to analyze correlations with microvessel density data. Results Microvessel density significantly correlated with the stromal score (r = 0.3209; P < 0.001). Patients with high microvessel density showed significantly poorer overall survival than those with low microvessel density both in the training series (4-year OS 54% vs. 78%; P = 0.004) and in the validation cohort (57% vs. 81%; P = 0.006). In multivariate analysis, in both groups high microvessel density was a statistically significant unfavorable prognostic factor independent of international prognostic index [training series: international prognostic index (relative risk 2.7; P = 0.003); microvessel density (relative risk 1.96; P = 0.002); validation cohort: international prognostic index (relative risk 4.74; P < 0.001); microvessel density (relative risk 2.4; P = 0.016)]. Conclusions These findings highlight the impact of angiogenesis in the outcome of patients with diffuse large B-cell lymphoma and the interest of evaluating antiangiogenic drugs in clinical trials. C1 [Cardesa-Salzmann, Teresa M.; Colomo, Luis; Gutierrez, Gonzalo; Jares, Pedro; Lopez-Guillermo, Armando; Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Chan, Wing C.; Weisenburger, Dennis] Univ Nebraska Med Ctr, Omaha, NE USA. [Climent, Fina] Hosp Univ Bellvitge, Lhospitalet De Llobregat, Spain. [Gonzalez-Barca, Eva; Mercadal, Santiago] Hosp Duran i Reynals, Inst Catala Oncol, Lhospitalet De Llobregat, Spain. [Arenillas, Leonor; Serrano, Sergio] Hosp del Mar, Barcelona, Spain. [Tubbs, Ray] Cleveland Clin, Cleveland, OH 44106 USA. [Delabie, Jan] Norwegian Radium Hosp, Oslo, Norway. [Gascoyne, Randy D.; Connors, Joseph M.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Mate, Jose L.] Hosp Germans Trias, Badalona, Spain. [Rimsza, Lisa] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Braziel, Rita] Oregon Hlth & Sci Univ, Portland, OR USA. [Rosenwald, Andreas] Univ Wurzburg, Wurzburg, Germany. [Lenz, Georg] Mol Krebsforschungszentrum MKFZ Charite Univ Med, Berlin, Germany. [Wright, George; Jaffe, Elaine S.; Staudt, Louis] NCI, NIH, Bethesda, MD 20892 USA. RP Lopez-Guillermo, A (reprint author), Hosp Clin Barcelona, Dept Hematol, Calle Villarroel 170, E-08036 Barcelona, Spain. EM alopezg@clinic.ub.es RI Lenz, Georg/I-6844-2012; Colomo, Luis/A-2259-2016; OI Campo, elias/0000-0001-9850-9793; Colomo, Luis/0000-0001-5236-5085; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Arenillas, Leonor/0000-0002-8176-7179 FU Ministry of Education and Science of Spain [SAF 2008 03630-O, FIS PI 070409]; Red Tematica de Investigacion Cooperativa en Cancer RTICC [U.2006-RET2039-O] FX this work was supported by a grant from the Ministry of Education and Science of Spain (SAF 2008 03630-O (EC), FIS PI 070409 (ALG) and by the Red Tematica de Investigacion Cooperativa en Cancer RTICC U.2006-RET2039-O (EC) NR 30 TC 28 Z9 31 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUL PY 2011 VL 96 IS 7 BP 996 EP 1001 DI 10.3324/haematol.2010.037408 PG 6 WC Hematology SC Hematology GA 792FX UT WOS:000292727200009 PM 21546504 ER PT J AU Wu, JW Wang, SP Alvarez, F Casavant, S Gauthier, N Abed, L Soni, KG Yang, GS Mitchell, GA AF Wu, Jiang Wei Wang, Shu Pei Alvarez, Fernando Casavant, Stephanie Gauthier, Nicolas Abed, Lynda Soni, Krishnakant G. Yang, Gongshe Mitchell, Grant A. TI Deficiency of Liver Adipose Triglyceride Lipase in Mice Causes Progressive Hepatic Steatosis SO HEPATOLOGY LA English DT Article ID HORMONE-SENSITIVE LIPASE; FATTY LIVER; INSULIN-RESISTANCE; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; MURINE STEATOHEPATITIS; METABOLIC SYNDROME; ENERGY-METABOLISM; DISEASE; TISSUE AB Accumulation of cytoplasmic triacylglycerol (TG) underlies hepatic steatosis, a major cause of cirrhosis. The pathways of cytoplasmic TG metabolism are not well known in hepatocytes, but evidence suggests an important role in lipolysis for adipose triglyceride lipase (ATGL). We created mice with liver-specific inactivation of Pnpla2, the ATGL gene. These ATGLLKO mice had severe progressive periportal macrovesicular and pericentral microvesicular hepatic steatosis (73, 150, and 226 mu mol TG/g liver at 4, 8, and 12 months, respectively). However, plasma levels of glucose, TG, and cholesterol were similar to those of controls. Fasting 3-hydroxybutyrate level was normal, but in thin sections of liver, beta oxidation of palmitate was decreased by one-third in ATGLLKO mice compared with controls. Tests of very low-density lipoprotein production, glucose, and insulin tolerance and gluconeogenesis from pyruvate were normal. Plasma alanine aminotransferase levels were elevated in ATGLLKO mice, but histological estimates of inflammation and fibrosis and messenger RNA (mRNA) levels of tumor necrosis factor-a and interleukin-6 were similar to or lower than those in controls. ATGLLKO cholangiocytes also showed cytoplasmic lipid droplets, demonstrating that ATGL is also a major lipase in cholangiocytes. There was a 50-fold reduction of hepatic diacylglycerol acyltransferase 2 mRNA level and a 2.7-fold increase of lipolysosomes in hepatocytes (P < 0.001), suggesting reduced TG synthesis and increased lysosomal degradation of TG as potential compensatory mechanisms. Conclusion: Compared with the hepatic steatosis of obesity and diabetes, steatosis in ATGL deficiency is well tolerated metabolically. ATGLLKO mice will be useful for studying the pathophysiology of hepatic steatosis. (HEPATOLOGY 2011;54:122-132) C1 [Wu, Jiang Wei; Yang, Gongshe] NW A&F Univ, Coll Anim Sci & Technol, Lab Anim Fat Deposit & Muscle Dev, Yangling, Shaanxi, Peoples R China. [Wu, Jiang Wei; Wang, Shu Pei; Casavant, Stephanie; Gauthier, Nicolas; Mitchell, Grant A.] Univ Montreal, Div Med Genet, Dept Pediat, Montreal, PQ H3T 1C5, Canada. [Alvarez, Fernando] Univ Montreal, Div Gastroenterol Hepatol & Nutr, Dept Pediat, Montreal, PQ H3T 1C5, Canada. [Abed, Lynda] Univ Montreal, CHU St Justine, Dept Pathol, Montreal, PQ H3T 1C5, Canada. [Soni, Krishnakant G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. RP Yang, GS (reprint author), NW A&F Univ, Coll Anim Sci & Technol, Lab Anim Fat Deposit & Muscle Dev, Yangling, Shaanxi, Peoples R China. EM gsyang999@hotmail.com; grant.mitchell@recherche-ste.justine.qc.ca FU Canadian Institutes of Health Research [221920] FX Supported by Canadian Institutes of Health Research Operating Grant 221920 (to G. A. M.). NR 39 TC 78 Z9 81 U1 1 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2011 VL 54 IS 1 BP 122 EP 132 DI 10.1002/hep.24338 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788JH UT WOS:000292440700017 PM 21465509 ER PT J AU Park, O Wang, H Weng, HL Feigenbaum, L Li, H Yin, S Ki, SH Yoo, SH Dooley, S Wang, FS Young, HA Gao, B AF Park, Ogyi Wang, Hua Weng, Honglei Feigenbaum, Lionel Li, Hai Yin, Shi Ki, Sung Hwan Yoo, Seong Ho Dooley, Steven Wang, Fu-Sheng Young, Howard A. Gao, Bin TI In Vivo Consequences of Liver-Specific Interleukin-22 Expression in Mice: Implications for Human Liver Disease Progression SO HEPATOLOGY LA English DT Article ID HEPATITIS-C; MOUSE MODEL; IL-22; INFLAMMATION; HEPATOCYTES; CELLS; STAT3; ACTIVATION; PSORIASIS; CYTOKINES AB Interleukin-22 (IL-22), which acts as either a proinflammatory or anti-inflammatory cytokine in various disease models, is markedly up-regulated in chronic liver diseases, including hepatitis B and C. In this report, we demonstrate a strong correlation between IL-22 expression in the liver with active, inflammatory human liver disease. To clarify the role of IL-22 up-regulation in the pathogenesis of liver diseases, liver-specific IL-22 transgenic (IL-22TG) mice, under the control of albumin promoter, were developed. Despite elevated IL-22 serum levels ranging from 4,000 to 7,000 pg/mL, IL-22TG mice developed normally without obvious adverse phenotypes or evidence of chronic inflammation (except for slightly thicker epidermis and minor inflammation of the skin) compared with wild-type mice. Interestingly, IL-22TG mice were completely resistant to concanavalin A induced T cell hepatitis with minimal effect on liver inflammation and had accelerated liver regeneration after partial hepatectomy. Although they did not spontaneously develop liver tumors, IL-22TG mice were more susceptible to diethylnitrosamine-induced liver cancer. Microarray analyses revealed that a variety of antioxidant, mitogenic, acute phase genes were up-regulated in the livers of IL-22TG mice compared with those from wild-type mice. Conclusion: These findings indicate that localized production of IL-22 in the liver promotes hepatocyte survival and proliferation but primes the liver to be more susceptible to tumor development without significantly affecting liver inflammation. (HEPATOLOGY 2011;54:252-261) C1 [Park, Ogyi; Wang, Hua; Yin, Shi; Ki, Sung Hwan; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Yoo, Seong Ho] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Weng, Honglei; Dooley, Steven] Univ Heidelberg, Med Clin, Med Fac Mannheim, D-6800 Mannheim, Germany. [Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Young, Howard A.] NCI, Expt Immunol Lab, Canc Inflammat Program, NIH, Frederick, MD 21701 USA. [Li, Hai] Shanghai Jiao Tong Univ, Dept Gastroenterol, Renji Hosp, Shanghai 200030, Peoples R China. [Wang, Fu-Sheng] Beijing 302 Hosp, Res Ctr Biol Therapy, Beijing, Peoples R China. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism; National Cancer Institute; German Federal Ministry for Education and Research (BMBF) FX Supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism (B.G.) and the National Cancer Institute (H.A.Y), and by the German Federal Ministry for Education and Research (BMBF) grants "Virtual Liver" and "Cell Therapy" (H.W., S.D.). NR 27 TC 85 Z9 96 U1 2 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2011 VL 54 IS 1 BP 252 EP 261 DI 10.1002/hep.24339 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788JH UT WOS:000292440700029 PM 21465510 ER PT J AU Horiguchi, N Gao, B AF Horiguchi, Norio Gao, Bin TI Inflammation Does Not Always Kill Hepatocytes During Liver Damage Reply SO HEPATOLOGY LA English DT Letter ID SIGNAL TRANSDUCER; TRANSCRIPTION 3; MACROPHAGES; ACTIVATOR; INJURY; MICE C1 [Horiguchi, Norio; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Horiguchi, Norio] Gunma Univ, Dept Med & Mol Sci, Grad Sch Med, Gunma, Japan. RP Horiguchi, N (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. NR 5 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2011 VL 54 IS 1 BP 367 EP 367 DI 10.1002/hep.24383 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788JH UT WOS:000292440700039 ER PT J AU Brunt, EM Kleiner, DE Behling, C Contos, MJ Cummings, OW Ferrell, LD Torbenson, MS Yeh, M AF Brunt, Elizabeth M. Kleiner, David E. Behling, Cynthia Contos, Melissa J. Cummings, Oscar W. Ferrell, Linda D. Torbenson, Michael S. Yeh, Matthew TI Misuse of Scoring Systems SO HEPATOLOGY LA English DT Letter ID FATTY LIVER-DISEASE C1 [Brunt, Elizabeth M.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Kleiner, David E.] NCI, Dept Labs, NIH, Bethesda, MD 20892 USA. [Contos, Melissa J.] Virginia Commonwealth Univ, Dept Pathol, Richmond, VA USA. [Behling, Cynthia] Sharp Mem Hosp & Rehabil Ctr, San Diego, CA USA. [Cummings, Oscar W.] Indiana Univ, Dept Pathol, Indianapolis, IN 46204 USA. [Ferrell, Linda D.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Torbenson, Michael S.] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. [Yeh, Matthew] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. RP Brunt, EM (reprint author), Washington Univ, Dept Pathol & Immunol, St Louis, MO 63130 USA. OI Kleiner, David/0000-0003-3442-4453 NR 5 TC 14 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2011 VL 54 IS 1 BP 369 EP 370 DI 10.1002/hep.24347 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788JH UT WOS:000292440700042 PM 21488072 ER PT J AU Lok, AS Everhart, JE AF Lok, Anna S. Everhart, James E. TI Occult Hepatitis B Virus Infection and Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C Reply SO HEPATOLOGY LA English DT Letter C1 [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Everhart, James E.] NIDDK, NIH, Bethesda, MD USA. RP Lok, AS (reprint author), Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI 48109 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2011 VL 54 IS 1 BP 374 EP 374 DI 10.1002/hep.24410 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788JH UT WOS:000292440700048 ER PT J AU Guo, XC Johnson, RC O'Brien, SJ AF Guo, Xiuchan Johnson, Randall C. O'Brien, Stephen J. TI Association Between Human Leukocyte Antigen DP Gene Polymorphisms and Chronic Hepatitis B in a Chinese Population Reply SO HEPATOLOGY LA English DT Letter ID GENOME-WIDE ASSOCIATION C1 [Guo, Xiuchan] Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Johnson, Randall C.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Guo, XC (reprint author), Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Inst Viral Dis Control & Prevent, Beijing, Peoples R China. NR 3 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2011 VL 54 IS 1 BP 375 EP 376 DI 10.1002/hep.24448 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788JH UT WOS:000292440700050 ER PT J AU Kim, KH Ryan, MJ Estep, JE Miniard, BM Rudge, TL Peggins, JO Broadt, TL Wang, MH Preuss, MA Siegal, GP Hemminki, A Harris, RD Aurigemma, R Curiel, DT Alvarez, RD AF Kim, Kenneth H. Ryan, Michael J. Estep, James E. Miniard, Brock M. Rudge, Thomas L. Peggins, James O. Broadt, Trevor L. Wang, Minghui Preuss, Meredith A. Siegal, Gene P. Hemminki, Akseli Harris, Raymond D. Aurigemma, Rosemarie Curiel, David T. Alvarez, Ronald D. TI A New Generation of Serotype Chimeric Infectivity-Enhanced Conditionally Replicative Adenovirals: The Safety Profile of Ad5/3-Delta 24 in Advance of a Phase I Clinical Trial in Ovarian Cancer Patients SO HUMAN GENE THERAPY LA English DT Article ID GENE-TRANSFER EFFICIENCY; ONCOLYTIC ADENOVIRUS; ORTHOTOPIC MODELS; EFFICACY; VECTORS; THERAPY; TROPISM AB Conditionally replicative adenoviral (CRAd) virotherapy represents a promising therapeutic approach for cancer. We have demonstrated that a serotype chimeric adenoviral 5/3 fiber-knob modification achieves enhanced ovarian cancer infectivity, conditional replication, and oncolytic activity. This study evaluated the safety of intraperitoneal (IP) Ad5/3-Delta 24 in advance of a phase I clinical trial in gynecologic cancers. Syrian hamster cohorts were treated with IP Ad5/3-Delta 24 or control buffer for 3 consecutive days and euthanized on study days 8, 17, 57, and 89. Blood and tissue samples were harvested from each animal. For biodistribution studies, presence and quantitation of viral levels within samples were determined via quantitative polymerase chain reaction. For safety studies, animals were assessed for adverse vector-related tissue or laboratory effects. In the biodistribution study, low levels of Ad5/3-Delta 24 DNA were noted outside of the abdominal cavity. Viral DNA levels in tissues obtained from the peritoneal cavity peaked at day 8 and declined thereafter. In the safety study, no specific histopathologic changes were attributable to virus administration. Hematologic findings noted in the 1 x 10(11) viral particles (vp)/dose group on Days 4 and/or 8 were indicative of an Ad5/3-Delta 24-specific generalized inflammatory response; these findings resolved by day 56. The no observable adverse effect level was determined to be 1 x 10(10) vp/dose. This study elucidates the safety profile of IP administration of the serotype chimeric infectivity-enhanced CRAd, Ad5/3-Delta 24, and provides guidance for a planned phase I trial for patients with recurrent gynecologic cancers. C1 [Kim, Kenneth H.; Alvarez, Ronald D.] Univ Alabama, Div Gynecol Oncol, Birmingham, AL 35249 USA. [Ryan, Michael J.; Estep, James E.; Miniard, Brock M.; Rudge, Thomas L.] Battelle Biomed Res Ctr, W Jefferson, OH 43162 USA. [Peggins, James O.] NCI, Toxicol & Pharmacol Branch, Frederick, MD 21702 USA. [Broadt, Trevor L.] NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Wang, Minghui; Preuss, Meredith A.; Curiel, David T.] Univ Alabama, Div Human Gene Therapy, Birmingham, AL 35249 USA. [Siegal, Gene P.] Univ Alabama, Dept Pathol, Birmingham, AL 35249 USA. [Hemminki, Akseli] Univ Helsinki, Finnish Inst Mol Med, Canc Gene Therapy Grp, Mol Canc Biol Program,Transplantat Lab,Haartman I, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Cent Hosp, HUSLAB, Helsinki, Finland. [Harris, Raymond D.] NCI, Virol Res & Dev Lab, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Aurigemma, Rosemarie] NCI, Biol Resources Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Alvarez, RD (reprint author), Univ Alabama, Div Gynecol Oncol, 176F RM 10250,619 19th St, Birmingham, AL 35249 USA. EM ronald.alvarez@ccc.uab.edu FU National Institutes of Health (NIH) [5R01CA121187]; National Cancer Institute, NIH [N01-CO-12400]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute [N01-CM-42200] FX This work was supported by National Institutes of Health (NIH) grant 5R01CA121187 and has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under Contract No. N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.; This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute under Contract No. N01-CM-42200. NR 23 TC 10 Z9 10 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUL PY 2011 VL 22 IS 7 BP 821 EP 828 DI 10.1089/hum.2010.180 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 792IT UT WOS:000292737600007 PM 21171861 ER PT J AU Pinheiro, A Lanning, D Alves, PC Mage, RG Knight, KL van der Loo, W Esteves, PJ AF Pinheiro, Ana Lanning, Dennis Alves, Paulo C. Mage, Rose G. Knight, Katherine L. van der Loo, Wessel Esteves, Pedro J. TI Molecular bases of genetic diversity and evolution of the immunoglobulin heavy chain variable region (IGHV) gene locus in leporids SO IMMUNOGENETICS LA English DT Review DE Leporids; Rabbit; IGHV; Evolution; Immunoglobulin repertoire ID RABBIT ORYCTOLAGUS-CUNICULUS; AMINO-ACID-SEQUENCE; ALLOTYPE-SUPPRESSED RABBITS; E ALLELIC POLYMORPHISM; H-MUTANT RABBITS; LIGHT-CHAIN; B-LOCUS; ANTIBODY REPERTOIRE; VH-GENE; NATURAL-POPULATIONS AB The rabbit has long been a model for studies of the immune system. Work using rabbits contributed both to the battle against infectious diseases such as rabies and syphilis, and to our knowledge, of antibodies' structure, function, and regulated expression. With the description of rabbit Ig allotypes, the discovery of different gene segments encoding immunoglobulins became possible. This challenged the "one gene-one protein" dogma. The observation that rabbit allotypic specificities of the variable regions were present on IgM and IgG molecules also led to the hypothesis of Ig class switching. Rabbit allotypes contributed to the documentation of phenomena such as allelic exclusion and imbalance in production of allelic gene products. During the last 30 years, the rabbit Ig allotypes revealed a number of unique features, setting them apart from mice, humans, and other mammals. Here, we review the most relevant findings concerning the rabbit IGHV. Among these are the preferential usage of one VH gene in VDJ rearrangements, the existence of trans-species polymorphism in the IGHV locus revealed by serology and confirmed by sequencing IGHV genes in Lepus, the unusually large genetic distances between allelic lineages and the fact that the antibody repertoire is diversified in this species only after birth. The whole genome sequence of a rabbit, plus re-sequencing of additional strains and related genera, will allow further evolutionary investigations of antibody variation. Continued research will help define the roles that genetic, allelic, and population diversity at antibody loci may play in host-parasite interactions. C1 [Pinheiro, Ana; Alves, Paulo C.; van der Loo, Wessel; Esteves, Pedro J.] Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal. [Pinheiro, Ana; Alves, Paulo C.] Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Oporto, Portugal. [Lanning, Dennis; Knight, Katherine L.] Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL 60153 USA. [Mage, Rose G.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Esteves, Pedro J.] CESPU, IPSN, Ctr Invest Tecnol Saude, P-4585116 Gandra, Portugal. RP Esteves, PJ (reprint author), Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, Campus Agrario Vairao, P-4485661 Vairao, Portugal. EM pjesteves@mail.icav.up.pt RI ALVES, Paulo Celio/B-5448-2009; Pinheiro, Ana/A-9902-2011; Esteves, Pedro/A-7537-2010; OI ALVES, Paulo Celio/0000-0003-4797-0939; Pinheiro, Ana/0000-0002-9047-954X; Esteves, Pedro/0000-0002-6055-8298; van der Loo, Wessel/0000-0003-1833-7122 FU Foundation for Science and Technology-Portugal [SFRH/BD/71252/2010, SFRH/BPD/27021/2006]; NIAID, NIH FX This work was supported by grants of Foundation for Science and Technology-Portugal to A.P. and P.J.E. (SFRH/BD/71252/2010 and SFRH/BPD/27021/2006), respectively, and the intramural program of the NIAID, NIH (R.G.M.). NR 115 TC 19 Z9 19 U1 0 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD JUL PY 2011 VL 63 IS 7 BP 397 EP 408 DI 10.1007/s00251-011-0533-9 PG 12 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 789ZS UT WOS:000292558900001 PM 21594770 ER PT J AU Greten, TF Manns, MP Korangy, F AF Greten, Tim F. Manns, Michael P. Korangy, Firouzeh TI Myeloid derived suppressor cells in human diseases SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Review DE Myeloid derived suppressor cells; Human; Tumor immunology ID COLONY-STIMULATING FACTOR; NATURAL-KILLER-CELLS; REGULATORY T-CELLS; CANCER-PATIENTS; HEPATOCELLULAR-CARCINOMA; DENDRITIC CELLS; IMMUNOSUPPRESSIVE ACTIVITY; ACTIVATED GRANULOCYTES; IMMUNE DYSFUNCTION; ANTITUMOR IMMUNITY AB Myeloid derived suppressor cells (MDSC) have been described as a heterogeneous cell population with potent immune suppressor function in mice. Limited data are available on MDSC in human diseases. Interpretation of these data is complicated by the fact that different markers have been used to analyze human MDSC subtypes in various clinical settings. Human MDSC are CD11b(+), CD33(+), HLA-DRneg/low and can be divided into granulocytic CD14(-) and monocytic CD14(+) subtypes. Interleukin 4R alpha, VEGFR, CD15 and CD66b have been suggested to be more specific markers for human MDSC, however these markers can only be found on some MDSC subsets. Until today the best marker for human MDSC remains their suppressor function, which can be either direct or indirect through the induction of regulatory T cells. Immune suppressor activity has been associated with high arginase 1 and iNOS activity as well as ROS production by MDSC. Not only in murine models, but even more importantly in patients with cancer, different drugs have been shown to either reverse the immune suppressor function of MDSC or directly target these cells. Systemic treatment with all-transretinoic acid has been shown to mature human MDSC and reverse their immune suppressor function. Alternatively, MDSC can be targeted by treatment with the multi-targeted receptor tyrosine kinase inhibitor sunitinib. This review will provide a comprehensive summary of the recent literature on human MDSC. (c) 2011 Published by Elsevier B.V. C1 [Greten, Tim F.; Korangy, Firouzeh] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. RP Greten, TF (reprint author), NCI, NIH, Med Oncol Branch, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer; Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health FX The authors' work was supported by the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer (M.P.M.) and in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (T.F.G.) NR 70 TC 179 Z9 193 U1 4 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD JUL PY 2011 VL 11 IS 7 SI SI BP 802 EP 807 DI 10.1016/j.intimp.2011.01.003 PG 6 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 791IX UT WOS:000292660000006 PM 21237299 ER PT J AU Chan, T Wiltrout, RH Weiss, JM AF Chan, Tim Wiltrout, Robert H. Weiss, Jonathan M. TI Immunotherapeutic modulation of the suppressive liver and tumor microenvironments SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Review DE Tumor-associated macrophages; Myeloid derived suppressor cells; Regulatory dendritic cells; Regulatory T cells; Tumor immunotherapy; Liver microenvironment ID REGULATORY T-CELLS; PLASMACYTOID DENDRITIC CELLS; L-ARGININE METABOLISM; COLONY-STIMULATING FACTOR; INNATE IMMUNE-RESPONSES; NATURAL-KILLER-CELLS; IN-VIVO; HEPATOCELLULAR-CARCINOMA; MYELOID CELLS; KUPFFER CELLS AB The liver is an immunologically unique organ, consisting of resident hematopoietic and parenchymal cells which often contribute to a relatively tolerant microenvironment It is also becoming increasingly clear that tumor-induced immunosuppression occurs via many of the same cellular mechanisms which contribute to the tolerogenic liver microenvironment. Myeloid cells, consisting of dendritic cells (DC), macrophages and myeloid derived suppressor cells (MDSC), have been implicated in providing a tolerogenic liver environment and immune dysfunction within the tumor microenvironment which can favor tumor progression. As we increase our understanding of the biological mechanisms involved for each phenotypic and/or functionally distinct leukocyte subset, immunotherapeutic strategies can be developed to overcome the inherent barriers to the development of improved strategies for the treatment of liver disease and tumors. In this review, we discuss the principal myeloid cell-based contributions to immunosuppression that are shared between the liver and tumor microenvironments. We further highlight immune-based strategies shown to modulate immunoregulatory cells within each microenvironment and enhance anti-tumor responses. Published by Elsevier B.V. RP Weiss, JM (reprint author), NCI Frederick Bldg 560,Room 31-18, Frederick, MD 21702 USA. EM weissj@ncifcrf.gov FU Intramural NIH HHS [Z99 CA999999] NR 173 TC 14 Z9 15 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD JUL PY 2011 VL 11 IS 7 SI SI BP 879 EP 889 DI 10.1016/j.intimp.2010.12.024 PG 11 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 791IX UT WOS:000292660000016 PM 21241810 ER PT J AU Lee-Young, RS Ayala, JE Fueger, PT Mayes, WH Kang, L Wasserman, DH AF Lee-Young, R. S. Ayala, J. E. Fueger, P. T. Mayes, W. H. Kang, L. Wasserman, D. H. TI Obesity impairs skeletal muscle AMPK signaling during exercise: role of AMPK alpha 2 in the regulation of exercise capacity in vivo SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE muscle glucose uptake; exercise tolerance; exercise training; diet ID ACTIVATED PROTEIN-KINASE; INSULIN-RESISTANCE; GLUCOSE-UPTAKE; NITRIC-OXIDE; MOUSE; CONTRACTION; TRANSPORT; GLUT4; MICE AB Objective: Skeletal muscle AMP-activated protein kinase (AMPK)alpha 2 activity is impaired in obese, insulin-resistant individuals during exercise. We determined whether this defect contributes to the metabolic dysregulation and reduced exercise capacity observed in the obese state. Design: C57BL/6J wild-type (WT) mice and/or mice expressing a kinase dead AMPK alpha 2 subunit in skeletal muscle (alpha 2-KD) were fed chow or high-fat (HF) diets from 3 to 16 weeks of age. At 15 weeks, mice performed an exercise stress test to determine exercise capacity. In WT mice, muscle glucose uptake and skeletal muscle AMPK alpha 2 activity was assessed in chronically catheterized mice (carotid artery/jugular vein) at 16 weeks. In a separate study, HF-fed WT and alpha 2-KD mice performed 5 weeks of exercise training (from 15 to 20 weeks of age) to test whether AMPK alpha 2 is necessary to restore work tolerance. Results: HF-fed WT mice had reduced exercise tolerance during an exercise stress test, and an attenuation in muscle glucose uptake and AMPK alpha 2 activity during a single bout of exercise (P<0.05 versus chow). In chow-fed alpha 2-KD mice, running speed and time were impaired similar to 45 and similar to 55%, respectively (P<0.05 versus WT chow); HF feeding further reduced running time similar to 25% (P<0.05 versus alpha 2-KD chow). In response to 5 weeks of exercise training, HF-fed WT and alpha 2-KD mice increased maximum running speed similar to 35% (P<0.05 versus pre-training) and maintained body weight at pre-training levels, whereas body weight increased in untrained HF WT and alpha 2-KD mice. Exercise training restored running speed to levels seen in healthy, chow-fed mice. Conclusion: HF feeding impairs AMPK alpha 2 activity in skeletal muscle during exercise in vivo. Although this defect directly contributes to reduced exercise capacity, findings in HF-fed alpha 2-KD mice show that AMPK alpha 2-independent mechanisms are also involved. Importantly, alpha 2-KD mice on a HF-fed diet adapt to regular exercise by increasing exercise tolerance, demonstrating that this adaptation is independent of skeletal muscle AMPK alpha 2 activity. International Journal of Obesity (2011) 35, 982-989; doi: 10.1038/ijo.2010.220; published online 16 November 2010 C1 [Lee-Young, R. S.; Ayala, J. E.; Fueger, P. T.; Mayes, W. H.; Kang, L.; Wasserman, D. H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Ayala, J. E.; Wasserman, D. H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP Lee-Young, RS (reprint author), Baker IDI Heart & Diabet Inst, Cellular & Mol Metab Lab, Div Metab & Obes, Melbourne, Vic 3004, Australia. EM robert.lee-young@bakeridi.edu RI Fueger, Patrick/G-8956-2013 FU National Institutes of Health [U24 DK-59637, R01 DK-54902]; American Diabetes Association FX This work was supported by National Institutes of Health Grants U24 DK-59637 and R01 DK-54902 (to DHW). RS Lee-Young was supported by a Mentor-Based Fellowship from the American Diabetes Association. NR 22 TC 16 Z9 17 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2011 VL 35 IS 7 BP 982 EP 989 DI 10.1038/ijo.2010.220 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 791DB UT WOS:000292641300012 PM 21079619 ER PT J AU Tammemagi, CM Pinsky, PF Caporaso, NE Kvale, PA Hocking, WG Church, TR Riley, TL Commins, J Oken, MM Berg, CD Prorok, PC AF Tammemagi, C. Martin Pinsky, Paul F. Caporaso, Neil E. Kvale, Paul A. Hocking, William G. Church, Timothy R. Riley, Thomas L. Commins, John Oken, Martin M. Berg, Christine D. Prorok, Philip C. TI Lung Cancer Risk Prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Models and Validation SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BODY-MASS INDEX; OXIDATIVE DNA-DAMAGE; CHRONIC INFLAMMATION; SUSCEPTIBILITY LOCUS; AFRICAN-AMERICANS; SMOKERS; SMOKING; COHORT; DISEASE; WOMEN AB Introduction Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately. Methods Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided. Results During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites. Conclusion The PLCO lung cancer risk models demonstrate high discrimination and calibration. C1 [Tammemagi, C. Martin] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Berg, Christine D.] NIH, Early Detect Res Grp, Canc Prevent Div, Natl Canc Inst, Bethesda, MD 20892 USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kvale, Paul A.] Henry Ford Hlth Syst, Div Pulm & Crit Care Med, Detroit, MI USA. [Hocking, William G.] Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol, Marshfield, WI USA. [Church, Timothy R.] Univ Minnesota, Dept Environm Hlth Sci, Minneapolis, MN USA. [Riley, Thomas L.; Commins, John] Informat Management Serv Inc, Rockville, MD USA. [Oken, Martin M.] N Mem Hlth Care, Hubert H Humphrey Canc Ctr, Robbinsdale, MN USA. [Prorok, Philip C.] NIH, Biometry Res Grp, Canc Prevent Div, Natl Canc Inst, Bethesda, MD 20892 USA. RP Tammemagi, CM (reprint author), Brock Univ, Dept Community Hlth Sci, 500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada. EM martin.tammemagi@brocku.ca RI Berg , Christine/K-1047-2014; OI Hocking, William/0000-0002-0690-3759; Church, Timothy R./0000-0003-3292-5035 FU Division of Cancer Prevention, National Cancer Institute, National Institute of Health, Department of Health and Human Services; National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial FX This research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institute of Health, Department of Health and Human Services. The funders did not have any involvement in the design of this ancillary study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.; This report describes an ancillary study in the National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, which is a federally funded registered clinical trial (ClinicalTrials.gov Identifier: NCT00002540). The authors thank the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Most importantly, we acknowledge the study participants for their contributions to making this study possible. We thank Professor Frank E. Harrell, Jr, for helpful guidance regarding risk prediction modeling and interpretation. Dr C. Martin Tammemagi's involvement in the PLCO has been through his affiliation with Henry Ford Health System in Detroit, Michigan. NR 66 TC 101 Z9 104 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 13 BP 1058 EP 1068 DI 10.1093/jnci/djr173 PG 11 WC Oncology SC Oncology GA 790BF UT WOS:000292562800012 PM 21606442 ER PT J AU Sastry, M Xu, L Georgiev, IS Bewley, CA Nabel, GJ Kwong, PD AF Sastry, Mallika Xu, Ling Georgiev, Ivelin S. Bewley, Carole A. Nabel, Gary J. Kwong, Peter D. TI Mammalian production of an isotopically enriched outer domain of the HIV-1 gp120 glycoprotein for NMR spectroscopy SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Adenovirus vector; Eukaryotic expression; HIV-1 envelope; Isotope enrichment; N-linked glycosylation ID IMMUNODEFICIENCY-VIRUS TYPE-1; ESCHERICHIA-COLI; RESONANCE ASSIGNMENTS; RECOMBINANT PROTEINS; STRUCTURAL BASIS; HUMAN CD2; IN-VITRO; ADENOVIRUS; VECTORS; CELLS AB NMR spectroscopic characterization of the structure or the dynamics of proteins generally requires the production of samples isotopically enriched in (15)N, (13)C, or (2)H. The bacterial expression systems currently in use to obtain isotopic enrichment, however, cannot produce a number of eukaryotic proteins, especially those that require post-translational modifications such as N-linked glycosylation for proper folding or activity. Here, we report the use of an adenovirus vector-based mammalian expression system to produce isotopically enriched (15)N or (15)N/(13)C samples of an outer domain variant of the HIV-1 gp120 envelope glycoprotein with 15 sites of N-linked glycosylation. Yields for the (15)N- and (15)N/(13)C-labeled gp120s after affinity chromatography were 45 and 44 mg/l, respectively, with an average of over 80% isotope incorporation. Recognition of the labeled gp120 by cognate antibodies that recognize complex epitopes showed affinities comparable to the unlabeled protein. NMR spectra, including (1)H-(15)N and (1)H-(13)C HSQCs, (15)N-edited NOESY-HSQC, and 3D HNCO, were of high quality, with signal-to-noise consistent with an efficient level of isotope incorporation, and with chemical shift dispersion indicative of a well-folded protein. The exceptional protein yields, good isotope incorporation, and ability to obtain well-folded post-translationally modified proteins make this mammalian system attractive for the production of isotopically enriched eukaryotic proteins for NMR spectroscopy. C1 [Sastry, Mallika; Xu, Ling; Georgiev, Ivelin S.; Nabel, Gary J.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM pdkwong@nih.gov FU NIH (NIAID); NIH (NIDDK) FX We thank the NMR staff at the New York Structural Biology Consortium for assistance with instrumentation. We also thank Mary Ann Gawinowicz of the Protein Core Facility at Columbia University for N terminal sequencing and mass spectrometry, L. Shapiro for editorial assistance with the manuscript, and T. Waybright and T. Veenstra at the NCI for assistance with mass spectral data acquisition. We also thank the members of the structural biology and structural bioinformatics core sections at the Vaccine Research Center for insightful comments and discussions. Support for this work was provided by the Intramural Program of the NIH (NIAID and NIDDK). NR 47 TC 11 Z9 11 U1 0 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUL PY 2011 VL 50 IS 3 BP 197 EP 207 DI 10.1007/s10858-011-9506-4 PG 11 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 791HV UT WOS:000292656700002 PM 21667299 ER PT J AU Hu, KN Qiang, W Tycko, R AF Hu, Kan-Nian Qiang, Wei Tycko, Robert TI A general Monte Carlo/simulated annealing algorithm for resonance assignment in NMR of uniformly labeled biopolymers SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Sequential assignment; Solid state NMR; Magic-angle spinning; Multidimensional spectroscopy ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; IMMUNOGLOBULIN BINDING DOMAIN; SPECTRIN SH3 DOMAIN; HUMAN PRION PROTEIN; ANGLE-SPINNING NMR; HET-S PRION; AMYLOID FIBRILS; SIDE-CHAIN; BACKBONE RESONANCES AB We describe a general computational approach to site-specific resonance assignments in multidimensional NMR studies of uniformly (15)N,(13)C-labeled biopolymers, based on a simple Monte Carlo/simulated annealing (MCSA) algorithm contained in the program MCASSIGN2. Input to MCASSIGN2 includes lists of multidimensional signals in the NMR spectra with their possible residue-type assignments (which need not be unique), the biopolymer sequence, and a table that describes the connections that relate one signal list to another. As output, MCASSIGN2 produces a high-scoring sequential assignment of the multidimensional signals, using a score function that rewards good connections (i.e., agreement between relevant sets of chemical shifts in different signal lists) and penalizes bad connections, unassigned signals, and assignment gaps. Examination of a set of high-scoring assignments from a large number of independent runs allows one to determine whether a unique assignment exists for the entire sequence or parts thereof. We demonstrate the MCSA algorithm using two-dimensional (2D) and three-dimensional (3D) solid state NMR spectra of several model protein samples (alpha-spectrin SH3 domain and protein G/B1 microcrystals, HET-s(218-289) fibrils), obtained with magic-angle spinning and standard polarization transfer techniques. The MCSA algorithm and MCASSIGN2 program can accommodate arbitrary combinations of NMR spectra with arbitrary dimensionality, and can therefore be applied in many areas of solid state and solution NMR. C1 [Hu, Kan-Nian; Qiang, Wei; Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Qiang, Wei/I-1053-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases within National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases within the National Institutes of Health. Computational facilities of the Helix Systems at the National Institutes of Health were used in this work. NR 36 TC 22 Z9 22 U1 0 U2 20 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUL PY 2011 VL 50 IS 3 BP 267 EP 276 DI 10.1007/s10858-011-9517-1 PG 10 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 791HV UT WOS:000292656700009 PM 21710190 ER PT J AU Johnson, RL Hwang, JY Arnold, LA Huang, RL Wichterman, J Augustinaite, I Austin, CP Inglese, J Guy, RK Huang, WW AF Johnson, Ronald L. Hwang, Jong Yeon Arnold, Leggy A. Huang, Ruili Wichterman, Jennifer Augustinaite, Indre Austin, Christopher P. Inglese, James Guy, R. Kiplin Huang, Wenwei TI A Quantitative High-Throughput Screen Identifies Novel Inhibitors of the Interaction of Thyroid Receptor beta with a Peptide of Steroid Receptor Coactivator 2 SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE thyroid receptor; small molecule; HTS; coactivator; protein-protein interaction ID NUCLEAR HORMONE RECEPTORS; CO-REPRESSOR; SRC FAMILY; BINDING; SUPERFAMILY; ANISOTROPY; LIBRARIES; ASSAY AB The thyroid hormone receptors (TR) are members of the nuclear hormone receptor (NHR) superfamily that regulate development, growth, and metabolism. Upon ligand binding, TR releases bound corepressors and recruits coactivators to modulate target gene expression. Steroid receptor coactivator 2 (SRC2) is an important coregulator that interacts with TR beta to activate gene transcription. To identify novel inhibitors of the TR beta and SRC2 interaction, the authors performed a quantitative high-throughput screen (qHTS) of a TR beta-SRC2 fluorescence polarization assay against more than 290 000 small molecules. The qHTS assayed compounds at 6 concentrations up to 92 mu M to generate titration-response curves and determine the potency and efficacy of all compounds. The qHTS data set enabled the characterization of actives for structure-activity relationships as well as for potential artifacts such as fluorescence interference. Selected qHTS actives were tested in the screening assay using fluoroprobes labeled with Texas Red or fluorescein. The retest identified 19 series and 4 singletons as active in both assays with 40% or greater efficacy, free of compound interference, and not toxic to mammalian cells. Selected compounds were tested as independent samples, and a methylsulfonylnitrobenzoate series inhibited the TR beta-SRC2 interaction with 5 mu M IC(50). This series represents a new class of thyroid hormone receptor-coactivator modulators. (Journal of Biomolecular Screening 2011; 16: 618-627) C1 [Johnson, Ronald L.; Huang, Ruili; Wichterman, Jennifer; Austin, Christopher P.; Inglese, James; Huang, Wenwei] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Hwang, Jong Yeon; Arnold, Leggy A.; Augustinaite, Indre; Guy, R. Kiplin] St Jude Childrens Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA. RP Johnson, RL (reprint author), NHGRI, Chem Genom Ctr, NIH, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM rjohnso2@mail.nih.gov RI Guy, Rodney/J-7107-2013 OI Guy, Rodney/0000-0002-9638-2060 FU National Institutes of Health [DK58080]; NIH Roadmap for Medical Research; National Human Genome Research Institute, National Institutes of Health; American Lebanese Syrian Associated Charities; St. Jude Children's Research Hospital FX We thank Sam Michael for automation assistance, Paul Shinn and Danielle Van Leer for compound management, Bill Leister, Chris LeClair, and Jeremy Smith for analytical chemistry, Rajarshi Guha for informatics, and Ryan MacArthur for preparation of three dimensional plots. This work was supported by the National Institutes of Health (grant number DK58080); the NIH Roadmap for Medical Research; the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; the American Lebanese Syrian Associated Charities; and St. Jude Children's Research Hospital. NR 35 TC 7 Z9 7 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2011 VL 16 IS 6 BP 618 EP 627 DI 10.1177/1087057111402199 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 790DW UT WOS:000292569700005 PM 21482722 ER PT J AU Greenhouse, B Ho, B Hubbard, A Njama-Meya, D Narum, DL Lanar, DE Dutta, S Rosenthal, PJ Dorsey, G John, CC AF Greenhouse, Bryan Ho, Benjamin Hubbard, Alan Njama-Meya, Denise Narum, David L. Lanar, David E. Dutta, Sheetij Rosenthal, Philip J. Dorsey, Grant John, Chandy C. TI Antibodies to Plasmodium falciparum Antigens Predict a Higher Risk of Malaria But Protection From Symptoms Once Parasitemic SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID LIVER-STAGE ANTIGEN-1; MEROZOITE SURFACE PROTEIN-1; CLINICAL MALARIA; HIGHLAND AREA; CIRCUMSPOROZOITE PROTEIN; VACCINE CANDIDATES; ESCHERICHIA-COLI; UGANDAN CHILDREN; WESTERN KENYA; TRANSMISSION AB Background. Associations between antibody responses to Plasmodium falciparum antigens and protection against symptomatic malaria have been difficult to ascertain, in part because antibodies are potential markers of both exposure to P. falciparum and protection against disease. Methods. We measured IgG responses to P. falciparum circumsporozoite protein, liver-stage antigen 1, apical-membrane antigen 1 (AMA-1), and merozoite surface proteins (MSP) 1 and 3, in children in Kampala, Uganda, and measured incidence of malaria before and after antibody measurement. Results. Stronger responses to all 5 antigens were associated with an increased risk of clinical malaria (P < .01) because of confounding with prior exposure to P. falciparum. However, with use of another assessment, risk of clinical malaria once parasitemic, stronger responses to AMA-1, MSP-1, and MSP-3 were associated with protection (odds ratios, 0.34, 0.36, and 0.31, respectively, per 10-fold increase; P < .01). Analyses assessing antibodies in combination suggested that any protective effect of antibodies was overestimated by associations between individual responses and protection. Conclusions. Using the risk of symptomatic malaria once parasitemic as an outcome may improve detection of associations between immune responses and protection from disease. Immunoepidemiology studies designed to detect mechanisms of immune protection should integrate prior exposure into the analysis and evaluate multiple immune responses. C1 [Greenhouse, Bryan; Rosenthal, Philip J.; Dorsey, Grant] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Hubbard, Alan] Univ Calif Berkeley, Div Biostat, Berkeley, CA 94720 USA. [Ho, Benjamin; John, Chandy C.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Njama-Meya, Denise] Makerere Univ, Kampala, Uganda. [Narum, David L.] NIAID, Malaria Vaccine Dev Branch, Rockville, MD USA. [Lanar, David E.; Dutta, Sheetij] Walter Reed Army Inst Res, Div Malaria Vaccine Dev, Silver Spring, MD USA. RP Greenhouse, B (reprint author), Univ Calif San Francisco, Dept Med, Box 0811, San Francisco, CA 94143 USA. EM bgreenhouse@medsfgh.ucsf.edu OI Greenhouse, Bryan/0000-0003-0287-9111 FU National Institute of Allergy and Infectious Disease (NIAID) [AI052142, AI056270]; Doris Duke Charitable Foundation [2004047]; National Institutes of Health, NIAID, Laboratory of Malaria Immunology and Vaccinology FX This work was supported by the National Institute of Allergy and Infectious Disease (NIAID) (AI052142, AI056270) and the Doris Duke Charitable Foundation (2004047). This work was funded in part by the Intramural Research Program of the National Institutes of Health, NIAID, Laboratory of Malaria Immunology and Vaccinology. NR 50 TC 37 Z9 37 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2011 VL 204 IS 1 BP 19 EP 26 DI 10.1093/infdis/jir223 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AV UT WOS:000292561800005 PM 21628654 ER PT J AU Wentzensen, N Rodriguez, AC Viscidi, R Herrero, R Hildesheim, A Ghosh, A Morales, J Wacholder, S Guillen, D Alfaro, M Safaeian, M Burk, RD Schiffman, M AF Wentzensen, Nicolas Cecilia Rodriguez, Ana Viscidi, Raphael Herrero, Rolando Hildesheim, Allan Ghosh, Arpita Morales, Jorge Wacholder, Sholom Guillen, Diego Alfaro, Mario Safaeian, Mahboobeh Burk, Robert D. Schiffman, Mark TI A Competitive Serological Assay Shows Naturally Acquired Immunity to Human Papillomavirus Infections in the Guanacaste Natural History Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID POPULATION-BASED COHORT; COSTA-RICA; TYPE-16; WOMEN; ANTIBODIES; SEROPREVALENCE; NEUTRALIZATION; GARDASIL(R); RESPONSES; CANCER AB Background. A competitive Luminex Immunoassay (cLIA) has been developed to measure neutralizing antibodies against human papillomavirus (HPV) types 6, 11, 16 and 18. Methods. In a cohort of 974 women from the Guanacaste Natural History Study, we studied the relationship of baseline cLIA and virus-like particle (VLP) enzyme-linked immunosorbent assay (ELISA) (HPV16 and HPV18 only) seropositivity to measures of HPV exposure, HPV DNA positivity, number of sexual partners, cytology findings, and age. We then studied immunity against subsequent infection with HPV6, 11, 16, 18 and related types over a 7-year period. Results. cLIA seroprevalence varied with previous exposure; the prevalence of cLIA results positive for HPV16 and HPV18 was lower than the prevalence of positive VLP ELISA responses. cLIA and VLP ELISA positivity predicted protection from subsequent infections with concordant types. The combined odds ratio for HPV16 and HPV18 cLIA positivity was 0.41 (95% confidence interval [CI], 0.21-0.80), and the combined odds ratio for the HPV16 and HPV18 VLP ELISA positivity was 0.65 (95% CI, 0.46-0.93). Of individual types, statistical significance was only reached for HPV16 cLIA positivity (odds ratio, 0.44; 95% CI, 0.15-0.94). Conclusions. Both assays showed an association between positive results and significant protection from subsequent infections for HPV16 and HPV18 combined. cLIA seroprevalence was lower than VLP ELISA, suggesting that the assay detects a subset of antibodies following natural infection that are specifically linked to immunity against subsequent HPV infection. C1 [Wentzensen, Nicolas; Hildesheim, Allan; Ghosh, Arpita; Wacholder, Sholom; Safaeian, Mahboobeh; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Viscidi, Raphael] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NIH; National Cancer Institute FX The Intramural Research Program of the NIH and the National Cancer Institute. NR 21 TC 32 Z9 32 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2011 VL 204 IS 1 BP 94 EP 102 DI 10.1093/infdis/jir209 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AV UT WOS:000292561800014 PM 21628663 ER PT J AU Chun, TW Murray, D Justement, JS Hallahan, CW Moir, S Kovacs, C Fauci, AS AF Chun, Tae-Wook Murray, Danielle Justement, J. Shawn Hallahan, Claire W. Moir, Susan Kovacs, Colin Fauci, Anthony S. TI Relationship Between Residual Plasma Viremia and the Size of HIV Proviral DNA Reservoirs in Infected Individuals Receiving Effective Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID INTENSIFICATION; GUT; REPLICATION; ACTIVATION; BURDEN AB Residual plasma viremia (<50 copies/mL) persists in certain human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART); however, the relationship between the degree of residual plasma viremia, the size of HIV reservoirs, and the level of immune activation has not been delineated. Here, we demonstrate that residual plasma viremia correlates with the size of the CD4(+) T cell viral reservoir, but not with markers of immune activation, suggesting that reactivation of the latent viral reservoir may not be the sole source of residual plasma viremia. Novel therapeutic strategies aimed at targeting the source of residual viremia may be necessary to achieve viral eradication. C1 [Chun, Tae-Wook; Murray, Danielle; Justement, J. Shawn; Moir, Susan; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Hallahan, Claire W.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Kovacs, Colin] Univ Toronto, Dept Med, Toronto, ON M5S 1A1, Canada. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 15 TC 91 Z9 92 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2011 VL 204 IS 1 BP 135 EP 138 DI 10.1093/infdis/jir208 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AV UT WOS:000292561800018 PM 21628667 ER PT J AU Lai, LL Kwa, S Kozlowski, PA Montefiori, DC Ferrari, G Johnson, WE Hirsch, V Villinger, F Chennareddi, L Earl, PL Moss, B Amara, RR Robinson, HL AF Lai, Lilin Kwa, SueFen Kozlowski, Pamela A. Montefiori, David C. Ferrari, Guido Johnson, Welkin E. Hirsch, Vanessa Villinger, Francois Chennareddi, Lakshmi Earl, Patricia L. Moss, Bernard Amara, Rama Rao Robinson, Harriet L. TI Prevention of Infection by a Granulocyte-Macrophage Colony-Stimulating Factor Co-Expressing DNA/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID T-HELPER-CELL; MYELOID SUPPRESSOR-CELLS; TRACT DENDRITIC CELLS; GM-CSF DNA; RHESUS MACAQUES; NEUTRALIZING ANTIBODIES; CONTROL REPLICATION; CONJUGATE VACCINES; HUMORAL IMMUNITY; TYPE-1 INFECTION AB A simian immunodeficiency virus (SIV) vaccine coexpressing granulocyte-macrophage colony stimulating factor (GM-CSF) prevented infection in 71% of macaques that received 12 rectal challenges. The SIVsmE660 challenge had the tropism of incident human immunodeficiency virus (HIV) infections and a similar genetic distance from the SIV239 vaccine as intraclade HIV isolates. The heterologous prime-boost vaccine regimen used recombinant DNA for priming and recombinant modified vaccinia Ankara for boosting. Co-expression of GM-CSF in the DNA prime enhanced the avidity of elicited immunoglobulin G for SIV envelope glycoproteins, the titers of neutralizing antibody for easy-to-neutralize SIV isolates, and antibody-dependent cellular cytotoxicity. Impressively, the co-expressed GM-CSF increased vaccine-induced prevention of infection from 25% in the non-GM-CSF co-expressing vaccine group to 71% in the GM-CSF co-expressing vaccine group. The prevention of infection showed a strong correlation with the avidity of the elicited Env-specific antibody for the Env of the SIVsmE660 challenge virus (r = 0.9; P < .0001). C1 [Robinson, Harriet L.] GeoVax Inc, GeoVax Labs, Smyrna, GA 30080 USA. [Lai, Lilin; Kwa, SueFen; Villinger, Francois; Chennareddi, Lakshmi; Amara, Rama Rao] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Amara, Rama Rao] Emory Univ, Dept Microbiol & Immunol, Vaccine Res Ctr, Atlanta, GA 30322 USA. [Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, Gene Therapy Program, New Orleans, LA USA. [Montefiori, David C.; Ferrari, Guido] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Johnson, Welkin E.] Harvard Univ, New England Natl Primate Res Ctr, Southborough, MA USA. [Hirsch, Vanessa; Earl, Patricia L.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Robinson, HL (reprint author), GeoVax Inc, GeoVax Labs, 1900 Lake Pk Dr,Ste 380, Smyrna, GA 30080 USA. EM hrobinson@geovax.com RI Ferrari, Guido/A-6088-2015 FU Integrated Preclinical/Clinical AIDS Vaccine Development program project [5U19 AI074073]; NIH [AI30034, AI083118]; Emory University [CFAR P30 AI050409]; NCRR/NIH [P30 RR00165, 30 RR00168] FX This research was supported by an Integrated Preclinical/Clinical AIDS Vaccine Development program project 5U19 AI074073 (HLR), NIH grants AI30034 (DCM) and AI083118 (WEJ), the Emory University CFAR P30 AI050409 and by NCRR/NIH base grants P30 RR00165(YNPRC) and P30 RR00168 (NEPRC) NR 50 TC 60 Z9 60 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2011 VL 204 IS 1 BP 164 EP 173 DI 10.1093/infdis/jir199 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 790AV UT WOS:000292561800022 PM 21628671 ER PT J AU Schwaninger, AE Meyer, MR Huestis, MA Maurer, HH AF Schwaninger, Andrea E. Meyer, Markus R. Huestis, Marilyn A. Maurer, Hans H. TI Development and validation of LC-HRMS and GC-NICI-MS methods for stereoselective determination of MDMA and its phase I and II metabolites in human urine SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE stereoselective method; MDMA; phase I metabolites; phase II metabolites; urine ID CHROMATOGRAPHY-MASS-SPECTROMETRY; DESIGNER DRUGS; MAIN METABOLITES; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; ENANTIOSELECTIVE MEASUREMENT; STEREOCHEMICAL ANALYSIS; CLINICAL TOXICOLOGY; MDEA ENANTIOMERS; AMPHETAMINE; MDA AB 3,4-Methylenedioxymethamphetamine (MDMA) is a racemic drug of abuse and its R- and S-enantiomers are known to differ in their dose-response curve. The S-enantiomer was shown to be eliminated at a higher rate than the R-enantiomer most likely explained by stereoselective metabolism that was observed in various in vitro experiments. The aim of this work was the development and validation of methods for evaluating the stereoselective elimination of phase I and particularly phase II metabolites of MDMA in human urine. Urine samples were divided into three different methods. Method A allowed stereoselective determination of the 4-hydroxy-3-methoxymethamphetamine (HMMA) glucuronides and only achiral determination of the intact sulfate conjugates of HMMA and 3,4-dihydroxymethamphetamine (DHMA) after C18 solid-phase extraction by liquid chromatography-high-resolution mass spectrometry with electrospray ionization. Method B allowed the determination of the enantiomer ratios of DHMA and HMMA sulfate conjugates after selective enzymatic cleavage and chiral analysis of the corresponding deconjugated metabolites after chiral derivatization with S-heptafluorobutyrylprolyl chloride using gas chromatography-mass spectrometry with negative-ion chemical ionization. Method C allowed the chiral determination of MDMA and its unconjugated metabolites using method B without sulfate cleavage. The validation process including specificity, recovery, matrix effects, process efficiency, accuracy and precision, stabilities and limits of quantification and detection showed that all methods were selective, sensitive, accurate and precise for all tested analytes. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Schwaninger, Andrea E.; Meyer, Markus R.; Maurer, Hans H.] Univ Saarland, Inst Expt & Clin Pharmacol & Toxicol, Dept Expt & Clin Toxicol, D-66421 Homburg, Saar, Germany. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Maurer, HH (reprint author), Univ Saarland, Inst Expt & Clin Pharmacol & Toxicol, Dept Expt & Clin Toxicol, D-66421 Homburg, Saar, Germany. EM hans.maurer@uks.eu RI Meyer, Markus/B-9293-2009; OI Steuer, Andrea Eva/0000-0001-8983-2353 FU Medical Faculty, Saarland University, Homburg FX The authors would like to thank their colleagues Jessika Hunsicker, Daniela Remane, Carsten Schroder, Gabriele Ulrich and Armin A. Weber, and ThermoFisher Scientific for their helpful support. This work was financially supported by HOMFOR 2010, the research fund of the Medical Faculty, Saarland University, Homburg. NR 38 TC 20 Z9 20 U1 1 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD JUL PY 2011 VL 46 IS 7 BP 603 EP 614 DI 10.1002/jms.1929 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 790OK UT WOS:000292598700001 PM 21656610 ER PT J AU Xu, Y Okuda, M Hser, YI Hasin, D Liu, SM Grant, BF Blanco, C AF Xu, Yang Okuda, Mayumi Hser, Yih-Ing Hasin, Deborah Liu, Shang-Min Grant, Bridget F. Blanco, Carlos TI Twelve-month prevalence of psychiatric disorders and treatment-seeking among Asian Americans/Pacific Islanders in the United States: Results from the National Epidemiological Survey on Alcohol and Related Conditions SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Epidemiology; Psychiatric disorders; Asian American; Pacific Islanders; Mental health; Treatment utilization ID MENTAL-HEALTH-SERVICES; COMORBIDITY SURVEY REPLICATION; ETHNIC-MINORITY GROUPS; DSM-IV DISORDERS; LOS-ANGELES; HELP-SEEKING; DEPRESSION; AMERICAN; GENDER; PROGRAMS AB To compare the 12-month prevalence of psychiatric disorders in Asian Americans/Pacific Islanders in contrast to non-Hispanic whites; and further compare persistence and treatment-seeking rates for psychiatric disorders among Asian American/Pacific Islanders and non-Hispanic whites, analyses from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, Wave 1 (n = 43,093) were conducted for the subsample of 1332 Asian Americans/Pacific Islanders (596 men and 736 women) and 24.507 non-Hispanic whites (10,845 men and 13,662 women). The past 12-month prevalence for any psychiatric disorder was significantly lower in Asian American/Pacific Islander males and females than non-Hispanic white males and females. Asian American/Pacific Islander males were less likely than non-Hispanic white males to have any mood, anxiety, substance use, and personality disorders, whereas the prevalence of mood disorders among Asian American/Pacific Islander females did not differ from those of non-Hispanic white females. In some cases, such as drug use disorders, both male and female Asian Americans/Pacific Islanders were more likely to have more persistent disorders than non-Hispanic whites. Compared to non-Hispanic white females, Asian American/Pacific Islander females had lower rates of treatment-seeking for any mood/anxiety disorders. Although less prevalent than among non-Hispanic whites, psychiatric disorders are not uncommon among Asian Americans/Pacific Islanders. The lower treatment-seeking rates for mood/anxiety disorders in Asian American/Pacific Islander females underscore the unmet needs for psychiatric service among this population. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Hasin, Deborah; Blanco, Carlos] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York State Psychiat Inst, New York, NY 10032 USA. [Xu, Yang; Okuda, Mayumi; Hasin, Deborah; Liu, Shang-Min; Blanco, Carlos] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hser, Yih-Ing] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90025 USA. [Hasin, Deborah] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Blanco, C (reprint author), Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York State Psychiat Inst, 1051 Riverside Dr,Unit 69, New York, NY 10032 USA. EM cb255@columbia.edu RI Blanco, Carlos/I-4906-2013; Okuda, Mayumi/L-6210-2013; Xu, Yang/B-5543-2016 OI Blanco, Carlos/0000-0001-6187-3057; Okuda, Mayumi/0000-0002-3479-5599; FU Pfizer; GlaxoSmithKline; NIH [DA019606, DA020783, DA023200, DA023973, MH076051, P30DA016383, K05DA0176648]; American Foundation for Suicide Prevention; New York State Psychiatric Institute; [AA014223-03] FX Dr. Blanco has received research support from Pfizer and GlaxoSmithKline. Drs. Xu, Okuda, Hser, Grant, and Hasin and Ms. Liu report no competing interests.; Funding for this study was provided by NIH grants DA019606, DA020783, DA023200, DA023973 and MH076051 (Dr. Blanco), NIH grants P30DA016383 and K05DA0176648 (Dr. Hser), a grant from the American Foundation for Suicide Prevention (Dr. Blanco), AA014223-03 (Dr. Hasin), and the New York State Psychiatric Institute (Drs. Blanco, Hasin). NR 64 TC 11 Z9 11 U1 3 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2011 VL 45 IS 7 BP 910 EP 918 DI 10.1016/j.jpsychires.2010.12.009 PG 9 WC Psychiatry SC Psychiatry GA 791LY UT WOS:000292667900008 PM 21238989 ER PT J AU Beesdo-Baum, K Winkel, S Pine, DS Hoyer, J Hofler, M Lieb, R Wittchen, HU AF Beesdo-Baum, Katja Winkel, Susanne Pine, Daniel S. Hoyer, Juergen Hoefler, Michael Lieb, Roselind Wittchen, Hans-Ulrich TI The diagnostic threshold of generalized anxiety disorder in the community: A developmental perspective SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE DSM-5; Diagnostic criteria; Classification; Epidemiology; Community study ID DSM-III-R; COMORBIDITY SURVEY REPLICATION; MAJOR DEPRESSION; MENTAL-DISORDERS; DURATION REQUIREMENT; SYMPTOM CRITERION; YOUNG-ADULTS; RISK-FACTORS; SELF-REPORT; IV AB Discussion surrounds the question as to whether criteria for generalized anxiety disorder (GAD) should change, particularly in youth. This study examines the effects of possible criteria changes on GAD prevalence and clinical correlates. DSM-IV GAD was assessed using the M-CIDI in a community sample of adolescents and young adults. Diagnostic thresholds were modified in two age spans (9-20 and 21-34 years) using a person-by-year data file (N = 38,534 cases). Relaxing the duration or excessiveness criteria led to the most pronounced changes in GAD prevalence, while relaxing frequency, uncontrollability, or associated-symptom criteria had smaller effects. A lower duration requirement increased rates more in older than younger age spans. Opposite effects occurred for changes in associated-symptoms or clinical-significance criteria. Broader GAD definitions identified cases in both age spans that appeared mostly milder than DSM-IV cases but that still differed from non-GAD cases in various clinical factors and validators. Developmental aspects require stronger consideration in future diagnostic systems. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Beesdo-Baum, Katja; Winkel, Susanne; Hoyer, Juergen; Hoefler, Michael; Wittchen, Hans-Ulrich] Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, D-01187 Dresden, Germany. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Lieb, Roselind] Univ Basel, Inst Psychol, Div Clin Psychol & Epidemiol, CH-4003 Basel, Switzerland. [Lieb, Roselind; Wittchen, Hans-Ulrich] Max Planck Inst Psychiat, D-80804 Munich, Germany. RP Beesdo-Baum, K (reprint author), Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, Chemnitzer St 46, D-01187 Dresden, Germany. EM beesdo@psychologie.tu-dresden.de RI Beesdo-Baum, Katja/A-5793-2012; Wittchen, Hans-Ulrich/A-8507-2014; Hoyer, Juergen/D-3619-2011; OI Hoyer, Juergen/0000-0002-1697-6732; Wittchen, Hans-Ulrich/0000-0002-6311-7711 FU German Federal Ministry of Education and Research (BMBF) [01EB9405/6, 01EB 9901/6, EB01016200, 01EB0140, 01EB0440]; Deutsche Forschungsgemeinschaft (DFG) [LA1148/1-1, WI2246/1-1, WI 709/7-1, WI 709/8-1] FX This work is part of the Early Developmental Stages of Psychopathology (EDSP) Study which was funded by the German Federal Ministry of Education and Research (BMBF) project no. 01EB9405/6, 01EB 9901/6, EB01016200, 01EB0140, and 01EB0440. Part of the field work and analyses were also additionally supported by grants of the Deutsche Forschungsgemeinschaft (DFG) LA1148/1-1, WI2246/1-1, WI 709/7-1, and WI 709/8-1. The funding sources had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. NR 62 TC 14 Z9 14 U1 6 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2011 VL 45 IS 7 BP 962 EP 972 DI 10.1016/j.jpsychires.2010.12.007 PG 11 WC Psychiatry SC Psychiatry GA 791LY UT WOS:000292667900015 PM 21227450 ER PT J AU Denisco, RC Kenna, GA O'Neil, MG Kulich, RJ Moore, PA Kane, WT Mehta, NR Hersh, EV Katz, NP AF Denisco, Richard C. Kenna, George A. O'Neil, Michael G. Kulich, Ronald J. Moore, Paul A. Kane, William T. Mehta, Noshir R. Hersh, Elliot V. Katz, Nathaniel P. TI Prevention of prescription opioid abuse The role of the dentist SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE Opioids; abuse; diversion; addiction; misuse; substance abuse; pain; dentists ID PAIN MEDICATION; SCHOOL-DISTRICT; NONMEDICAL USE; DENTAL PAIN; DRUG-ABUSE; MANAGEMENT; IBUPROFEN; SURGERY; PATIENT AB Background. Opioids are analgesics that have potential for misuse, abuse or addiction. Up to an estimated 23 percent of prescribed doses are used nonmedically. As prescribers of 12 percent of immediate-release (IR) opioids in the United States, dentists can minimize the potential for misuse or abuse. Methods. The authors participated in a two-day meeting in March 2010 cohosted by Tufts Health Care Institute Program on Opioid Risk Management, Boston, and Tufts University School of Dental Medicine, Boston. The purpose of the meeting was to synthesize available opioid abuse literature and data from a 2010 survey regarding West Virginia dentists' analgesic prescribing practices, identify dentists' roles in prescribing opioids that are used nonmedically, highlight practices that dentists can implement and identify research gaps. Results. Dentists can play a role in minimizing opioid abuse through patient education, careful patient assessment and referral for substance abuse treatment when indicated, and using tools such as prescription monitoring programs. Research is needed to determine the optimal number of doses needed to treat dental-related pain. Conclusions. Dentists cannot assume that their prescribing of opioids does not affect the opioid abuse problem in the United States. The authors suggest that dentists, along with other prescribers, take steps to identify problems and minimize prescription opioid abuse through greater prescriber and patient education; use of peer-reviewed recommendations for analgesia; and, when indicated, the tailoring of the appropriate and legitimate prescribing of opioids to adequately treat pain. Practice Implications. The authors encourage dentists to incorporate practical safeguards when prescribing opioids, consistently educate patients about how to secure unused opioids properly, screen patients for substance use disorders and develop a referral network for the treatment of substance use disorders. C1 [Kenna, George A.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Denisco, Richard C.] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Rockville, MD USA. [Kenna, George A.; Katz, Nathaniel P.] Tufts Hlth Care Inst Program Opioid Risk Manageme, Boston, MA USA. [O'Neil, Michael G.] Univ Charleston, Sch Pharm, Ctr Excellence Educ & Prevent Drug Divers & Subst, Charleston, WV USA. [Kulich, Ronald J.] Massachusetts Gen Hosp, Ctr Pain Med, Boston, MA 02114 USA. [Kulich, Ronald J.] Harvard Univ, Sch Med, Boston, MA USA. [Moore, Paul A.] Univ Pittsburgh, Sch Dent Med, Dept Dent Anesthesiol, Pittsburgh, PA 15260 USA. [Kane, William T.] Missouri Dent Assoc Well Being Program, Jefferson City, MO USA. [Mehta, Noshir R.] Tufts Univ, Sch Dent Med, Dept Gen Dent, Boston, MA 02111 USA. [Mehta, Noshir R.] Tufts Univ, Sch Dent Med, Craniofacial Pain Ctr, Boston, MA 02111 USA. [Hersh, Elliot V.] Univ Penn, Sch Dent Med, Div Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Katz, Nathaniel P.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. RP Kenna, GA (reprint author), Brown Univ, Ctr Alcohol & Addict Studies, Box G-S121-5, Providence, RI 02912 USA. EM George_Kenna@Brown.edu FU Endo Pharmaceuticals, Newark, Del.; Grunenthal, Aachen, Germany; King Pharmaceuticals [now part of Pfizer, New York City]; Dominion Diagnostics, North Kingstown, R.I.; Covdien, Dublin; Purdue Pharma, Stamford, Conn. FX The authors thank Amy Rosenstein, Rosemarie Curran, Rosalie Phillips and Sarah Haile from the Tufts Health Care Institute for their administrative support. In addition, the authors thank the supporters of the Tufts Health Care Institute Program on Opioid Risk Management (Endo Pharmaceuticals, Newark, Del.; Grunenthal, Aachen, Germany; King Pharmaceuticals [now part of Pfizer, New York City]; Dominion Diagnostics, North Kingstown, R.I.; Covdien, Dublin; and Purdue Pharma, Stamford, Conn.) for their financial support of The Role of Dentists in Preventing Opioid Abuse Meeting in March 2010, as well as Angela Casey for her assistance in writing this article. NR 80 TC 25 Z9 28 U1 0 U2 7 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUL PY 2011 VL 142 IS 7 BP 800 EP 810 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 790HM UT WOS:000292579100011 PM 21719802 ER PT J AU Shea, MK Houston, DK Tooze, JA Davis, CC Johnson, MA Hausman, DB Cauley, JA Bauer, DC Tylavsky, F Harris, TB Kritchevsky, SB AF Shea, M. Kyla Houston, Denise K. Tooze, Janet A. Davis, Cralen C. Johnson, Mary Ann Hausman, Dorothy B. Cauley, Jane A. Bauer, Douglas C. Tylavsky, Frances Harris, Tamara B. Kritchevsky, Stephen B. CA Hlth Aging Body Composition Study TI Correlates and Prevalence of Insufficient 25-Hydroxyvitamin D Status in Black and White Older Adults: The Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE vitamin D; insufficiency; race; prevalence; determinants ID VITAMIN-D INSUFFICIENCY; NUTRITION EXAMINATION SURVEY; RANDOMIZED-CONTROLLED-TRIAL; 3RD NATIONAL-HEALTH; SERUM 25-HYDROXYVITAMIN-D; D DEFICIENCY; AFRICAN-AMERICANS; PLASMA 25-HYDROXYVITAMIN-D; ELDERLY POPULATION; HYPOVITAMINOSIS-D AB OBJECTIVES: To determine the prevalence and correlates of vitamin D insufficiency in black and white older adults. DESIGN: Cross-sectional. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Nine hundred seventy-seven black and 1,604 white adults aged 70 to 81. MEASUREMENTS: Logistic regression and classification and regression tree analysis were used to identify correlates of vitamin D insufficiency (25-hydroxyvitamin D (25(OH)D) <30 ng/mL) separately in blacks and whites. RESULTS: The prevalence of 25(OH)D insufficiency was 84% in blacks and 57% in whites. Seventy-six percent of blacks and 56% of whites did not take a multivitamin; those who did not take a multivitamin were more likely to be vitamin D insufficient (odds ratio (OR) = 5.17 (95% confidence interval (CI) = 3.47-7.70) for blacks; OR = 2.56, 95% CI = 2.05-3.19 for white). Additional risk factors for vitamin D insufficiency were vitamin D-containing supplement use, female sex, and obesity in blacks; and winter season, low dietary vitamin D intake, obesity, type 2 diabetes mellitus, and female sex in whites. CONCLUSION: Vitamin D insufficiency was more prevalent in blacks than whites. Not consuming a multivitamin increased the odds of vitamin D insufficiency in blacks and whites. Knowledge of additional risk factors such as dietary intake and comorbid conditions may help identify older adults who are likely to be vitamin D insufficient. J Am Geriatr Soc 59: 1165-1174, 2011. C1 [Shea, M. Kyla] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Dept Internal Med,Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. [Johnson, Mary Ann; Hausman, Dorothy B.] Univ Georgia, Dept Foods & Nutr, Athens, GA 30602 USA. [Cauley, Jane A.] Univ Pittsburgh, Div Epidemiol, Pittsburgh, PA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tylavsky, Frances] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RP Shea, MK (reprint author), Wake Forest Univ, Sch Med, Sticht Ctr Aging, Dept Internal Med,Sect Gerontol & Geriatr Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM kshea@wfubmc.edu OI Kritchevsky, Stephen/0000-0003-3336-6781; Cauley, Jane A/0000-0003-0752-4408 FU Novartis; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG029364]; Wake Forest University Claude D. Pepper Older Americans Independence Center [P30-AG21332]; National Institutes of Health, NIA FX DKH receives speaker honoraria from Abbott Nutrition Health Institute. JAC receives grant support from Novartis (to study Zoledronic acid treatment).; Health ABC was funded by the National Institute on Aging (NIA; N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106). This work was also supported by the NIA (R01-AG029364), the Wake Forest University Claude D. Pepper Older Americans Independence Center (P30-AG21332), and the Intramural Research Program of the National Institutes of Health, NIA. NR 48 TC 26 Z9 26 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2011 VL 59 IS 7 BP 1165 EP 1174 DI 10.1111/j.1532-5415.2011.03476.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 791VT UT WOS:000292696100001 PM 21668915 ER PT J AU Sack, U Walther, W Scudiero, D Selby, M Kobelt, D Lemm, M Fichtner, I Schlag, PM Shoemaker, RH Stein, U AF Sack, Ulrike Walther, Wolfgang Scudiero, Dominic Selby, Mike Kobelt, Dennis Lemm, Margit Fichtner, Iduna Schlag, Peter M. Shoemaker, Robert H. Stein, Ulrike TI Novel Effect of Antihelminthic Niclosamide on S100A4-Mediated Metastatic Progression in Colon Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article AB Background Metastasis formation in colon cancer severely reduces the survival rate in patients. S100A4, a calcium-binding protein, is implicated in promoting metastasis formation in colon cancer. Methods To identify a transcription inhibitor of S100A4, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a S100A4 promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 mu M niclosamide to analyze the effect on S100A4 mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. Results Reduced S100A4 mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P<.01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P=.001). Conclusion Niclosamide inhibits S100A4-induced metastasis formation in a mouse model of colon cancer and has therapeutic potential. C1 [Walther, Wolfgang; Stein, Ulrike] Charite, Expt & Clin Res Ctr, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Scudiero, Dominic; Selby, Mike; Shoemaker, Robert H.] Natl Canc Inst Frederick, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. [Schlag, Peter M.] Charite, Charite Comprehens Canc Ctr, D-13125 Berlin, Germany. RP Sack, U (reprint author), Charite, Expt & Clin Res Ctr, Max Delbruck Ctr Mol Med, Robert Rossle St 10, D-13125 Berlin, Germany. EM ustein@mdc-berlin.de FU German Research Association [STE 671/8-1]; Alexander von Humboldt Foundation; Max-Delbruck-Center for Molecular Medicine Helmholtz Association FX German Research Association (STE 671/8-1 to USt and PMS), the Alexander von Humboldt Foundation (to USt and WW), and the Max-Delbruck-Center for Molecular Medicine Helmholtz Association fellowship (to USa). NR 40 TC 67 Z9 69 U1 1 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 13 BP 1018 EP 1036 DI 10.1093/jnci/djr190 PG 19 WC Oncology SC Oncology GA 790BF UT WOS:000292562800009 PM 21685359 ER PT J AU Petracci, E Decarli, A Schairer, C Pfeiffer, RM Pee, D Masala, G Palli, D Gail, MH AF Petracci, Elisabetta Decarli, Adriano Schairer, Catherine Pfeiffer, Ruth M. Pee, David Masala, Giovanna Palli, Domenico Gail, Mitchell H. TI Risk Factor Modification and Projections of Absolute Breast Cancer Risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article AB Background Although modifiable risk factors have been included in previous models that estimate or project breast cancer risk, there remains a need to estimate the effects of changes in modifiable risk factors on the absolute risk of breast cancer. Methods Using data from a case-control study of women in Italy (2569 case patients and 2588 control subjects studied from June 1, 1991, to April 1, 1994) and incidence and mortality data from the Florence Registries, we developed a model to predict the absolute risk of breast cancer that included five non-modifiable risk factors (reproductive characteristics, education, occupational activity, family history, and biopsy history) and three modifiable risk factors (alcohol consumption, leisure physical activity, and body mass index). The model was validated using independent data, and the percent risk reduction was calculated in high-risk subgroups identified by use of the Lorenz curve. Results The model was reasonably well calibrated (ratio of expected to observed cancers = 1.10, 95% confidence interval [CI] = 0.96 to 1.26), but the discriminatory accuracy was modest. The absolute risk reduction from exposure modifications was nearly proportional to the risk before modifying the risk factors and increased with age and risk projection time span. Mean 20-year reductions in absolute risk among women aged 65 years were 1.6% (95% CI = 0.9% to 2.3%) in the entire population, 3.2% (95% CI = 1.8% to 4.8%) among women with a positive family history of breast cancer, and 4.1% (95% CI = 2.5% to 6.8%) among women who accounted for the highest 10% of the total population risk, as determined from the Lorenz curve. Conclusions These data give perspective on the potential reductions in absolute breast cancer risk from preventative strategies based on lifestyle changes. Our methods are also useful for calculating sample sizes required for trials to test lifestyle interventions. C1 [Petracci, Elisabetta; Schairer, Catherine; Pfeiffer, Ruth M.; Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Decarli, Adriano] Univ Milan, Dept Occupat Hlth, Branch Med Stat & Biometry, Milan, Italy. [Decarli, Adriano] Fdn IRCSS Ist Nazl Tumori, Milan, Italy. [Masala, Giovanna; Palli, Domenico] ISPO Canc Prevent & Res Inst, Mol & Nutr Epidemiol Unit, Florence, Italy. [Pee, David] Informat Management Serv Inc, Rockville, MD USA. RP Petracci, E (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Plaza S,EPS 8049, Bethesda, MD 20892 USA. EM elisa-betta.petracci@gmail.com; gailm@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Petracci, Elisabetta/K-1520-2016; Decarli, Adriano/C-3129-2017; OI Masala, Giovanna/0000-0002-5758-9069; Petracci, Elisabetta/0000-0001-9456-3514; Decarli, Adriano/0000-0003-1451-8292; PALLI, Domenico/0000-0002-5558-2437 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Associazione Italiana per la Ricerca sul Cancro [AIRC IG 10415] FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health and the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 10415 to A.D.). NR 37 TC 28 Z9 28 U1 2 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2011 VL 103 IS 13 BP 1037 EP 1048 DI 10.1093/jnci/djr172 PG 12 WC Oncology SC Oncology GA 790BF UT WOS:000292562800010 PM 21705679 ER PT J AU Rizzo, G Abuhamad, AZ Benacerraf, BR Chaoui, R Corral, E D' Addario, V Espinoza, J Lee, W Alberto, LTM Pooh, R Sepulveda, W Sinkovskaya, E Vinals, F Volpe, P Pietrolucci, ME Arduini, D AF Rizzo, Giuseppe Abuhamad, Alfred Z. Benacerraf, Beryl R. Chaoui, Rabih Corral, Edgardo D' Addario, Vincenzo Espinoza, Jimmy Lee, Wesley Merce Alberto, Luis T. Pooh, Ritsuko Sepulveda, Waldo Sinkovskaya, Elena Vinals, Fernando Volpe, Paolo Pietrolucci, Maria Elena Arduini, Domenico TI Collaborative Study on 3-Dimensional Sonography for the Prenatal Diagnosis of Central Nervous System Defects SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE congenital central nervous system defects; fetal neurosonography; prenatal diagnosis; 3-dimensional sonography ID FETAL-BRAIN; CORPUS-CALLOSUM; INTERNET LINK; NEUROSONOGRAPHY; ANOMALIES; ROUTINE; VOLUMES; ECHOCARDIOGRAPHY; STANDARDIZATION; VISUALIZATION AB Objectives-Prenatal diagnosis of central nervous system (CNS) anomalies by 2-dimensional sonography is challenging because of difficulties in obtaining complete visualization of the fetal brain during routine examinations, which is necessary for identification of its axial, coronal, and sagittal planes. Three-dimensional (3D) sonography has been introduced as a tool for studying the fetal CNS because of its ability to facilitate examinations of the fetal brain. The objective of this study was to determine inter-center agreement in diagnosing CNS defects by review of 3D volume data sets. Methods-This study included 11 centers with expertise in 3D fetal neurosonography. A total of 217 fetuses with and without confirmed CNS defects were scanned after 18 weeks' gestation, and their volume data sets were uploaded onto a centralized file transfer protocol server and later analyzed by all of the centers. Intercenter agreement was determined using a kappa statistic for multiple raters. Results-All volumes were made anonymous and sent to the centers for blinded analysis with the exception of the data sets they had themselves previously uploaded. For identification of fetuses with CNS defects, the sensitivity, specificity, positive and negative predictive values, and false-positive and -negative rates were 93.3%, 96.5%, 96.5%, 93.3%, 3.5%, and 6.7%, respectively. No differences were found in the efficacy of the diagnostic indices according to either the route of acquisition (transabdominal or transvaginal) or the gestational age at diagnosis (18-24 or >24 weeks). Intercenter agreement was excellent (kappa = 0.92; 95% confidence interval, 0.88-0.97). Conclusions-Among centers with technical expertise, remote review of 3D sonographic volumes of the fetal CNS resulted in an accurate and reliable method for diagnosis of fetal brain malformations. C1 [Rizzo, Giuseppe; Pietrolucci, Maria Elena; Arduini, Domenico] Univ Roma Tor Vergata, Dept Obstet & Gynecol, I-00186 Rome, Italy. [Abuhamad, Alfred Z.; Sinkovskaya, Elena] Eastern Virginia Med Sch, Div Maternal Fetal Med, Dept Obstet & Gynecol, Norfolk, VA 23501 USA. [Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Chaoui, Rabih] Prenatal Diag & Human Genet, Berlin, Germany. [Corral, Edgardo; Sepulveda, Waldo] Univ Santiago Chile, San Jose Hosp, Maternal Fetal Med Unit, Dept Obstet & Gynecol, Santiago, Chile. [D' Addario, Vincenzo] Univ Med Sch, Dept Gynecol Obstet & Neonatol, Bari, Italy. [Espinoza, Jimmy; Lee, Wesley] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48072 USA. [Espinoza, Jimmy; Lee, Wesley] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Merce Alberto, Luis T.] Natl Ctr Ultrasonog Gynecol & Obstet, Madrid, Spain. [Pooh, Ritsuko] CRIFM Clin Res Inst Fetal Med, Osaka, Japan. [Vinals, Fernando] Clin Sanatorio Aleman, Ctr AGB Ultrasonog, Concepcion, Chile. [Volpe, Paolo] Azienda Sanit Locale Bari, Di Venere & Sarcone Hosp, Fetal Med Unit, Bari, Italy. RP Rizzo, G (reprint author), Univ Roma Tor Vergata, Dept Obstet & Gynecol, Fatebenefratelli S Giovanni Calabita Hosp, Isola Tiberina 89, I-00186 Rome, Italy. EM giuseppe.rizzo@uniroma2.it OI RIZZO, Giuseppe/0000-0002-5525-4353 NR 23 TC 13 Z9 13 U1 0 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUL PY 2011 VL 30 IS 7 BP 1003 EP 1008 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 788HF UT WOS:000292435300017 PM 21705734 ER PT J AU Katki, HA Kinney, WK Fetterman, B Lorey, T Poitras, NE Cheung, L Demuth, F Schiffman, M Wacholder, S Castle, PE AF Katki, Hormuzd A. Kinney, Walter K. Fetterman, Barbara Lorey, Thomas Poitras, Nancy E. Cheung, Li Demuth, Franklin Schiffman, Mark Wacholder, Sholom Castle, Philip E. TI Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice SO LANCET ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; INTRAEPITHELIAL NEOPLASIA; CONVENTIONAL CYTOLOGY; SCREENING-TESTS; FOLLOW-UP; DNA; HPV; METAANALYSIS; MANAGEMENT; PERSISTENCE AB Background Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. Methods We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331 818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. Findings In 315 061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100 000 women per year, slightly higher than for the 306 969 who were both negative by HPV and Pap testing (3.2 per 100 000), and half the cancer risk of the 319 177 who were negative by Pap testing (7.5 per 100 000). 313 465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16 757 positive by HPV testing (12.1% vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86% vs 0.16%; p=0.004). 12 208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or worse, 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. Interpretation For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. C1 [Katki, Hormuzd A.; Schiffman, Mark; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. [Fetterman, Barbara; Lorey, Thomas; Poitras, Nancy E.] Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li; Demuth, Franklin] Informat Management Serv Inc, Silver Spring, MD USA. [Castle, Philip E.] Amer Soc Clin Pathologists, Washington, DC USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; OI Cheung, Li/0000-0003-1625-4331 FU NIH/National Cancer Institute; American Cancer Society (WKK); Women's Health Research Institute at Kaiser Permanente Northern California; US National Cancer Institute/NIH/DHHS; American Cancer Society FX This research was supported, in part, by the Intramural Research Program of the NIH/National Cancer Institute, and by the American Cancer Society (WKK). The authors acknowledge the support of the Women's Health Research Institute at Kaiser Permanente Northern California. We thank David Check (US National Cancer Institute) for help in preparing the figures. We thank J Thomas Cox (University of California, Santa Barbara) for assisting with the chart review to verify all reported cervical cancers.; Funding Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society. NR 49 TC 225 Z9 243 U1 3 U2 17 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 JUL PY 2011 VL 12 IS 7 BP 663 EP 672 DI 10.1016/S1470-2045(11)70145-0 PG 10 WC Oncology SC Oncology GA 791CU UT WOS:000292640200018 PM 21684207 ER PT J AU Fowke, JH Gao, YT Chow, WH Cai, QY Shu, XO Li, HL Ji, BT Rothman, N Yang, G Chung, FL Zheng, W AF Fowke, Jay H. Gao, Yu-Tang Chow, Wong-Ho Cai, Qiuyin Shu, Xiao-Ou Li, Hong-lan Ji, Bu-Tian Rothman, Nat Yang, Gong Chung, Fung-Lung Zheng, Wei TI Urinary isothiocyanate levels and lung cancer risk among non-smoking women: A prospective investigation SO LUNG CANCER LA English DT Article DE Isothiocyanate; Lung neoplasm; Diet; Genetic susceptibility; Women ID OXIDATIVE DNA-DAMAGE; CRUCIFEROUS VEGETABLES; DIETARY ISOTHIOCYANATES; WATERCRESS CONSUMPTION; BRUSSELS-SPROUTS; NEVER SMOKERS; CELLS; INDOLE-3-CARBINOL; POLYMORPHISMS; GLUTATHIONE AB Background: Aside from tobacco carcinogen metabolism, isothiocyanates (ITC) from cruciferous vegetables may induce apoptosis or steroid metabolism to reduce lung cancer risk. To separate the effect of these divergent mechanisms of action, we investigated the association between urinary ITC levels and lung cancer risk among non-smoking women. Methods: We conducted a nested case-control within the Shanghai Women's Health Study. Subjects included 209 incident lung cancer cases who never used tobacco, and 787 individually matched nonsmoking controls. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) summarizing the association between urinary ITC levels and lung cancer. Secondary analyses stratified the ITC-lung cancer analyses by menopausal status, exposure to environmental tobacco smoke, and GSTM1 and GSTT1 genotypes. Results: Urinary ITC levels were not significantly associated with lower lung cancer risk among nonsmoking women, regardless of exposure to environmental tobacco smoke or menopausal status. Furthermore, this association was not modified by GSTT1 genotype. However, an inverse association was suggested among women with a GSTM1-positive genotype (Q1: OR = 1.0 (reference); Q2: OR = 0.35 (0.14, 0.89); Q3: OR = 0.47 (0.20, 1.10); Q4: OR = 0.63 (0.35, 1.54), p-trend = 0.38). In contrast, lung cancer risk was positively associated with urinary ITC levels among women with the GSTM1-null genotype (Q1: OR = 1.0 (reference); Q2: OR = 1.67 (0.80, 3.50); Q3: OR = 1.54 (0.71, 3.33); Q4: OR = 2.22 (1.05, 4.67), p-trend = 0.06). Conclusion: Urinary ITC levels were not associated overall with lower lung cancer risk among non-smoking women, but secondary analyses suggested an interaction between urinary ITC levels, GSTM1 genotype, and lung cancer risk. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Fowke, Jay H.; Cai, Qiuyin; Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Gao, Yu-Tang; Li, Hong-lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho; Ji, Bu-Tian; Rothman, Nat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chung, Fung-Lung] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Fowke, JH (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, 2525 W End Ave,6th Floor,Suite 600, Nashville, TN 37203 USA. EM jay.fowke@vanderbilt.edu FU USPHS [R37 CA70867] FX Funding provided by USPHS Grant R37 CA70867. NR 43 TC 10 Z9 10 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD JUL PY 2011 VL 73 IS 1 BP 18 EP 24 DI 10.1016/j.lungcan.2010.10.024 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 788KH UT WOS:000292443300003 PM 21122939 ER PT J AU Kuntz, KM Lansdorp-Vogelaar, I Rutter, CM Knudsen, AB van Ballegooijen, M Savarino, JE Feuer, EJ Zauber, AG AF Kuntz, Karen M. Lansdorp-Vogelaar, Iris Rutter, Carolyn M. Knudsen, Amy B. van Ballegooijen, Marjolein Savarino, James E. Feuer, Eric J. Zauber, Ann G. TI A Systematic Comparison of Microsimulation Models of Colorectal Cancer: The Role of Assumptions about Adenoma Progression SO MEDICAL DECISION MAKING LA English DT Article DE microsimulation; colorectal cancer; screening ID FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED-TRIAL; COST-EFFECTIVENESS ANALYSIS; SERVICES TASK-FORCE; LARGE-INTESTINE; LARGE-BOWEL; CLINICAL GUIDELINES; MEDICARE POPULATION; POLYPS; AUTOPSY AB Background. As the complexity of microsimulation models increases, concerns about model transparency are heightened. Methods. The authors conducted model "experiments" to explore the impact of variations in "deep" model parameters using 3 colorectal cancer (CRC) models. All natural history models were calibrated to match observed data on adenoma prevalence and cancer incidence but varied in their underlying specification of the adenocarcinoma process. The authors projected CRC incidence among individuals with an underlying adenoma or preclinical cancer v. those without any underlying condition and examined the impact of removing adenomas. They calculated the percentage of simulated CRC cases arising from adenomas that developed within 10 or 20 years prior to cancer diagnosis and estimated dwell time-defined as the time from the development of an adenoma to symptom-detected cancer in the absence of screening among individuals with a CRC diagnosis. Results. The 20-year CRC incidence among 55-year-old individuals with an adenoma or preclinical cancer was 7 to 75 times greater than in the condition-free group. The removal of all adenomas among the subgroup with an underlying adenoma or cancer resulted in a reduction of 30% to 89% in cumulative incidence. Among CRCs diagnosed at age 65 years, the proportion arising from adenomas formed within 10 years ranged between 4% and 67%. The mean dwell time varied from 10.6 to 25.8 years. Conclusions. Models that all match observed data on adenoma prevalence and cancer incidence can produce quite different dwell times and very different answers with respect to the effectiveness of interventions. When conducting applied analyses to inform policy, using multiple models provides a sensitivity analysis on key (unobserved) "deep" model parameters and can provide guidance about specific areas in need of additional research and validation. C1 [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN 55455 USA. [Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Rutter, Carolyn M.; Savarino, James E.] Grp Hlth Res Inst, Ctr Hlth Studies, Seattle, WA USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Kuntz, KM (reprint author), Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, MMC 729,420 Delaware St SE, Minneapolis, MN 55455 USA. EM kmkuntz@umn.edu FU National Cancer Institute [U01-CA-088204, U01-CA-097426, U01-CA-097427, U01-CA-115953] FX Received 15 January 2009 from the Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis (KMK); Department of Public Health, Erasmus MC, Rotterdam, the Netherlands (IL-V, MvB); Center for Health Studies, Group Health Research Institute, Seattle, Washington (CMR, JES); Institute for Technology Assessment, Massachusetts General Hospital, Boston (ABK); Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland (EJF); and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY (AGZ). This research was supported by the National Cancer Institute (U01-CA-088204, U01-CA-097426, U01-CA-097427, and U01-CA-115953). Revision accepted for publication 5 April 2011. NR 48 TC 28 Z9 29 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL-AUG PY 2011 VL 31 IS 4 BP 530 EP 539 DI 10.1177/0272989X11408730 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 792HL UT WOS:000292732800004 PM 21673186 ER PT J AU van Ballegooijen, M Rutter, CM Knudsen, AB Zauber, AG Savarino, JE Lansdorp-Vogelaar, I Boer, R Feuer, EJ Habbema, JDF Kuntz, KM AF van Ballegooijen, Marjolein Rutter, Carolyn M. Knudsen, Amy B. Zauber, Ann G. Savarino, James E. Lansdorp-Vogelaar, Iris Boer, Rob Feuer, Eric J. Habbema, J. Dik F. Kuntz, Karen M. TI Clarifying Differences in Natural History between Models of Screening: The Case of Colorectal Cancer SO MEDICAL DECISION MAKING LA English DT Article DE microsimulation; natural history; colorectal cancer; screening models; standard model output ID SOCIETY-TASK-FORCE; COST-EFFECTIVENESS; DECISION-ANALYSIS; COLONOGRAPHY; SURVEILLANCE; STRATEGIES AB Background. Microsimulation models are important decision support tools for screening. However, their complexity makes them difficult to understand and limits realization of their full potential. Therefore, it is important to develop documentation that clarifies their structure and assumptions. The authors demonstrate this problem and explore a solution for natural history using 3 independently developed colorectal cancer screening models. Methods. The authors first project effectiveness and cost-effectiveness of colonoscopy screening for the 3 models (CRC-SPIN, SimCRC, and MISCAN). Next, they provide a conventional presentation of each model, including information on structure and parameter values. Finally, they report the simulated reduction in clinical cancer incidence following a one-time complete removal of adenomas and preclinical cancers for each model. They call this new measure the maximum clinical incidence reduction (MCLIR). Results. Projected effectiveness varies widely across models. For example, estimated mortality reduction for colonoscopy screening every 10 years from age 50 to 80 years, with surveillance in adenoma patients, ranges from 65% to 92%. Given only conventional information, it is difficult to explain these differences, largely because differences in structure make parameter values incomparable. In contrast, the MCLIR clearly shows the impact of model differences on the key feature of natural history, the dwell time of preclinical disease. Dwell times vary from 8 to 25 years across models and help explain differences in projected screening effectiveness. Conclusions. The authors propose a new measure, the MCLIR, which summarizes the implications for predicted screening effectiveness of differences in natural history assumptions. Including the MCLIR in the standard description of a screening model would improve the transparency of these models. C1 [van Ballegooijen, Marjolein; Lansdorp-Vogelaar, Iris; Boer, Rob; Habbema, J. Dik F.] Erasmus MC, Dept Publ Hlth, NL-3000 CA Rotterdam, Netherlands. [Rutter, Carolyn M.; Savarino, James E.] Grp Hlth Res Inst, Seattle, WA USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Washington, DC USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. RP van Ballegooijen, M (reprint author), Erasmus MC, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM m.vanballegooijen@erasmusmc.nl RI Boer, Rob/E-6473-2015 OI Boer, Rob/0000-0003-0680-001X FU National Institutes of Health/National Cancer Institute [U01-CA-088204, U01-CA-097427, U01-CA-097426, U01-CA-115953] FX Received 18 July 2010 from the Department of Public Health, Erasmus MC, Rotterdam, the Netherlands (MvB, IL-V, RB, JDFH); Group Health Research Institute, Seattle, Washington (CMR, JES); Institute for Technology Assessment, Massachusetts General Hospital, Boston (ABK); Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (AGZ); Division of Cancer Control and Population Sciences, National Cancer Institute, Washington, DC (EJF); and Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis (KMK). This work was supported by the National Institutes of Health/National Cancer Institute (U01-CA-088204, U01-CA-097427, U01-CA-097426, and U01-CA-115953). Revision accepted for publication 4 April 2011. NR 24 TC 15 Z9 15 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL-AUG PY 2011 VL 31 IS 4 BP 540 EP 549 DI 10.1177/0272989X11408915 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 792HL UT WOS:000292732800005 PM 21673187 ER PT J AU Shogan, PJ Folio, L AF Shogan, Paul J. Folio, Les TI Situs Inversus Totalis SO MILITARY MEDICINE LA English DT Article ID CONGENITAL HEART-DISEASE; VISCEROATRIAL SITUS; ADULTS AB We present a case of situs inversus totalis. A 22-month-old infant presented with cyanosis, double-inlet left ventricle, severe pulmonary stenosis, and concern for underlying visceroatrial abnormalities. Chest (Fig. 1) and abdominal (Fig. 2) radiographs were obtained. Abdominal sonography was performed to clarify the presence of splenic tissue and further define the relationships of the inferior vena cava and abdominal aorta (Figs. 3-7). This case demonstrates typical radiographic and sonographic findings of situs inversus totalis and shows the utility of sonography. C1 [Shogan, Paul J.] Walter Reed Army Med Ctr, Dept Radiol, Natl Capital Consortium, Washington, DC 20307 USA. [Shogan, Paul J.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. [Folio, Les] NIH, Bethesda, MD 20892 USA. RP Shogan, PJ (reprint author), Walter Reed Army Med Ctr, Dept Radiol, Natl Capital Consortium, Washington, DC 20307 USA. NR 7 TC 2 Z9 2 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD JUL PY 2011 VL 176 IS 7 BP 840 EP 843 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 792XO UT WOS:000292783900018 PM 22128729 ER PT J AU Yap, MN Bernstein, HD AF Yap, Mee-Ngan Bernstein, Harris D. TI The translational regulatory function of SecM requires the precise timing of membrane targeting SO MOLECULAR MICROBIOLOGY LA English DT Article ID SIGNAL RECOGNITION PARTICLE; ESCHERICHIA-COLI; PROTEIN-TRANSLOCATION; DEPENDENT TRANSLOCATION; CYTOPLASMIC MEMBRANE; NASCENT POLYPEPTIDE; TRIGGER FACTOR; A-SITE; EXPORT; SECRETION AB In Escherichia coli, secA expression is regulated at the translational level by an upstream gene (secM) that encodes a presecretory protein. SecM contains a C-terminal sequence motif that induces a transient translation arrest. Inhibition of SecM membrane targeting prolongs the translation arrest and increases SecA synthesis by concomitantly altering the structure of the secM-secA mRNA. Here we show that the SecM signal peptide plays an essential role in this regulatory process by acting as a molecular timer that co-ordinates membrane targeting with the synthesis of the arrest motif. We found that signal peptide mutations that alter targeting kinetics and insertions or deletions that change the distance between the SecM signal peptide and the arrest motif perturb the balance between the onset and release of arrest that is required to regulate SecA synthesis. Furthermore, we found that the strength of the interaction between the ribosome and the SecM arrest motif is calibrated to ensure the release of arrest upon membrane targeting. Our results strongly suggest that several distinctive features of the SecM protein evolved as a consequence of constraints imposed by the ribosome and the Sec machinery. C1 [Yap, Mee-Ngan; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; NIH [GM094212] FX We thank Yihong Ye for critical reading of the manuscript. We also thank Wanyoike Kang'ethe, Don Oliver and P. C. Tai for providing antisera. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by an NIH K99/R00 award (GM094212) to M.-N.Y. NR 48 TC 9 Z9 9 U1 3 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2011 VL 81 IS 2 BP 540 EP 553 DI 10.1111/j.1365-2958.2011.07713.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 790CX UT WOS:000292567200019 PM 21635582 ER PT J AU Beylin, D Chrisman, CJ Weingarten, M AF Beylin, David Chrisman, Cara J. Weingarten, Michael TI Granting you success SO NATURE BIOTECHNOLOGY LA English DT Editorial Material C1 [Beylin, David; Chrisman, Cara J.; Weingarten, Michael] NCI, Small Business Innovat Res Dev Ctr, Bethesda, MD 20892 USA. RP Beylin, D (reprint author), NCI, Small Business Innovat Res Dev Ctr, Bethesda, MD 20892 USA. EM ncisbir@mail.nih.gov NR 0 TC 2 Z9 2 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2011 VL 29 IS 7 BP 567 EP 570 DI 10.1038/bioe.2011.5 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 790NM UT WOS:000292595200008 PM 21874663 ER PT J AU Klesges, RC Ebbert, JO Morgan, GD Sherrill-Mittleman, D Asfar, T Talcott, WG DeBon, M AF Klesges, Robert C. Ebbert, Jon O. Morgan, Glen D. Sherrill-Mittleman, Deborah Asfar, Taghrid Talcott, Wayne G. DeBon, Margaret TI Impact of Differing Definitions of Dual Tobacco Use: Implications for Studying Dual Use and a Call for Operational Definitions SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SMOKELESS-TOBACCO; NORTHERN SWEDEN; NICOTINE DEPENDENCE; CIGARETTE-SMOKING; CANCER MORTALITY; POLYTOBACCO USE; RISK BEHAVIORS; HARM REDUCTION; CONCURRENT USE; SNUFF USE AB Concomitant use of two forms of tobacco is an increasing public health concern, yet there is little consensus regarding a consistent definition of so-called "dual use." We defined dual use as cigarette and smokeless tobacco (ST) consumption with either product used daily or nondaily. We analyzed a cohort of 36,013 Air Force recruits. We categorized dual tobacco use across 2 dimensions, type of tobacco products (cigarettes, ST, or others), and the frequency of use (daily vs. nondaily). We determined how varying the definition impacted the prevalence estimates and evaluated the prevalence estimate based on our recommended definition of dual use. Multivariate logistic regression analysis was used to evaluate the risk profile of dual users of ST and cigarettes versus mono users of ST and mono users of cigarettes. Varying definitions of dual use vary prevalence estimates 50-fold (0.5%-25.3%). Including only ST and cigarettes narrows the prevalence estimate to less than 4-fold (2.0%-9.7%). Dual users are more likely to be young Caucasian males, with lower education, and from families with relatively higher incomes. Compared with mono users, dual users of cigarettes and ST have a distinct pattern of risk profiles. Depending on the definition of dual use, markedly different prevalence and risk profiles are observed. Dual users of ST and cigarettes are a unique group of tobacco users. We propose a common definition of dual use to advance our understanding of this unique group. C1 [Klesges, Robert C.; Talcott, Wayne G.; DeBon, Margaret] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38105 USA. [Klesges, Robert C.; Sherrill-Mittleman, Deborah; Asfar, Taghrid] St Jude Childrens Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Ebbert, Jon O.] Mayo Clin, Div Primary Care Internal Med, Rochester, MN USA. [Morgan, Glen D.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Klesges, RC (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, 66 N Pauline,Suite 633, Memphis, TN 38105 USA. EM bob.klesges@stjude.org FU National Cancer Institute [CA127964]; National Heart, Lung, and Blood Institute [HL053478] FX This work was supported by research grants (CA127964) from the National Cancer Institute and from the National Heart, Lung, and Blood Institute (HL053478). NR 54 TC 28 Z9 28 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUL PY 2011 VL 13 IS 7 BP 523 EP 531 DI 10.1093/ntr/ntr032 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 790CI UT WOS:000292565700003 PM 21436298 ER PT J AU Eddy, J Vallur, AC Varma, S Liu, HF Reinhold, WC Pommier, Y Maizels, N AF Eddy, Johanna Vallur, Aarthy C. Varma, Sudir Liu, Hongfang Reinhold, William C. Pommier, Yves Maizels, Nancy TI G4 motifs correlate with promoter-proximal transcriptional pausing in human genes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; TOPOISOMERASE-I; G-QUADRUPLEX; BINDING SPECIFICITY; GENOMIC INSTABILITY; ESCHERICHIA-COLI; EUKARYOTIC CELLS; 1ST INTRON; DNA; SEQUENCE AB The RNA Pol II transcription complex pauses just downstream of the promoter in a significant fraction of human genes. The local features of genomic structure that contribute to pausing have not been defined. Here, we show that genes that pause are more G-rich within the region flanking the transcription start site (TSS) than RefSeq genes or non-paused genes. We show that enrichment of binding motifs for common transcription factors, such as SP1, may account for G-richness upstream but not downstream of the TSS. We further show that pausing correlates with the presence of a GrIn1 element, an element bearing one or more G4 motifs at the 5'-end of the first intron, on the non-template DNA strand. These results suggest potential roles for dynamic G4 DNA and G4 RNA structures in cis-regulation of pausing, and thus genome-wide regulation of gene expression, in human cells. C1 [Eddy, Johanna; Maizels, Nancy] NCI, Mol & Cellular Biol Grad Program, NIH, Bethesda, MD 20892 USA. [Vallur, Aarthy C.; Maizels, Nancy] NCI, Dept Immunol, NIH, Bethesda, MD 20892 USA. [Varma, Sudir; Liu, Hongfang; Reinhold, William C.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liu, Hongfang] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Seattle, WA 98195 USA. [Maizels, Nancy] Univ Washington, Dept Biochem, Sch Med, Seattle, WA 98195 USA. RP Maizels, N (reprint author), Univ Washington, Dept Immunol, Sch Med, Box 357650, Seattle, WA 98195 USA. EM maizels@u.washington.edu RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU US National Cancer Institute [P01 CA77852]; Basic and Cancer Immunology Training Grant [CA009537]; US National Institutes of Health [R01 GM41712]; NIH [R01 GM65988]; Cancer Research Institute; National Cancer Institute, Center for Cancer Research [Z01 BC 006150-19LMP] FX US National Cancer Institute (P01 CA77852 to N.M.); Basic and Cancer Immunology Training Grant (CA009537 to J.E.); US National Institutes of Health (R01 GM41712 and NIH R01 GM65988 to N.M.); Cancer Research Institute Tumor Immunology Predoctoral Training Grant (to J.E.); Intramural Research Program of the National Cancer Institute, Center for Cancer Research support (Z01 BC 006150-19LMP to Y.P. and W.C.R.). Funding for open access charge: P01 NCI CA77852. NR 47 TC 38 Z9 39 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2011 VL 39 IS 12 BP 4975 EP 4983 DI 10.1093/nar/gkr079 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 790CA UT WOS:000292564900014 PM 21371997 ER PT J AU Reyes, A He, J Mao, CC Bailey, LJ Di Re, M Sembongi, H Kazak, L Dzionek, K Holmes, JB Cluett, TJ Harbour, ME Fearnley, IM Crouch, RJ Conti, MA Adelstein, RS Walker, JE Holt, IJ AF Reyes, A. He, J. Mao, C. C. Bailey, L. J. Di Re, M. Sembongi, H. Kazak, L. Dzionek, K. Holmes, J. B. Cluett, T. J. Harbour, M. E. Fearnley, I. M. Crouch, R. J. Conti, M. A. Adelstein, R. S. Walker, J. E. Holt, I. J. TI Actin and myosin contribute to mammalian mitochondrial DNA maintenance SO NUCLEIC ACIDS RESEARCH LA English DT Article ID II-B; NUCLEOIDS; PROTEIN; MEMBRANE; ORGANIZATION; CYTOSKELETON; CELLS; IDENTIFICATION; LOCALIZATION; MACHINERY AB Mitochondrial DNA maintenance and segregation are dependent on the actin cytoskeleton in budding yeast. We found two cytoskeletal proteins among six proteins tightly associated with rat liver mitochondrial DNA: non-muscle myosin heavy chain IIA and beta-actin. In human cells, transient gene silencing of MYH9 (encoding non-muscle myosin heavy chain IIA), or the closely related MYH10 gene (encoding non-muscle myosin heavy chain IIB), altered the topology and increased the copy number of mitochondrial DNA; and the latter effect was enhanced when both genes were targeted simultaneously. In contrast, genetic ablation of non-muscle myosin IIB was associated with a 60% decrease in mitochondrial DNA copy number in mouse embryonic fibroblasts, compared to control cells. Gene silencing of beta-actin also affected mitochondrial DNA copy number and organization. Protease-protection experiments and iodixanol gradient analysis suggest some beta-actin and non-muscle myosin heavy chain IIA reside within human mitochondria and confirm that they are associated with mitochondrial DNA. Collectively, these results strongly implicate the actomyosin cytoskeleton in mammalian mitochondrial DNA maintenance. C1 [Reyes, A.; He, J.; Mao, C. C.; Bailey, L. J.; Di Re, M.; Sembongi, H.; Kazak, L.; Dzionek, K.; Holmes, J. B.; Cluett, T. J.; Fearnley, I. M.; Walker, J. E.; Holt, I. J.] MRC, Mitochondrial Biol Unit, Cambridge, England. [Holmes, J. B.; Crouch, R. J.] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Harbour, M. E.] Cambridge Inst Med Res, Cambridge, England. [Conti, M. A.; Adelstein, R. S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Holt, IJ (reprint author), MRC, Mitochondrial Biol Unit, Cambridge, England. EM holt@mrc-mbu.cam.ac.uk OI Adelstein, Robert/0000-0002-8683-2144 FU Medical Research Council; European Union; Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Heart; Chang Gung Memorial Hospital, Lin-Kou, Taiwan [CMRPG360491-2, 380651, NSC 97-2321-B-182A-002-MY2] FX Medical Research Council; the European Union; the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Heart; Lung and Blood Institute; National Institutes of Health and grants [CMRPG360491-2, 380651, NSC 97-2321-B-182A-002-MY2] from the Chang Gung Memorial Hospital, Lin-Kou, Taiwan (to C.C.M.). Funding for open access charge: Medical Research Council. NR 32 TC 34 Z9 37 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2011 VL 39 IS 12 BP 5098 EP 5108 DI 10.1093/nar/gkr052 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 790CA UT WOS:000292564900023 PM 21398640 ER PT J AU Kang, HS Okamoto, K Takeda, Y Beak, JY Gerrish, K Bortner, CD DeGraff, LM Wada, T Xie, W Jetten, AM AF Kang, Hong Soon Okamoto, Kyoko Takeda, Yukimasa Beak, Ju Youn Gerrish, Kevin Bortner, Carl D. DeGraff, Laura M. Wada, Taira Xie, Wen Jetten, Anton M. TI Transcriptional profiling reveals a role for ROR alpha in regulating gene expression in obesity-associated inflammation and hepatic steatosis SO PHYSIOLOGICAL GENOMICS LA English DT Article DE staggerer mice; obesity; metabolic syndrome; macrophage; insulin-resistance; diabetes; retinoid-related orphan receptors ID ORPHAN NUCLEAR RECEPTOR; DIET-INDUCED OBESITY; INDUCED LUNG INFLAMMATION; ADIPOSE-TISSUE; DEFICIENT MICE; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; RETINOIC ACID; ADIPOCYTE DIFFERENTIATION; MACROPHAGE ACCUMULATION AB Retinoid-related orphan receptor (ROR)alpha 4 is the major ROR alpha isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR alpha-deficient staggerer mice (ROR alpha(sg/sg)) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR alpha(sg/sg) mice. In contrast, overexpression of ROR alpha in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR alpha(sg/sg) liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR alpha. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR alpha(sg/sg) mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR alpha(sg/sg) WAT. Moreover, ROR alpha(sg/sg) mice fed with an HFD were protected from the development of insulin resistance. ROR alpha(sg/sg) mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR alpha plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR alpha may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. C1 [Kang, Hong Soon; Okamoto, Kyoko; Takeda, Yukimasa; Beak, Ju Youn; DeGraff, Laura M.; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin] NIEHS, Microarray Grp, NIH, Res Triangle Pk, NC 27709 USA. [Bortner, Carl D.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Wada, Taira; Xie, Wen] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA USA. [Wada, Taira; Xie, Wen] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov RI Xie, Wen/M-1768-2016; OI Jetten, Anton/0000-0003-0954-4445 FU NIEHS [Z01-ES-101586] FX This research was supported by the Intramural Research Program of the NIEHS (Z01-ES-101586). NR 62 TC 29 Z9 30 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JUL PY 2011 VL 43 IS 13 BP 818 EP 828 DI 10.1152/physiolgenomics.00206.2010 PG 11 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 792IF UT WOS:000292735600004 PM 21540300 ER PT J AU Jeppesen, DK Bohr, VA Stevnsner, T AF Jeppesen, Dennis Kjolhede Bohr, Vilhelm A. Stevnsner, Tinna TI DNA repair deficiency in neurodegeneration SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE DNA repair; Genomic instability; Reactive oxygen species; Neurodegeneration; Aging; Mitochondria; Cockayne syndrome; Alzheimer's disease; Parkinson's disease; Werner syndrome ID BASE-EXCISION-REPAIR; STRAND BREAK REPAIR; WERNER-SYNDROME PROTEIN; SYNDROME GROUP-B; RNA-POLYMERASE-II; AMYOTROPHIC-LATERAL-SCLEROSIS; CELL NUCLEAR ANTIGEN; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE BRAIN; SUBSTANTIA-NIGRA NEURONS AB Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Jeppesen, Dennis Kjolhede; Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. [Jeppesen, Dennis Kjolhede; Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Stevnsner, T (reprint author), Univ Aarhus, Dept Mol Biol, Danish Ctr Mol Gerontol, CF Moellers Alle 3,Build 1130, DK-8000 Aarhus C, Denmark. EM tvs@mb.au.dk FU Danish Cancer Society; The Velux Foundation FX D.K. Jeppesen was supported by the Danish Cancer Society and part of this work was supported by a grant from The Velux Foundation to the Danish Aging Research Center. NR 459 TC 119 Z9 128 U1 5 U2 34 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JUL PY 2011 VL 94 IS 2 BP 166 EP 200 DI 10.1016/j.pneurobio.2011.04.013 PG 35 WC Neurosciences SC Neurosciences & Neurology GA 791OL UT WOS:000292674400006 PM 21550379 ER PT J AU Mitchell, JB AF Mitchell, James B. TI Chasing Free Radicals in Cells and Tissues AWARD SO RADIATION RESEARCH LA English DT Editorial Material ID SEMIAUTOMATED COLORIMETRIC ASSAY; OXYGEN ENHANCEMENT RATIO; GLUTATHIONE DEPLETION; PHOTODYNAMIC THERAPY; LUNG-CANCER; BUTHIONINE SULFOXIMINE; NITROXIDE COMPOUNDS; CONTRAST AGENTS; CYTO-TOXICITY; REDOX STATUS C1 NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NR 39 TC 0 Z9 0 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2011 VL 176 IS 1 BP 1 EP 7 DI 10.1667/RR2626.1 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 788JT UT WOS:000292441900001 PM 21545292 ER PT J AU DiCarlo, AL Poncz, M Cassatt, DR Shah, JR Czarniecki, CW Maidment, BW AF DiCarlo, Andrea L. Poncz, Mortimer Cassatt, David R. Shah, Jui R. Czarniecki, Christine W. Maidment, Bert W. TI Development and Licensure of Medical Countermeasures for Platelet Regeneration after Radiation Exposure SO RADIATION RESEARCH LA English DT Editorial Material ID BODY IRRADIATION; IN-VIVO; THROMBOPOIETIN; MICE; THROMBOCYTOPENIA; PANCYTOPENIA; ANTIBODIES; SURVIVAL; GROWTH; MODELS C1 [DiCarlo, Andrea L.; Cassatt, David R.; Shah, Jui R.; Czarniecki, Christine W.; Maidment, Bert W.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Poncz, Mortimer] Childrens Hosp Philadelphia, Div Pediat Hematol, Philadelphia, PA 19104 USA. RP DiCarlo, AL (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 6610 Rockledge Dr,Room 5301, Bethesda, MD 20892 USA. EM cohena@niaid.nih.gov NR 23 TC 6 Z9 6 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2011 VL 176 IS 1 BP 134 EP 137 DI 10.1667/RR2610.1 PG 4 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 788JT UT WOS:000292441900014 PM 21545289 ER PT J AU Ramkumar, HL Brooks, BP Cao, XG Tamura, D DiGiovanna, JJ Kraemer, KH Chan, CC AF Ramkumar, Hema L. Brooks, Brian P. Cao, Xiaoguang Tamura, Deborah DiGiovanna, John J. Kraemer, Kenneth H. Chan, Chi-Chao TI Ophthalmic Manifestations and Histopathology of Xeroderma Pigmentosum: Two Clinicopathological Cases and a Review of the Literature SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE ciliary body hamartoma; ocular pathology; optic atrophy xeroderma pigmentosum; pigmentary retinal degeneration ID SQUAMOUS-CELL CARCINOMA; DNA-REPAIR DEFICIENCY; OCULAR MANIFESTATIONS; NEUROLOGICAL DISEASE; COCKAYNES SYNDROME; SKIN-CANCER; ULTRAVIOLET-RADIATION; MALIGNANT-MELANOMA; BLACK-FAMILY; CONJUNCTIVAL AB Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the ultraviolet (UV) exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. We report the clinical history and ocular pathology of two white women who had xeroderma pigmentosum with neurological degeneration: Case 1 (died at age 44 years) and Case 2 (died at age 45 years). Case 1, with mutations in the XPA gene, had more than 180 basal cell carcinomas of her skin and eyelids and died from complications of neurodegeneration. Case 2, with mutations in the XPD gene, was sun-protected and had three skin cancers. She died from complications of neurodegeneration and pneumonia. Both patients had bilateral pinguecula, corneal pannus, and exposure keratopathy. Case 1 had bilateral optic atrophy, and Case 2 had bilateral peripheral retinal pigmentary degeneration. Both patients developed retinal gliosis. The ophthalmic manifestations and pathology of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neurodegeneration of the retina. (Surv Ophthalmol 56:348-361, 2011. Published by Elsevier Inc.) C1 [Ramkumar, Hema L.; Cao, Xiaoguang; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ramkumar, Hema L.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Ramkumar, Hema L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Brooks, Brian P.] NEI, Unit Pediat Dev & Genet Ophthalmol, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Cao, Xiaoguang] Peking Univ, Dept Ophthalmol, Peoples Hosp, Beijing 100871, Peoples R China. [Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Ramkumar, Hema/0000-0002-1452-0694 FU Howard Hughes Medical Institute; National Eye Institute; Center for Cancer Research of the National Cancer Institute, National Institutes of Health FX The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. Publication of this research was supported by the Howard Hughes Medical Institute, the Intramural Research Programs of the National Eye Institute, and the Center for Cancer Research of the National Cancer Institute, National Institutes of Health. NR 97 TC 17 Z9 17 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JUL-AUG PY 2011 VL 56 IS 4 BP 348 EP 361 DI 10.1016/j.survophthal.2011.03.001 PG 14 WC Ophthalmology SC Ophthalmology GA 790KD UT WOS:000292586000005 PM 21684361 ER PT J AU Rein, A Datta, SAK Jones, CP Musier-Forsyth, K AF Rein, Alan Datta, Siddhartha A. K. Jones, Christopher P. Musier-Forsyth, Karin TI Diverse interactions of retroviral Gag proteins with RNAs SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; ROUS-SARCOMA-VIRUS; HIV-1 NUCLEOCAPSID PROTEIN; ACID CHAPERONE ACTIVITY; PRIMER BINDING-SITE; ASSEMBLY IN-VITRO; REVERSE TRANSCRIPTION; GENOMIC RNA; VIRAL-RNA AB Retrovirus particles are constructed from a single virus-encoded protein, termed Gag. Given that assembly is an essential step in the viral replication cycle, it is a potential target for antiviral therapy. However, such an approach has not yet been exploited because of the lack of fundamental knowledge concerning the structures and interactions responsible for assembly. Assembling an infectious particle entails a remarkably diverse array of interactions, both specific and nonspecific, between Gag proteins and RNAs. These interactions are essential for the construction of the particle, for packaging of the viral RNA into the particle, and for placement of the primer for viral DNA synthesis. Recent results have provided some new insights into each of these interactions. In the case of HIV-1 Gag, it is clear that more than one domain of the protein contributes to Gag RNA interaction. C1 [Rein, Alan; Datta, Siddhartha A. K.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Jones, Christopher P.; Musier-Forsyth, Karin] Ohio State Univ, Dept Chem, Ctr Retroviral Res, Columbus, OH 43210 USA. [Jones, Christopher P.; Musier-Forsyth, Karin] Ohio State Univ, Dept Biochem, Ctr Retroviral Res, Columbus, OH 43210 USA. [Jones, Christopher P.; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM reina@mail.nih.gov OI Datta, Siddhartha/0000-0002-4098-7490 FU NIH, National Cancer Institute, Center for Cancer Research; NIH [R01 GM065056, T32 GM008512] FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by NIH Grant R01 GM065056 (to K.M.-F.). C.P.J. was supported by NIH Training Grant T32 GM008512. We thank Kevin Weeks for Figure 3. NR 85 TC 45 Z9 45 U1 0 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD JUL PY 2011 VL 36 IS 7 BP 373 EP 380 DI 10.1016/j.tibs.2011.04.001 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 792DO UT WOS:000292720900004 PM 21550256 ER PT J AU Molina, KM Kiely, M AF Molina, Kristine M. Kiely, Michele TI Understanding Depressive Symptoms among High-Risk, Pregnant, African-American Women SO WOMENS HEALTH ISSUES LA English DT Article ID INTIMATE PARTNER VIOLENCE; MOOD REGULATION EXPECTANCIES; STRESSFUL LIFE EVENTS; SUBSTANCE USE; HEALTH BEHAVIORS; SOCIAL SUPPORT; CHECKLIST HSCL; PREVALENCE; POSTPARTUM; DISTRESS AB Purpose: Depression has been shown to be a risk factor of poor pregnancy outcomes among African-American women. The goal of this study was to examine both risk and protective factors of depressive symptoms among urban, high-risk African-American, pregnant women. Methods: Data were drawn from a larger randomized controlled trial, Health Outcomes of Pregnancy Education that was a part of the National Institutes of Health-DC Initiative to Reduce Infant Mortality in Minority Populations in the District of Columbia. For purposes of the present study, a sample of African-American pregnant women (n = 1,044) were recruited from six urban prenatal care clinics. Baseline depressive symptoms were assessed using the Hopkins Symptom Checklist-Depression Scale. Results: Forty-four. percent of women were confirmed as moderately to severely depressed at baseline. In multivariate linear regression analysis among the total sample, maternal age, intimate partner violence, illicit drug and alcohol use during pregnancy, and reproductive history (no live birth/only loss; no live birth/no loss) were associated with increased depressive symptoms. Being very happy about the pregnancy, having emotional support from others, and reporting more positive expectancies about the ability to regulate negative moods were associated with decreased depressive symptoms. Conclusion: Results highlight the importance of attending to the context of high-risk, African-American, pregnant women, paying attention to both risk and protective factors of poor psychological well-being. Implications for future research in this area are discussed. Copyright (C) 2011 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Molina, Kristine M.] Univ Michigan, Dept Psychol, Joint PhD Program Personal Social Contexts Psycho, Ann Arbor, MI 48109 USA. [Molina, Kristine M.] Univ Michigan, Womens Studies Dept, Ann Arbor, MI 48109 USA. [Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. RP Molina, KM (reprint author), Univ Michigan, Dept Psychol, Joint PhD Program Personal Social Contexts Psycho, 530 Church St,East Hall, Ann Arbor, MI 48109 USA. EM kmolida@umich.edu; kielym@mail.nih.gov FU NICHD NIH HHS [5U18HD31206, 3U18HD030445, U18 HD036104, U18 HD030445, 3U18HD03919, 3U18HD030447, 5U18HD036104, U18 HD030447, U18 HD031206] NR 50 TC 4 Z9 5 U1 5 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD JUL-AUG PY 2011 VL 21 IS 4 BP 293 EP 303 DI 10.1016/j.whi.2011.01.008 PG 11 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 792XZ UT WOS:000292785000007 PM 21565525 ER PT J AU Kim, SE Bahta, M Lountos, GT Ulrich, RG Burke, TR Waugh, DS AF Kim, Sung-Eun Bahta, Medhanit Lountos, George T. Ulrich, Robert G. Burke, Terrence R., Jr. Waugh, David S. TI Isothiazolidinone (IZD) as a phosphoryl mimetic in inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID PROMISCUOUS INHIBITORS; BIDENTATE INHIBITORS; CRYSTAL-STRUCTURES; 1B INHIBITORS; DESIGN; PHOSPHOTYROSINE; MECHANISM; LIBRARY; MODEL; CRYSTALLOGRAPHY AB Isothiazolidinone (IZD) heterocycles can act as effective components of protein tyrosine phosphatase (PTP) inhibitors by simultaneously replicating the binding interactions of both a phosphoryl group and a highly conserved water molecule, as exemplified by the structures of several PTP1B-inhibitor complexes. In the first unambiguous demonstration of IZD interactions with a PTP other than PTP1B, it is shown by X-ray crystallography that the IZD motif binds within the catalytic site of the Yersinia pestis PTP YopH by similarly displacing a highly conserved water molecule. It is also shown that IZD-based bidentate ligands can inhibit YopH in a nonpromiscuous fashion at low micromolar concentrations. Hence, the IZD moiety may represent a useful starting point for the development of YopH inhibitors. C1 [Kim, Sung-Eun; Bahta, Medhanit; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Lountos, George T.; Waugh, David S.] NCI, Ctr Macromol Crystallog, Frederick, MD 21702 USA. [Ulrich, Robert G.] USA, Lab Mol Immunol, Med Res Inst Infect Dis, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, POB B, Frederick, MD 21702 USA. EM tburke@helix.nih.gov; waughd@mail.nih.gov RI Burke, Terrence/N-2601-2014; Lountos, George/B-3983-2015 FU NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health; Joint Science and Technology Office of the Department of Defense FX Appreciation is expressed to Afroz Sultana (LMI) for technical support and to Joseph Tropea and Scott Cherry (MCL) for purification of YopH. Electrospray mass-spectrometry experiments were conducted on the LC/ESMS instrument maintained by the Biophysics Resource in the Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick. This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health and the Joint Science and Technology Office of the Department of Defense. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 49 TC 13 Z9 13 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2011 VL 67 BP 639 EP 645 DI 10.1107/S0907444911018610 PN 7 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 788RD UT WOS:000292461200006 PM 21697602 ER PT J AU Armani, M Tangrea, MA Shapiro, B Emmert-Buck, MR Smela, E AF Armani, Michael Tangrea, Michael A. Shapiro, Benjamin Emmert-Buck, Michael R. Smela, Elisabeth TI Quantifying mRNA levels across tissue sections with 2D-RT-qPCR SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Tissue lysis; RNA purification; Gene expression mapping; Tissue section; PCR ID BRAIN GENE-EXPRESSION; IN-SITU HYBRIDIZATION; POLYMERASE-CHAIN-REACTION; BREAST-CANCER; RT-PCR; DNA; AMPLIFICATION; PURIFICATION; PROCESSOR; MOUSE AB Measurement of mRNA levels across tissue samples facilitates an understanding of how genes function and what their roles are in disease. Quantifying low-abundance mRNA requires a workflowthat preserves spatial information, isolates RNA, and performs reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR). This is complex because these steps are typically performed in three separate platforms. In the present study, we describe two-dimensional RT-qPCR (2D-RT-qPCR), a method that quantifies RNA across tissues sections in a single integrated platform. The method uses the grid format of a multi-well plate to macrodissect tissue sections and preserve the spatial location of the RNA; this also eliminates the need for physical homogenization of the tissue. A new lysis and nucleic acid purification protocol is performed in the same multi-well plate, followed by RT-qPCR. The feasibility 2D-RT-qPCR was demonstrated on a variety of tissue types. Potential applications of the technology as a high-throughput tissue analysis platform are discussed. C1 [Smela, Elisabeth] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Armani, Michael; Shapiro, Benjamin] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Armani, Michael; Tangrea, Michael A.; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Pathol Lab, Bethesda, MD 20892 USA. RP Smela, E (reprint author), Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. EM buckm@mail.nih.gov; smela@umd.edu RI Shapiro, Benjamin/H-6176-2011; Smela, Elisabeth/B-9911-2011 OI Smela, Elisabeth/0000-0003-3921-2265 FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JUL PY 2011 VL 400 IS 10 BP 3383 EP 3393 DI 10.1007/s00216-011-5062-8 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 789IE UT WOS:000292508200021 PM 21559756 ER PT J AU Sampson, JN Kidd, KK Kidd, JR Zhao, HY AF Sampson, Joshua N. Kidd, Kenneth K. Kidd, Judith R. Zhao, Hongyu TI Selecting SNPs to Identify Ancestry SO ANNALS OF HUMAN GENETICS LA English DT Article DE Ancestry; ethnicity; SNPs; error rate; allele frequency; genotype; AIM; bootstrap; FOSSIL ID HUMAN-POPULATION STRUCTURE; GENETIC ASSOCIATION; PHYLOGENETIC TREES; CROSS-VALIDATION; MARKERS; ORIGIN; STRATIFICATION; DIVERSITY; INFERENCE; PANELS AB An individual's genotypes at a group of single-nucleotide polymorphisms (SNPs) can be used to predict that individual's ethnicity or ancestry. In medical studies, knowledge of a subject's ancestry can minimize possible confounding, and in forensic applications, such knowledge can help direct investigations. Our goal is to select a small subset of SNPs, from the millions already identified in the human genome, that can predict ancestry with a minimal error rate. The general form for this variable selection procedure is to estimate the expected error rates for sets of SNPs using a training dataset and consider those sets with the lowest error rates given their size. The quality of the estimate for the error rate determines the quality of the resulting SNPs. As the apparent error rate performs poorly when either the number of SNPs or the number of populations is large; we propose a new estimate, the Improved Bayesian Estimate. We demonstrate that selection procedures based on this estimate produce small sets of SNPs that can accurately predict ancestry. We also provide a list of the 100 optimal SNPs for identifying ancestry. C1 [Sampson, Joshua N.] NCI, Bethesda, MD 20892 USA. [Kidd, Kenneth K.; Kidd, Judith R.; Zhao, Hongyu] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Zhao, Hongyu] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Sampson, JN (reprint author), 6120 Execut Blvd,8038, Bethesda, MD 20892 USA. EM joshua.sampson@nih.gov FU NIJ [2007-DN-BX-K197, 2010-DN-BX-K225]; National Institute of Justice, Office of Justice Programs, US Department of Justice FX This work was supported, in part, by NIJ grants 2007-DN-BX-K197 and 2010-DN-BX-K225 to KKK awarded by the National Institute of Justice, Office of Justice Programs, US Department of Justice. Points of view in this document are those of the authors and do not necessarily represent the official position or policies of the US Department of Justice. NR 31 TC 2 Z9 2 U1 1 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD JUL PY 2011 VL 75 BP 539 EP 553 DI 10.1111/j.1469-1809.2011.00656.x PN 4 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 787FA UT WOS:000292360800010 PM 21668909 ER PT J AU Friesen, MC Coble, JB Katki, HA Ji, BT Xue, SZ Lu, W Stewart, PA AF Friesen, Melissa C. Coble, Joseph B. Katki, Hormuzd A. Ji, Bu-Tian Xue, Shouzheng Lu, Wei Stewart, Patricia A. TI Validity and Reliability of Exposure Assessors' Ratings of Exposure Intensity by Type of Occupational Questionnaire and Type of Rater SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE dust; exposure assessment; foundry industry; population-based studies; professional judgment; reliability; textile industry; validity ID INTERRATER AGREEMENT; VALIDATION; CARCINOGENS; INDUSTRY AB Methods: Subjects from three foundries (n = 72) and three textile plants (n = 74) in Shanghai, China, completed an occupational history (OH) and an industry-specific questionnaire (IQ). Six total dust measurements were collected per subject and were used to calculate a subject-specific measurement mean, which was used as the gold standard. Six raters independently ranked the intensity of each subject's current job on an ordinal scale (1-4) based on the OH alone and on the OH and IQ together. Aggregate ratings were calculated for the group, for industrial hygienists, and for occupational physicians. We calculated intra-class correlation coefficients (ICCs) to evaluate the reliability of the raters. We calculated the correlation between the subject-specific measurement means and the ratings to evaluate the raters' validity. Analyses were stratified by industry, type of questionnaire, and type of rater. We also examined the agreement between the ratings by exposure category, where the subject-specific measurement means were categorized into two and four categories. Results: The reliability and validity measures were higher for the aggregate ratings than for the ratings from the individual raters. The group's performance was maximized with three raters. Both the reliability and validity measures were higher for the foundry industry than for the textile industry. The ICCs were consistently lower in the OH/IQ round than in the OH round in both industries. In contrast, the correlations with the measurement means were higher in the OH/IQ round than in the OH round for the foundry industry (group rating, OH/IQ: Spearman rho = 0.77; OH: rho = 0.64). No pattern by questionnaire type was observed for the textile industry (group rating, Spearman rho = 0.50, both assessment rounds). For both industries, the agreement by exposure category was higher when the task was reduced to discriminating between two versus four exposure categories. Conclusions: Assessments based on professional judgment may reduce misclassification by using two or three raters, by using questionnaires that systematically collect task information, and by defining intensity categories that are distinguishable by the raters. However, few studies have the resources to use multiple raters and these additional efforts may not be adequate for obtaining valid subjective ratings. Thus, improving exposure assessment approaches for studies that rely on professional judgment remain an important research need. C1 [Friesen, Melissa C.; Coble, Joseph B.; Katki, Hormuzd A.; Ji, Bu-Tian; Xue, Shouzheng; Stewart, Patricia A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lu, Wei] Shanghai Municipal Ctr Dis Control, Shanghai, Peoples R China. RP Friesen, MC (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Friesen, Melissa/A-5362-2009 FU National Cancer Institute FX Intramural Research Program at the National Cancer Institute. NR 30 TC 10 Z9 10 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JUL PY 2011 VL 55 IS 6 BP 601 EP 611 DI 10.1093/annhyg/mer019 PG 11 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 789XX UT WOS:000292553900007 PM 21511891 ER PT J AU Hines, CJ Deddens, JA Coble, J Kamel, F Alavanja, MCR AF Hines, Cynthia J. Deddens, James A. Coble, Joseph Kamel, Freya Alavanja, Michael C. R. TI Determinants of Captan Air and Dermal Exposures among Orchard Pesticide Applicators in the Agricultural Health Study SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE agriculture; captan; dermal exposure-pesticides; determinants of exposure; exposure assessment-mixed models; orchards; pesticide exposure; variance components ID FARM APPLICATORS; ALGORITHM; FAMILIES; WORKERS; FRANCE AB Methods: External exposure metrics included personal air, hand rinse, and dermal patch samples collected from each applicator on 2 days in 2002-2003. A 24-h urine sample was also collected. Exposure determinants were identified for each external metric using multiple linear regression models via the NLMIXED procedure in SAS. The AHS algorithm was adjusted, consistent with the identified determinants. Mixed-effect models were used to evaluate the correlation between the adjusted and unadjusted algorithm and urinary captan metabolite levels. Results: Consistent determinants of captan exposure were a measure of application size (kilogram of captan sprayed or application method), wearing chemical-resistant (CR) gloves and/or a coverall/suit, repairing spray equipment, and product formulation. Application by airblast was associated with a 4- to 5-fold increase in exposure as compared to hand spray. Exposure reduction to the hands, right thigh, and left forearm from wearing CR gloves averaged similar to 80%, to the right and left thighs and right forearm from wearing a coverall/suit by similar to 70%. Applicators using wettable powder formulations had significantly higher air, thigh, and forearm exposures than those using liquid formulations. Application method weights in the AHS algorithm were adjusted to nine for airblast and two for hand spray; protective equipment reduction factors were adjusted to 0.2 (CR gloves), 0.3 (coverall/suit), and 0.1 (both). Conclusions: Adjustment of application method, CR glove, and coverall weights in the AHS algorithm based on our exposure determinant findings substantially improved the correlation between the AHS algorithm and urinary metabolite levels. C1 [Hines, Cynthia J.; Deddens, James A.] NIOSH, Cincinnati, OH 45226 USA. [Deddens, James A.] Univ Cincinnati, Dept Math Sci, Cincinnati, OH 45221 USA. [Coble, Joseph; Alavanja, Michael C. R.] NCI, Rockville, MD 20892 USA. [Kamel, Freya] NIEHS, Res Triangle Pk, NC 27709 USA. RP Hines, CJ (reprint author), NIOSH, 4676 Columbia Pkwy,R-14, Cincinnati, OH 45226 USA. EM chines@cdc.gov OI Kamel, Freya/0000-0001-5052-6615 FU National Institute for Occupational Safety and Health; National Institutes of Health, National Cancer Institute [Z01-CP010119]; National Institute of Environmental Health Sciences [Z01-ES049030] FX This work has been supported in part by the Intramural research program of the National Institute for Occupational Safety and Health; National Institutes of Health, National Cancer Institute (Z01-CP010119); National Institute of Environmental Health Sciences (Z01-ES049030). NR 27 TC 9 Z9 10 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JUL PY 2011 VL 55 IS 6 BP 620 EP 633 DI 10.1093/annhyg/mer008 PG 14 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 789XX UT WOS:000292553900009 PM 21427168 ER PT J AU Sutton, M Mills, JL Molloy, AM Troendle, JF Brody, LC Conley, M Mc Donnell, R Scott, JM Kirke, PN AF Sutton, Marie Mills, James L. Molloy, Anne M. Troendle, James F. Brody, Lawrence C. Conley, Mary Mc Donnell, Robert Scott, John M. Kirke, Peadar N. TI Maternal Folate, Vitamin B12 and Homocysteine Levels in Pregnancies Affected by Congenital Malformations Other Than Neural Tube Defects SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article ID FOLIC-ACID FORTIFICATION; PERICONCEPTIONAL MULTIVITAMIN USE; OROFACIAL CLEFTS; BIRTH-DEFECTS; MICROBIOLOGICAL ASSAY; CLINICAL GENETICS; HEART-DEFECTS; ORAL CLEFTS; RISK; SUPPLEMENTATION C1 [Sutton, Marie] Hlth Res Board, Evidence Ctr, Child Hlth Epidemiol Unit, Dublin 2, Ireland. [Mills, James L.; Troendle, James F.; Conley, Mary] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Molloy, Anne M.] Trinity Coll Dublin, Sch Med, Dublin, Ireland. [Troendle, James F.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. [Mc Donnell, Robert] Dr Steevens Hosp, Hlth Informat Unit, Dept Publ Hlth, Hlth Serv, Dublin, Ireland. [Scott, John M.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland. RP Sutton, M (reprint author), Hlth Res Board, Evidence Ctr, Child Hlth Epidemiol Unit, 3rd Floor,Knockmaun House,42-47 Lower Mt St, Dublin 2, Ireland. EM msutton@hrb.ie OI Molloy, Anne/0000-0002-1688-9049 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Health Research Board of Ireland FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Health Research Board of Ireland. NR 33 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD JUL PY 2011 VL 91 IS 7 BP 610 EP 615 DI 10.1002/bdra.20817 PG 6 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 790PY UT WOS:000292602900003 PM 21591245 ER PT J AU Athar, M Kopelovich, L AF Athar, Mohammad Kopelovich, Levy TI Rapamycin and mTORC1 Inhibition in the Mouse: Skin Cancer Prevention SO CANCER PREVENTION RESEARCH LA English DT Article ID MAMMALIAN TARGET; MOTIF PHOSPHORYLATION; CELL-GROWTH; MODEL; AKT; CARCINOGENESIS; TUMORIGENESIS; MICE; ACTIVATION; EVEROLIMUS AB Therapeutic and preventive effects of rapamycin include reduced risk of nonmelanoma skin cancer (NMSC). In this issue of the journal (beginning on page 1011), Checkley and colleagues report that rapamycin inhibits mTOR complex 1 in murine epidermis, thereby inhibiting tumor promotion mediated by tetradecanoyl phorbol-13 acetate in association with a strong anti-inflammatory effect. Rapamycin is an immunosuppressive drug for preventing graft rejection in organ transplant recipients and reduces the risk of NMSC and Kaposi's sarcoma in this population, albeit by mechanisms distinct from immunosuppression. Important future directions include identifying molecular predictors of rapamycin/ rapalog sensitivity or resistance (potentially, for example, PI3K pathway alterations and KRAS mutations) and combined nonrapalog, mTOR-targeting approaches, all of which should increase efficacy and minimize toxicity. Cancer Prev Res; 4(7); 957-61. (C)2011 AACR. C1 [Athar, Mohammad] Univ Alabama Birmingham, Dept Dermatol, Skin Dis Res Ctr, Birmingham, AL 35294 USA. [Athar, Mohammad] Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL 35294 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kopelovich, L (reprint author), NCI, NIH, DCP, Execut Plaza N,Suite 2114,6130 Execut Blvd, Bethesda, MD 20892 USA. EM kopelovl@mail.nih.gov FU NCI NIH HHS [R01 CA138998, N01 CN043301, 1R01CA138998, N01-CN-43300, R01 CA138998-02]; NIAMS NIH HHS [P30 AR050948, P30 AR050948-07, P30AR050948]; NIEHS NIH HHS [R21ES017494, R01 ES015323-05, R21 ES017494, R21 ES017494-02, R01 ES015323] NR 58 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2011 VL 4 IS 7 BP 957 EP 961 DI 10.1158/1940-6207.CAPR-11-0266 PG 5 WC Oncology SC Oncology GA 788MN UT WOS:000292449200003 PM 21733819 ER PT J AU Mao, JT Roth, MD Fishbein, MC Aberle, DR Zhang, ZF Rao, JY Tashkin, DP Goodglick, L Holmes, EC Cameron, RB Dubinett, SM Elashoff, R Szabo, E Elashoff, D AF Mao, Jenny T. Roth, Michael D. Fishbein, Michael C. Aberle, Denise R. Zhang, Zuo-Feng Rao, Jian Yu Tashkin, Donald P. Goodglick, Lee Holmes, E. Carmack Cameron, Robert B. Dubinett, Steven M. Elashoff, Robert Szabo, Eva Elashoff, David TI Lung Cancer Chemoprevention with Celecoxib in Former Smokers SO CANCER PREVENTION RESEARCH LA English DT Article ID C-REACTIVE PROTEIN; BRONCHIAL EPITHELIUM; CYCLOOXYGENASE-2 INHIBITORS; ACTIVE SMOKERS; HIGH-RISK; TRIAL; PREVENTION; INTERLEUKIN-10; MACROPHAGES; BUDESONIDE AB Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2-selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age >= 45, >= 30 pack-years of smoking, >= 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease. Cancer Prev Res; 4(7); 984-93. (C)2011 AACR. C1 [Mao, Jenny T.] Univ New Mexico, New Mexico VA Hlth Care Syst, Pulm & Crit Care Sect, Albuquerque, NM 87108 USA. [Mao, Jenny T.; Roth, Michael D.; Tashkin, Donald P.; Dubinett, Steven M.] Univ Calif Los Angeles, Sch Publ Hlth, Div Pulm & Crit Care Med, Los Angeles, CA 90024 USA. [Fishbein, Michael C.; Rao, Jian Yu; Goodglick, Lee; Dubinett, Steven M.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA. [Aberle, Denise R.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Radiol, Los Angeles, CA 90024 USA. [Holmes, E. Carmack; Cameron, Robert B.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Surg, Los Angeles, CA 90024 USA. [Elashoff, Robert; Elashoff, David] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Elashoff, David] Univ Calif Los Angeles, Sch Publ Hlth, Dept Med, David Geffen Sch Med UCLA, Los Angeles, CA 90024 USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Szabo, Eva] NCI, Canc Prevent Div, Rockville, MD USA. RP Mao, JT (reprint author), Univ New Mexico, New Mexico VA Hlth Care Syst, Pulm & Crit Care Sect, Albuquerque, NM 87108 USA. EM jenny.mao@va.gov OI Aberle, Denise/0000-0002-8858-3401 FU National Cancer Institute [U01CA096134]; Early Detection Research Network NCI [CA-86366]; Pfizer Inc. FX This work was supported by a grant from the National Cancer Institute (JTM, U01CA096134), and in part by the Early Detection Research Network NCI (LG, CA-86366). Pfizer Inc. provided support for study drugs and plasma celecoxib measurements. NR 40 TC 38 Z9 38 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2011 VL 4 IS 7 BP 984 EP 993 DI 10.1158/1940-6207.CAPR-11-0078 PG 10 WC Oncology SC Oncology GA 788MN UT WOS:000292449200006 PM 21733822 ER PT J AU Morris, PG Hudis, CA Giri, D Morrow, M Falcone, DJ Zhou, XK Du, BH Brogi, E Crawford, CB Kopelovich, L Subbaramaiah, K Dannenberg, AJ AF Morris, Patrick G. Hudis, Clifford A. Giri, Dilip Morrow, Monica Falcone, Domenick J. Zhou, Xi Kathy Du, Baoheng Brogi, Edi Crawford, Carolyn B. Kopelovich, Levy Subbaramaiah, Kotha Dannenberg, Andrew J. TI Inflammation and Increased Aromatase Expression Occur in the Breast Tissue of Obese Women with Breast Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID BODY-MASS INDEX; TUMOR-NECROSIS-FACTOR; ADIPOSE-TISSUE; INSULIN-RESISTANCE; MACROPHAGE INFILTRATION; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; GENE-EXPRESSION; WEIGHT-LOSS; PROGNOSIS AB Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. In humans, obesity causes subclinical inflammation in visceral and subcutaneous adipose tissue, characterized by necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS). Recently, we found increased numbers of CLS, activation of the NF-kappa B transcription factor, and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity -> inflammation axis is important for the development and progression of breast cancer. Here, our main objective was to determine if the findings in mouse models of obesity translated to women. Breast tissue was obtained from 30 women who underwent breast surgery. CLS of the breast (CLS-B) was found in nearly 50% (14 of 30) of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index (P < 0.001) and adipocyte size (P = 0.01). Increased NF-kappa B binding activity and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, our results suggest that the obesity -> inflammation -> aromatase axis is present in the breast tissue of most overweight and obese women. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis. Cancer Prev Res; 4(7); 1021-9. (C)2011 AACR. C1 [Morris, Patrick G.; Hudis, Clifford A.; Crawford, Carolyn B.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Giri, Dilip; Brogi, Edi] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Morrow, Monica] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Falcone, Domenick J.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Zhou, Xi Kathy] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Du, Baoheng; Subbaramaiah, Kotha; Dannenberg, Andrew J.] Weill Cornell Med Coll, Weill Cornell Canc Ctr, Dept Med, New York, NY USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Dannenberg, AJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 525 E 68th St,Room F-206, New York, NY 10065 USA. EM ksubba@med.cornell.edu; ajdannen@med.cornell.edu FU NCI [N01-CN-43302]; Breast Cancer Research Foundation; Botwinick-Wolfensohn Foundation; Kochavi Breast Cancer Prevention Fund FX This work was supported by NCI N01-CN-43302 (to A.J. Dannenberg), the Breast Cancer Research Foundation (to A.J. Dannenberg, C.A. Hudis), the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick; to A.J. Dannenberg), and the Kochavi Breast Cancer Prevention Fund (to C.A. Hudis). NR 40 TC 146 Z9 147 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2011 VL 4 IS 7 BP 1021 EP 1029 DI 10.1158/1940-6207.CAPR-11-0110 PG 9 WC Oncology SC Oncology GA 788MN UT WOS:000292449200010 PM 21622727 ER PT J AU Mackenzie, GG Ouyang, N Xie, G Vrankova, K Huang, LQ Sun, Y Komninou, D Kopelovich, L Rigas, B AF Mackenzie, Gerardo G. Ouyang, Nengtai Xie, Gang Vrankova, Kvetoslava Huang, Liqun Sun, Yu Komninou, Despina Kopelovich, Levy Rigas, Basil TI Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID INDUCED CELL-DEATH; THIOREDOXIN SYSTEM; ANTIINFLAMMATORY DRUGS; OXIDATIVE STRESS; KAPPA-B; CHEMOPREVENTION; INHIBITION; POLYAMINES; TUMOR; ASPIRIN AB The nonsteroidal anti-inflammatory drug (NSAID) sulindac and the ornithine decarboxylase (ODC) antagonist difluoromethylornithine (DFMO), individually and together, are effective inhibitors of colon carcinogenesis. However, chronic use of sulindac is associated with significant side effects. We evaluated the chemopreventive efficacy of phospho-sulindac (P-S, OXT-328), an apparently safe derivative of sulindac, together with DFMO, in HT-29 human colon cancer xenografts. Nude mice were divided into four groups as follows: group 1 received vehicle (corn oil); group 2 received P-S (100 mg/kg/d) by oral gavage; group 3 received DFMO (2% in drinking water); and group 4 received P-S (100 mg/kg/d) by gavage plus DFMO (2% in drinking water; P-S/DFMO). Eighteen days after implantation, compared with controls, tumor volume was inhibited 65.9% by P-S, 52.9% by DFMO, and 70.9% by P-S/DFMO (P < 0.01 for all). P-S/DFMO reduced cell proliferation 27.1% and increased apoptosis 38.9% compared with controls (P < 0.05 for both). Compared with controls, P-S reduced the levels of thioredoxin-1 (Trx-1) and thioredoxin reductase (TrxR), whereas DFMO reduced polyamine content (putrescine and spermidine) and TrxR levels. Importantly, P-S/DFMO decreased putrescine and spermidine levels and the expression of Trx-1, TrxR, and cyclooxygenase (COX) 2. Of these molecular targets, TrxR most consistently correlated with tumor growth. Study results show that P-S/DFMO is an efficacious drug combination for colon cancer prevention and also show the safety of P-S, which may overcome the limiting side effects of conventional sulindac. P-S/DFMO has an intricate mechanism of action extending beyond polyamines and including the thioredoxin system, an emerging regulator of chemoprevention. P-S/DFMO merits further evaluation. Cancer Prev Res; 4(7); 1052-60. (C)2011 AACR. C1 [Rigas, Basil] SUNY Stony Brook, Canc Prevent Div, Dept Med, HSC, Stony Brook, NY 11794 USA. [Komninou, Despina] Medicon Pharmaceut Inc, New York, NY USA. [Kopelovich, Levy] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Rigas, B (reprint author), SUNY Stony Brook, Canc Prevent Div, Dept Med, HSC, T17-080, Stony Brook, NY 11794 USA. EM basil.rigas@stonybrook.edu FU NIH [R01-CA139453, R01CA13945402, 1N01CN43302WA22] FX The work was supported by NIH grants R01-CA139453, R01CA13945402, and 1N01CN43302WA22. NR 30 TC 22 Z9 23 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2011 VL 4 IS 7 BP 1052 EP 1060 DI 10.1158/1940-6207.CAPR-11-0067 PG 9 WC Oncology SC Oncology GA 788MN UT WOS:000292449200013 PM 21464038 ER PT J AU Rosenberg, SA Yang, JC Sherry, RM Kammula, US Hughes, MS Phan, GQ Citrin, DE Restifo, NP Robbins, PF Wunderlich, JR Morton, KE Laurencot, CM Steinberg, SM White, DE Dudley, ME AF Rosenberg, Steven A. Yang, James C. Sherry, Richard M. Kammula, Udai S. Hughes, Marybeth S. Phan, Giao Q. Citrin, Deborah E. Restifo, Nicholas P. Robbins, Paul F. Wunderlich, John R. Morton, Kathleen E. Laurencot, Carolyn M. Steinberg, Seth M. White, Donald E. Dudley, Mark E. TI Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; CANCER REGRESSION; TRANSFER THERAPY; ADOPTIVE TRANSFER; RECOMBINANT INTERLEUKIN-2; NASOPHARYNGEAL CARCINOMA; TRANSPLANT PATIENTS; MALIGNANT-MELANOMA; AUTOLOGOUS TUMOR; BONE-MARROW AB Purpose: Most treatments for patients with metastatic melanoma have a low rate of complete regression and thus overall survival in these patients is poor. We investigated the ability of adoptive cell transfer utilizing autologous tumor-infiltrating lymphocytes (TIL) to mediate durable complete regressions in heavily pretreated patients with metastatic melanoma. Experimental Design: Ninety-three patients with measurable metastatic melanoma were treated with the adoptive transfer of autologous TILs administered in conjunction with interleukin-2 following a lymphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of these patients had progressive disease following a prior systemic treatment. Median potential follow-up was 62 months. Results: Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) in the 3 trials using lymphodepleting preparative regimens (chemotherapy alone or with 2 or 12 Gy irradiation) were 49%, 52%, and 72%, respectively. Twenty of the 93 patients (22%) achieved a complete tumor regression, and 19 have ongoing complete regressions beyond 3 years. The actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders were 100% and 93%. The likelihood of achieving a complete response was similar regardless of prior therapy. Factors associated with objective response included longer telomeres of the infused cells, the number of CD8(+)CD27(+) cells infused, and the persistence of the infused cells in the circulation at 1 month (all P(2) < 0.001). Conclusions: Cell transfer therapy with autologous TILs can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment. Clin Cancer Res; 17(13); 4550-7. (C) 2011 AACR. C1 [Rosenberg, Steven A.; Yang, James C.; Sherry, Richard M.; Kammula, Udai S.; Hughes, Marybeth S.; Phan, Giao Q.; Restifo, Nicholas P.; Robbins, Paul F.; Wunderlich, John R.; Morton, Kathleen E.; Laurencot, Carolyn M.; White, Donald E.; Dudley, Mark E.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Citrin, Deborah E.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, CRC-10,10 Ctr Dr,Room 3-3940, Bethesda, MD 20892 USA. EM sar@nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 SC003811-33] NR 42 TC 628 Z9 651 U1 4 U2 59 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2011 VL 17 IS 13 BP 4550 EP 4557 DI 10.1158/1078-0432.CCR-11-0116 PG 8 WC Oncology SC Oncology GA 788LO UT WOS:000292446600036 PM 21498393 ER PT J AU Pasricha, PJ Colvin, R Yates, K Hasler, WL Abell, TL Unalp-Arida, A Nguyen, L Farrugia, G Koch, KL Parkman, HP Snape, WJ Lee, L Tonascia, J Hamilton, F AF Pasricha, Pankaj J. Colvin, Ryan Yates, Katherine Hasler, William L. Abell, Thomas L. Uenalp-Arida, Aynur Nguyen, Linda Farrugia, Gianrico Koch, Kenneth L. Parkman, Henry P. Snape, William J. Lee, Linda Tonascia, James Hamilton, Frank TI Characteristics of Patients With Chronic Unexplained Nausea and Vomiting and Normal Gastric Emptying SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE GCSI; Digestion; PAGI-SYM; PAGI-QOL ID CARDINAL SYMPTOM INDEX; ELECTRICAL-STIMULATION; DYSPEPTIC SYMPTOMS; PROXIMAL STOMACH; PANCREAS-KIDNEY; GASTROPARESIS; VALIDATION; PREVALENCE; PREDICTORS; DISORDERS AB BACKGROUND & AIMS: Chronic nausea and vomiting with normal gastric emptying is a poorly understood syndrome; we analyzed its characteristics. METHODS: We collected and analyzed data from 425 patients with chronic nausea and vomiting, enrolled at 6 centers by the Gastroparesis Clinical Research Consortium in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry. RESULTS: Among the patients, 319 (75%) had delayed emptying, defined by the results of a standardized, low-fat meal, and 106 had normal gastric emptying. Patients with or without delayed emptying did not differ in age, sex, or race, although those with normal gastric emptying were less likely to be diabetic. Symptom severity indexes were similar between groups for nausea, retching, vomiting, stomach fullness, inability to complete a meal, feeling excessively full after meals, loss of appetite, bloating, and visibly larger stomach. There were no differences in health care utilization, quality of life indexes, depression, or trait anxiety scores. However, state anxiety scores were slightly higher among patients with delayed gastric emptying. Total gastroparesis cardinal symptom index scores were not correlated with gastric retention after 2 or 4 hours in either group. Patients with the syndrome were not adequately captured by the stand-alone criteria for the Rome III diagnoses of chronic idiopathic nausea and functional vomiting. With rare exceptions, the diagnosis remained stable after a 48-week follow-up period. CONCLUSIONS: Patients with nausea and vomiting with normal gastric emptying represent a significant medical problem and are, for the most part, indistinguishable from those with gastroparesis. This syndrome is not categorized in the medical literature-it might be a separate clinical entity. C1 [Pasricha, Pankaj J.] Stanford Univ, Sch Med, Div Gastroenterol & Hepatol, Palo Alto, CA 94305 USA. [Colvin, Ryan; Yates, Katherine; Uenalp-Arida, Aynur; Lee, Linda; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Hasler, William L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Abell, Thomas L.] Univ Mississippi, Jackson, MS 39216 USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Koch, Kenneth L.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Parkman, Henry P.] Temple Univ, Philadelphia, PA 19122 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Hamilton, Frank] NIDDK, Bethesda, MD USA. RP Pasricha, PJ (reprint author), Stanford Univ, Sch Med, Div Gastroenterol & Hepatol, 300 Pasteur Dr,Room M211,Alway Bldg, Palo Alto, CA 94305 USA. EM Pasricha@stanford.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] 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, and U01DK074008). NR 28 TC 56 Z9 56 U1 0 U2 3 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 JUL PY 2011 VL 9 IS 7 BP 567 EP U89 DI 10.1016/j.cgh.2011.03.003 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 788TS UT WOS:000292467900015 PM 21397732 ER PT J AU Abu Dayyeh, BK Yang, M Fuchs, BC Karl, DL Yamada, S Sninsky, JJ O'Brien, TR Dienstag, JL Tanabe, KK Chung, RT AF Abu Dayyeh, Barham K. Yang, May Fuchs, Bryan C. Karl, Daniel L. Yamada, Suguru Sninsky, John J. O'Brien, Thomas R. Dienstag, Jules L. Tanabe, Kenneth K. Chung, Raymond T. CA HALT-C Trial Grp TI A Functional Polymorphism in the Epidermal Growth Factor Gene Is Associated With Risk for Hepatocellular Carcinoma SO GASTROENTEROLOGY LA English DT Article DE Liver Disease; Cancer; Tumor; Prognosis; HCV ID SERUM ALPHA-FETOPROTEIN; CHRONIC LIVER-DISEASE; CHRONIC HEPATITIS-C; EGF POLYMORPHISM; CIRRHOTIC LIVER; EXPRESSION; RECEPTOR; REGENERATION; DIAGNOSIS; MICE AB BACKGROUND & AIMS: A single nucleotide polymorphism 61*G (rs4444903) in the epidermal growth factor (EGF) gene has been associated, in 2 case-control studies, with hepatocellular carcinoma (HCC). We tested associations between demographic, clinical, and genetic data and development of HCC, and developed a simple predictive model in a cohort of patients with chronic hepatitis C and advanced fibrosis. METHODS: Black and white subjects from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial (n = 816) were followed up prospectively for development of a definite or presumed case of HCC for a median time period of 6.1 years. We used the Cox proportional hazards regression model to determine the hazard ratio for risk of HCC and to develop prediction models. RESULTS: Subjects with EGF genotype G/G had a higher adjusted risk for HCC than those with genotype A/A (hazard ratio, 2.10; 95% confidence interval, 1.05-4.23; P = .03). After adjusting for EGF genotype, blacks had no increased risk of HCC risk compared with whites. Higher serum levels of EGF were observed among subjects with at least one G allele (P = .08); the subset of subjects with EGF G/G genotype and above-median serum levels of EGF had the highest risk of HCC. We developed a simple prediction model that included the EGF genotype to identify patients at low, intermediate, and high risk for HCC; 6-year cumulative HCC incidences were 2.3%, 10.4%, and 26%, respectively. CONCLUSIONS: We associated the EGF genotype G/G with increased risk for HCC; differences in its frequency among black and white subjects might account for differences in HCC incidence between these groups. We developed a model that incorporates EGF genotype and demographic and clinical variables to identify patients at low, intermediate, and high risk for HCC. C1 [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Fuchs, Bryan C.; Karl, Daniel L.; Yamada, Suguru; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Abu Dayyeh, Barham K.; Dienstag, Jules L.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02114 USA. [Fuchs, Bryan C.; Karl, Daniel L.; Yamada, Suguru; Tanabe, Kenneth K.] Harvard Univ, Dept Surg, Sch Med, Boston, MA 02114 USA. [Yang, May] New England Res Inst, Watertown, MA 02172 USA. [Sninsky, John J.] Celera Corp, Alameda, CA USA. [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Chung, RT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Warren 1007C,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org FU Hoffmann-La Roche, Inc (now Genentech); Schering-Plough (now Merck); Novartis; Romark; National Institutes of Health [DK078772]; Vertex Pharmaceuticals; National Cancer Institute [5 K01 CA140861-02]; 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; National Center for Research Resources, National Institutes of Health; Celera Corporation; National Institutes of Health FX These authors disclose the following: Raymond Chung receives research support from Hoffmann-La Roche, Inc (now Genentech), Schering-Plough (now Merck), Novartis, and Romark; is a consultant for Merck, Pfizer, and Gilead; and is supported by National Institutes of Health grant number DK078772. John Sninsky is an employee and has equity interest in Celera Corporation. Jules Dienstag receives research support from Vertex Pharmaceuticals; serves on the data monitoring committee for Schering-Plough Research Institute, Human Genome Sciences, and Medtronic; is on the Ad hoc Hepatitis Advisory Board for Boehringer-Ingelheim; Antiviral Advisory Board for Gilead Sciences; is an ad hoc consultant (with stock options) for Achillion; is on the Clinical Advisory Board (with stock options) for Nucleonics; and is on the Scientific Advisory Board (with stock options) for Metabasis. Kenneth Tanabe received honoraria for a scientific lecture on January 1, 2008, from Vertex. Bryan Fuchs is supported by a K award from the National Cancer Institute (5 K01 CA140861-02). The remaining authors disclose no conflicts.; This study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases. 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. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc (now Genentech), and Celera Corporation through Cooperative Research and Development Agreements with the National Institutes of Health. NR 40 TC 61 Z9 62 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2011 VL 141 IS 1 BP 141 EP 149 DI 10.1053/j.gastro.2011.03.045 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 786IX UT WOS:000292299700035 PM 21440548 ER PT J AU Hong, LE Yang, X Wonodi, I Hodgkinson, CA Goldman, D Stine, OC Stein, ES Thaker, GK AF Hong, L. E. Yang, X. Wonodi, I. Hodgkinson, C. A. Goldman, D. Stine, O. C. Stein, E. S. Thaker, G. K. TI A CHRNA5 allele related to nicotine addiction and schizophrenia SO GENES BRAIN AND BEHAVIOR LA English DT Article DE alpha 5; comorbidity; nAChR; nicotine addiction; schizophrenia; smoking ID RECEPTOR SUBUNIT GENE; BIPOLAR DISORDER; HEAVY SMOKING; LUNG-CANCER; SUSCEPTIBILITY LOCUS; LINKAGE ANALYSIS; CANDIDATE GENES; ASSOCIATION; DEPENDENCE; RISK AB Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, one could hypothesize that genes associated with smoking might be overrepresented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia, and thus difficult to explain the increased smoking in schizophrenia. A functional smoking-related nicotinic acetylcholine receptor alpha 5 subunit gene (CHRNA5) nonsynonymous single nucleotide polymorphism (SNP) rs16969968 (Asp398Asn) has recently been discovered and replicated. As such, we tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in schizophrenia patient smokers (P = 0.001) and control smokers (P = 0.029). Furthermore, the same risk allele is significantly associated with schizophrenia in both Caucasian (P = 0.022) and African-American (P = 0.006) nonsmoker schizophrenia patients compared with control nonsmokers. Intriguingly, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, but whether this SNP contributes to the increased smoking prevalence in schizophrenia patients requires additional studies. C1 [Hong, L. E.; Yang, X.; Wonodi, I.; Thaker, G. K.] Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MD 21228 USA. [Hodgkinson, C. A.; Goldman, D.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Stine, O. C.] Univ Maryland, Genom Core Facil, GCRC, Sch Med, Baltimore, MD 21228 USA. [Stein, E. S.] NIDA, Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD USA. RP Hong, LE (reprint author), Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, POB 21247, Baltimore, MD 21228 USA. EM ehong@mprc.umaryland.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIDA; NIAAA; National Institutes of Health [DA027680, MH085646, MH077852]; Maryland Cigarette Restitution Fund Program FX Support was received from the NIDA and NIAAA Intramural Research Programs, National Institutes of Health grants DA027680, MH085646, MH077852 and the Maryland Cigarette Restitution Fund Program. NR 43 TC 20 Z9 20 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2011 VL 10 IS 5 BP 530 EP 535 DI 10.1111/j.1601-183X.2011.00689.x PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 788PM UT WOS:000292456900003 PM 21418140 ER PT J AU Kirkland, PA Reidy, M Masison, DC AF Kirkland, P. Aaron Reidy, Michael Masison, Daniel C. TI Functions of Yeast Hsp40 Chaperone Sis1p Dispensable for Prion Propagation but Important for Prion Curing and Protection From Prion Toxicity SO GENETICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; GUANIDINE-HYDROCHLORIDE; PSI+ PRION; SHUTTLE VECTORS; ATPASE ACTIVITY; CO-CHAPERONES; DNAJ PROTEIN; IN-VIVO; HSP70; HSP104 AB Replication of amyloid-based yeast prions [PSI(+)], [URE3], and [PIN(+)] depends on the protein disaggregation machinery that includes Hsp104, Hsp70, and Hsp40 molecular chaperones. Yet, overexpressing Hsp104 cures cells of [PSI(+)] prions. An Hsp70 mutant (Ssa1-21p) antagonizes propagation of [PSI(+)] in a manner resembling elevated Hsp104. The major cytosolic Hsp40 Sis1p is the only Hsp40 required for replication of these prions, but its role in [PSI(+)] curing is unknown. Here we find that all nonessential functional regions of Sis1p are dispensable for [PSI(+)] propagation, suggesting that other Hsp40's might provide Hsp40 functions required for [PSI(+)] replication. Conversely, several Sis1p functions were important for promoting antiprion effects of both Ssa1-21p and Hsp104, which implies a link between the antiprion effects of these chaperones and suggests that Sis1p is a specific Hsp40 important for [PSI(+)] curing. These contrasting findings suggest that the functions of Hsp104 that are important for propagation and elimination of [PSI(+)] are either distinct or specified by different Hsp40's. This work also uncovered a growth inhibition caused by [PSI(+)] when certain functions of Sis1p were absent, suggesting that Sis1p protects cells from cytotoxicity caused by [PSI(+)] prions. C1 [Kirkland, P. Aaron; Reidy, Michael; Masison, Daniel C.] NIH, Lab Biochem & Genet, NIDDK, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIH, Lab Biochem & Genet, NIDDK, Bldg 8,Room 225,8 Ctr Dr, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov OI Reidy, Michael/0000-0002-9290-7595 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD FX We thank Giman Jung and Guo-Chiuan Hung for plasmid construction, Deepak Sharma for assistance in manuscript preparation, and Elizabeth Craig (University of Wisconsin, Madison) for generously providing several SIS1 plasmid constructs and antibodies. This work was supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. NR 53 TC 24 Z9 26 U1 1 U2 7 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2011 VL 188 IS 3 BP 565 EP 577 DI 10.1534/genetics.111.129460 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 789TJ UT WOS:000292538900008 PM 21555396 ER PT J AU Stottmann, RW Moran, JL Turbe-Doan, A Driver, E Kelley, M Beier, DR AF Stottmann, R. W. Moran, J. L. Turbe-Doan, A. Driver, E. Kelley, M. Beier, D. R. TI Focusing Forward Genetics: A Tripartite ENU Screen for Neurodevelopmental Mutations in the Mouse SO GENETICS LA English DT Article ID PLANAR CELL POLARITY; NEURAL-TUBE DEFECTS; CORTICAL DEVELOPMENT; CASPASE-3-DEFICIENT MICE; LUNG DEVELOPMENT; CASPASE 3; MUTANT; PROTEIN; IDENTIFICATION; MUTAGENESIS AB The control of growth, patterning, and differentiation of the mammalian forebrain has a large genetic component, and many human disease loci associated with cortical malformations have been identified. To further understand the genes involved in controlling neural development, we have performed a forward genetic screen in the mouse (Mus musculus) using ENU mutagenesis. We report the results from our ENU screen in which we biased our ascertainment toward mutations affecting neurodevelopment. Our screen had three components: a careful morphological and histological examination of forebrain structure, the inclusion of a retinoic acid response element-lacZ reporter transgene to highlight patterning of the brain, and the use of a genetically sensitizing locus, Lis1/Pafah1b1, to predispose animals to neurodevelopmental defects. We recovered and mapped eight monogenic mutations, seven of which affect neurodevelopment. We have evidence for a causal gene in four of the eight mutations. We describe in detail two of these: a mutation in the planar cell polarity gene scribbled homolog (Drosophila) (Scrib) and a mutation in caspase-3 (Casp3). We find that refining ENU mutagenesis in these ways is an efficient experimental approach and that investigation of the developing mammalian nervous system using forward genetic experiments is highly productive. C1 [Stottmann, R. W.; Moran, J. L.; Turbe-Doan, A.; Beier, D. R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet Dept Med, Boston, MA 02115 USA. [Driver, E.; Kelley, M.] Natl Inst Deafness & Other Communicat Disorders, Dev Neurosci Sect, Bethesda, MD 20892 USA. RP Beier, DR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet Dept Med, Ave Louis Pasteur, Boston, MA 02115 USA. EM beier@receptor.med.harvard.edu OI Moran, Jennifer/0000-0002-5664-4716; Driver, Elizabeth/0000-0002-5618-1053 FU National Institutes of Health [R01HD0306404, R01MH081187, F32HD053198] FX We thank A. Tilt, H. Qiu, S. Hines, A. Bolton, and S. Nicholson for assistance in screening and mapping; M. Lun, Y. Yun, and M. Prysak for assistance with animal husbandry; and J. Min for assistance with caspase-3 immunohistochemistry. We thank U. Drager (University of Massachusetts Medical School) for the RARE-lacZ mouse line, Lisa Good-rich (Harvard Medical School) for the looptail mice, and A. Wynshaw-Boris (University of California at San Francisco) for the Lis1 mouse. Funding for this project is from the National Institutes of Health (grants R01HD0306404 and R01MH081187 to D. R. B. and grant F32HD053198 to R.W.S.). NR 44 TC 18 Z9 18 U1 0 U2 2 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2011 VL 188 IS 3 BP 615 EP 624 DI 10.1534/genetics.111.126862 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 789TJ UT WOS:000292538900012 PM 21515572 ER PT J AU Masciari, S Dewanwala, A Stoffel, EM Lauwers, GY Zheng, H Achatz, MI Riegert-Johnson, D Foretova, L Silva, EM Digianni, L Verselis, SJ Schneider, K Li, FP Fraumeni, J Garber, JE Syngal, S AF Masciari, Serena Dewanwala, Akriti Stoffel, Elena M. Lauwers, Gregory Y. Zheng, Hui Achatz, Maria Isabel Riegert-Johnson, Douglas Foretova, Lenka Silva, Edaise M. Digianni, Lisa Verselis, Sigitas J. Schneider, Katherine Li, Frederick P. Fraumeni, Joseph Garber, Judy E. Syngal, Sapna TI Gastric cancer in individuals with Li-Fraumeni syndrome SO GENETICS IN MEDICINE LA English DT Article DE Li Fraumeni syndrome; gastric cancer; hereditary gastric cancer syndromes; germline mutations; TP53 ID FAMILIAL ADENOMATOUS POLYPOSIS; BRCA1 MUTATION CARRIERS; P53 GERMLINE MUTATIONS; E-CADHERIN GENE; BREAST-CANCER; COLORECTAL-CANCER; CHILDHOOD-CANCER; DIFFUSE; TP53; RISK AB Purpose: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome. Methods: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens. Results: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24-74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies. Conclusions: Early-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer. Genet Med 2011:13(7):651-657. C1 [Masciari, Serena; Dewanwala, Akriti; Stoffel, Elena M.; Digianni, Lisa; Schneider, Katherine; Li, Frederick P.; Garber, Judy E.; Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Stoffel, Elena M.; Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zheng, Hui] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Boston, MA USA. [Achatz, Maria Isabel] Hosp AC Camargo Fund Antonio Prudente, Dept Oncogenet, Sao Paulo, Brazil. [Achatz, Maria Isabel] Natl Inst Sci & Technol Oncogen, Sao Paulo, Brazil. [Riegert-Johnson, Douglas] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Jacksonville, FL 32224 USA. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Silva, Edaise M.] Hosp AC Camargo Fund Antonio Prudente, Dept Anat Pathol, Sao Paulo, Brazil. [Verselis, Sigitas J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fraumeni, Joseph] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Syngal, S (reprint author), Dana Farber Canc Inst, Div Populat Sci, 44 Binney St,SM 209, Boston, MA 02115 USA. EM ssyngal@partners.org RI Achatz, Maria Isabel /C-5751-2013; Oncogenomica, Inct/H-9999-2013 OI Achatz, Maria Isabel /0000-0001-6894-1219; FU Charles A. King Trust; Bank of America (Boston, MA); Humane Society of the Commonwealth of Massachusetts; US National Cancer Institute [K24 CA 113433]; Harvard Catalyst/The Harvard Clinical and Translational Science Center [UL1 RR 025758]; STARR Foundation; [MZ0 MOU 2005] FX This work was supported by Charles A. King Trust, Bank of America Fellowship, Co-Trustee (Boston, MA) and The Humane Society of the Commonwealth of Massachusetts Postdoctoral Research Fellowship (S.M.), the US National Cancer Institute Grant K24 CA 113433 (S.S.), Scholars in Clinical Science Program of Harvard Catalyst/The Harvard Clinical and Translational Science Center (Award no. UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers), and supported, in part, by the STARR Foundation. Genetic testing in CR (L.F.) was supported by Grant MZ0 MOU 2005. The authors are grateful to the Li-Fraumeni patients and families who kindly consented over the years to be part of the DFCI/NCI LFS registry. NR 51 TC 39 Z9 40 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL PY 2011 VL 13 IS 7 BP 651 EP 657 DI 10.1097/GIM.0b013e31821628b6 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 789TC UT WOS:000292538200008 PM 21552135 ER PT J AU Chen, JC AF Chen, Jichun TI Hematopoietic stem cell development, aging and functional failure SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE Hematopoietic stem cells; Ontogeny; Niche; Senescence; Bone marrow failure ID BONE-MARROW FAILURE; TELOMERASE REVERSE-TRANSCRIPTASE; ACQUIRED APLASTIC-ANEMIA; UMBILICAL-CORD BLOOD; SLAM FAMILY RECEPTORS; COLONY FORMING CELLS; FETAL LIVER; PROGENITOR CELLS; MOUSE MODEL; DYSKERATOSIS-CONGENITA AB Hematopoietic stem cells (HSCs) are found in yolk sac, fetal liver, umbilical cord blood, placenta, and amniotic fluid during mammalian embryonic development. In adults, HSCs reside in marrow cavity of long bones where they self-renew and differentiate to replenish short-lived mature blood cells. HSCs exist in very low frequencies within specific "niches" where they interact with the surrounding environment through molecular associations. Overall HSC function can last much longer than a normal lifetime, but HSCs do show functional senescence with characteristic features of decreased self-renewal, reduced clonal stability, reduced homing and engraftment, and biased lineage commitment. The progressive shortening of telomeres with increasing age, especially under conditions with specific mutations in the telomerase gene complex, could predispose patients to HSC dysfunction and bone marrow failure diseases. Continuous investigation into HSC biology should facilitate the utilization of HSCs as a therapeutic modality and helps to prevent HSC malfunction. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Clin Res Ctr Room 3E-5132,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov FU NIH FX This work was supported by NIH intramural research funds. NR 109 TC 6 Z9 7 U1 0 U2 3 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD JUL PY 2011 VL 94 IS 1 BP 3 EP 10 DI 10.1007/s12185-011-0856-1 PG 8 WC Hematology SC Hematology GA 789JX UT WOS:000292512900002 PM 21523336 ER PT J AU Goveas, JS Espeland, MA Hogan, P Dotson, V Tarima, S Coker, LH Ockene, J Brunner, R Woods, NF Wassertheil-Smoller, S Kotchen, JM Resnick, S AF Goveas, Joseph S. Espeland, Mark A. Hogan, Patricia Dotson, Vonetta Tarima, Sergey Coker, Laura H. Ockene, Judith Brunner, Robert Woods, Nancy F. Wassertheil-Smoller, Sylvia Kotchen, Jane M. Resnick, Susan TI Depressive symptoms, brain volumes and subclinical cerebrovascular disease in postmenopausal women: The Women's Health Initiative MRI Study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Late-life depression; Regional brain volumes; Subclinical cerebrovasailar disease; Structural magnetic resonance imaging ID MILD COGNITIVE IMPAIRMENT; LATE-LIFE DEPRESSION; WHITE-MATTER HYPERINTENSITIES; CONJUGATED EQUINE ESTROGENS; RECURRENT MAJOR DEPRESSION; GERIATRIC DEPRESSION; MAGNETIC-RESONANCE; HIPPOCAMPAL VOLUME; ALZHEIMER-DISEASE; WHIMS-MRI AB Objective: Late-life depressive symptoms (DS) increase the risk of incident mild cognitive impairment and probable dementia in the elderly. Our objectives were to examine the relationship between elevated DS and regional brain volumes including frontal lobe subregions, hippocampus and amygdala, and to determine whether elevated DS were associated with increased subclinical cerebrovascular disease in postmenopausal women. Methods: DS were assessed an average of 8 years prior to structural brain MRI in 1372 women. The 8-item Burnam regression algorithm was used to define DS with a cut-point of 0.009. Adjusting for potential confounders, mean differences in total brain, frontal lobe subregions, hippocampus and amygdala volumes and total ischemic lesion volumes in the basal ganglia and the cerebral white and gray matter outside the basal ganglia were compared between women with and without DS. Results: Depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. After full adjustment, DS at baseline were associated with smaller superior and middle frontal gyral volumes. Hippocampal and amygdala volumes, and ischemic lesion volumes were similar in depressed and non-depressed women. Limitations: Depression was not assessed based on semi-structured interview, and MRI scans were obtained cross-sectionally rather than longitudinally. Longitudinal MRI assessments will be necessary to define the temporal relationships between DS and frontal lobe volumes. Conclusions: Elevated DS were associated with lower volumes in certain frontal lobe subregions but not in the medial temporal lobe structures. Our findings support the role of frontal lobe structures in late-life DS among women. (C) 2011 Elsevier B.V. All rights reserved. C1 [Goveas, Joseph S.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Espeland, Mark A.; Hogan, Patricia; Coker, Laura H.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth, Winston Salem, NC USA. [Dotson, Vonetta] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL USA. [Tarima, Sergey; Kotchen, Jane M.] Med Coll Wisconsin, Dept Populat Hlth, Milwaukee, WI 53226 USA. [Ockene, Judith] Univ Massachusetts, Dept Prevent & Behav Med, Amherst, MA 01003 USA. [Brunner, Robert] Univ Nevada, Sch Med, Dept Family & Community Med, Reno, NV 89557 USA. [Woods, Nancy F.] Univ Washington, Seattle, WA 98195 USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Resnick, Susan] NIA, Lab Personal & Cognit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Goveas, JS (reprint author), Med Coll Wisconsin, Dept Psychiat, Milwaukee, WI 53226 USA. EM jgoveas@mcw.edu RI Dotson, Vonetta/K-6090-2015; OI Dotson, Vonetta/0000-0002-3043-3320 FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Wyeth Pharmaceuticals; National Institute on Aging, NIH FX The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6,32108-9,32111-13,32115,32118-32119,32122,42107-26,42129-32, and 44221. The active study drug and placebo were supplied by Wyeth-Ayerst Research Laboratories, Philadelphia, Pennsylvania.; The Women's Health Initiative Memory Study was funded in part by Wyeth Pharmaceuticals as an ancillary study to the WHI. Wyeth Pharmaceuticals did not participate in the design and conduct of the studies, in the collection, analysis and interpretation of the data, or in preparation, review or approval of this manuscript. Dr. Susan M. Resnick is funded by the Intramural Research Program, National Institute on Aging, NIH. NR 62 TC 24 Z9 25 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL PY 2011 VL 132 IS 1-2 BP 275 EP 284 DI 10.1016/j.jad.2011.01.020 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 788IK UT WOS:000292438400037 PM 21349587 ER PT J AU Cooper, SD Fletcher, BL Silinski, MAR Brown, SS Lodge, JW Fernando, RA Collins, BJ AF Cooper, Stephen D. Fletcher, Brenda L. Silinski, Melanie A. Rehder Brown, Sherri S. Lodge, Jon W. Fernando, Reshan A. Collins, Bradley J. TI Determination of L-Ephedrine, Pseudoephedrine, and Caffeine in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID DIETARY-SUPPLEMENTS; PHARMACOLOGY; COMBINATION; ALKALOIDS C1 [Cooper, Stephen D.; Fletcher, Brenda L.; Silinski, Melanie A. Rehder; Brown, Sherri S.; Lodge, Jon W.; Fernando, Reshan A.] RTI Int, Res Triangle Pk, NC 27709 USA. [Collins, Bradley J.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Cooper, SD (reprint author), RTI Int, POB 12194, Res Triangle Pk, NC 27709 USA. FU National Institute of Environmental Health Sciences [N01-ES-65554] FX This project has been funded in whole or in part with federal funds from the National Institute of Environmental Health Sciences under Contract No. N01-ES-65554. The authors thank Dr. Brian F. Thomas of RTI International and Dr. Cynthia S. Smith of NIEHS/NTP for reviewing this work. NR 14 TC 5 Z9 5 U1 0 U2 5 PU PRESTON PUBL INC PI NILES PA 6600 W TOUHY AVE, NILES, IL 60714-4588 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD JUL-AUG PY 2011 VL 35 IS 6 BP 341 EP 348 PG 8 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 787HV UT WOS:000292368100003 PM 21740690 ER PT J AU Boyce, AM Gafni, RI AF Boyce, Alison M. Gafni, Rachel I. TI Approach to the Child with Fractures SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID X-RAY ABSORPTIOMETRY; PEDIATRIC OFFICIAL POSITIONS; BONE-MINERAL DENSITY; BISPHOSPHONATE-INDUCED OSTEOPETROSIS; INTRAVENOUS PAMIDRONATE THERAPY; OSTEOGENESIS-IMPERFECTA; CEREBRAL-PALSY; PHYSICAL-ACTIVITY; ORAL ALENDRONATE; CLINICAL-TRIAL AB Evaluation of the child with fractures is challenging, as no clear guidelines exist to distinguish traumatic from pathological fractures. Although most fractures in childhood are benign, recurrent fractures may be associated with a wide variety of primary skeletal diseases as well as secondary causes, necessitating a careful history and physical exam to guide the evaluation. There is no "goldstandard" for the evaluation and treatment of children with fractures and low bone mineral density (BMD); therefore, the diagnosis of osteoporosis in a pediatric patient should be made using a combination of clinical and radiographic features. Interpretation of bone densitometry in growing patients presents a unique set of challenges because areal BMD measured by dual-energy x-ray absorptiometry depends on multiple dynamic variables. Interpretation of pediatric dual-energy x-ray absorptiometry should be based on Z-scores (SD scores compared to age, sex, and ethnicity-matched controls), using normative databases specific to the brand of densitometer and the patient population. Given the skeleton's ability to recover from low BMD through modeling and remodeling, optimizing management of underlying conditions leading to bone fragility is the initial step. Conservative measures including calcium and vitamin D supplementation and weight-bearing physical activity are important interventions that should not be overlooked. The use of bisphosphonates in children and adolescents is controversial due to lack of long-term efficacy and safety data and should be limited to clinical trials and compassionate therapy in children with significantly compromised quality of life. Close monitoring is required, and further study is necessary to assess their long-term safety and efficacy in children. (J Clin Endocrinol Metab 96: 1943-1952, 2011) C1 [Gafni, Rachel I.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Boyce, Alison M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Gafni, RI (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 30,Room 228,30 Convent Dr,MSC 4320, Bethesda, MD 20892 USA. EM gafnir@mail.nih.gov NR 76 TC 17 Z9 17 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2011 VL 96 IS 7 BP 1943 EP 1952 DI 10.1210/jc.2010-2546 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 788OO UT WOS:000292454500026 PM 21734001 ER PT J AU Lindsay, JR Oldfield, EH Stratakis, CA Nieman, LK AF Lindsay, John R. Oldfield, Edward H. Stratakis, Constantine A. Nieman, Lynnette K. TI The Postoperative Basal Cortisol and CRH Tests for Prediction of Long-Term Remission from Cushing's Disease after Transsphenoidal Surgery SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; DEXAMETHASONE-SUPPRESSION TEST; PITUITARY SURGERY; DIFFERENTIAL-DIAGNOSIS; STIMULATION TEST; RISK-FACTORS; CURE; RECURRENCE; RADIOIMMUNOASSAY; MANAGEMENT AB Context: Selective adenomectomy via transsphenoidal surgery induces remission of Cushing's disease (CD) in most patients. Although an undetectable postoperative serum cortisol (< 2 mu g/dl) has been advocated as an index of remission, there is no consensus on predictors of recurrence. Objective: We hypothesized that patients with subnormal cortisol (2-4.9 mu g/dl) might achieve long-term remission and that postoperative responses to CRH might predict recurrence. Design, Setting, and Participants: We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery. Intervention and Main Outcome Measures: Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10. Results: Follow-up duration was median 11 yr (range 1-22.8 yr). Fewer patients achieved a cortisol nadir below 2 mu g/dl (87%) than below 5 mu g/dl (98%), yet recurrence rates were similar (< 2 mu g/dl, 9.5%; < 5 mu g/dl, 10.4%; 2-4.9 mu g/dl, 20%; not significant). CRH-stimulated cortisol (P < 0.002) and ACTH(P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred. Conclusions: A postoperative cortisol below 2 mu g/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 mu g/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up. (J Clin Endocrinol Metab 96: 2057-2064, 2011) C1 [Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Adult & Reprod Endocrinol, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Training Program, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lindsay, John R.] Western Hlth & Social Care Trust, Altnagelvin Area Hosp, Derry BT4, Londonderry, North Ireland. RP Nieman, LK (reprint author), Bldg 10 CRC,Room 1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurologic Disorders and Stroke, National Institutes of Health FX The intramural programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurologic Disorders and Stroke, National Institutes of Health, supported this work. NR 34 TC 40 Z9 43 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2011 VL 96 IS 7 BP 2057 EP 2064 DI 10.1210/jc.2011-0456 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 788OO UT WOS:000292454500042 PM 21508126 ER PT J AU Baron, S Finbloom, J Horowitz, J Bekisz, J Morrow, A Zhao, TM Fey, S Schmeisser, H Balinsky, C Miyake, K Clark, C Zoon, K AF Baron, Samuel Finbloom, Joel Horowitz, Julie Bekisz, Joseph Morrow, Angel Zhao, Tongmao Fey, Samuel Schmeisser, Hana Balinsky, Corey Miyake, Kotaro Clark, Christopher Zoon, Kathryn TI Near Eradication of Clinically Relevant Concentrations of Human Tumor Cells by Interferon-Activated Monocytes In Vitro SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID TUMORICIDAL ACTIVITY; BREAST-CARCINOMA; BLOOD MONOCYTES; DENDRITIC CELLS; CANCER-PATIENTS; THERAPY; INFILTRATION; ALPHA; RECRUITMENT; MECHANISMS AB We have previously reported that low concentrations of interferon (IFN)-activated monocytes exert near-eradicative cytocidal activity against low concentrations of several human tumor cells in vitro. In the present study, we examined 7 human tumor cell lines and 3 diploid lines in the presence or absence of 10 ng/mL IFN alpha 2a and monocytes. The results confirmed strong cytocidal activity against 4 of 7 tumor lines but none against 3 diploid lines. To model larger in vivo tumors, we increased the target cell concentration and determined the concentration of IFN alpha 2a and monocytes, required for cell death. We found that increasing the tumor cell concentration from 10- to 100-fold (10(5) cells/well) required an increase in the concentration of IFNs by over 100-fold and monocytes by 10-fold. High concentrations of monocytes could sometimes kill tumor or diploid cells in the absence of IFN. We may conclude that killing of high concentrations of tumor or diploid cells required high concentrations of monocytes that could sometimes kill in the absence of IFN. Thus, high concentrations of tumor cells required high concentrations of IFN and monocytes to cause near eradication of tumor cells. These findings may have clinical implications. C1 [Baron, Samuel; Finbloom, Joel; Horowitz, Julie; Bekisz, Joseph; Morrow, Angel; Zhao, Tongmao; Fey, Samuel; Schmeisser, Hana; Balinsky, Corey; Miyake, Kotaro; Clark, Christopher; Zoon, Kathryn] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Baron, Samuel] Univ Texas Med Branch, Galveston, TX USA. RP Zoon, K (reprint author), NIAID, Cytokine Biol Sect, NIH, Bldg 33,Room 33-2N09G-2,33 North Dr, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 34 TC 7 Z9 7 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD JUL PY 2011 VL 31 IS 7 BP 569 EP 573 DI 10.1089/jir.2010.0153 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 788LW UT WOS:000292447400007 PM 21323569 ER PT J AU Ribot, EJ Martinez-Santiesteban, FM Simedrea, C Steeg, PS Chambers, AF Rutt, BK Foster, PJ AF Ribot, Emeline J. Martinez-Santiesteban, Francisco M. Simedrea, Carmen Steeg, Patricia S. Chambers, Ann F. Rutt, Brian K. Foster, Paula J. TI In Vivo Single Scan Detection of Both Iron-Labeled Cells and Breast Cancer Metastases in the Mouse Brain Using Balanced Steady-State Free Precession Imaging at 1.5 T SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE MRI; b-SSFP; iron; cancer; metastasis; brain ID CENTRAL-NERVOUS-SYSTEM; CELLULAR MRI; OXIDE PARTICLES; SSFP; RESOLUTION; INJURY; MODEL AB Purpose: To simultaneously detect iron-labeled cancer cells and brain tumors in vivo in one scan, the balanced steady-state free precession (b-SSFP) imaging sequence was optimized at 1.5 T on mice developing brain metastases subsequent to the injection of micron-sized iron oxide particle-labeled human breast cancer cells. Materials and Methods: b-SSFP sequence parameters (repetition time, flip angle, and receiver bandwidth) were varied and the signal-to-noise ratio, contrast between the brain and tumors, and the number of detected iron-labeled cells were evaluated. Results: Optimal b-SSFP images were acquired with a 26 msec repetition time, 35 degrees flip angle, and bandwidth of +/- 21 kHz. b-SSFP images were compared with T(2)-weighted 2D fast spin echo (FSE) and 3D spoiled gradient recalled echo (SPGR) images. The mean tumor-brain contrast-to-noise ratio and the ability to detect iron-labeled cells were the highest in the b-SSFP images. Conclusion: A single b-SSFP scan can be used to visualize both iron-labeled cells and brain metastases. C1 [Ribot, Emeline J.; Martinez-Santiesteban, Francisco M.; Foster, Paula J.] Univ Western Ontario, Imaging Res Labs, Robarts Res Inst, London, ON N6A 5K8, Canada. [Simedrea, Carmen; Chambers, Ann F.] London Reg Canc Program, London, ON, Canada. [Steeg, Patricia S.] NCI, Womens Cancers Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Chambers, Ann F.; Foster, Paula J.] Univ Western Ontario, Dept Med Biophys, London, ON N6A 5K8, Canada. [Rutt, Brian K.] Stanford Univ, Dept Radiol, Richard M Lucas Ctr Imaging, Stanford, CA 94305 USA. RP Foster, PJ (reprint author), Univ Western Ontario, Imaging Res Labs, Robarts Res Inst, 100 Perth Dr,Rm 1200B, London, ON N6A 5K8, Canada. EM pfos-ter@imaging.robarts.ca RI Foster, Paula/M-2201-2013; Chambers, Ann/L-6285-2015 OI Foster, Paula/0000-0002-4868-3395; Chambers, Ann/0000-0002-9509-5123 FU US Department of Defense [W81XWH-06-2-0033]; London Regional Cancer Program; Canada Research Chair in Oncology; National Cancer Institute FX Contract grant sponsor: US Department of Defense Breast Cancer Research Program; Contract grant number: W81XWH-06-2-0033 (to P.S.S., A.F.C., P.J.F.); Contract grant sponsors: Translational Breast Cancer Fellowship from the London Regional Cancer Program (to E.J.R.); Canada Research Chairs Program (Canada Research Chair in Oncology to A.F.C.); Intramural Program of the National Cancer Institute (to P.S.S.). NR 22 TC 10 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUL PY 2011 VL 34 IS 1 BP 231 EP 238 DI 10.1002/jmri.22593 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 788CA UT WOS:000292421800029 PM 21698713 ER PT J AU Patterson, GH AF Patterson, G. H. TI Highlights of the optical highlighter fluorescent proteins SO JOURNAL OF MICROSCOPY LA English DT Review DE Fluorescence microscopy; photoactivation; photoconversion; photoswitching ID CORRELATION SPECTROSCOPY; GENERATION; NANOSCOPY; DYNAMICS; BRIGHT; PHOTOCONVERSION; CONVERSION; MUTANTS; CELLS AB The development of super-resolution microscopy techniques using molecular localization, such as photoactivated localization microscopy, fluorescence photoactivated localization microscopy, stochastic optical reconstruction microscopy, photoactivated localization microscopy with independent running acquisition and many others, has heightened interest in molecules that will be grouped here into a category referred to as 'optical highlighter' fluorescent proteins. This review will survey many of the advances in development of fluorescent proteins for optically highlighting sub-populations of fluorescently labelled molecules. C1 Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bethesda, MD 20892 USA. RP Patterson, GH (reprint author), Natl Inst Biomed Imaging & Bioengn, Biophoton Sect, NIH, Bldg 13,Room 3E33,13 S Drive, Bethesda, MD 20892 USA. EM pattersg@mail.nih.gov FU National Institutes of Health; National Institute of Biomedical Imaging and Bioengineering FX I thank Yan Fu for critical reading of this manuscript. This work was supported by the intramural Research Program of the National Institutes of Health, including the National Institute of Biomedical Imaging and Bioengineering. NR 33 TC 22 Z9 22 U1 0 U2 19 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 JUL PY 2011 VL 243 IS 1 BP 1 EP 7 DI 10.1111/j.1365-2818.2011.03505.x PG 7 WC Microscopy SC Microscopy GA 788XT UT WOS:000292478400001 PM 21623791 ER PT J AU Coutellier, L Logemann, A Rusnak, M Usdin, TB AF Coutellier, L. Logemann, A. Rusnak, M. Usdin, T. B. TI Maternal Absence of the Parathyroid Hormone 2 Receptor Affects Postnatal Pup Development SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE lactation; TIP39/PTH2-R system; prolactin; pup development ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; DOPAMINERGIC NEURONAL-ACTIVITY; THYROTROPIN-RELEASING-HORMONE; TUBEROINFUNDIBULAR PEPTIDE; 39 RESIDUES; FEMALE RATS; PROLACTIN SECRETION; LACTATION; BEHAVIOR; PREGNANCY AB During the lactation period, mothers have a variety of adaptive changes in brain physiology and behaviour that allow them to properly raise their pups. The exact circuitries and mechanisms responsible for these changes are not fully understood. Recent evidence suggests that the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) and its receptor, the parathyroid hormone 2 receptor (PTH2-R), contribute to these mechanisms. To further investigate this idea, we evaluated the growth rate of pups from dams with a genetically inactivated PTH2-R (PTH2-R-KO), as well as maternal behavioural and neuroendocrine parameters. We observed that PTH2R-KO-reared pups had a slowed growth rate. This was associated with a reduced volume of milk yielded by PTH2-R-KO dams after 30-min suckling compared to wild-type (WT) dams when pups were returned after 5 h of separation. Our data suggest a reduced sensitivity of PTH2-R-KO dams to pup stimulation. We also observed a significant reduction in suckling-induced c-Fos expression in the paraventricular hypothalamic nucleus and signs of lower prolactin levels in the PTH2-R-KO dams. Our data suggest that the reduced growth rate of PTH2-R-KO-reared pups was likely the result of alterations in the milk-production pathway rather than modifications in behaviour. Although PTH2-R-KO dams showed increased anxiety in the elevated zero-maze test, no differences from WT dams in maternal behaviour were observed. Taken together, our findings suggest the involvement of the TIP39/PTH2-R system in the pathways involved in the successful development of the pups. C1 [Coutellier, L.; Logemann, A.; Rusnak, M.; Usdin, T. B.] NIMH, Sect Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), 35 Convent Dr,Room 1B-215, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU NIH, National Institute of Mental Health FX This research was supported by the Intramural Program of the NIH, National Institute of Mental Health. The authors declare that there are no conflicts of interest. NR 36 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD JUL PY 2011 VL 23 IS 7 BP 612 EP 619 DI 10.1111/j.1365-2826.2011.02149.x PG 8 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 788SU UT WOS:000292465500008 PM 21535248 ER PT J AU Perdivara, I Peddada, SD Miller, FW Tomer, KB Deterding, LJ AF Perdivara, Irina Peddada, Shyamal D. Miller, Frederick W. Tomer, Kenneth B. Deterding, Leesa J. TI Mass Spectrometric Determination of IgG Subclass-Specific Glycosylation Profiles in Siblings Discordant for Myositis Syndromes SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE myositis; plasma; twin-sibling clinical study; antibody glycosylation; glycopeptide; mass spectrometry ID IDIOPATHIC INFLAMMATORY MYOPATHIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ORDER-RESTRICTED INFERENCE; RHEUMATOID-ARTHRITIS; DIAGNOSTIC-CRITERIA; ANTIINFLAMMATORY ACTIVITY; BINDING LECTIN; N-GLYCANS; DISEASE; AUTOANTIBODIES AB Many autoimmune conditions are believed to result from chronic inflammation as a consequence of the interaction of genetic and environmental factors in susceptible individuals. One common feature in some autoimmune diseases is the decrease in terminal galactosylation of the constant region N-glycan of the total plasma immunoglobulin. To determine whether a similar pattern is characteristic for the autoimmune disorder myositis, we analyzed the antibody subclass specific glycosylation in patients with myositis, their asymptomatic siblings, and healthy unrelated age- and sex-matched controls. The antibody subclass specific glycosylation was determined from the LC-MS analyses of the IgG glycopeptides generated by trypsin digestion of the antibody heavy chain. The glycosylation profiles of the IgG subclasses were determined relative to the total abundance of all glycoforms. We found elevated amounts of glycoforms lacking terminal galactose in myositis patients. Pairwise statistical analyses reveals that galactosylation is statistically different between the myositis patients and control groups. Furthermore, the trend analysis for glycosylation indicates a pattern of decreasing galactosylation in the order controls >= siblings >= myositis patients, suggesting the existence of a genetic, immune-related predisposition in the group of asymptomatic siblings that can be detected before the onset of clinical symptoms at the level of plasma proteins. C1 [Perdivara, Irina; Tomer, Kenneth B.; Deterding, Leesa J.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Peddada, Shyamal D.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Miller, Frederick W.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Deterding, LJ (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM deterdi2@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012; Tomer, Kenneth/E-8018-2013; OI Miller, Frederick/0000-0003-2831-9593 FU NIH, National Institutes of Environmental Health Sciences [ES050171, ES101074-07, ES045005-14] FX This research was supported by the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences, projects ES050171, ES101074-07, ES045005-14. We acknowledge the technical assistance of Dr. Terrance O'Hanlon (NIEHS/NIH) in the preparation of the patient samples, Dr. Jason Williams (NIEHS/NIH) and Dr. Alina Zamfir (University of Aurel Vlaicu Arad) for critical review of the manuscript, and the NIEHS Protein Microcharacterization Core Facility for assistance with in-gel digestions. NR 59 TC 16 Z9 16 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUL PY 2011 VL 10 IS 7 BP 2969 EP 2978 DI 10.1021/pr200397h PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 788AI UT WOS:000292417400010 PM 21609021 ER PT J AU Derbala, MF Amer, AM Almohanadi, M John, A Amin, A John, A Sharma, M Alkaabi, SR Al Dweik, NZ Pasic, F Yaqoob, R Butt, MT Shebl, FM AF Derbala, M. F. Amer, A. M. Almohanadi, M. John, A. Amin, A. John, A. Sharma, M. Alkaabi, S. R. Al Dweik, N. Z. Pasic, F. Yaqoob, R. Butt, M. T. Shebl, F. M. TI Hepatitis C virus genotype 4 with normal transaminases: histological changes, schistosomiasis and response to treatment SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE HCV; persistently normal alanine aminotransferase; response to treatment ID NORMAL ALANINE AMINOTRANSFERASE; PEGINTERFERON ALPHA-2A; PLUS RIBAVIRIN; RISK-FACTORS; INFECTION; EGYPT; DISEASE; LIVER; CARRIERS; MANSONI AB Among individuals with chronic hepatitis C virus (HCV) infection, approximately 30% of patients show persistently normal alanine aminotransferase (PNALT). Individuals with PNALT have been historically excluded from antiviral treatment. However, some studies have reported sudden worsening of disease in patients with PNALT, suggesting the need to treat such individuals. To evaluate this further, we compared fibrosis severity and response to treatment in patients with PNALT to patients with abnormal ALT. In addition, we investigated whether liver histology and schistosomiasis affect response to treatment differently in those with PNALT and abnormal ALT. A retrospective cohort study of 176 HCV-Genotype 4 (HCV-G4) patients treated with pegylated interferon (PEG-IFN) and ribavirin. Of 176 cases studied, 53 (30.1%) had normal ALT. Prevalence of pretreatment severe fibrosis, sustained virological response (SVR) and relapse were not significantly different in patients with PNALT (26%, 66% and 5.7% respectively) compared to those with abnormal ALT (32.5%, 60.7%, and 6.6% respectively). Multivariable logistic regression revealed that pretreatment ALT, pretreatment viral load, inflammation and schistosomiasis were not significantly associated with SVR [OR (95% CI), 0.75 (0.34-1.65); 0.92 (0.61-1.37); 1.64 (0.64-4.18); 0.90 (0.44-1.84) respectively]. Severe fibrosis was the only significant predictor of SVR [OR (95% CI), 0.38 (0.14-0.99)]. PNALT does not reflect the degree of fibrotic changes or predict SVR. Furthermore, schistosomiasis is a predictor of neither fibrosis nor poor response in patients with PNALT. Severe fibrosis is a strong and independent predictor of response to treatment. Therefore, it is important to treat individuals with PNALT levels regardless of schistosomiasis. C1 [Derbala, M. F.; Almohanadi, M.; John, A.; Amin, A.; Sharma, M.; Alkaabi, S. R.; Al Dweik, N. Z.; Pasic, F.; Yaqoob, R.; Butt, M. T.] Hamad Hosp, Dept Gastroenterol & Hepatol, Doha, Qatar. [Amer, A. M.] Hamad Hosp, Hematol Sect, Dept Lab Med & Pathol, Doha, Qatar. [John, A.] Hamad Hosp, Med Res Ctr, Doha, Qatar. [Shebl, F. M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Shebl, F. M.] Natl Liver Inst, Publ Hlth Branch, Menoufia, Egypt. RP Derbala, MF (reprint author), Hamad Med Corp, Dept Gastroenterol & Hepatol, POB 3050, Doha, Qatar. EM moutazderbala@hotmail.com FU Intramural NIH HHS [Z99 CA999999] NR 25 TC 3 Z9 3 U1 0 U2 0 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 JUL PY 2011 VL 18 IS 7 BP E258 EP E262 DI 10.1111/j.1365-2893.2010.01403.x PG 5 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 785XE UT WOS:000292265400014 PM 21108700 ER PT J AU An, L Warach, S Shen, J AF An, Li Warach, Steven Shen, Jun TI Spectral Localization by Imaging Using Multielement Receiver Coils SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRS; CSI; SLIM; stroke; tumor ID MAGNETIC-RESONANCE; SPECTROSCOPY; BRAIN; SENSE; NMR; MRI AB A new spectral localization technique for in vivo magnetic resonance spectroscopy is introduced. Structural information extracted from anatomical imaging is used for defining compartments which provide the basis for spectral localization. The inherent spatial heterogeneity of multiple receiver coil elements is used along with optional phase encoding to resolve signals from different compartments. This technique allows a few compartmental spectra to be reconstructed from multichannel data acquired with no or very few phase encoding steps, resulting in short scan time and high efficiency. Alternatively, this technique also allows a significant number of compartmental spectra to be reconstructed if sufficient phase encoding steps are used. A procedure is developed to semiautomatically generate a significant number of compartments of comparable sizes, which allows one to obtain spectra from small regions of interest with curvilinear shapes. This may be useful for obtaining spectra from relatively small stroke lesions or tumors. Phantom experiments and in vivo magnetic resonance spectroscopy of stroke patients have been performed to demonstrate this technique. Magn Reson Med 66:1-10,2011. (C) 2011 Wiley-Liss, Inc. C1 [An, Li; Warach, Steven] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Shen, Jun] NIMH, NIH, Bethesda, MD 20892 USA. RP An, L (reprint author), Bldg 10,Room B1D733,10 Ctr Dr,MSC 1063, Bethesda, MD 20892 USA. EM lian1025@gmail.com FU NIH; NINDS; NIMH FX Grant sponsors: NIH, NINDS, NIMH (intramural programs). NR 19 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2011 VL 66 IS 1 BP 1 EP 10 DI 10.1002/mrm.22783 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 788DH UT WOS:000292425100001 PM 21287595 ER PT J AU Blaimer, M Ponce, IP Breuer, FA Jakob, PM Griswold, MA Kellman, P AF Blaimer, Martin Ponce, Irene P. Breuer, Felix A. Jakob, Peter M. Griswold, Mark A. Kellman, Peter TI Temporal Filtering Effects in Dynamic Parallel MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE dynamic MRI; parallel MRI; GRAPPA; TSENSE; k-t SENSE; temporal filtering ID K-T SENSE; GRAPPA; RECONSTRUCTION AB Autocalibrated parallel MRI methods such as TSENSE or k-t SENSE have been presented for dynamic imaging studies as they are able to provide images with high temporal resolution. One key element of these techniques is the temporal averaging of the undersampled raw data to obtain an unaliased image. This image represents the temporal average (also known as direct current, DC) and is used to derive the reconstruction parameters. In this work, we show that aliasing artifacts can be introduced in the DC signal obtained from the undersampled raw data. These artifacts lead to undesired temporal filtering effects when the DC signal is used for coil sensitivity calibration or when the DC signal is subtracted from the raw data. It is demonstrated that the temporal filtering effects can be reduced significantly by filtering the DC signal. Magn Reson Med 66:192-198, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Blaimer, Martin; Breuer, Felix A.; Jakob, Peter M.] Res Ctr Magnet Resonance Bavaria MRB, Dept Diagnost Imaging, D-97074 Wurzburg, Germany. [Ponce, Irene P.; Jakob, Peter M.] Univ Wurzburg, Dept Expt Phys 5, Wurzburg, Germany. [Griswold, Mark A.] Univ Hosp Cleveland, Dept Radiol, Cleveland, OH 44106 USA. [Griswold, Mark A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Blaimer, M (reprint author), Res Ctr Magnet Resonance Bavaria MRB, Dept Diagnost Imaging, D-97074 Wurzburg, Germany. EM blaimer@mr-bavaria.de OI Jakob, Peter/0000-0002-3481-5545 NR 18 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2011 VL 66 IS 1 BP 192 EP 198 DI 10.1002/mrm.22795 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 788DH UT WOS:000292425100022 PM 21695723 ER PT J AU Kwon, D Little, MP Miller, DL AF Kwon, Deukwoo Little, Mark P. Miller, Donald L. TI Reference air kerma and kerma-area product as estimators of peak skin dose for fluoroscopically guided interventions SO MEDICAL PHYSICS LA English DT Article DE peak skin dose; reference air kerma; kerma-area product ID RADIOLOGY PROCEDURES; RAD-IR; RADIATION; GUIDELINES; CARDIOLOGY; TIME AB Purpose: To determine more accurate regression formulas for estimating peak skin dose (PSD) from reference air kerma (RAK) or kerma-area product (KAP). Methods: After grouping of the data from 21 procedures into 13 clinically similar groups, assessments were made of optimal clustering using the Bayesian information criterion to obtain the optimal linear regressions of (log-transformed) PSD vs RAK, PSD vs KAP, and PSD vs RAK and KAP. Results: Three clusters of clinical groups were optimal in regression of PSD vs RAK, seven clusters of clinical groups were optimal in regression of PSD vs KAP, and six clusters of clinical groups were optimal in regression of PSD vs RAK and KAP. Prediction of PSD using both RAK and KAP is significantly better than prediction of PSD with either RAK or KAP alone. The regression of PSD vs RAK provided better predictions of PSD than the regression of PSD vs KAP. The partial-pooling (clustered) method yields smaller mean squared errors compared with the complete-pooling method. Conclusion: PSD distributions for interventional radiology procedures are log-normal. Estimates of PSD derived from RAK and KAP jointly are most accurate, followed closely by estimates derived from RAK alone. Estimates of PSD derived from KAP alone are the least accurate. Using a stochastic search approach, it is possible to cluster together certain dissimilar types of procedures to minimize the total error sum of squares. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3590358] C1 [Kwon, Deukwoo; Little, Mark P.; Miller, Donald L.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. EM mark.little@nih.gov OI Little, Mark/0000-0003-0980-7567 FU Navy Bureau of Medicine and Surgery, Washington, D.C. [NNMC.2008.0044]; National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The Chief, Navy Bureau of Medicine and Surgery, Washington, D.C., Clinical Investigation Program sponsored this study, Grant No. NNMC.2008.0044. This research was partially supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 28 TC 11 Z9 11 U1 0 U2 2 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2011 VL 38 IS 7 BP 4196 EP 4204 DI 10.1118/1.3590358 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 789NB UT WOS:000292521100036 PM 21859021 ER PT J AU Liu, JM Kabadi, S Van Uitert, R Petrick, N Deriche, R Summers, RM AF Liu, Jiamin Kabadi, Suraj Van Uitert, Robert Petrick, Nicholas Deriche, Rachid Summers, Ronald M. TI Improved computer-aided detection of small polyps in CT colonography using interpolation for curvature estimation SO MEDICAL PHYSICS LA English DT Article DE curvature estimation; polyp detection; interpolation; Deriche filter ID COLONIC POLYPS; FALSE POSITIVES; OBSERVER; CAD; POPULATION; REDUCTION; IMAGES; PERFORMANCE; EVOLUTION; DIAGNOSIS AB Purpose: Surface curvatures are important geometric features for the computer-aided analysis and detection of polyps in CT colonography (CTC). However, the general kernel approach for curvature computation can yield erroneous results for small polyps and for polyps that lie on haustral folds. Those erroneous curvatures will reduce the performance of polyp detection. This paper presents an analysis of interpolation's effect on curvature estimation for thin structures and its application on computer-aided detection of small polyps in CTC. Methods: The authors demonstrated that a simple technique, image interpolation, can improve the accuracy of curvature estimation for thin structures and thus significantly improve the sensitivity of small polyp detection in CTC. Results: Our experiments showed that the merits of interpolating included more accurate curvature values for simulated data, and isolation of polyps near folds for clinical data. After testing on a large clinical data set, it was observed that sensitivities with linear, quadratic B-spline and cubic B-spline interpolations significantly improved the sensitivity for small polyp detection. Conclusions: The image interpolation can improve the accuracy of curvature estimation for thin structures and thus improve the computer-aided detection of small polyps in CTC. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3596529] C1 [Liu, Jiamin; Kabadi, Suraj; Van Uitert, Robert; Summers, Ronald M.] NIH, Imaging Biomarkers & Computer Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Deriche, Rachid] French Natl Inst Res Comp Sci & Control, Sophia Antipolis, France. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Computer Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM rms@nih.gov FU NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. We thank Dr. Perry Pickhardt, Dr. J. Richard Choi, and Dr. William Schindler for providing CT colonography data. NR 44 TC 5 Z9 5 U1 0 U2 5 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2011 VL 38 IS 7 BP 4276 EP 4284 DI 10.1118/1.3596529 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 789NB UT WOS:000292521100044 PM 21859029 ER PT J AU Ying, ZG Yong, C Udupa, JK Miller, RW AF Ying Zhuge Yong Cao Udupa, Jayaram K. Miller, Robert W. TI Parallel fuzzy connected image segmentation on GPU SO MEDICAL PHYSICS LA English DT Article DE image segmentation; fuzzy connectedness; fuzzy affinity; GPU ID OBJECT DEFINITION; ALGORITHMS; QUANTIFICATION; PRINCIPLES; SYSTEM AB Purpose: Image segmentation techniques using fuzzy connectedness (FC) principles have shown their effectiveness in segmenting a variety of objects in several large applications. However, one challenge in these algorithms has been their excessive computational requirements when processing large image datasets. Nowadays, commodity graphics hardware provides a highly parallel computing environment. In this paper, the authors present a parallel fuzzy connected image segmentation algorithm implementation on NVIDIA's compute unified device Architecture (CUDA) platform for segmenting medical image data sets. Methods: In the FC algorithm, there are two major computational tasks: (i) computing the fuzzy affinity relations and (ii) computing the fuzzy connectedness relations. These two tasks are implemented as cuda kernels and executed on GPU. A dramatic improvement in speed for both tasks is achieved as a result. Results: Our experiments based on three data sets of small, medium, and large data size demonstrate the efficiency of the parallel algorithm, which achieves a speed-up factor of 24.4x, 18.1x, and 10.3x, correspondingly, for the three data sets on the NVIDIA Tesla C1060 over the implementation of the algorithm on CPU, and takes 0.25, 0.72, and 15.04 s, correspondingly, for the three data sets. Conclusions: The authors developed a parallel algorithm of the widely used fuzzy connected image segmentation method on the NVIDIA GPUs, which are far more cost- and speed-effective than both cluster of workstations and multiprocessing systems. A near-interactive speed of segmentation has been achieved, even for the large data set. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3599725] C1 [Ying Zhuge; Miller, Robert W.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yong Cao] Virginia Polytech Inst & State Univ, Dept Comp Sci, Blacksburg, VA 24060 USA. [Udupa, Jayaram K.] Univ Penn, Dept Radiol, Med Image Proc Grp, Philadelphia, PA 19104 USA. RP Ying, ZG (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhugey@mail.nih.gov FU National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the National Cancer Institute, NIH. NR 35 TC 0 Z9 1 U1 2 U2 5 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2011 VL 38 IS 7 BP 4365 EP 4371 DI 10.1118/1.3599725 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 789NB UT WOS:000292521100052 ER PT J AU Zhang, CY Elkahloun, AG Liao, HL Delaney, S Saber, B Morrow, B Prendergast, GC Hollander, MC Gills, JJ Dennis, PA AF Zhang, Chunyu Elkahloun, Abdel G. Liao, Hongling Delaney, Shannon Saber, Barbara Morrow, Betsy Prendergast, George C. Hollander, M. Christine Gills, Joell J. Dennis, Phillip A. TI Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID LUNG-CANCER CELLS; TUMOR-SUPPRESSOR PROTEIN; PROSTATE-CANCER; GENE-EXPRESSION; RHOB EXPRESSION; BREAST-CANCER; KINASE; PATHWAY; TRANSFORMATION; PROGRESSION AB Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non-small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity. Mol Cancer Ther; 10(7); 1137-48. (C) 2011 AACR. C1 [Zhang, Chunyu; Delaney, Shannon; Saber, Barbara; Morrow, Betsy; Hollander, M. Christine; Gills, Joell J.; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Liao, Hongling] NCI Frederick, Sequencing Facil, SAIC Frederick, Gaithersburg, MD USA. [Prendergast, George C.] Lankenau Inst Med Res, Wynnewood, PA USA. RP Dennis, PA (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 37 Convent Dr,Rm 1118B, Bethesda, MD 20892 USA. EM dennisp@mail.nih.gov FU NIH, NCI, Center for Cancer Research; NCI, NIH, under contract NCI [NO1-CO-12400] FX This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and in part with federal funds from the NCI, NIH, under contract NCI Contract NO1-CO-12400. NR 43 TC 5 Z9 5 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2011 VL 10 IS 7 BP 1137 EP 1148 DI 10.1158/1535-7163.MCT-10-1028 PG 12 WC Oncology SC Oncology GA 789FA UT WOS:000292498500002 PM 21551261 ER PT J AU Legrain, P Aebersold, R Archakov, A Bairoch, A Bala, K Beretta, L Bergeron, J Borchers, CH Corthals, GL Costello, CE Deutsch, EW Domon, B Hancock, W He, FC Hochstrasser, D Marko-Varga, G Salekdeh, GH Sechi, S Snyder, M Srivastava, S Uhlen, M Wu, CH Yamamoto, T Paik, YK Omenn, GS AF Legrain, Pierre Aebersold, Ruedi Archakov, Alexander Bairoch, Amos Bala, Kumar Beretta, Laura Bergeron, John Borchers, Christoph H. Corthals, Garry L. Costello, Catherine E. Deutsch, Eric W. Domon, Bruno Hancock, William He, Fuchu Hochstrasser, Denis Marko-Varga, Gyorgy Salekdeh, Ghasem Hosseini Sechi, Salvatore Snyder, Michael Srivastava, Sudhir Uhlen, Mathias Wu, Cathy H. Yamamoto, Tadashi Paik, Young-Ki Omenn, Gilbert S. TI The Human Proteome Project: Current State and Future Direction SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID DATABASE; ASSAYS AB After the successful completion of the Human Genome Project, the Human Proteome Organization has recently officially launched a global Human Proteome Project (HPP), which is designed to map the entire human protein set. Given the lack of protein-level evidence for about 30% of the estimated 20,300 protein-coding genes, a systematic global effort will be necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP research groups will use the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge bases. The HPP participants will take advantage of the output and cross-analyses from the ongoing Human Proteome Organization initiatives and a chromosome-centric protein mapping strategy, termed C-HPP, with which many national teams are currently engaged. In addition, numerous biologically driven and disease-oriented projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents, and tools for protein studies and analyses, and a stronger basis for personalized medicine. The Human Proteome Organization urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators. Molecular & Cellular Proteomics 10: 10.1074/mcp.M111.009993, 1-5, 2011. C1 [Legrain, Pierre] CEA, Div Life Sci, Fontenay Aux Roses, France. [Aebersold, Ruedi] ETH, Dept Biol, Inst Mol Syst Biol, Zurich, Switzerland. [Aebersold, Ruedi] Univ Zurich, Fac Sci, CH-8006 Zurich, Switzerland. [Archakov, Alexander] Russian Acad Med Sci, Inst Biomed Chem, Moscow, Russia. [Bairoch, Amos] SIB, Geneva, Switzerland. [Bairoch, Amos; Hochstrasser, Denis] Univ Geneva, Geneva, Switzerland. [Bala, Kumar] Bridge4Bio, Biotechnol, San Francisco, CA USA. [Beretta, Laura] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Bergeron, John] McGill Univ, Montreal, PQ, Canada. [Borchers, Christoph H.] Univ Victoria, Prote Ctr, Victoria, BC V8W 2Y2, Canada. [Corthals, Garry L.] Univ Turku, Turku Ctr Biotechnol, Turku, Finland. [Corthals, Garry L.] Abo Akad Univ, Turku, Finland. [Costello, Catherine E.] Boston Univ, Boston, MA 02215 USA. [Deutsch, Eric W.] Inst Syst Biol, Seattle, WA USA. [Domon, Bruno] Luxembourg Univ, Luxembourg, Luxembourg. [Hancock, William] Northeastern Univ, Boston, MA 02115 USA. [He, Fuchu] Beijing Proteome Res Ctr, Beijing, Peoples R China. [Marko-Varga, Gyorgy] Lund Univ, Lund, Sweden. [Salekdeh, Ghasem Hosseini] Royan Inst, Tehran, Iran. [Sechi, Salvatore] NIDDK, NIH, Bethesda, MD USA. [Snyder, Michael] Stanford Univ, Palo Alto, CA 94304 USA. [Srivastava, Sudhir] NCI, NIH, Bethesda, MD 20892 USA. [Uhlen, Mathias] Royal Inst Technol, Stockholm, Sweden. [Wu, Cathy H.] PIR, Newark, DE USA. [Wu, Cathy H.] Univ Delaware, Newark, DE USA. [Yamamoto, Tadashi] Niigata Univ, Niigata, Japan. [Paik, Young-Ki] Yonsei Univ, Seoul 120749, South Korea. [Omenn, Gilbert S.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Legrain, P (reprint author), CEA, Div Life Sci, Fontenay Aux Roses, France. EM pierre.legrain@cea.fr; paikyk@yonsei.ac.kr; gomenn@umich.edu RI Crozier, Laura/A-4821-2010; Archakov, Alexander/B-5194-2012; Salekdeh, Ghasem Hosseini/E-4198-2012; Corthals, Garry/G-9417-2016; Salekdeh, Ghasem Hosseini/R-8716-2016 OI Costello, Catherine/0000-0003-1594-5122; Bairoch, Amos/0000-0003-2826-6444; Omenn, Gilbert S./0000-0002-8976-6074; Corthals, Garry/0000-0001-9423-5596; NR 15 TC 65 Z9 65 U1 2 U2 23 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUL PY 2011 VL 10 IS 7 DI 10.1074/mcp.M111.009993 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 789UJ UT WOS:000292541500012 ER PT J AU Armaleo, D Sun, XM Culberson, C AF Armaleo, Daniele Sun, Xiameng Culberson, Chicita TI Insights from the first putative biosynthetic gene cluster for a lichen depside and depsidone SO MYCOLOGIA LA English DT Article DE Cladonia grayi; depsides; depsidones; lichen fungi; metabolic gene clusters; polyketide synthases; secondary metabolites; symbiosis ID POLYKETIDE SYNTHASE GENES; FUNGAL; PHYLOGENY; METABOLITES; EVOLUTION; ACID; MYCOBIONT; ENZYMES; ACCUMULATION; ASCOMYCOTA AB The genes for polyketide synthases (PKSs), enzymes that assemble the carbon backbones of many secondary metabolites, often cluster with other secondary pathway genes. We describe here the first lichen PKS cluster likely to be implicated in the biosynthesis of a depside and a depsidone, compounds in a class almost exclusively produced by lichen fungi (mycobionts). With degenerate PCR with primers biased toward presumed PKS genes for depsides and depsidones we identified among the many PKS genes in Cladonia grayi four (CgrPKS1346) potentially responsible for grayanic acid (GRA), the orcinol depsidone characteristic of this lichen. To single out a likely GRA PKS we compared mRNA and GRA induction in mycobiont cultures using the four candidate PKS genes plus three controls; only CgrPKS16 expression closely matched GRA induction. CgrPKS16 protein domains were compatible with orcinol depside biosynthesis. Phylogenetically CgrPKS16 fell in a new subclade of fungal PKSs uniquely producing orcinol compounds. In the C. grayi genom e CgrPKS16 clustered with a CytP450 and an O-methyltransferase gene, appropriately matching the three compounds in the GRA pathway. Induction, domain organization, phylogeny and cluster pathway correspondence in indicated that the CgrPKS16 cluster is most likely responsible for GRA biosynthesis. Specifically we propose that (i) a single PKS synthesizes two aromatic rings and links them into a depside, (ii) the depside to depsidone transition requires only a cytochrome P450 and (iii) lichen compounds evolved early in the radiation of filamentous fungi. C1 [Armaleo, Daniele; Culberson, Chicita] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Sun, Xiameng] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Armaleo, D (reprint author), Duke Univ, Dept Biol, Durham, NC 27708 USA. EM darmaleo@duke.edu NR 66 TC 24 Z9 24 U1 1 U2 27 PU ALLEN PRESS INC PI LAWRENCE PA 810 E 10TH ST, LAWRENCE, KS 66044 USA SN 0027-5514 J9 MYCOLOGIA JI Mycologia PD JUL-AUG PY 2011 VL 103 IS 4 BP 741 EP 754 DI 10.3852/10-335 PG 14 WC Mycology SC Mycology GA 787XE UT WOS:000292409200006 PM 21289108 ER PT J AU De Lucca, AJ Boue, S Sien, T Cleveland, TE Walsh, TJ AF De Lucca, Anthony J. Boue, Stephen Sien, Tin Cleveland, Thomas E. Walsh, Thomas J. TI Silver enhances the in vitro antifungal activity of the saponin, CAY-1 SO MYCOSES LA English DT Article DE Aspergillus; Fusarium; fungicidal; saponin; CAY-1; silver ID ANTIMICROBIAL ACTIVITIES; CANDIDA-ALBICANS; RESISTANCE; COMPLEXES; BACTERIA; BURNS; MODEL; EDTA AB The fungicidal properties of purified CAY-1, dissolved silver ion and ethylenediamine tetraacetic acid (EDTA) separately were studied in vitro as were the abilities of silver and EDTA to enhance CAY-1 fungicidal properties. Non-germinated and germinating conidia of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Fusarium verticillioides (Fusarium moniliforme), Fusarium oxysporum and Fusarium solani were incubated separately with CAY-1 (0-24.8 mu g ml(-1)), silver (0-111.1 mu g ml(-1)), and EDTA (0-2400 mu g ml(-1)). Controls consisted of non-germinated or germinated conidia in test medium. To assess combined activity, compounds, based on the sub-lethal doses of each as defined in the initial experiments, were combined and tested in bioassays. Controls for the mixed sets consisted of non-germinated or germinated conidia only or with the sub-lethal CAY-1 test concentrations. The minimum inhibitory concentrations (MICs) for CAY-1 and silver, both separate and combined, were determined. Viability assays showed CAY-1 activity only against the germinating conidia of A. flavus, A. niger and F. solani. Silver was active against the germinating conidia of all fungi and the non-germinated conidia of F. oxysporum and F. solani. Combined silver and CAY-1 produced significant viability loss at concentrations not effective separately. EDTA was not fungicidal separately and did not enhance CAY-1 fungicidal properties. MIC data showed that CAY-1 plus silver had an additive effect. Results indicate that dissolved silver was fungicidal in vitro and enhanced the fungicidal properties of CAY-1 at concentrations ineffective when tested separately. C1 [De Lucca, Anthony J.; Boue, Stephen; Cleveland, Thomas E.] ARS, So Reg Res Ctr, USDA, New Orleans, LA USA. [Sien, Tin; Walsh, Thomas J.] NCI, NIH, Bethesda, MD USA. RP De Lucca, AJ (reprint author), 1100 Robert E Lee Blvd, New Orleans, LA 70124 USA. EM adelucca@srrc.ars.usda.gov NR 26 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUL PY 2011 VL 54 IS 4 BP E1 EP E9 DI 10.1111/j.1439-0507.2009.01811.x PG 9 WC Dermatology; Mycology SC Dermatology; Mycology GA 789FY UT WOS:000292501600001 PM 20002309 ER PT J AU Jovanovic-Talisman, T Zilman, A AF Jovanovic-Talisman, Tijana Zilman, Anton TI NANOBIOTECHNOLOGY Building a basic nanomachine SO NATURE NANOTECHNOLOGY LA English DT News Item ID NUCLEAR-PORE COMPLEX; SINGLE-MOLECULE; SELECTIVE TRANSPORT; TRANSLOCATION C1 [Jovanovic-Talisman, Tijana] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Zilman, Anton] Univ Toronto, Dept Phys, Toronto, ON M5S 1A7, Canada. RP Jovanovic-Talisman, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM talismant@mail.nih.gov; zilmana@physics.utoronto.ca RI Boskovic, Danijel/C-4129-2012; OI Jovanovic-Talisman, Tijana/0000-0003-1928-4763 NR 13 TC 1 Z9 1 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 EI 1748-3395 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD JUL PY 2011 VL 6 IS 7 BP 397 EP 398 PG 3 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 788RV UT WOS:000292463000004 PM 21731070 ER PT J AU Bonnemann, CG AF Bonnemann, Carsten G. TI The collagen VI-related myopathies: muscle meets its matrix SO NATURE REVIEWS NEUROLOGY LA English DT Review ID CONGENITAL MUSCULAR-DYSTROPHY; IN-FRAME DELETION; BETHLEM-MYOPATHY; ULLRICH-DISEASE; MITOCHONDRIAL DYSFUNCTION; CONNECTIVE-TISSUE; TRIPLE-HELIX; COL6A1 GENE; BINDING-PROPERTIES; GLYCINE MUTATIONS AB The collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes-COL6A1, COL6A2, and COL6A3-can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy. C1 NINDS, Neuromuscular Neurogenet Disorders Childhood Sect, Neurogenet Branch, NIH, Bethesda, MD 20824 USA. RP Bonnemann, CG (reprint author), NINDS, Neuromuscular Neurogenet Disorders Childhood Sect, Neurogenet Branch, NIH, POB 5801, Bethesda, MD 20824 USA. EM carsten.bonnemann@nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 121 TC 65 Z9 68 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD JUL PY 2011 VL 7 IS 7 BP 379 EP 390 DI 10.1038/nrneurol.2011.81 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 789FQ UT WOS:000292500400007 PM 21691338 ER PT J AU Gross, RA Knopman, DS Cascino, GD Corboy, JR Elkind, MSV Engel, AG Mink, JW Ransohoff, RM Uitti, RJ Worrall, BB AF Gross, Robert A. Knopman, David S. Cascino, Gregory D. Corboy, John R. Elkind, Mitchell S. V. Engel, Andrew G. Mink, Jonathan W. Ransohoff, Richard M. Uitti, Ryan J. Worrall, Bradford B. TI Untitled SO NEUROLOGY LA English DT Editorial Material C1 [Gross, Robert A.] UCB, Berkeley, CA USA. [Elkind, Mitchell S. V.] Bristol Myers Squibb Co, New York, NY 10154 USA. [Elkind, Mitchell S. V.] Boehringer Ingelheim Inc, Ingelheim, Germany. [Worrall, Bradford B.] NHLBI, AREDS2, Bethesda, MD USA. [Worrall, Bradford B.] NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 2011 VL 77 IS 1 BP 5 EP 11 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 789TB UT WOS:000292538100003 ER PT J AU Kaminski, RM Rogawski, MA AF Kaminski, Rafal M. Rogawski, Michael A. TI 11 beta-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis SO NEUROPHARMACOLOGY LA English DT Article DE Neurosteroid; Allotetrahydrodeoxycorticosterone; Steroid 11 beta-hydroxylase (CYP11B1) inhibitor; Metyrapone; Etomidate; Finasteride ID GENERAL ANESTHETIC ETOMIDATE; ANTICONVULSANT ACTIVITY; A RECEPTOR; ADRENAL STEROIDOGENESIS; GABA(A) RECEPTORS; PLASMA ACTH; RAT-BRAIN; METYRAPONE; ACID; BIOSYNTHESIS AB Steroid 11 beta-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABA(A) receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is a potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but is markedly more potent at 6 h (ED50, 30 mg/kg). Similarly, etomidate is also protective at 30 min and 6 h (ED50 values, 4.5 and 1.7 mg/kg). Finasteride, an inhibitor of neurosteroid synthesis, attenuated the anticonvulsant effects of both CYP11B1 inhibitors at 6 h, but not 30 min following their injection. Plasma THDOC levels measured by liquid chromatography-mass spectrometry were markedly increased 6 h after injection of both CYP11B1 inhibitors and this increase was attenuated by finasteride pretreatment. We conclude that inhibition of CYP11B1 causes delayed seizure protection due to slow build-up of neurosteroids. Early seizure protection is independent of neurosteroids. Published by Elsevier Ltd. C1 [Rogawski, Michael A.] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [Rogawski, Michael A.] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Kaminski, Rafal M.; Rogawski, Michael A.] Natl Inst Neurol Disorders & Stroke, Epilepsy Res Sect, NIH, Bethesda, MD USA. RP Rogawski, MA (reprint author), Univ Calif Davis, Dept Neurol, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA. EM rogawski@ucdavis.edu RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU Intramural NIH HHS [Z01 NS002877-14] NR 37 TC 8 Z9 8 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUL-AUG PY 2011 VL 61 IS 1-2 BP 133 EP 137 DI 10.1016/j.neuropharm.2011.03.019 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 787WU UT WOS:000292408200015 PM 21458468 ER PT J AU Burr, JS Jenkins, TL Harrison, R Meert, K Anand, KJS Berger, JT Zimmerman, J Carcillo, J Dean, JM Newth, CJL Willson, DF Sanders, RC Pollack, MM Harvill, E Nicholson, CE AF Burr, Jeri S. Jenkins, Tammara L. Harrison, Rick Meert, Kathleen Anand, K. J. S. Berger, John T. Zimmerman, Jerry Carcillo, Joseph Dean, J. Michael Newth, Christopher J. L. Willson, Douglas F. Sanders, Ronald C., Jr. Pollack, Murray M. Harvill, Eric Nicholson, Carol E. TI The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study: Collaborative research in pediatric critical care medicine SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE pertussis; respiratory failure; study design; out-comes; multiple organ system failure; advanced life support ID EXTRACORPOREAL MEMBRANE-OXYGENATION; IMMUNIZATION PRACTICES ACIP; BORDETELLA-PERTUSSIS; INTENSIVE-CARE; UNITED-STATES; PULMONARY-HYPERTENSION; NOSOCOMIAL PERTUSSIS; ADVISORY-COMMITTEE; INFANT PERTUSSIS; YOUNG INFANTS AB Objective: To provide an updated overview of critical pertussis to the pediatric critical care community and describe a study of critical pertussis recently undertaken. Setting: The six sites, seven hospitals of the Collaborative Pediatric Critical Care Research Network, and 17 outside sites at academic medical centers with pediatric intensive care units. Results: Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in US children, especially among infants. In pediatric intensive care units, Bordetella pertussis is a community-acquired pathogen associated with critical illness and death. The incidence of medical and developmental sequelae in critical pertussis survivors remains unknown, and the appropriate strategies for treatment and support remain unclear. The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study has begun to evaluate critical pertussis in a prospective cohort. Conclusion: Research is urgently needed to provide an evidence base that might optimize management for critical pertussis, a serious, disabling, and too often fatal illness for U. S. children and those in the developing world. (Pediatr Crit Care Med 2011; 12:387-392) C1 [Burr, Jeri S.] Univ Utah, Salt Lake City, UT 84112 USA. [Jenkins, Tammara L.; Nicholson, Carol E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Harrison, Rick] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Meert, Kathleen] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Anand, K. J. S.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Berger, John T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Willson, Douglas F.] Univ Virginia, Childrens Hosp, Charlottesville, VA USA. [Sanders, Ronald C., Jr.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Pollack, Murray M.] Phoenix Childrens Hosp, Phoenix, AZ USA. [Harvill, Eric] Penn State Univ, University Pk, PA 16802 USA. RP Burr, JS (reprint author), Univ Utah, Salt Lake City, UT 84112 USA. EM jeri.burr@hsc.utah.edu OI Jardine, David/0000-0001-9000-271X; Anand, Kanwaljeet/0000-0001-6498-1483 FU NCRR NIH HHS [UL1 RR025014]; NIAID NIH HHS [R56 AI065507, R56 AI065507-01A2]; NICHD NIH HHS [U01 HD049934, U10 HD050096, UG1 HD049981, UG1 HD050096]; NIGMS NIH HHS [R01 GM083113, R01 GM083113-04] NR 58 TC 10 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD JUL PY 2011 VL 12 IS 4 BP 387 EP 392 DI 10.1097/PCC.0b013e3181fe4058 PG 6 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 788ME UT WOS:000292448200007 PM 21057366 ER PT J AU Ryan, P Atreya, C AF Ryan, Patricia Atreya, Chintamani TI Blood Cell MicroRNAs: What Are They and What Future Do They Hold? SO TRANSFUSION MEDICINE REVIEWS LA English DT Review ID HUMAN PLATELETS; MICROPROCESSOR COMPLEX; PROTEIN-SYNTHESIS; EXPRESSION; STORAGE; ERYTHROCYTES; BIOGENESIS; BIOMARKERS; PATHWAYS; GENOMICS AB The advent of blood component storage revolutionized health care by allowing for a managed supply of transfusion quality blood products. During storage, blood components undergo a series of physiological changes that affect the product quality, which ultimately can interfere with the safety and efficacy of such products after transfusion. Despite continuous improvements in blood component quality and safety, it is still desirable to have in vitro standard markers of measurable characteristics that predict blood component safety and efficacy in vivo following their transfusion. Over the last decade, research on the feasibility of using microRNAs as biomarkers for various clinical manifestations and cellular pathologies has exploded. Here, we review the literature on blood cell microRNAs and discuss the potential of these molecules to act as measurable characteristics (product biomarkers) for stored blood component quality and safety. Published by Elsevier Inc. C1 [Ryan, Patricia; Atreya, Chintamani] US FDA, Sect Cell Biol, Lab Cellular Hematol, Div Hematol,Off Blood Res & Review,Ctr Biol Evalu, Rockville, MD 20857 USA. RP Atreya, C (reprint author), Bldg 29A,Room 2C-11,NIH Campus,8800 Rockville Pik, Bethesda, MD 20892 USA. EM Chintamani.Atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research FX PR is a recipient of-a postdoctoral fellowship at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an intra-agency agreement between the US Department of Energy and the US Food and Drug Administration. The authors thank Drs Ketha and Rao. Center for Biologics Evaluation and Research, Food and Drug Administration, for their review of this manuscript. NR 40 TC 3 Z9 3 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 0887-7963 J9 TRANSFUS MED REV JI Transf. Med. Rev. PD JUL PY 2011 VL 25 IS 3 BP 247 EP 251 DI 10.1016/j.tmrv.2011.01.005 PG 5 WC Hematology SC Hematology GA 789AH UT WOS:000292485200007 PM 21419598 ER PT J AU Kwako, LE Glass, N Campbell, J Melvin, KC Barr, T Gill, JM AF Kwako, Laura E. Glass, Nancy Campbell, Jacquelyn Melvin, Kristal C. Barr, Taura Gill, Jessica M. TI Traumatic Brain Injury in Intimate Partner Violence: A Critical Review of Outcomes and Mechanisms SO TRAUMA VIOLENCE & ABUSE LA English DT Review DE intimate partner violence; traumatic brain injury; neuropsychological functioning; postconcussive syndrome; PTSD ID POSTTRAUMATIC-STRESS-DISORDER; 18 US STATES/TERRITORIES; PHYSICAL HEALTH; BATTERED WOMEN; NEUROTROPHIC FACTOR; FEMALE VICTIMS; RISK-FACTORS; CHILDHOOD MALTREATMENT; INTERPERSONAL VIOLENCE; ADVERSE EXPERIENCES AB The prevalence of intimate partner violence (IPV) is striking, as are its consequences to the lives of women. The IPV often includes physical assault, which can include injuries to the head and attempted strangulation injuries. Both types of injuries can result in traumatic brain injury (TBI). The TBI sustained during IPV often occurs over time, which can increase the risk for health declines and postconcussive syndrome (PCS). Current studies have identified sequelae of cognitive dysfunction, posttraumatic stress disorder, and depression in women experiencing IPV, yet, most fail to determine the role of TBI in the onset and propagation of these disorders. Although imaging studies indicate functional differences in neuronal activation in IPV, they also have not considered the possibility of TBI contributing to these outcomes. This review highlights the significant gaps in current findings related to neuropsychological complications and medical and psychosocial symptoms that likely result in greater morbidity, as well as the societal costs of failing to acknowledge the association of IPV and TBI in women. C1 [Kwako, Laura E.; Barr, Taura] NINR, NIH, Bethesda, MD 20892 USA. [Campbell, Jacquelyn] Johns Hopkins Univ, Sch Nursing, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gill, Jessica M.] George Mason Univ, Sch Nursing, Fairfax, VA 22030 USA. [Gill, Jessica M.] Krasnow Inst Adv Study, Fairfax, VA USA. RP Kwako, LE (reprint author), NIAAA, NIH, Bethesda, MD USA. EM laura.kwako@nih.gov NR 92 TC 23 Z9 23 U1 13 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1524-8380 J9 TRAUMA VIOLENCE ABUS JI Trauma Violence Abus. PD JUL PY 2011 VL 12 IS 3 BP 115 EP 126 DI 10.1177/1524838011404251 PG 12 WC Criminology & Penology; Family Studies; Social Work SC Criminology & Penology; Family Studies; Social Work GA 788QS UT WOS:000292460100001 PM 21511686 ER PT J AU Lahousse, SA Hoenerhoff, M Collins, J Ton, TVT Masinde, T Olson, D Rebolloso, Y Koujitani, T Tomer, KB Hong, HHL Bucher, J Sills, RC AF Lahousse, S. A. Hoenerhoff, M. Collins, J. Ton, T-V. T. Masinde, T. Olson, D. Rebolloso, Y. Koujitani, T. Tomer, K. B. Hong, H-H. L. Bucher, J. Sills, R. C. TI Gene Expression and Mutation Assessment Provide Clues of Genetic and Epigenetic Mechanisms in Liver Tumors of Oxazepam-Exposed Mice SO VETERINARY PATHOLOGY LA English DT Article DE mouse; liver; cancer; beta-catenin; DNA methylation; epigenetics; microarray; oxidative stress ID BETA-CATENIN MUTATIONS; B6C3F1 MICE; HEPATOCELLULAR CARCINOMAS; OXIDATIVE STRESS; HEPATOCARCINOGEN OXAZEPAM; DNA METHYLATION; GC-RICH; MOUSE; CARCINOGENESIS; TUMORIGENESIS AB Liver tumors from a previous National Toxicology Program study were examined using global gene expression and mutation analysis to define the mechanisms of carcinogenesis in mice exposed to oxazepam. Five hepatocellular adenomas and 5 hepatocellular carcinomas from male B6C3F1 mice exposed to 5000 ppm oxazepam and 6 histologically normal liver samples from control animals were examined. One of the major findings in the study was upregulation of the Wnt/beta-catenin signaling pathway. Genes that activate beta-catenin, such as Sox4, were upregulated, whereas genes that inhibit Wnt signaling, such as APC and Crebbp, were downregulated. In addition, liver tumors from oxazepam-exposed mice displayed beta-catenin mutations and increased protein expression of glutamine synthetase, a downstream target in the Wnt signaling pathway. Another important finding in this study was the altered expression of oxidative stress-related genes, specifically increased expression of cytochrome p450 genes, including Cyp1a2 and Cyp2b10, and decreased expression of genes that protect against oxidative stress, such as Sod2 and Cat. Increased oxidative stress was confirmed by measuring isoprostane expression using mass spectrometry. Furthermore, global gene expression identified altered expression of genes that are associated with epigenetic mechanisms of cancer. There was decreased expression of genes that are hypermethylated in human liver cancer, including tumor suppressors APC and Pten. Oxazepam-induced tumors also exhibited decreased expression of genes involved in DNA methylation (Crebbp, Dnmt3b) and histone modification (Sirt1). These data suggest that formation of hepatocellular adenomas and carcinomas in oxazepam-exposed mice involves alteration of the Wnt signaling pathway, oxidative stress, and potential epigenetic alterations. C1 [Lahousse, S. A.; Hoenerhoff, M.; Ton, T-V. T.; Masinde, T.; Olson, D.; Rebolloso, Y.; Koujitani, T.; Hong, H-H. L.; Sills, R. C.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC USA. [Collins, J.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, Res Triangle Pk, NC USA. [Tomer, K. B.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC USA. [Bucher, J.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. RP Sills, RC (reprint author), Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC USA. EM sills@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU National Institute of Environmental Health Sciences/National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences/National Institutes of Health. NR 30 TC 7 Z9 7 U1 0 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD JUL PY 2011 VL 48 IS 4 BP 875 EP 884 DI 10.1177/0300985810390019 PG 10 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 787RV UT WOS:000292395300016 PM 21147764 ER PT J AU Storry, JR Castilho, L Daniels, G Flegel, WA Garratty, G Francis, CL Moulds, JM Moulds, JJ Olsson, ML Poole, J Reid, ME Rouger, P van der Schoot, E Scott, M Smart, E Tani, Y Yu, LC Wendel, S Westhoff, C Yahalom, V Zelinski, T AF Storry, J. R. Castilho, L. Daniels, G. Flegel, W. A. Garratty, G. Francis, C. L. Moulds, J. M. Moulds, J. J. Olsson, M. L. Poole, J. Reid, M. E. Rouger, P. van der Schoot, E. Scott, M. Smart, E. Tani, Y. Yu, L. -C. Wendel, S. Westhoff, C. Yahalom, V. Zelinski, T. TI International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Berlin report SO VOX SANGUINIS LA English DT Article DE blood groups; genetics; terminology ID GROUP SYSTEM; P-PHENOTYPE; SURFACE-ANTIGENS; EXPRESSION; COMMITTEE; CLONING C1 [Storry, J. R.] Univ & Reg Labs, SE-22185 Lund, Sweden. [Castilho, L.] Univ Campinas Hemocentro, Campinas, Brazil. [Daniels, G.; Poole, J.; Scott, M.] NHSBT, Bristol Inst Transfus Sci, Bristol, Avon, England. [Daniels, G.; Poole, J.; Scott, M.] NHSBT, IBGRL, Bristol, Avon, England. [Flegel, W. A.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Garratty, G.] Amer Red Cross Blood Serv, Pomona, CA USA. [Francis, C. L.; Reid, M. E.; Westhoff, C.] New York Blood Ctr, New York, NY 10021 USA. [Moulds, J. M.; Moulds, J. J.] LifeShare Blood Ctr, Shreveport, LA USA. [Olsson, M. L.] Lund Univ, Dept Lab Med, Div Haematol & Transfus Med, Lund, Sweden. [Rouger, P.] Ctr Natl Reference Grp Sanguines, Paris, France. [van der Schoot, E.] Sanquin Res CLB, Amsterdam, Netherlands. [Tani, Y.] Osaka Red Cross Blood Ctr, Osaka, Japan. [Yu, L. -C.] Mackay Mem Hosp, Taipei, Taiwan. [Yu, L. -C.] Natl Taiwan Univ, Taipei 10764, Taiwan. [Wendel, S.] Hosp Sirio Libanes, Blood Bank, Sao Paulo, Brazil. [Yahalom, V.] NBGRL Magen David Adom, Ramat Gan, Israel. [Zelinski, T.] Rh Lab, Winnipeg, MB, Canada. RP Storry, JR (reprint author), Univ & Reg Labs, Klinikgatan 21, SE-22185 Lund, Sweden. EM jill.storry@med.lu.se RI Castilho, Lilian/F-6123-2012 OI Castilho, Lilian/0000-0002-3104-647X NR 23 TC 38 Z9 41 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2011 VL 101 IS 1 BP 77 EP 82 DI 10.1111/j.1423-0410.2010.01462.x PG 6 WC Hematology SC Hematology GA 789VM UT WOS:000292545500011 PM 21401621 ER PT J AU Jumpertz, R Le, DS Turnbaugh, PJ Trinidad, C Bogardus, C Gordon, JI Krakoff, J AF Jumpertz, Reiner Duc Son Le Turnbaugh, Peter J. Trinidad, Cathy Bogardus, Clifton Gordon, Jeffrey I. Krakoff, Jonathan TI Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID DIET-INDUCED OBESITY; RESTING METABOLIC-RATE; WEIGHT-LOSS; BODY-WEIGHT; OVERWEIGHT; ADOLESCENTS; EXPENDITURE; ECOLOGY; INDIANS; WOMEN AB Background: Studies in mice indicate that the gut microbiome influences both sides of the energy-balance equation by contributing to nutrient absorption and regulating host genes that affect adiposity. However, it remains uncertain as to what extent gut microbiota are an important regulator of nutrient absorption in humans. Objective: With the use of a carefully monitored inpatient study cohort, we tested how gut bacterial community structure is affected by altering the nutrient load in lean and obese individuals and whether their microbiota are correlated with the efficiency of dietary energy harvest. Design: We investigated dynamic changes of gut microbiota during diets that varied in caloric content (2400 compared with 3400 kcal/d) by pyrosequencing bacterial 16S ribosomal RNA (rRNA) genes present in the feces of 12 lean and 9 obese individuals and by measuring ingested and stool calories with the use of bomb calorimetry. Results: The alteration of the nutrient load induced rapid changes in the gut microbiota. These changes were directly correlated with stool energy loss in lean individuals such that a 20% increase in Firmicutes and a corresponding decrease in Bacteroidetes were associated with an increased energy harvest of approximate to 150 kcal. A high degree of over-feeding in lean individuals was accompanied by a greater fractional decrease in stool energy loss. Conclusions: These results show that the nutrient load is a key variable that can influence the gut (fecal) bacterial community structure over short time scales. Furthermore, the observed associations between gut microbes and nutrient absorption indicate a possible role of the human gut microbiota in the regulation of the nutrient harvest. This trial was registered at clinicaltrials. gov as NCT00414063. Am J Clin Nutr 2011;94:58-65. C1 [Jumpertz, Reiner] NIDDK, Obes & Diabet Clin Res Sect, NIH, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. [Duc Son Le] Nutr Ctr Ho Chi Minh City, Ho Chi Minh City, Vietnam. [Turnbaugh, Peter J.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Turnbaugh, Peter J.; Gordon, Jeffrey I.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO USA. RP Jumpertz, R (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, Dept Hlth & Human Serv, 4212 N 16th St, Phoenix, AZ 85016 USA. EM jumpertzr@mail.nih.gov OI Turnbaugh, Peter/0000-0002-0888-2875 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [DK78669, GM068763] FX Supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and National Institutes of Health grants DK78669 (to JIG) and GM068763 (to PJT). NR 33 TC 274 Z9 287 U1 22 U2 159 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2011 VL 94 IS 1 BP 58 EP 65 DI 10.3945/ajcn.110.010132 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 779QK UT WOS:000291794800011 PM 21543530 ER PT J AU Hall, KD Chow, CC AF Hall, Kevin D. Chow, Carson C. TI Estimating changes in free-living energy intake and its confidence interval SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID WITHIN-SUBJECT VARIATION; BODY-WEIGHT-CHANGE; FAT-FREE MASS; FOOD-INTAKE; METABOLIC ADAPTATION; EXPENDITURE; OBESITY; INTERRELATIONSHIPS; INDIVIDUALITY; MAINTENANCE AB Background: Free-living energy intake in humans is notoriously difficult to measure but is required to properly assess outpatient weight-control interventions. Objective: Our objective was to develop a simple methodology that uses longitudinal body weight measurements to estimate changes in energy intake and its 95% CI in individual subjects. Design: We showed how an energy balance equation with 2 parameters can be derived from any mathematical model of human metabolism. We solved the energy balance equation for changes in free-living energy intake as a function of body weight and its rate of change. We tested the predicted changes in energy intake by using weight-loss data from controlled inpatient feeding studies as well as simulated free-living data from a group of "virtual study subjects" that included realistic fluctuations in body water and day-to-day variations in energy intake. Results: Our method accurately predicted individual energy intake changes with the use of weight-loss data from controlled inpatient feeding experiments. By applying the method to our simulated free-living virtual study subjects, we showed that daily weight measurements over periods >28 d were required to obtain accurate estimates of energy intake change with a 95% CI of <300 kcal/d. These estimates were relatively insensitive to initial body composition or physical activity level. Conclusions: Frequent measurements of body weight over extended time periods are required to precisely estimate changes in energy intake in free-living individuals. Such measurements are feasible, relatively inexpensive, and can be used to estimate diet adherence during clinical weight-management programs. Am J Clin Nutr 2011;94:66-74. C1 [Hall, Kevin D.; Chow, Carson C.] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Lab Biol Modeling, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Chow, Carson/A-7970-2009 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX Supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 32 TC 25 Z9 25 U1 2 U2 10 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2011 VL 94 IS 1 BP 66 EP 74 DI 10.3945/ajcn.111.014399 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 779QK UT WOS:000291794800012 PM 21562087 ER PT J AU Mason, C Xiao, LR Imayama, I Duggan, CR Bain, C Foster-Schubert, KE Kong, A Campbell, KL Wang, CY Neuhouser, ML Li, L Jeffery, RW Robien, K Alfano, CM Blackburn, GL McTiernan, A AF Mason, Caitlin Xiao, Liren Imayama, Ikuyo Duggan, Catherine R. Bain, Carolyn Foster-Schubert, Karen E. Kong, Angela Campbell, Kristin L. Wang, Ching-Yun Neuhouser, Marian L. Li, Li Jeffery, Robert W. Robien, Kim Alfano, Catherine M. Blackburn, George L. McTiernan, Anne TI Effects of weight loss on serum vitamin D in postmenopausal women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID PLACEBO-CONTROLLED TRIAL; 25-HYDROXYVITAMIN D; CARDIOVASCULAR-DISEASE; DOUBLE-BLIND; PHYSICAL-ACTIVITIES; OBESE-PATIENTS; D DEFICIENCY; CANCER RISK; ORLISTAT; ASSOCIATION AB Background: Low concentrations of circulating vitamin D are common with obesity and may represent a potential mechanism explaining the elevated risk of certain cancers and cardiovascular outcomes observed in individuals who are overweight or obese. Objective: The objective of this study was to investigate the effects of 12 mo of weight loss through caloric restriction, exercise intervention, or both on serum 25-hydroxyvitamin D [25(OH) D] concentrations. Design: Overweight and obese postmenopausal women (n = 439) were randomly assigned to 1 of 4 groups: 1) diet modification (n = 118), 2) exercise (n = 117), 3) diet + exercise (n = 117), or 4) control (n = 87). The diet intervention was a group-based reduced-calorie program with a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous intensity aerobic activity daily for 5 d/wk. Serum 25(OH)D concentrations were measured by using a competitive chemiluminescent immunoassay at baseline and 12 mo. Results: No significant change in serum 25(OH)D was found between the intervention and control groups. Women who lost <5%, 5-9.9%, 10-14.9%, or >= 15% of baseline weight had mean increases in 25(OH)D of 2.1, 2.7, 3.3, and 7.7 ng/mL, respectively (P for trend = 0.002). Baseline vitamin D status did not modify the effect of the interventions on weight loss or body-composition changes at the 12-mo follow-up. Conclusion: A greater degree of weight loss, achieved through either a reduced-calorie diet or increased exercise, is associated with increased circulating 25(OH)D concentrations. This trial is registered at clinicaltrials.gov as NCT00470119. Am J Clin Nutr 2011;94:95-103. C1 [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Prevent Ctr, Seattle, WA 98104 USA. [Foster-Schubert, Karen E.; Wang, Ching-Yun; Neuhouser, Marian L.; McTiernan, Anne] Univ Washington, Seattle, WA 98195 USA. [Kong, Angela] Univ Illinois, Chicago, IL USA. [Campbell, Kristin L.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Li, Li] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Jeffery, Robert W.; Robien, Kim] Univ Minnesota, Minneapolis, MN USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Blackburn, George L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Nutr, Boston, MA 02215 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, Prevent Ctr, M4-B874,POB 19024, Seattle, WA 98104 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015; Biguzzi, Felipe/E-4724-2015; OI Duggan, Catherine/0000-0001-7369-4021; Robien, Kim/0000-0002-2120-2280 FU NIH [R01 CA102504, U54-CA116847, 5KL2RR025015-03]; NCI [R25 CA94880, 2R25CA057699-16]; Canadian Institutes of Health Research FX Supported by grants NIH R01 CA102504 and NIH U54-CA116847. KEF-S was supported by grant NIH 5KL2RR025015-03. AK was supported by grants NCI R25 CA94880 and NCI 2R25CA057699-16. CM and KLC were supported by a Canadian Institutes of Health Research Fellowship Award. NR 43 TC 39 Z9 40 U1 3 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2011 VL 94 IS 1 BP 95 EP 103 DI 10.3945/ajcn.111.015552 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 779QK UT WOS:000291794800015 PM 21613554 ER PT J AU Yetley, EA Coates, PM Johnson, CL AF Yetley, Elizabeth A. Coates, Paul M. Johnson, Clifford L. TI Overview of a roundtable on NHANES monitoring of biomarkers of folate and vitamin B-12 status: measurement procedure issues SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article AB A roundtable dialogue to discuss "NHANES Monitoring of Biomarkers of Folate and Vitamin B-12 Status" took place in July 2010. This article provides an overview of the meeting and this supplement issue. Although the focus of the roundtable dialogue was on the measurement of folate and vitamin B-12 status biomarkers in NHANES, this article also describes the relevance and importance of these issues for clinical and research laboratories. The roundtable identified the microbiological assay (MA) as the gold standard for measurement of serum and red blood cell folate concentrations. The roundtable noted that differences in results between the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA) that NHANES1991-1994 and 1999-2006 used and the MA that NHANES 2007-2010 used will require adjustment equations to evaluate time trends. The roundtable found that the close agreement between the serum results for the MA and liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedures supported the conversion to LC-MS/MS for serum folate in future NHANES. The roundtable recognized the uncertainty about whether subclinical vitamin B-12 deficiency is a public health concern but encouraged reinstatement of at least one circulating vitamin B-12 measure and one functional vitamin B-12 status measure in future NHANES. The use of serum vitamin B-12 and plasma methylmalonic acid would provide continuity with past NHANES. The roundtable supported the continued use of the National Institute of Standards and Technology (NIST) reference materials in NHANES biomarker analyses and the further development of additional reference materials by the NIST. Am J Clin Nutr 2011;94(suppl):297S-302S. C1 [Yetley, Elizabeth A.; Coates, Paul M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Johnson, Clifford L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Coates, PM (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01,MSC 7517, Bethesda, MD 20892 USA. EM beth@yetley.com; coatesp@od.nih.gov FU Office of Dietary Supplements, NIH; National Center for Health Statistics, CDC FX Supported by the National Center for Health Statistics, CDC, and the Office of Dietary Supplements, NIH. NR 11 TC 14 Z9 14 U1 0 U2 6 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2011 VL 94 IS 1 BP 297S EP 302S DI 10.3945/ajcn.111.017392 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 779QK UT WOS:000291794800044 PM 21593504 ER EF