FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bowles, HR AF Bowles, Heather R. TI Measurement of Active and Sedentary Behaviors: Closing the Gaps in Self-Report Methods SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Editorial Material C1 NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Bowles, HR (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 5 TC 20 Z9 20 U1 0 U2 1 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD JAN PY 2012 VL 9 SU 1 BP S1 EP S4 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 885FR UT WOS:000299764400001 PM 22287442 ER PT J AU Hagstromer, M Ainsworth, BE Kwak, L Bowles, HR AF Hagstromer, Maria Ainsworth, Barbara E. Kwak, Lydia Bowles, Heather R. TI A Checklist for Evaluating the Methodological Quality of Validation Studies on Self-Report Instruments for Physical Activity and Sedentary Behavior SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE external validity; internal validity; reporting; questionnaire ID GROUP RANDOMIZED-TRIALS; STATISTICAL-METHODS; ASSESSING AGREEMENT; UPDATED GUIDELINES; VALIDITY; QUESTIONNAIRES; EPIDEMIOLOGY; STATEMENT; DESIGN; ADULTS AB Context: The quality of methodological papers assessing physical activity instruments depends upon the rigor of a study's design. Objectives: We present a checklist to assess key criteria for instrument validation studies. Process: A Medline/PubMed search was performed to identify guidelines for evaluating the methodological quality of instrument validation studies. Based upon the literature, a pilot version of a checklist was developed consisting of 21 items with 3 subscales: 1) quality of the reported data (9 items: assess whether the reported information is sufficient to make an unbiased assessment of the findings); 2) external validity of the results (3 items: assess the extent to which the findings are generalizable); 3) internal validity of the study (9 items: assess the rigor of the study design). The checklist was tested for interrater reliability and feasibility with 6 raters. Findings: Raters viewed the checklist as helpful for reviewing studies. They suggested minor wording changes for 8 items to clarify intent. One item was divided into 2 items for a total of 22 items. Discussion: Checklists may be useful to assess the quality of studies designed to validate physical activity instruments. Future research should test checklist internal consistency, test-retest reliability, and criterion validity. C1 [Hagstromer, Maria] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden. [Ainsworth, Barbara E.] Arizona State Univ, Coll Nursing & Hlth Innovat, Program Exercise & Wellness, Phoenix, AZ USA. [Kwak, Lydia] Karolinska Inst, Dept Biosci, Huddinge, Sweden. [Bowles, Heather R.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Hagstromer, M (reprint author), Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden. NR 31 TC 9 Z9 9 U1 1 U2 6 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD JAN PY 2012 VL 9 SU 1 BP S29 EP S36 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 885FR UT WOS:000299764400005 PM 22287445 ER PT J AU Troiano, RP Gabriel, KKP Welk, GJ Owen, N Sternfeld, B AF Troiano, Richard P. Gabriel, Kelley K. Pettee Welk, Gregory J. Owen, Neville Sternfeld, Barbara TI Reported Physical Activity and Sedentary Behavior: Why Do You Ask? SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE self-report; accelerometer; assessment method ID PUBLIC-HEALTH; RELIABILITY; PREVENTION; VALIDITY; TIME; RISK; TOO AB Context: Advances in device-based measures have led researchers to question the value of reported measures of physical activity or sedentary behavior. The premise of the Workshop on Measurement of Active and Sedentary Behaviors: Closing the Gaps in Self-Report Methods, held in July 2010, was that assessment of behavior by self-report is a valuable approach. Objective: To provide suggestions to optimize the value of reported physical activity and sedentary behavior, we 1) discuss the constructs that devices and reports of behavior can measure, 2) develop a framework to help guide decision-making about the best approach to physical activity and sedentary behavior assessment in a given situation, and 3) address the potential for combining reported behavior methods with device-based monitoring to enhance both approaches. Process: After participation in a workshop breakout session, coauthors summarized the ideas presented and reached consensus on the material presented here. Conclusions: To select appropriate physical activity assessment methods and correctly interpret the measures obtained, researchers should carefully consider the purpose for assessment, physical activity constructs of interest, characteristics of the population and measurement tool, and the theoretical link between the exposure and outcome of interest. C1 [Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Bethesda, MA USA. [Gabriel, Kelley K. Pettee] Univ Texas Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Austin, TX USA. [Welk, Gregory J.] Iowa State Univ, Dept Hlth & Human Performance, Ames, IA USA. [Owen, Neville] Univ Queensland, Dept Populat Hlth, Brisbane, Qld, Australia. [Sternfeld, Barbara] Kaiser Permanente, Div Res, Oakland, CA USA. RP Troiano, RP (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MA USA. RI Owen, Neville/K-5986-2012 NR 31 TC 35 Z9 35 U1 1 U2 8 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD JAN PY 2012 VL 9 SU 1 BP S68 EP S75 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 885FR UT WOS:000299764400009 PM 22287450 ER PT J AU Nelson, RF AF Nelson, R. F. TI Glycinergic neurons process images SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID AMACRINE CELLS; CONE PATHWAYS; CAT RETINA; FIELD C1 NINDS, NIH, Basic Neurosci Program, Bethesda, MD 20892 USA. RP Nelson, RF (reprint author), NINDS, NIH, Basic Neurosci Program, 5625 Fishers Lane,Room TS-09, Bethesda, MD 20892 USA. EM nelsonr@ninds.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JAN PY 2012 VL 590 IS 2 BP 239 EP 240 DI 10.1113/jphysiol.2011.224584 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 876IS UT WOS:000299101800002 PM 22247262 ER PT J AU Daye, PM Blohm, G Lefevre, P AF Daye, Pierre M. Blohm, Gunnar Lefevre, Philippe TI Target motion direction influence on tracking performance and head tracking strategies in head-unrestrained conditions SO JOURNAL OF VISION LA English DT Article DE eye-head coordination; head-free; head-unrestrained; pursuit eye movements ID COMPLEX 2-DIMENSIONAL TRAJECTORIES; PREDICTIVE SMOOTH-PURSUIT; FELINE NECK MUSCLES; FOREL FIELD-H; EYE; MOVEMENTS; COORDINATION; MOTONEURONS; EXCITATION; ACTIVATION AB We examined subjects' behavior when they tracked periodic oscillating targets moving along a randomly oriented ramp with the head free to move. This study focuses on the effect of target motion direction on pursuit performance and on head tracking strategies used by human subjects to coordinate eye and head movements. Our analyses revealed that the gaze tracking gain was modulated by both target oscillation frequency and target motion direction. We found that pursuit gain was modulated by the target motion direction: vertical pursuit being less accurate than horizontal pursuit. While gaze tracking was sensitive to target frequency and orientation, head behavior was less modulated by a change of target frequency than by a change of target motion direction. Additionally, subjects had two main strategies for moving their head: They oriented their head to favor rotations around either the head dorsoventral (target motion directions <20 deg) or mediolateral axis (target motion directions >70 deg). In between, the subjects did not choose a consistent rotation axis for identical target motion directions. C1 [Daye, Pierre M.] NEI, Lab Sensimotor Res, NIH, Bethesda, MD 20892 USA. [Daye, Pierre M.; Lefevre, Philippe] Catholic Univ Louvain, ICTEAM, B-1348 Louvain, Belgium. [Daye, Pierre M.; Lefevre, Philippe] Catholic Univ Louvain, IoNS, B-1200 Brussels, Belgium. [Blohm, Gunnar] Queens Univ, Ctr Neurosci Studies, Kingston, ON, Canada. RP Daye, PM (reprint author), NEI, Lab Sensimotor Res, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM pierre.daye@gmail.com FU Fonds National de la Recherche Scientifique, Action de Recherche Concertee (Belgium); Belgian State, Science Policy Office; NSERC (Canada); ORF (Canada); CFI (Canada); Botterell Foundation (Queen's University, Kingston, ON, Canada); National Eye Institute, NIH, DHHS FX Support for this work was provided by Fonds National de la Recherche Scientifique, Action de Recherche Concertee (Belgium). This paper presents research results of the Belgian Network Dynamical Systems, Control and Optimization, funded by the Interuniversity Attraction Poles Programmes, initiated by the Belgian State, Science Policy Office. This work has been supported by NSERC (Canada), ORF (Canada), CFI (Canada) and the Botterell Foundation (Queen's University, Kingston, ON, Canada). One of the authors (PMD) was supported in part by the intramural research program of the National Eye Institute, NIH, DHHS. NR 22 TC 3 Z9 3 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 1534-7362 J9 J VISION JI J. Vision PY 2012 VL 12 IS 1 AR 23 DI 10.1167/12.1.23 PG 12 WC Ophthalmology SC Ophthalmology GA 884TN UT WOS:000299731800023 ER PT J AU Ferrucci, L de Cabo, R Knuth, ND Studenski, S AF Ferrucci, Luigi de Cabo, Rafa Knuth, Nicolas D. Studenski, Stephanie TI Of Greek Heroes, Wiggling Worms, Mighty Mice, and Old Body Builders SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID MUSCLE STRENGTH; SKELETAL-MUSCLE; MASS; HEALTH; SARCOPENIA; WOMEN; PREDICTORS; DISABILITY; MOBILITY; QUALITY C1 [Ferrucci, Luigi] NIA, Clin Res Branch, Clin Unit, Harbor Hosp,NIH, Baltimore, MD 21225 USA. [Studenski, Stephanie] Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA 15260 USA. RP Ferrucci, L (reprint author), NIA, Clin Res Branch, Clin Unit, Harbor Hosp,NIH, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS; NIA NIH HHS [P30 AG024827] NR 22 TC 10 Z9 11 U1 1 U2 5 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 JAN PY 2012 VL 67 IS 1 BP 13 EP 16 DI 10.1093/gerona/glr046 PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 885PQ UT WOS:000299791700002 PM 22113943 ER PT J AU Hicks, GE Shardell, M Alley, DE Miller, RR Bandinelli, S Guralnik, J Lauretani, F Simonsick, EM Ferrucci, L AF Hicks, Gregory E. Shardell, Michelle Alley, Dawn E. Miller, Ram R. Bandinelli, Stefania Guralnik, Jack Lauretani, Fulvio Simonsick, Eleanor M. Ferrucci, Luigi TI Absolute Strength and Loss of Strength as Predictors of Mobility Decline in Older Adults: The InCHIANTI Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Strength; Sarcopenia; Mobility decline ID MUSCLE STRENGTH; PHYSICAL-DISABILITY; MUSCULAR STRENGTH; MEANINGFUL CHANGE; SARCOPENIA; RELIABILITY; PERFORMANCE; WOMEN; MASS; MEN AB Theoretical definitions of sarcopenia traditionally emphasize age-related loss of muscle strength; however, most analyses of the association between strength and mobility examine strength at a single time point. This study sought to identify sex-specific cutpoints for muscle strength and power (at one time point) and 3-year changes in strength and power that would maximize prediction of 3-year mobility decline. Longitudinal analysis of 934 adults aged >= 65 years enrolled in the Invecchiare in Chianti study was conducted. Grip strength, knee extension strength, and lower extremity power were measured at baseline and 3 years postenrollment. Mobility function (gait speed and self-reported mobility disability) was measured at 3 and 6 years postenrollment. Classification and regression tree analysis was used to predict mobility decline from Years 3 to 6. Men with knee extension strength < 19.2 kg and grip strength < 39.0 kg had clinically meaningful declines in gait speed of .24 m/s. Furthermore, men with power < 105 W were nearly nine times more likely to develop incident mobility disability (likelihood ratio = 8.68; 95% confidence interval = 3.91, 19.44). Among women, knee extension strength < 18.0 kg was associated with a minimal gait speed decline of 0.06 m/s, and women with leg power < 64 W were three times more likely to develop incident mobility disability (likelihood ratio = 3.01; 95% confidence interval = 1.79, 5.08). Three-year changes in strength and power did not predict mobility decline in either sex. Findings suggest that strength and power measured at one time point are more predictive of mobility decline than 3-year changes and that low strength and power are particularly powerful risk factors in men. C1 [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Hicks, Gregory E.; Shardell, Michelle; Alley, Dawn E.; Miller, Ram R.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Div Gerontol, Baltimore, MD 21201 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Geriatr Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Lab Movement Anal, Parma, Italy. [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. RP Hicks, GE (reprint author), Univ Delaware, Dept Phys Therapy, 313 McKinly Lab, Newark, DE 19716 USA. EM ghicks@udel.edu RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Italian Ministry of Health; U.S. National Institute on Aging [263 MD 916413, 263 MD 821336]; National Institutes of Health [K23 AG019161]; [R21HD057274]; [K12 HD043489]; [R01 AG029315] FX The InCHIANTI study was supported by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (contracts 263 MD 916413 and 263 MD 821336). Dr. G. E. H. was supported by grant R21HD057274, Dr. D. E. A. was supported by grant K12 HD043489, Dr. M. S. was supported by grant R01 AG029315, and Dr. R. M. M. was supported by grant K23 AG019161 from the National Institutes of Health. NR 34 TC 61 Z9 66 U1 3 U2 20 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 JAN PY 2012 VL 67 IS 1 BP 66 EP 73 DI 10.1093/gerona/glr055 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 885PQ UT WOS:000299791700008 PM 21546582 ER PT J AU Kalyani, RR Metter, EJ Ramachandran, R Chia, CW Saudek, CD Ferrucci, L AF Kalyani, Rita R. Metter, E. Jeffrey Ramachandran, Ramona Chia, Chee W. Saudek, Christopher D. Ferrucci, Luigi TI Glucose and Insulin Measurements From the Oral Glucose Tolerance Test and Relationship to Muscle Mass SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Glucose; Insulin; Muscle; Older adults ID SKELETAL-MUSCLE; BODY-COMPOSITION; OLDER-ADULTS; COMPUTED-TOMOGRAPHY; PHYSICAL ACTIVITIES; STRENGTH; HEALTH; DISABILITY; WOMEN; COMORBIDITIES AB Diabetes is associated with decreased muscle mass. The effect of higher levels of glucose and insulin on muscle mass has not been studied in individuals without diabetes. We sought to determine the relationship of insulin and glucose measurements from the oral glucose tolerance test (OGTT) with muscle mass in persons without diabetes. We analyzed data from 587 participants in the Baltimore Longitudinal Study of Aging (mean age 67.3 years, range 26-95 years) without diabetes who underwent a 2-hour OGTT, including glucose and insulin measurements taken every 20 minutes and assessment of midthigh muscle cross-sectional area by computed tomography, taken as a proxy measure of muscle mass. Linear regression models and Bayesian model averaging were used to explore the independent cross-sectional association of various OGTT-derived measures and midthigh muscle cross-sectional area, independent of confounders. Individually, fasting glucose, fasting insulin, OGTT glucose (40, 60, 80, 100, and 120 minutes), OGTT insulin (20, 60, 80, 100, and 120 minutes), homeostasis model assessment of insulin resistance, integrated glucose area, and integrated insulin area were inversely associated, and the Matsuda index was positively associated, with the midthigh muscle cross-sectional area (standardized to body weight) after adjustment for age, sex, race, height, physical activity, and peroneal motor nerve conduction velocity (all ps <.05). When considered together, the Matsuda index and fasting glucose were the strongest predictors of lower midthigh muscle cross-sectional area after covariate adjustment. Higher fasting and OGTT values of both glucose and insulin are associated with lower muscle mass. Longitudinal studies are needed to verify whether individuals free of diabetes that have higher glucose and insulin during an OGTT are at risk for accelerated muscle mass decline with aging. C1 [Kalyani, Rita R.; Saudek, Christopher D.] Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol & Metab, Baltimore, MD 21287 USA. [Metter, E. Jeffrey; Ramachandran, Ramona; Chia, Chee W.; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Kalyani, RR (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol & Metab, 1830 E Monument St,Suite 333, Baltimore, MD 21287 USA. EM rrastogi@jhmi.edu FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 30 TC 19 Z9 19 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 JAN PY 2012 VL 67 IS 1 BP 74 EP 81 DI 10.1093/gerona/glr022 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 885PQ UT WOS:000299791700009 PM 21350243 ER PT J AU Miki, M Ball, DW Linnoila, RI AF Miki, Makoto Ball, Douglas W. Linnoila, R. Ilona TI Insights into the achaete-scute homolog-1 gene (hASH1) in normal and neoplastic human lung SO LUNG CANCER LA English DT Article DE Achaete-scute homolog-1; Synaptophysin; Neuroendocrine; Lung development; Lung carcinogenesis; Small cell lung cancer; Non-small cell lung cancer; Human ID HELIX TRANSCRIPTION FACTORS; NEUROENDOCRINE DIFFERENTIATION; CELL-POPULATIONS; CANCER; EXPRESSION; CARCINOMAS; MASH1; CHEMOTHERAPY; ENDOCRINE; FEATURES AB Achaete-scute homolog-1 (ASH1) is pivotal for the development of pulmonary neuroendocrine (NE) cells. We examined human ASH1 (hASH1) expression across a comprehensive panel of human lung cancer cell lines, primary human lung tumors and normal fetal and post-natal lungs. While hASH1 was a cardinal feature of NE carcinomas, a subgroup of non-NE lung cancers also exhibited expression of this factor. Twenty lung cancer cell lines out of 33 were positive for hASH1 mRNA by reverse transcription PCR, including 6/6 small cell carcinomas (SCLC), 5/5 carcinoids, 6/7 non-SCLC with NE features, and 3/14 other non-SCLC. Among human primary tumors, 2/2 SCLC, 5/5 pulmonary carcinoids. and 10/41 non-SCLC (only 4 of which had NE features) were positive for hASH1 by immunohistochemistry and RNA-RNA in situ hybridization. In normal human fetal lung, the expression of hASH1 and the neural marker synaptophysin was highly concordant in neuroepithelial bodies and solitary NE cells, while the rest of the epithelium was negative. In childhood and adulthood, the markers became progressively discordant, with a majority of hASH1-immunoreactive foci (69%) being negative for synaptophysin in adults, potentially representing dormant NE cell progenitors. We conclude that hASH1 provides an early indication of NE program in human lung. Published by Elsevier Ireland Ltd. C1 [Miki, Makoto; Linnoila, R. Ilona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ball, Douglas W.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21231 USA. [Ball, Douglas W.] Johns Hopkins Med Inst, Ctr Oncol, Baltimore, MD 21231 USA. RP Linnoila, RI (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, 37 Convent Dr,Bg 37,Room 1056B, Bethesda, MD 20850 USA. EM linnoila@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs. Michael Birrer and Eva Szabo for stimulating and critical discussions of this work, and Sandy Jensen and Dr. Mae Jean Miller for technical assistance. This work was funded by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 37 TC 19 Z9 21 U1 0 U2 0 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 JAN PY 2012 VL 75 IS 1 BP 58 EP 65 DI 10.1016/j.lungcan.2011.05.019 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 881AB UT WOS:000299450600008 PM 21684625 ER PT J AU Malley, JD Kruppa, J Dasgupta, A Malley, KG Ziegler, A AF Malley, J. D. Kruppa, J. Dasgupta, A. Malley, K. G. Ziegler, A. TI Probability Machines Consistent Probability Estimation Using Nonparametric Learning Machines SO METHODS OF INFORMATION IN MEDICINE LA English DT Article DE Brier score; consistency; random forest; k nearest neighbor; logistic regression; probability estimation ID NEAREST-NEIGHBOR ESTIMATE; LOGISTIC-REGRESSION; STATISTICAL VIEW; RANDOM FORESTS; CLASSIFICATION; CONVERGENCE; PREDICTION; NETWORK AB Background: Most machine learning approaches only provide a classification for binary responses. However, probabilities are required for risk estimation using individual patient characteristics. It has been shown recently that every statistical learning machine known to be consistent for a nonparametric regression problem is a probability machine that is provably consistent for this estimation problem. Objectives: The aim of this paper is to show how random forests and nearest neighbors can be used for consistent estimation of individual probabilities. Methods: Two random forest algorithms and two nearest neighbor algorithms are described in detail for estimation of individual probabilities. We discuss the consistency of random forests, nearest neighbors and other learning machines in detail. We conduct a simulation study to illustrate the validity of the methods. We exemplify the algorithms by analyzing two well-known data sets on the diagnosis of appendicitis and the diagnosis of diabetes in Pima Indians. Results: Simulations demonstrate the validity of the method. With the real data application, we show the accuracy and practicality of this approach. We provide sample code from R packages in which the probability estimation is already available. This means that all calculations can be performed using existing software. Conclusions: Random forest algorithms as well as nearest neighbor approaches are valid machine learning methods for estimating individual probabilities for binary responses. Freely available implementations are available in R and may be used for applications. C1 [Kruppa, J.; Ziegler, A.] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, D-23562 Lubeck, Germany. [Malley, J. D.] NIH, Ctr Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dasgupta, A.] NIAMSD, Clin Sci Sect, NIH, Bethesda, MD 20892 USA. [Malley, K. G.] Malley Res Programming, Rockville, MD USA. RP Ziegler, A (reprint author), Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Campus Lubeck,Maria Goeppert Str 1, D-23562 Lubeck, Germany. EM ziegler@imbs.uni-luebeck.de OI Ziegler, Andreas/0000-0002-8386-5397 FU European Union (ENGAGE) [201413]; German Ministry of Research and Education [01GS0831]; intramural funding of the University of Lubeck; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Center for Information Technology, National Institutes of Health, USA FX The authors are extremely grateful to Joan Bailey-Wilson and Gerard Biau for valuable discussions and to Sholom M. Weiss for making the appendicitis data available. Funding: AZ and JK are supported by the European Union (ENGAGE, 201413), the German Ministry of Research and Education (01GS0831) and intramural funding of the University of Lubeck. This work was partly supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AD) and the Center for Information Technology (JDM), National Institutes of Health, USA. NR 36 TC 27 Z9 27 U1 2 U2 6 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0026-1270 J9 METHOD INFORM MED JI Methods Inf. Med. PY 2012 VL 51 IS 1 BP 74 EP 81 DI 10.3414/ME00-01-0052 PG 8 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA 887DS UT WOS:000299907700010 PM 21915433 ER PT J AU Marshall, RS Festa, JR Cheung, YK Chen, R Pavol, MA Derdeyn, CP Clarke, WR Videen, TO Grubb, RL Adams, HP Powers, WJ Lazar, RM AF Marshall, R. S. Festa, J. R. Cheung, Y. K. Chen, R. Pavol, M. A. Derdeyn, C. P. Clarke, W. R. Videen, T. O. Grubb, R. L. Adams, H. P. Powers, W. J. Lazar, R. M. TI Cerebral hemodynamics and cognitive impairment Baseline data from the RECON trial SO NEUROLOGY LA English DT Article ID CAROTID-ARTERY OCCLUSION; POSITRON-EMISSION-TOMOGRAPHY; TRANSIENT ISCHEMIC ATTACKS; IC BYPASS-SURGERY; CEREBROVASCULAR-DISEASE; PERFORMANCE; STENOSIS; AGE; ENDARTERECTOMY; INFARCTION AB Objective: To determine whether unihemispheral hemodynamic failure is independently associated with cognitive impairment among participants in the National Institute of Neurological Disorders and Stroke-sponsored, multicenter, randomized clinical trial, Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON). Methods: Forty-three patients were randomized into RECON after recent symptomatic carotid artery occlusion and asymmetrically increased oxygen extraction fraction (OEF) by PET (OEF ratio > 1.13), indicating stage II hemodynamic failure on the side of occlusion. The PET-positive patients were compared with 28 RECON-enrolled patients who met all clinical and radiographic inclusion/exclusion criteria but had no OEF asymmetry. A multivariable regression compared patients with PET OEF >1.13 or <= 1.13, stratifying by TIA vs stroke as the qualifying event. The dependent variable was a composite neurocognitive score derived from averaging age-normalized z scores on a test battery that included global and internal carotid artery (ICA) side-relevant hemisphere-specific tests. Results: There were no differences in demographic, clinical, or radiologic characteristics between the PET-positive and PET-negative patients except for PET OEF asymmetry. The unadjusted average neurocognitive z score was -1.45 for the PET-positive and -1.25 for the PET-negative patients, indicating cognitive impairment in both groups but no difference between them (p = 0.641). After adjustment for age, education, side of occlusion, depression, and previous stroke, there was a significant difference between PET-positive and PET-negative patients among those with TIA as a qualifying event (average z score = -1.41 vs -0.76, p = 0.040). Older age and right ICA side were also significant in this model. Conclusion: Hemodynamic failure is independently associated with cognitive impairment in patients with carotid occlusion. This finding establishes the physiologic parameter upon which the extracranial-intracranial bypass will be tested. Neurology (R) 2012; 78:250-255 C1 [Marshall, R. S.; Festa, J. R.; Cheung, Y. K.; Chen, R.; Pavol, M. A.; Lazar, R. M.] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Derdeyn, C. P.; Videen, T. O.; Grubb, R. L.] Washington Univ, St Louis, MO USA. [Clarke, W. R.; Adams, H. P.] Univ Iowa, Ames, IA USA. [Cheung, Y. K.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Powers, W. J.] Univ N Carolina, Chapel Hill, NC USA. RP Marshall, RS (reprint author), Columbia Univ, Med Ctr, New York, NY 10027 USA. EM rsm2@columbia.edu RI Chen, Robert/B-3899-2009; OI Chen, Robert/0000-0002-8371-8629; Derdeyn, Colin/0000-0002-5932-2683 FU NINDS [NS048212, NS42167, 5U01NS041895]; Richard and Jenny Levine Research Fund; NIH/NINDS; NIH (NINDS/NICHD/NHLBI); Terumo Heart, Inc.; EvaHeart Medical USA, Inc.; NIH (NIAMS/NINDS/NIDDK); Michael J. Fox Foundation; Barnes-Jewish Hospital Foundation; NIH (NINDS/NIAMS); NIH (NHLBI/NINDS/NICHD) FX Supported by NINDS NS048212 (R.S.M.), NS42167 (W.J.P.), and 5U01NS041895 (W.R.C.) and by The Richard and Jenny Levine Research Fund.; Dr. Marshall has a patent pending re: a novel use of a drug for post-stroke dystonia; receives publishing royalties for OnCall Neurology (Elsevier, 2003-present); has received speaker honoraria from Ferrer International; and receives research support from the NIH/NINDS. Dr. Festa receives research support from the NIH (NINDS/NICHD/NHLBI). Dr. Cheung serves on the editorial board of Biometrics; receives publishing royalties for Dose Finding by the Continual Reassessment Method (Chapman and Hall/CRC, 2011); serves as a consultant for Remedy and Estee Lauder; and receives research from the NIH/NINDS. R. Chen receives research support from the NIH/NINDS. Dr. Pavol receives research support from Terumo Heart, Inc., EvaHeart Medical USA, Inc., and the NIH/NINDS. Dr. Derdeyn serves on a scientific advisory boards for W. L. Gore and Associates and the NIH/NINDS; serves on the editorial boards of Stroke and the American Journal of Neuroradiology; is listed on patents re: a system for surgical repair of intracranial aneurysms and a method to stimulate peripheral nerves; receives research support from the NIH/NINDS; and holds stock options in nFocus, Inc. Dr. Clarke receives publishing royalties for Statistical Methods for the Analysis of Biomedical Data, 2nd edition (Wiley-Interscience, 2002) and receives research support from the NIH (NIAMS/NINDS/NIDDK). Dr. Videen receives research support from the NIH/NINDS and the Michael J. Fox Foundation. Dr. Grubb serves on the editorial board of the Journal of Neurosurgery and receives research support from the NIH/NINDS and the Barnes-Jewish Hospital Foundation. Dr. Adams serves on scientific advisory boards for Medtronic, Inc. and Merck Serono; serves on the editorial boards of Stroke, Journal of Stroke and Cerebrovascular Diseases, and Cerebrovascular Diseases; receives publishing royalties for Handbook of Cerebrovascular Diseases, 2nd edition (Informa Healthcare, 2004) and Principles of Cerebrovascular Disease (McGraw-Hill Professional, 2006); and receives research support from the NIH/NINDS. Dr. Powers serves on a scientific advisory board for the NIH Morehouse School of Medicine; serves on the editorial boards of Stroke and Journal of Cerebral Blood Flow and Metabolism; and receives research support from the NIH (NINDS/NIAMS). Dr. Lazar serves on the editorial board of Stroke and receives research support from the NIH (NHLBI/NINDS/NICHD). NR 36 TC 32 Z9 36 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN PY 2012 VL 78 IS 4 BP 250 EP 255 DI 10.1212/WNL.0b013e31824365d3 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 885OB UT WOS:000299787200008 PM 22238418 ER PT J AU Canuto, HC Fishbein, KW Huang, A Doty, SB Herbert, RA Peckham, J Pleshko, N Spencer, RG AF Canuto, H. C. Fishbein, K. W. Huang, A. Doty, S. B. Herbert, R. A. Peckham, J. Pleshko, N. Spencer, R. G. TI Characterization of skin abnormalities in a mouse model of osteogenesis imperfecta using high resolution magnetic resonance imaging and Fourier transform infrared imaging spectroscopy SO NMR IN BIOMEDICINE LA English DT Article DE MRI; Skin; Osteogenesis Imperfecta; FT-IR; Mouse Model ID COLLAGEN MUTATION DATABASE; IN-VIVO; ARTICULAR-CARTILAGE; CONNECTIVE-TISSUE; RELAXATION-TIMES; CHILD-ABUSE; MECHANICAL-PROPERTIES; HYDRATED COLLAGEN; MR MICROSCOPY; GOAT KNEE AB Evaluation of the skin phenotype in osteogenesis imperfecta (OI) typically involves biochemical measurements, such as histologic or biochemical assessment of the collagen produced from biopsy-derived dermal fibroblasts. As an alternative, the current study utilized non-invasive magnetic resonance imaging (MRI) microscopy and optical spectroscopy to define biophysical characteristics of skin in an animal model of OI. MRI of skin harvested from control, homozygous oim/oim and heterozygous oim/+ mice demonstrated several differences in anatomic and biophysical properties. Fourier transform infrared imaging spectroscopy (FT-IRIS) was used to interpret observed MRI signal characteristics in terms of chemical composition. Differences between wild-type and OI mouse skin included the appearance of a collagen-depleted lower dermal layer containing prominent hair follicles in the oim/oim mice, accounting for 55% of skin thickness in these. The MRI magnetization transfer rate was lower by 50% in this layer as compared to the upper dermis, consistent with lower collagen content. The MRI transverse relaxation time, T2, was greater by 30% in the dermis of the oim/oim mice compared to controls, consistent with a more highly hydrated collagen network. Similarly, an FT-IRIS-defined measure of collagen integrity was 30% lower in the oim/oim mice. We conclude that characterization of phenotypic differences between the skin of OI and wild-type mice by MRI and FT-IRIS is feasible, and that these techniques provide powerful complementary approaches for the analysis of the skin phenotype in animal models of disease. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Canuto, H. C.; Fishbein, K. W.; Spencer, R. G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Huang, A.; Doty, S. B.; Pleshko, N.] Hosp Special Surg, New York, NY 10021 USA. [Herbert, R. A.; Peckham, J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Pleshko, N.] Temple Univ, Dept Mech Engn, Philadelphia, PA 19122 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, NIH, Intramural Res Program, GRC 4D-06 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov RI Huang, Alice/L-2256-2015; OI Huang, Alice/0000-0002-5037-6829; Fishbein, Kenneth/0000-0002-6353-4603 FU NIH, National Institute on Aging; NIH [AR48337] FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and NIH grant AR48337 (NP). NR 61 TC 5 Z9 5 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD JAN PY 2012 VL 25 IS 1 BP 169 EP 176 DI 10.1002/nbm.1732 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 875ZF UT WOS:000299074600019 PM 21845737 ER PT J AU Bulut, G Hong, SH Chen, K Beauchamp, EM Rahim, S Kosturko, GW Glasgow, E Dakshanamurthy, S Lee, HS Daar, I Toretsky, JA Khanna, C Uren, A AF Bulut, G. Hong, S-H Chen, K. Beauchamp, E. M. Rahim, S. Kosturko, G. W. Glasgow, E. Dakshanamurthy, S. Lee, H-S Daar, I. Toretsky, J. A. Khanna, C. Ueren, A. TI Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells SO ONCOGENE LA English DT Article DE ezrin; osteosarcoma; metastasis; small molecule screening; drug discovery ID ERM PROTEINS; OSTEOGENIC-SARCOMA; PLASMA-MEMBRANE; BINDING-SITE; LINKER EZRIN; METASTASIS; EXPRESSION; SURVIVAL; IDENTIFICATION; CHEMOTHERAPY AB Ezrin is a multifunctional protein that connects the actin cytoskeleton to the extracellular matrix through transmembrane proteins. High ezrin expression is associated with lung metastasis and poor survival in cancer. We screened small molecule libraries for compounds that directly interact with ezrin protein using surface plasmon resonance to identify lead compounds. The secondary functional assays used for lead compound selection included ezrin phosphorylation as measured by immunoprecipitation and in vitro kinase assays, actin binding, chemotaxis, invasion into an endothelial cell monolayer, zebrafish and Xenopus embryonic development, mouse lung organ culture and an in vivo lung metastasis model. Two molecules, NSC305787 and NSC668394, that directly bind to ezrin with low micromolar affinity were selected based on inhibition of ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction and ezrin-mediated motility of osteosarcoma (OS) cells in culture. NSC305787 mimicked the ezrin morpholino phenotype, and NSC668394 caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of OS cells into mice, both molecules inhibited lung metastasis of ezrinsensitive cells, but not ezrin-resistant cells. The small molecule inhibitors NSC305787 and NSC668394 demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis. Oncogene (2012) 31, 269-281; doi:10.1038/onc.2011.245; published online 27 June 2011 C1 [Ueren, A.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, NRB, Washington, DC 20057 USA. [Hong, S-H; Khanna, C.] NCI, Tumor & Metastasis Biol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, H-S; Daar, I.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. RP Uren, A (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, NRB, 3970 Reservoir Rd NW,Room E312, Washington, DC 20057 USA. EM au26@georgetown.edu RI BULUT, GULAY/J-3180-2012; Lee, Hyun-Shik/G-3555-2011; OI Glasgow, Eric/0000-0001-7729-3954; Daar, Ira/0000-0003-2657-526X FU Children's Cancer Foundation of Baltimore; US Department of Defense [W81XWH-10-1-0137]; Brandon Carrington Lee Foundation; Go4theGoal; Dani's Foundation; Alex's Lemonade Stand Foundation; Liddy Shriver Sarcoma Initiative; Burroughs Wellcome Clinical Scientist Award in Translational Research; NIH [R01CA133662, R01CA138212]; Cancer Center [P30 CA051008] FX Support for our work came from the Children's Cancer Foundation of Baltimore (AU), US Department of Defense (W81XWH-10-1-0137, AU), Brandon Carrington Lee Foundation (G.K., AU), Go4theGoal, Dani's Foundation, Alex's Lemonade Stand Foundation, Liddy Shriver Sarcoma Initiative, Burroughs Wellcome Clinical Scientist Award in Translational Research (JT), and the NIH R01CA133662 (JT), R01CA138212 (JT) and Cancer Center Support Grant P30 CA051008 for use of Biacore Molecular Interaction Shared Resource. We would like to thank to Dr Anthony Bretscher (Cornell University) for providing the WT Ezrin construct, Developmental Therapeutics Program, NCI for providing the small molecule libraries. NR 44 TC 40 Z9 44 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN PY 2012 VL 31 IS 3 BP 269 EP 281 DI 10.1038/onc.2011.245 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 882DQ UT WOS:000299542100001 PM 21706056 ER PT J AU Lai, C Roschewski, M AF Lai, Catherine Roschewski, Mark TI Nodal Marginal Zone Lymphoma: Impersonalized Medicine THE TRAVERSE-GLEHEN ET AL ARTICLE REVIEWED SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID B-CELL LYMPHOMA; FOLLICULAR LYMPHOMA; RITUXIMAB; THERAPY; TRIAL C1 [Lai, Catherine] NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. [Roschewski, Mark] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. RP Lai, C (reprint author), NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. NR 19 TC 1 Z9 1 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JAN PY 2012 VL 26 IS 1 BP 104 EP + PG 3 WC Oncology SC Oncology GA 883UB UT WOS:000299659300013 PM 22393803 ER PT J AU Chewning, B Bylund, CL Shah, B Arora, NK Gueguen, JA Makoul, G AF Chewning, Betty Bylund, Carma L. Shah, Bupendra Arora, Neeraj K. Gueguen, Jennifer A. Makoul, Gregory TI Patient preferences for shared decisions: A systematic review SO PATIENT EDUCATION AND COUNSELING LA English DT Review DE Shared decision making; Patient preferences; Patient decisions ID CANCER-PATIENTS PREFERENCES; BREAST-CANCER; INFORMATION NEEDS; HEALTH-CARE; PROSTATE-CANCER; MAKING PREFERENCES; PARTICIPATION PREFERENCES; PHYSICIAN PERCEPTIONS; PROFESSIONAL CARERS; COLORECTAL-CANCER AB Objectives: Empirical literature on patient decision role preferences regarding treatment and screening was reviewed to summarize patients' role preferences across measures, time and patient population. Methods: Five databases were searched from January 1980 to December 2007 (1980-2007 Ovid MEDLINE, Cochrane Database of Systematic Reviews, PsychInfo, Web of Science and PubMed (2005-2007)). Eligible studies measured patient decision role preferences, described measures, presented findings as percentages or mean scores and were published in English from any country. Studies were compared by patient population, time of publication, and measure. Results: 115 studies were eligible. The majority of patients preferred sharing decisions with physicians in 63% of the studies. A time trend appeared. The majority of respondents preferred sharing decision roles in 71% of the studies from 2000 and later, compared to 50% of studies before 2000. Measures themselves, in addition to patient population, influenced the preferred decision roles reported. Conclusion: Findings appear to vary with the measure of preferred decision making used, time of the publication and characteristics of the population. Practice implications: The role preference measure itself must be considered when interpreting patient responses to a measure or question about a patient's preference for decision roles. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Chewning, Betty] Univ Wisconsin, Sch Pharm, Sonderegger Res Ctr, Madison, WI 53705 USA. [Bylund, Carma L.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY USA. [Shah, Bupendra] Arnold & Marie Schwartz Coll Pharm, Div Pharmaceut Sci, Brooklyn, NY USA. [Arora, Neeraj K.] NCI, Outcomes Res Branch, ARP, DCCPS, Bethesda, MD 20892 USA. [Gueguen, Jennifer A.] Mem Sloan Kettering Canc Ctr, Integrat Med Serv, New York, NY USA. [Makoul, Gregory] Univ Connecticut, Sch Med, St Francis Hosp & Med Ctr, Storrs, CT USA. RP Chewning, B (reprint author), Univ Wisconsin, Sch Pharm, Sonderegger Res Ctr, 777 Highland Ave, Madison, WI 53705 USA. EM bachewning@pharmacy.wisc.edu FU NIA NIH HHS [R01 AG018362] NR 140 TC 159 Z9 164 U1 11 U2 60 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JAN PY 2012 VL 86 IS 1 BP 9 EP 18 DI 10.1016/j.pec.2011.02.004 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 882RW UT WOS:000299582600003 PM 21474265 ER PT J AU Han, PKJ Klein, WMP Killam, B Lehman, T Massett, H Freedman, AN AF Han, Paul K. J. Klein, William M. P. Killam, Bill Lehman, Tom Massett, Holly Freedman, Andrew N. TI Representing randomness in the communication of individualized cancer risk estimates: Effects on cancer risk perceptions, worry, and subjective uncertainty about risk SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Risk communication; Uncertainty; Randomness; Cancer ID BREAST-CANCER; DECISION-MAKING; PROBABILITY; MODELS; INDEX; WOMEN AB Objective: To test the effect of novel representations of randomness on risk perceptions, worry, and subjective uncertainty about individualized colorectal cancer risk estimates. Methods: A web-based factorial experiment was conducted, in which 225 adults aged 40 years and older were provided with hypothetical individualized colorectal cancer risk estimates, using 5 different textual and visual representations varying in expressed randomness. Outcome measures were perceived cancer risk, cancer worry, and subjective uncertainty about cancer risk: the moderating effect of dispositional optimism was also examined. Results: Representational format was significantly associated with subjective uncertainty about cancer risk, but not with perceived cancer risk or worry. A format using software-based animation to express randomness dynamically led to the highest subjective uncertainty, although a static visual non-random format also increased uncertainty. Dispositional optimism moderated this effect: between-format differences in uncertainty were significant only for participants with low optimism. Conclusion: Representing randomness in individualized estimates of cancer risk increases subjective uncertainty about risk. A novel dynamic visual format produces the greatest effect, which is moderated by individual differences in optimism. Practice implications: Novel representations of randomness may be effective in improving people's understanding of the essential uncertainty pertaining to individualized cancer risk estimates. Published by Elsevier Ireland Ltd. C1 [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04105 USA. [Klein, William M. P.; Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Killam, Bill] User Ctr Design, Ashburn, VA 20147 USA. [Lehman, Tom] Acad Educ Dev, Ctr Social Mkt & Behav Change, Washington, DC USA. [Massett, Holly] NCI, Off Market Res & Evaluat, Bethesda, MD 20892 USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 39 Forest Ave, Portland, ME 04105 USA. EM hanp@mmc.org OI Han, Paul/0000-0003-0165-1940 FU Intramural NIH HHS [Z99 CA999999] NR 25 TC 17 Z9 17 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JAN PY 2012 VL 86 IS 1 BP 106 EP 113 DI 10.1016/j.pec.2011.01.033 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 882RW UT WOS:000299582600016 PM 21377311 ER PT J AU Schloesser, RJ Martinowich, K Manji, HK AF Schloesser, Robert J. Martinowich, Keri Manji, Husseini K. TI Mood-stabilizing drugs: mechanisms of action SO TRENDS IN NEUROSCIENCES LA English DT Review DE bipolar disorder; mood-stabilizing drugs; neurotrophic factors; synaptic plasticity; mania; lithium ID BIPOLAR DISORDER PATIENTS; DEEP BRAIN-STIMULATION; GRAY-MATTER VOLUME; TREATMENT-RESISTANT DEPRESSION; ANTIDEPRESSANT-INDUCED MANIA; NEONATAL-RAT HIPPOCAMPUS; LITHIUM-TREATED PATIENTS; NMDA RECEPTOR BLOCKADE; D-ASPARTATE ANTAGONIST; MAJOR DEPRESSION AB Mood-stabilizing drugs are the most widely prescribed pharmacological treatments for bipolar disorder, a disease characterized by recurrent episodes of mania and depression. Despite extensive clinical utilization, significant questions concerning their mechanisms of action remain. In recent years, a diverse set of molecular and cellular targets of these drugs has been identified. Based on these findings, downstream effects on neural and synaptic plasticity within key circuits have been proposed. Here, we discuss recent data, identify current challenges impeding progress and define areas for future investigation. Further understanding of the primary targets and downstream levels of convergence of mood-stabilizing drugs will guide development of novel therapeutic strategies and help translate discoveries into more effective treatments with less burdensome adverse-effect profiles. C1 [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ 08560 USA. [Schloesser, Robert J.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Martinowich, Keri] NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ 08560 USA. EM HManji@its.jnj.com RI Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU National Institute of Mental Health FX Support was provided by the National Institute of Mental Health Intramural Research Program. The figures and illustrations were designed and created by Anne K. Schlosser. NR 133 TC 42 Z9 42 U1 4 U2 21 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JAN PY 2012 VL 35 IS 1 SI SI BP 36 EP 46 DI 10.1016/j.tins.2011.11.009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 884MU UT WOS:000299713000005 PM 22217451 ER PT J AU Fontes, JD Lyass, A Massaro, JM Rienstra, M Dallmeier, D Schnabel, RB Wang, TJ Vasan, RS Lubitz, SA Magnani, JW Levy, D Ellinor, PT Fox, CS Benjamin, EJ AF Fontes, Joao D. Lyass, Asya Massaro, Joseph M. Rienstra, Michiel Dallmeier, Dhayana Schnabel, Renate B. Wang, Thomas J. Vasan, Ramachandran S. Lubitz, Steven A. Magnani, Jared W. Levy, Daniel Ellinor, Patrick T. Fox, Caroline S. Benjamin, Emelia J. TI Insulin Resistance and Atrial Fibrillation (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID METABOLIC SYNDROME; DIABETES-MELLITUS; RISK; ATHEROSCLEROSIS; ASSOCIATION; DISEASE; COHORT; MEN AB Diabetes mellitus and obesity are increasing in prevalence and are associated with an elevated risk of atrial fibrillation (AF). Given the aging of the United States population, AF is projected to concomitantly increase in prevalence in the upcoming decades. Both diabetes and obesity are associated with insulin resistance. Whether insulin resistance is an intermediate step for the development of AF is uncertain. We hypothesized that insulin resistance is associated with an increased risk of incident AF. We examined the association of insulin resistance with incident AF using multivariate Cox proportional hazards regression analysis adjusting for the established AF risk factors (i.e., age, gender, systolic blood pressure, hypertension treatment, PR interval, significant heart murmur, heart failure, and body mass index). Of the 3,023 eligible participants (55% women; mean age 59 years) representing 4,583 person-examinations (Framingham Offspring fifth and seventh examination cycles), 279 participants developed AF (9.3%) within <= 10 years of follow-up. With multivariate modeling, insulin resistance was not significantly associated with incident AF (hazard ratio comparing top quartile to other 3 quartiles of homeostatic model assessment index 1.18, 95% confidence interval 0.84 to 1.65, p = 0.34). In a community-based cohort with <= 10 years of follow-up, no significant association was observed between insulin resistance and incident AF. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:87-90) C1 [Fontes, Joao D.; Lyass, Asya; Massaro, Joseph M.; Rienstra, Michiel; Dallmeier, Dhayana; Schnabel, Renate B.; Wang, Thomas J.; Vasan, Ramachandran S.; Magnani, Jared W.; Levy, Daniel; Fox, Caroline S.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Fontes, Joao D.; Lyass, Asya; Massaro, Joseph M.; Rienstra, Michiel; Dallmeier, Dhayana; Schnabel, Renate B.; Wang, Thomas J.; Vasan, Ramachandran S.; Magnani, Jared W.; Levy, Daniel; Fox, Caroline S.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Fontes, Joao D.; Vasan, Ramachandran S.; Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Lyass, Asya; Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Rienstra, Michiel; Wang, Thomas J.; Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rienstra, Michiel] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands. [Dallmeier, Dhayana] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Dept Med 2, Mainz, Germany. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Benjamin, EJ (reprint author), NHLBI, Framingham, MA USA. EM emelia@bu.edu RI Schnabel, Renate/F-6527-2014; OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Institutes of Health/National Heart, Lung, Blood Institute (Bethesda, Maryland) [N01-HC-25195, 6R01-NS17950]; Boston University's Framingham Heart Study (Framingham, Massachusetts [RO1AG028321, 1RC1HL101056, 1R01HL102214, 1R01HL092577, R01HL104156, R21DA027021, K24HL105780]; National Institutes of Health (Bethesda, Maryland) [1RO1HL71039]; Deutsche Forschungsgemeinschaft (German Research Foundation) (Bonn, Germany) [SCHN 1149/1-1]; American Heart Association [09FTF2190028]; Netherlands Organization for Scientific Research (Den Haag, The Netherlands) [825.09.020]; Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative at Boston University (Boston, Massachusetts) FX This study was supported by grants N01-HC-25195 and 6R01-NS17950 from the National Institutes of Health/National Heart, Lung, Blood Institute (Bethesda, Maryland) and Boston University's Framingham Heart Study (Framingham, Massachusetts); grants RO1AG028321, 1RC1HL101056; and 1R01HL102214 (to E. J. Benjamin), 1R01HL092577 (to E. J. Benjamin and P.T. Ellinor), R01HL104156, R21DA027021, and K24HL105780 (to P. T. Ellinor), and 1RO1HL71039 (R. S. Vasan) from the National Institutes of Health (Bethesda, Maryland); Deutsche Forschungsgemeinschaft (German Research Foundation) (Bonn, Germany) Research Fellowship SCHN 1149/1-1 (to R. B. Schnabel); American Heart Association grant 09FTF2190028 (to J.W. Magnani); and Rubicon grant 825.09.020 (to M. Rienstra) from The Netherlands Organization for Scientific Research (Den Haag, The Netherlands). This work was also partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative at Boston University (Boston, Massachusetts) (available from: http://www.bumc.bu.edu/evanscenteribr/thearcs/the-arcs/atrial-fibrillati on-initiative-af-arc/). NR 19 TC 14 Z9 14 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 1 PY 2012 VL 109 IS 1 BP 87 EP 90 DI 10.1016/j.amjcard.2011.08.008 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 873RJ UT WOS:000298900400015 PM 21996140 ER PT J AU Ashida, S Wilkinson, AV Koehly, LM AF Ashida, Sato Wilkinson, Anna V. Koehly, Laura M. TI Social Influence and Motivation to Change Health Behaviors Among Mexican-Origin Adults: Implications for Diet and Physical Activity SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE Social Influence; Behavioral Motivation; Family Health History; Mexican-American; Prevention Research AB Purpose. To evaluate whether influence from social network members is associated with motivation to change dietary and physical activity behaviors. Design. Baseline assessment followed by mailing of family health history based personalized messages (2 weeks) and follow-up assessment (3 months). Setting. Families from an ongoing population-based cohort in Houston, Texas. Subjects. 475 adults from 161 Mexican-origin families. Out of 347 households contacted, 162 (47%) participated. Measures. Family health history, social networks, and motivation to change behaviors. Analysis. Two-level logistic regression modeling. Results. Having at least one network member who encourages one to eat more fruits and vegetables (p = .010) and to engage in regular physical activity (p = .046) was associated with motivation to change the relevant behavior. About 40% of the participants did not have encouragers for these behaviors. Conclusions. Identification of new encouragers within networks and targeting natural encouragers (e.g., children, spouses) may increase the efficacy of interventions to motivate behavioral changes among Mexican-origin adults. (Am J Health Promot 2012;26131:176-179.) C1 [Ashida, Sato] Univ Memphis, Div Social & Behav Sci, Sch Publ Hlth, Memphis, TN 38152 USA. [Ashida, Sato; Koehly, Laura M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Wilkinson, Anna V.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Ashida, S (reprint author), Univ Memphis, Div Social & Behav Sci, Sch Publ Hlth, Memphis, TN 38152 USA. EM sashida@memphis.edu FU Intramural NIH HHS [ZIA HG200335-05]; NCI NIH HHS [CA126988]; NHGRI NIH HHS [Z01HG200335] NR 10 TC 15 Z9 15 U1 1 U2 23 PU AMER JOURNAL HEALTH PROMOTION INC PI TROY PA PO BOX 1254, TROY, MI 48099-1254 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JAN-FEB PY 2012 VL 26 IS 3 BP 176 EP 179 DI 10.4278/ajhp.100107-QUAN-2 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 880ZE UT WOS:000299448300008 PM 22208416 ER PT J AU Nestadt, G Wang, Y Grados, MA Riddle, MA Greenberg, BD Knowles, JA Fyer, AJ McCracken, JT Rauch, SL Murphy, DL Rasmussen, SA Cullen, B Piacentini, J Geller, D Pauls, D Bienvenu, OJ Chen, Y Liang, KY Goes, FS Maher, B Pulver, AE Shugart, YY Valle, D Samuels, JF Chang, YC AF Nestadt, G. Wang, Y. Grados, M. A. Riddle, M. A. Greenberg, B. D. Knowles, J. A. Fyer, A. J. McCracken, J. T. Rauch, S. L. Murphy, D. L. Rasmussen, S. A. Cullen, B. Piacentini, J. Geller, D. Pauls, D. Bienvenu, O. J. Chen, Y. Liang, K. Y. Goes, F. S. Maher, B. Pulver, A. E. Shugart, Y. Y. Valle, D. Samuels, J. F. Chang, Y. C. TI Homeobox genes in obsessive-compulsive disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE OCD; PBX1; MEIS2; LMX1A; NANOG; genetic association ID OCD COLLABORATIVE GENETICS; EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTORS; POLARIZING REGION; SELF-RENEWAL; MUTANT MICE; DNA-BINDING; PBX MARKS; FAMILY; EXPRESSION AB Background: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. Methods: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. Results: Three SNPs are most strongly associated with OCD: rs11854486 (P=0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR)=11.1 homozygous and 1.6 heterozygous) and rs4625687 [P=0.00007 (after adjustment=0.06); GRR=2.4] on 15q; and rs4387163 (P=0.0002 (after adjustment=0.08); GRR=1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1 and LMX1A. Conclusions: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD. (C) 2011 Wiley Periodicals, Inc. C1 [Nestadt, G.; Wang, Y.; Grados, M. A.; Riddle, M. A.; Cullen, B.; Bienvenu, O. J.; Goes, F. S.; Pulver, A. E.; Samuels, J. F.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Greenberg, B. D.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Knowles, J. A.; Rasmussen, S. A.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, Manhattan, KS USA. [McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Rauch, S. L.; Geller, D.; Pauls, D.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Rauch, S. L.; Geller, D.; Pauls, D.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.; Geller, D.; Pauls, D.] Massachusetts Gen Hosp, Neurodev Genet Unit, Boston, MA 02114 USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Chen, Y.; Liang, K. Y.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Maher, B.] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Shugart, Y. Y.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Shugart, Y. Y.] NIMH, Genom Res Branch, Div Neurosci & Basic Behav Sci, NIH, Bethesda, MD 20892 USA. [Valle, D.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Chang, Y. C.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. RP Nestadt, G (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 600 N Wolfe St,Meyer 109, Baltimore, MD 21287 USA. EM gnestadt@jhmi.edu RI Maher, Brion/F-9185-2010; OI Samuels, Jack/0000-0002-6715-7905 FU National Institute of Health [R01-MH-50214, NIH/NCRR/OPD-GCRC RR00052] FX Grant sponsor: National Institute of Health; Grant numbers: R01-MH-50214, NIH/NCRR/OPD-GCRC RR00052. NR 62 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2012 VL 159B IS 1 BP 53 EP 60 DI 10.1002/ajmg.b.32001 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 868QC UT WOS:000298536800008 PM 22095678 ER PT J AU Judy, JT Seifuddin, F Mahon, PB Huo, YQ Goes, FS Jancic, D Schweizer, B Mondimore, FM MacKinnon, DF DePaulo, JR Gershon, ES McMahon, FJ Cutler, DJ Zandi, PP Potash, JB Willour, VL AF Judy, Jennifer T. Seifuddin, Fayaz Mahon, Pamela B. Huo, Yuqing Goes, Fernando S. Jancic, Dubravka Schweizer, Barbara Mondimore, Francis M. MacKinnon, Dean F. DePaulo, J. Raymond, Jr. Gershon, Elliot S. McMahon, Francis J. Cutler, David J. Zandi, Peter P. Potash, James B. Willour, Virginia L. TI Association study of serotonin pathway genes in attempted suicide SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE suicidal behavior; bipolar disorder; major depression ID RANDOMIZED CONTROLLED-TRIALS; GENOME-WIDE ASSOCIATION; DIAGNOSTIC INTERVIEW; REUPTAKE INHIBITORS; GENETICS; BEHAVIOR; DEPRESSION; DISORDERS; LINKAGE; SAMPLE AB Epidemiological studies, such as family, twin, and adoption studies, demonstrate the presence of a heritable component to both attempted and completed suicide. Some of this heritability is accounted for by the presence of comorbid psychiatric disorders, but the evidence also indicates that a portion of this heritability is specific to suicidality. The serotonergic system has been studied extensively in this phenotype, but findings have been inconsistent, possibly due to the presence of multiple susceptibility variants and/or genegene interactions. In this study, we genotyped 174 tag and coding single nucleotide polymorphisms (SNPs) from 17 genes within the serotonin pathway on 516 subjects with a major mood disorder and a history of a suicide attempt (cases) and 515 healthy controls, with the goal of capturing the common genetic variation across each of these candidate genes. We tested the 174 markers in single-SNP, haplotype, gene-based, and epistasis analyses. While these association analyses identified multiple marginally significant SNPs, haplotypes, genes, and interactions, none of them survived correction for multiple testing. Additional studies, including assessment in larger sample sets and deep resequencing to identify rare causal variants, may be required to fully understand the role that the serotonin pathway plays in suicidal behavior. (C) 2011 Wiley Periodicals, Inc. C1 [Potash, James B.; Willour, Virginia L.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. [Judy, Jennifer T.; Seifuddin, Fayaz; Mahon, Pamela B.; Huo, Yuqing; Goes, Fernando S.; Jancic, Dubravka; Schweizer, Barbara; Mondimore, Francis M.; MacKinnon, Dean F.; DePaulo, J. Raymond, Jr.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Gershon, Elliot S.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cutler, David J.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Zandi, Peter P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. RP Willour, VL (reprint author), Univ Iowa, Carver Coll Med, Dept Psychiat, 500 Newton Rd,Med Labs B002J, Iowa City, IA 52242 USA. EM virginia-willour@uiowa.edu OI McMahon, Francis/0000-0002-9469-305X FU National Institute of Mental Health [MH079240]; American Foundation for Suicide Prevention; Margaret Price Investigatorships FX Grant sponsor: National Institute of Mental Health; Grant number: MH079240; Grant sponsor: American Foundation for Suicide Prevention.; This work was supported by grants from the National Institute of Mental Health (MH079240 to V. L. W.) and the American Foundation for Suicide Prevention (V.L.W.). Dr. Willour and Dr. Potash were also supported by Margaret Price Investigatorships. Some DNA samples were prepared and distributed by Rutgers University under a contract from the NIMH. We are grateful to the many interviewers and diagnosticians who contributed to this project, and to the families who devoted their time and effort to the study. The Bipolar Disorder Phenome Group consists of Francis McMahon, Jo Steele, Justin Pearl, Layla Kassem, Victor Lopez from the Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; James Potash, Dean MacKinnon, Erin Miller, Jennifer Toolan from the Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD; Peter Zandi from the Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Thomas Schulze from the Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany; Evaristus Nwulia from the Department of Psychiatry, Howard University Hospital, Washington, D.C.; Sylvia Simpson from the Department of Psychiatry, University of Colorado at Denver, Denver, CO. Acknowledgment for Bipolar Disorder Biomaterials and Clinical Data: Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01MH46282, John Nurnberger M.D., Ph.D., Marvin Miller M.D., and Elizabeth Bowman M.D.; Washington University, St. Louis, MO, U01 MH46280, Theodore Reich M.D., Allison Goate Ph.D., and John Rice Ph.D.; Johns Hopkins University, Baltimore, MD U01 MH46274, J. Raymond DePaulo Jr M.D., Sylvia Simpson M.D., MPH, and Colin Stine Ph.D.; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon M.D., Diane Kazuba B.A., and Elizabeth Maxwell M.S.W. Data and biomaterials were collected as part of 10 projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1999 to 2003, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger M.D., Ph.D., Marvin J. Miller M.D., Elizabeth S. Bowman M.D., N. Leela Rau M.D., P. Ryan Moe M.D., Nalini Samavedy M.D., Rif El-Mallakh M.D. (at University of Louisville), Husseini Manji M.D. (at Wayne State University), Debra A. Glitz M.D. (at Wayne State University), Eric T. Meyer M.S., Carrie Smiley R.N., Tatiana Foroud Ph.D., Leah Flury M.S., Danielle M. Dick Ph.D., Howard Edenberg Ph.D.; Washington University, St. Louis, MO, R01 MH059534, John Rice Ph.D., Theodore Reich M.D., Allison Goate Ph.D., Laura Bierut M. D.; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis M.D., J. Raymond DePauloJr M.D., Dean F. MacKinnon M.D., Francis M. Mondimore M.D., James B. Potash M.D., Peter P. Zandi Ph.D., Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini M.D., Ph.D.; University of California at Irvine, CA, R01 MH60068, William Byerley M.D., and Mark Vawter M.D.; University of Iowa, IA, R01 MH059548, William Coryell M.D., and Raymond Crowe M.D.; ; University of Chicago, IL, R01 MH59535,Elliot Gershon, M.D., Judith Badner Ph. D., Francis McMahon M.D., Chunyu Liu Ph.D., Alan Sanders M.D., Maria Caserta, Steven Dinwiddie M.D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe M.D., Rebecca McKinney B. A.; Rush University, IL, R01 MH059556, William Scheftner M.D., Howard M. Kravitz D.O., M.P.H., Diana Marta B.S., Annette Vaughn-Brown MSN, RN, and Laurie Bederow MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J. McMahon M.D., Layla Kassem PsyD, Sevilla Detera-Wadleigh Ph.D., Lisa Austin Ph.D, Dennis L. Murphy M.D. Acknowledgment for Depression Sample Biomaterials and Clinical Data: Data and biomaterials were collected in six projects that participated in the National Institute of Mental Health (NIMH) Genetics of Recurrent Early-Onset Depression (GenRED) Project. From 1999 to 2003, the Principal Investigators and Co-Investigators were: New York State Psychiatric Institute, New York, NY, R01 MH060912, Myrna M. Weissman Ph. D. and James K. Knowles M.D., Ph. D.; University of Pittsburgh, Pittsburgh, PA, R01 MH060866, George S. Zubenko M.D., Ph.D. and Wendy N. Zubenko Ed. D., R.N., C.S.; Johns Hopkins University, Baltimore, R01 MH059552, J. Raymond DePaulo M.D., Melvin G. McInnis M.D., and Dean MacKinnon M. D.; University of Pennsylvania, Philadelphia, PA, RO1 MH61686, Douglas F. Levinson M.D. (GenRED coordinator), Madeleine M. Gladis Ph.D., Kathleen Murphy-Eberenz Ph.D., and Peter Holmans Ph.D. (University of Wales College of Medicine); University of Iowa, Iowa City, IA, R01 MH059542, Raymond R. Crowe M.D. and William H. Coryell M.D.; Rush University Medical Center, Chicago, IL, R01 MH059541-05, William A. Scheftner M.D., Rush-Presbyterian. Acknowledgment for Control Sample Biomaterials and Clinical Data: Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the "Molecular Genetics of Schizophrenia II'' (MGS-2) Collaboration. The Investigators and Co-Investigators are: ENH/Northwestern University, Evanston, IL, MH059571, Pablo V. Gejman M. D. (Collaboration Coordinator; P. I.), Alan R. Sanders M. D.; Emory University School of Medicine, Atlanta, GA, MH59587, Farooq Amin M. D. (P. I.); Louisiana State University Health Sciences Center; New Orleans, Louisiana, MH067257, Nancy Buccola APRN, BC, MSN (P.I.); University of California-Irvine, Irvine, CA, MH60870, William Byerley M.D. (P.I.); Washington University, St. Louis, MO, U01, MH060879, C. Robert Cloninger M.D. (P.I.); University of Iowa, IA, MH59566, Raymond Crowe M.D. (P.I.), Donald Black M.D.; University of Colorado, Denver, CO, MH059565, Robert Freedman M.D. (P.I.); University of Pennsylvania, Philadelphia, PA, MH061675, Douglas Levinson M.D. (P.I.); University of Queensland, Queensland, Australia, MH059588, Bryan Mowry M.D. (P.I.); Mt. Sinai School of Medicine, New York, NY, MH59586, Jeremy Silverman Ph.D. (P.I.). In addition, cord blood samples were collected by V L Nimgaonkar's Group at the University of Pittsburgh, as part of a Multi-Institutional Collaborative Research Project with J. Smoller M.D.D. Sc. and P. Sklar M.D., Ph.D. (Massachusetts General Hospital, grant MH 63420). NR 32 TC 6 Z9 6 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2012 VL 159B IS 1 BP 112 EP 119 DI 10.1002/ajmg.b.32008 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 868QC UT WOS:000298536800015 PM 22170779 ER PT J AU Goldman, SM Kamel, F Ross, GW Jewell, SA Bhudhikanok, GS Umbach, D Marras, C Hauser, RA Jankovic, J Factor, SA Bressman, S Lyons, KE Meng, C Korell, M Roucoux, DF Hoppin, JA Sandler, DP Langston, JW Tanner, CM AF Goldman, Samuel M. Kamel, Freya Ross, G. Webster Jewell, Sarah A. Bhudhikanok, Grace S. Umbach, David Marras, Connie Hauser, Robert A. Jankovic, Joseph Factor, Stewart A. Bressman, Susan Lyons, Kelly E. Meng, Cheryl Korell, Monica Roucoux, Diana F. Hoppin, Jane A. Sandler, Dale P. Langston, J. William Tanner, Caroline M. TI Head injury, alpha-synuclein Rep1, and Parkinson's disease SO ANNALS OF NEUROLOGY LA English DT Article ID TRAUMATIC BRAIN-INJURY; ENVIRONMENTAL RISK-FACTORS; CELL-DEATH; INFLAMMATORY RESPONSE; AMYLOID-BETA; RAT MODEL; EXPRESSION; POPULATION; ACCUMULATION; PATHOGENESIS AB Objective: To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding a-synuclein, modifies the association between head injury and Parkinson's disease (PD) risk. Methods: Participants in the Farming and Movement Evaluation (FAME) and the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), 2 independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to Parkinson's disease (PD) diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury. Results: Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9), and long Rep1 with increased risk (pooled OR, 1.4; 95% CI, 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR, 1.3; 95% CI, 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR, 5.4; 95% CI, 1.5-19; SEARCH OR, 2.3; 95% CI, 0.6-9.2; pooled OR, 3.5; 95% CI 1.4-9.2, p-interaction 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p 0.03). Interpretation: While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/ or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential. ANN NEUROL 2012; 71: 40-48 C1 [Goldman, Samuel M.; Jewell, Sarah A.; Bhudhikanok, Grace S.; Meng, Cheryl; Korell, Monica; Roucoux, Diana F.; Langston, J. William; Tanner, Caroline M.] Parkinsons Inst, Sunnyvale, CA 94085 USA. [Kamel, Freya; Hoppin, Jane A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Umbach, David] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Jewell, Sarah A.] German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany. [Marras, Connie] Univ Toronto, Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Hauser, Robert A.] Univ S Florida, Dept Neurol, Tampa, FL 33620 USA. [Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Factor, Stewart A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Bressman, Susan] Beth Israel Deaconess Med Ctr, Dept Neurol, New York, NY 10003 USA. [Lyons, Kelly E.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. RP Goldman, SM (reprint author), Parkinsons Inst, 675 Almanor Ave, Sunnyvale, CA 94085 USA. EM sgoldman@thepi.org RI Hauser, Robert/I-5372-2012; Goldman, Samuel/A-2225-2014; OI Jewell, Sarah/0000-0002-9877-2599; Goldman, Samuel/0000-0002-3039-9927; Sandler, Dale/0000-0002-6776-0018 FU NIH (National Institute of Environmental Health Sciences [NIEHS]) [Z01-ES044007, Z01-ES049030, R01-ES10803, U54 ES012077, NCI Z01-CP010119]; Michael J. Fox Foundation FX This research was supported in part by the Intramural Research Program of the NIH (National Institute of Environmental Health Sciences [NIEHS] Z01-ES044007, Z01-ES049030, R01-ES10803 (C. M. T.), U54 ES012077 (C. M. T., J.W.L.); NCI Z01-CP010119); Michael J. Fox Foundation (C. M. T., J. W. L.); Parkinson's Unity Walk; James and Sharron Clark. SEARCH was supported by an unrestricted grant from a group of current and former manufacturers of welding consumables awarded to The Parkinson's Institute. NR 68 TC 34 Z9 34 U1 0 U2 11 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 JAN PY 2012 VL 71 IS 1 BP 40 EP 48 DI 10.1002/ana.22499 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 880MW UT WOS:000299412200008 PM 22275250 ER PT J AU Bielekova, B McFarland, H AF Bielekova, Bibiana McFarland, Henry TI Comment on "Interleukin-2/Interleukin-2 Antibody Therapy Induces Target Organ Natural Killer Cells That Inhibit Central Nervous System Inflammation" SO ANNALS OF NEUROLOGY LA English DT Letter C1 [Bielekova, Bibiana; McFarland, Henry] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2012 VL 71 IS 1 BP 148 EP 149 DI 10.1002/ana.22547 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 880MW UT WOS:000299412200022 PM 22275261 ER PT J AU Friesen, MC Coble, JB Lu, W Shu, XO Ji, BT Xue, SZ Portengen, L Chow, WH Gao, YT Yang, G Rothman, N Vermeulen, R AF Friesen, Melissa C. Coble, Joseph B. Lu, Wei Shu, Xiao-Ou Ji, Bu-Tian Xue, Shouzheng Portengen, Lutzen Chow, Wong-Ho Gao, Yu-Tang Yang, Gong Rothman, Nathaniel Vermeulen, Roel TI Combining a Job-Exposure Matrix with Exposure Measurements to Assess Occupational Exposure to Benzene in a Population Cohort in Shanghai, China SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE benzene; job-exposure matrix; mixed-effects models; retrospective exposure assessment ID LONG-TERM TRENDS; RUBBER MANUFACTURING-INDUSTRY; RETROSPECTIVE EXPOSURE; COMPREHENSIVE EVALUATION; WOOD DUST; INHALABLE PARTICULATE; HISTORICAL EXPOSURES; INHALATION EXPOSURE; US INDUSTRIES; RISK AB Generic job-exposure matrices (JEMs) are often used in population-based epidemiologic studies to assess occupational risk factors when only the job and industry information of each subject is available. JEM ratings are often based on professional judgment, are usually ordinal or semi-quantitative, and often do not account for changes in exposure over time. We present an empirical Bayesian framework that combines ordinal subjective JEM ratings with benzene measurements. Our aim was to better discriminate between job, industry, and time differences in exposure levels compared to using a JEM alone. We combined 63 221 short-term area air measurements of benzene exposure (1954-2000) collected during routine health and safety inspections in Shanghai, China, with independently developed JEM intensity ratings for each job and industry using a mixed-effects model. The fixed-effects terms included the JEM intensity ratings for job and industry (both ordinal, 0-3) and a time trend that we incorporated as a b-spline. The random-effects terms included job (n = 33) and industry nested within job (n = 399). We predicted the benzene concentration in two ways: (i) a calibrated JEM estimate was calculated using the fixed-effects model parameters for calendar year and JEM intensity ratings; (ii) a job-/industry-specific estimate was calculated using the fixed-effects model parameters and the best linear unbiased predictors from the random effects for job and industry using an empirical Bayes estimation procedure. Finally, we applied the predicted benzene exposures to a prospective population-based cohort of women in Shanghai, China (n = 74 942). Exposure levels were 13 times higher in 1965 than in 2000 and declined at a rate that varied from 4 to 15% per year from 1965 to 1985, followed by a small peak in the mid-1990s. The job-/industry-specific estimates had greater differences between exposure levels than the calibrated JEM estimates (97.5th percentile/2.5th percentile exposure level, (BG)R(95B): 20.4 versus 3.0, respectively). The calibrated JEM and job-/industry-specific estimates were moderately correlated in any given year (Pearson correlation, r(p) = 0.58). We classified only those jobs and industries with a job or industry JEM exposure probability rating of 3 (> 50% of workers exposed) as exposed. As a result, 14.8% of the subjects and 8.7% of the employed person-years in the study population were classified as benzene exposed. The cumulative exposure metrics based on the calibrated JEM and job-/industry-specific estimates were highly correlated (r(p) = 0.88). We provide a useful framework for combining quantitative exposure data with expert-based exposure ratings in population-based studies that maximized the information from both sources. Our framework calibrated the ratings to a concentration scale between ratings and across time and provided a mechanism to estimate exposure when a job/industry group reported by a subject was not represented in the exposure database. It also allowed the job/industry groups' exposure levels to deviate from the pooled average for their respective JEM intensity ratings. C1 [Friesen, Melissa C.; Coble, Joseph B.; Ji, Bu-Tian; Xue, Shouzheng; Chow, Wong-Ho; Rothman, Nathaniel; Vermeulen, Roel] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Lu, Wei] Shanghai Municipal Ctr Dis Control, Shanghai, Peoples R China. [Shu, Xiao-Ou; Yang, Gong] Vanderbilt Univ, Div Epidemiol, Dept Med, Vanderbilt Epidemiol Ctr,Sch Med, Nashville, TN 37203 USA. [Portengen, Lutzen; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, Utrecht, Netherlands. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. RP Friesen, MC (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Vermeulen, Roel/F-8037-2011; Friesen, Melissa/A-5362-2009 OI Vermeulen, Roel/0000-0003-4082-8163; FU US National Institutes of Health [R37 CA70867]; National Institutes of Health [N02 CP1101066]; Shanghai Women's Health Study; Shanghai CDC FX US National Institutes of Health (R37 CA70867); Intramural Research Program of the National Institutes of Health (contract N02 CP1101066).; The authors thank the research staff of the Shanghai Women's Health Study and the Shanghai CDC for their support and contributions to the study. NR 57 TC 23 Z9 23 U1 0 U2 13 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 JAN PY 2012 VL 56 IS 1 BP 80 EP 91 DI 10.1093/annhyg/mer080 PG 12 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 879RN UT WOS:000299349800010 PM 21976309 ER PT J AU Yu, BB AF Yu, Binbing TI A minimum version of log-rank test for testing the existence of cancer cure using relative survival data SO BIOMETRICAL JOURNAL LA English DT Article DE Log-rank test; Relative survival; SEER Program; Test of noninferiority ID EFFICIENCY ROBUST-TESTS; LOGRANK TEST; MODELS AB Cancer survival is one of the most important measures to evaluate the effectiveness of treatment and early diagnosis. The ultimate goal of cancer research and patient care is the cure of cancer. As cancer treatments progress, cure becomes a reality for many cancers if patients are diagnosed early and get effective treatment. If a cure does exist for a certain type of cancer, it is useful to estimate the time of cure. For cancers that impose excess risk of mortality, it is informative to understand the difference in survival between cancer patients and the general cancer-free population. In population-based cancer survival studies, relative survival is the standard measure of excess mortality due to cancer. Cure is achieved when the survival of cancer patients is equivalent to that of the general population. This definition of cure is usually called the statistical cure, which is an important measure of burden due to cancer. In this paper, a minimum version of the log-rank test is proposed to test the equivalence of cancer patients' survival using the relative survival data. Performance of the proposed test is evaluated by simulation. Relative survival data from population-based cancer registries in SEER Program are used to examine patients' survival after diagnosis for various major cancer sites. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU National Institute on Aging FX This research was supported in part by the Intramural Research Program of the National Institute on Aging. The author thank the Associate Editor and two anonymous reviewers for their insightful comments and to thank Ms. Caroline Phillips for her conscientious and careful editorial help. NR 20 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD JAN PY 2012 VL 54 IS 1 SI SI BP 45 EP 60 DI 10.1002/bimj.201100069 PG 16 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 872VY UT WOS:000298839300003 PM 22213092 ER PT J AU Ankerst, DP Koniarski, T Liang, YY Leach, RJ Feng, ZD Sanda, MG Partin, AW Chan, DW Kagan, J Sokoll, L Wei, JT Thompson, IM AF Ankerst, Donna P. Koniarski, Tim Liang, Yuanyuan Leach, Robin J. Feng, Ziding Sanda, Martin G. Partin, Alan W. Chan, Daniel W. Kagan, Jacob Sokoll, Lori Wei, John T. Thompson, Ian M. TI Updating risk prediction tools: A case study in prostate cancer SO BIOMETRICAL JOURNAL LA English DT Article DE Calibration; Discrimination; Net benefit; Prostate cancer prevention trial; Risk prediction; Validation ID DECISION CURVE ANALYSIS; OPERATING CHARACTERISTICS; PREVENTION TRIAL; BREAST-CANCER; ROC CURVE; MODELS; MARKER; RECLASSIFICATION; STATISTICS; CALCULATOR AB Online risk prediction tools for common cancers are now easily accessible and widely used by patients and doctors for informed decision-making concerning screening and diagnosis. A practical problem is as cancer research moves forward and new biomarkers and risk factors are discovered, there is a need to update the risk algorithms to include them. Typically, the new markers and risk factors cannot be retrospectively measured on the same study participants used to develop the original prediction tool, necessitating the merging of a separate study of different participants, which may be much smaller in sample size and of a different design. Validation of the updated tool on a third independent data set is warranted before the updated tool can go online. This article reports on the application of Bayes rule for updating risk prediction tools to include a set of biomarkers measured in an external study to the original study used to develop the risk prediction tool. The procedure is illustrated in the context of updating the online Prostate Cancer Prevention Trial Risk Calculator to incorporate the new markers %freePSA and [-2]proPSA measured on an external casecontrol study performed in Texas, U.S.. Recent state-of-the art methods in validation of risk prediction tools and evaluation of the improvement of updated to original tools are implemented using an external validation set provided by the U.S. Early Detection Research Network. C1 [Ankerst, Donna P.] Tech Univ Muenchen, Dept Math, Unit M4, D-85748 Garching, Germany. [Ankerst, Donna P.; Liang, Yuanyuan; Leach, Robin J.; Thompson, Ian M.] UTHSCSA, Dept Urol, San Antonio, TX 78229 USA. [Ankerst, Donna P.; Liang, Yuanyuan] UTHSCSA, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Koniarski, Tim] Univ Regensburg, Int Real Estate Business Sch, D-93040 Regensburg, Germany. [Feng, Ziding] Fred Hutchinson Canc Res Ctr, Program Biostat & Biomath, Seattle, WA 98109 USA. [Sanda, Martin G.] Harvard Univ, Sch Med, Dept Urol, Boston, MA 02215 USA. [Sanda, Martin G.] Beth Israel Deaconess Med Ctr, Prostate Ctr, Boston, MA 02215 USA. [Partin, Alan W.; Chan, Daniel W.; Sokoll, Lori] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Partin, Alan W.; Chan, Daniel W.; Sokoll, Lori] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Kagan, Jacob] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Rockville, MD USA. [Wei, John T.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. RP Ankerst, DP (reprint author), Tech Univ Muenchen, Dept Math, Unit M4, Boltzmannstr 3, D-85748 Garching, Germany. EM ankerst@ma.tum.de RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; Wei, John/E-8967-2012 FU National Institutes of Health [CA086402, CA054174, CA86323, UO1CA113913]; EDRN [CA115102]; National Cancer Institute Cancer Center [CTRC: 5P30 CA0541474-18] FX This research was supported by National Institutes of Health grants CA086402, CA054174, CA86323, UO1CA113913, EDRN grant CA115102, and a National Cancer Institute Cancer Center support grant to the UTHSCSA CTRC: 5P30 CA0541474-18. The authors thank the SABOR and EDRN participants. NR 33 TC 17 Z9 17 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD JAN PY 2012 VL 54 IS 1 SI SI BP 127 EP 142 DI 10.1002/bimj.201100062 PG 16 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 872VY UT WOS:000298839300008 PM 22095849 ER PT J AU Sakurai, A Doci, C Gutkind, JS AF Sakurai, Atsuko Doci, Colleen Gutkind, J. Silvio TI Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer SO CELL RESEARCH LA English DT Review DE semaphorin; signaling; angiogenesis; lymphangiogenesis; cancer ID ENDOTHELIAL-GROWTH-FACTOR; LYMPH-NODE METASTASIS; NUCLEOTIDE EXCHANGE FACTORS; TUMOR-INDUCED ANGIOGENESIS; GTPASE-ACTIVATING PROTEIN; FACTOR-C; FACTOR RECEPTOR-3; BREAST-CANCER; SUPPRESSOR GENE; CELL MOTILITY AB Angiogenesis, the formation of new blood vessels from preexisting vasculature, is essential for many physiological processes, and aberrant angiogenesis contributes to some of the most prevalent human diseases, including cancer. Angiogenesis is controlled by delicate balance between pro- and anti-angiogenic signals. While pro- angiogenic signaling has been extensively investigated, how developmentally regulated, naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood. In this review, we summarize the current knowledge on how semaphorins and their receptors, plexins and neuropilins, control normal and pathological angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells. This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies. C1 [Sakurai, Atsuko; Doci, Colleen; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 105 TC 52 Z9 56 U1 0 U2 9 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYAND ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD JAN PY 2012 VL 22 IS 1 BP 23 EP 32 DI 10.1038/cr.2011.198 PG 10 WC Cell Biology SC Cell Biology GA 879EQ UT WOS:000299312900007 PM 22157652 ER PT J AU Ryan, PM Bourdi, M Korrapati, MC Proctor, WR Vasquez, RA Yee, SB Quinn, TD Chakraborty, M Pohl, LR AF Ryan, Pauline M. Bourdi, Mohammed Korrapati, Midhun C. Proctor, William R. Vasquez, Ronald A. Yee, Steven B. Quinn, Timothy D. Chakraborty, Mala Pohl, Lance R. TI Endogenous Interleukin-4 Regulates Glutathione Synthesis Following Acetaminophen-Induced Liver Injury in Mice SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; INDUCED HEPATOTOXICITY; MOUSE-LIVER; IMMUNE-RESPONSES; COVALENT BINDING; OXIDATIVE STRESS; GENE-EXPRESSION; CRUCIAL ROLE; CD-1 MICE; T-CELLS AB In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating glutathione (GSH) synthesis. In the present studies, the protective role of IL-4 in AILI was established definitively by showing that C57BL/6J mice made deficient in IL-4 genetically (IL-4(-/-)) or by depletion with an antibody, were more susceptible to ALLI than mice not depleted of IL-4. The increased susceptibility of IL-4(-/-) mice was not due to elevated levels of hepatic APAP-protein adducts but was associated with a prolonged reduction in hepatic GSH that was attributed to decreased gene expression of gamma-glutamylcysteine ligase (gamma-GCL). Moreover, administration of recombinant IL-4 to IL-4(-/-) mice postacetaminophen treatment diminished the severity of liver injury and increased gamma-GCL and GSH levels. We also report that the prolonged reduction of GSH in APAP-treated IL-4(-/-) mice appeared to contribute toward increased liver injury by causing a sustained activation of c-Jun-N-terminal kinase (JNK) since levels of phosphorylated JNK remained significantly higher in the IL-4(-/-) mice up to 24 h after APAP treatment. Overall, these results show for the first time that IL-4 has a role in regulating the synthesis of GSH in the liver under conditions of cellular stress. This mechanism appears to be responsible at least in part for the protective role of IL-4 against AILI in mice and may have a similar role not only in AILI in humans but also in pathologies of the liver caused by other drugs and etiologies. C1 [Ryan, Pauline M.; Bourdi, Mohammed; Korrapati, Midhun C.; Proctor, William R.; Vasquez, Ronald A.; Yee, Steven B.; Quinn, Timothy D.; Chakraborty, Mala; Pohl, Lance R.] NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Ctr Immunol,NIH, Bethesda, MD 20892 USA. RP Pohl, LR (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Ctr Immunol,NIH, 9000 Rockville Pike,Bldg 10,Room 8N110, Bethesda, MD 20892 USA. EM pohll@nih.gov FU National Institutes of Health; National Heart Lung and Blood Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Heart Lung and Blood Institute. NR 62 TC 19 Z9 19 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JAN PY 2012 VL 25 IS 1 BP 83 EP 93 DI 10.1021/tx2003992 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 875KL UT WOS:000299028700010 PM 22107450 ER PT J AU Bjarnason, T Bendtsen, P Arnarsson, AM Borup, I Iannotti, RJ Lofstedt, P Haapasalo, I Niclasen, B AF Bjarnason, Thoroddur Bendtsen, Pernille Arnarsson, Arsaell M. Borup, Ina Iannotti, Ronald J. Lofstedt, Petra Haapasalo, Ilona Niclasen, Birgit TI Life Satisfaction Among Children in Different Family Structures: A Comparative Study of 36 Western Societies SO CHILDREN & SOCIETY LA English DT Article DE health and well-being; international childhoods; welfare ID SCHOOL-AGED CHILDREN; NONRESIDENT FATHERS; EMOTIONAL DISTRESS; DIVORCE; BEHAVIORS; ARRANGEMENTS; METAANALYSIS; DELINQUENCY; ADOLESCENTS; ADJUSTMENT AB This paper examines differences in life satisfaction among children in different family structures in 36 western, industrialised countries (n = 184 496). Children living with both biological parents reported higher levels of life satisfaction than children living with a single parent or parentstep-parent. Children in joint physical custody reported significantly higher levels of life satisfaction than their counterparts in other types of non-intact families. Controlling perceived family affluence, the difference between joint physical custody families and single mother or motherstepfather families became non-significant. Difficulties in communicating with parents were strongly associated with less life satisfaction but did not mediate the relation between family structure and life satisfaction. Children in the Nordic countries characterised by strong welfare systems reported significantly higher levels of life satisfaction in all living arrangements except in single father households. Differences in economic inequality between countries moderated the association between certain family structures, perceived family affluence and life satisfaction. C1 [Bjarnason, Thoroddur] Univ Akureyri, Dept Social Sci, IS-600 Akureyri, Iceland. [Bendtsen, Pernille] Univ Copenhagen, Copenhagen, Denmark. [Borup, Ina] Nord Sch Publ Hlth, Gothenburg, Sweden. [Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Lofstedt, Petra] Karolinska Inst, Stockholm, Sweden. [Haapasalo, Ilona] Univ Jyvaskyla, Jyvaskyla, Finland. [Niclasen, Birgit] Greenland Inst Hlth Res, Nuuk, Greenland. RP Bjarnason, T (reprint author), Univ Akureyri, Dept Social Sci, IS-600 Akureyri, Iceland. EM thorodd@unak.is OI Bendtsen, Pernille/0000-0003-4031-738X NR 40 TC 14 Z9 14 U1 6 U2 56 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-0605 J9 CHILD SOC JI Child. Soc. PD JAN PY 2012 VL 26 IS 1 BP 51 EP 62 DI 10.1111/j.1099-0860.2010.00324.x PG 12 WC Social Work SC Social Work GA 867UM UT WOS:000298480300006 ER PT J AU Roger, VL O'Donnell, CJ AF Roger, Veronique L. O'Donnell, Christopher J. TI Population Health, Outcomes Research, and Prevention Example of the American Heart Association 2020 Goals SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Editorial Material DE prevention; delivery of health care; outcomes assessment ID CLINICAL-PRACTICE GUIDELINES; NEW-YORK-CITY; CARDIOVASCULAR-DISEASE; CARE; BEHAVIOR; ERA C1 [Roger, Veronique L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Roger, Veronique L.] Mayo Clin, Div Cardiovasc Dis, Dept Internal Med, Rochester, MN 55905 USA. [O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Dept Internal Med, Boston, MA 02114 USA. RP Roger, VL (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. EM roger.veronique@mayo.edu FU Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [R01 HL059205-13, R01 HL072435, R01 HL072435-08, R01 HL59205, R01 HL059205, R01 HL72435] NR 25 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JAN PY 2012 VL 5 IS 1 BP 6 EP 8 DI 10.1161/CIRCOUTCOMES.111.964734 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 880ML UT WOS:000299411100002 PM 22253367 ER PT J AU Pavkov, ME Knowler, WC Lemley, KV Mason, CC Myers, BD Nelson, RG AF Pavkov, Meda E. Knowler, William C. Lemley, Kevin V. Mason, Clinton C. Myers, Bryan D. Nelson, Robert G. TI Early Renal Function Decline in Type 2 Diabetes SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; SERUM CYSTATIN-C; KIDNEY-FUNCTION; PIMA-INDIANS; MICROALBUMINURIA; PROGRESSION; GFR; INDIVIDUALS; NEPHROPATHY; CREATININE AB Background and objectives Early decline in GFR may reflect progressive kidney disease in type 1 diabetes, but its predictive value in type 2 diabetes is uncertain. Design, setting, participants, & measurements In this longitudinal study, GFR was measured serially over approximately 4.0 years in 195 Pima Indians with type 2 diabetes. Renal function decline (RFD) was defined during this initial period by an average GFR loss >= 3.3%/yr, as defined previously in type 1 diabetes. Subsequently, participants were followed for up to 17.8 years to ESRD onset, death, or December 31, 2010, whichever came first. Results RFD prevalence during the initial period was 32% in 68 participants with normal baseline albuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 42% in 88 with microalbuminuria (ACR 30 to <300 mg/g), and 74% in 39 with macroalbuminuria (ACR >= 300 mg/g; P<0.001). The cumulative incidence of ESRD 10 years after the initial period was 41% in those with RFD and 15% in those without (P<0.001); 41 of the 49 ESRD cases (83.7%) occurred in participants who had or developed macroalbuminuria during the initial period. When adjusted for age, sex, diabetes duration, and hemoglobin A1c, the ESRD hazard rate was 4.78 times (95% confidence interval, 2.39-9.58) as high in those with RFD as in those without; further adjustment for albuminuria attenuated this association (hazard ratio, 1.79; 95% confidence interval, 0.82-3.91). Conclusions In type 2 diabetes, loss of GFR often occurs before the onset of macroalbuminuria, but a decline predictive of ESRD is strongly dependent on progression to macroalbuminuria. Clin J Am Soc Nephrol 7: 78-84, 2012. doi: 10.2215/CJN.07610711 C1 [Pavkov, Meda E.] Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. [Knowler, William C.; Mason, Clinton C.; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. [Lemley, Kevin V.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90033 USA. [Myers, Bryan D.] Stanford Univ, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Pavkov, ME (reprint author), Ctr Dis Control & Prevent, 4770 Buford Hwy NE,MS-K10, Atlanta, GA 30341 USA. EM mpavkov@cdc.gov RI Nelson, Robert/B-1470-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 23 TC 27 Z9 29 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JAN PY 2012 VL 7 IS 1 BP 78 EP 84 DI 10.2215/CJN.07610711 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 877RD UT WOS:000299198700014 PM 22076874 ER PT J AU Semba, RD Fink, JC Sun, K Cappola, AR Dalal, M Crasto, C Ferrucci, L Fried, LP AF Semba, Richard D. Fink, Jeffrey C. Sun, Kai Cappola, Anne R. Dalal, Mansi Crasto, Candace Ferrucci, Luigi Fried, Linda P. TI Serum Fibroblast Growth Factor-23 and Risk of Incident Chronic Kidney Disease in Older Community-Dwelling Women SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; FGF-23; FGF23; PROGRESSION; MORTALITY; EQUATION AB Background and objectives Elevated circulating fibroblast growth factor 23 (FGF23) predicts progression of CKD, but it is unknown whether circulating FGF23 independently predicts incident CKD. This study aimed to determine whether circulating FGF23 predicts incident CKD in community-dwelling women. Design, setting, participants, & measurements This study examined the relationship of intact serum FGF23, 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D), 25-hydroxyvitamin D (25[OH]D), parathyroid hormone, calcium, and phosphate with prevalent and incident CKD in 701 disabled women, >= 65 years of age, from the Women's Health and Aging Study I in Baltimore, Maryland, from 1993 to 1997. Incident CKD was defined as a low estimated GFR (eGFR) <60 ml/min per 1.73 m(2) only, low eGFR <60 ml/min per 1.73 m(2) and a >= 25% decline in eGFR from baseline, and an increase in serum creatinine (>= 0.4 mg/dl) at follow-up. Results At baseline, 381 women (54.3%) had stage 3 CKD. Of 307 women without CKD at baseline, 63 (20.5%) developed stage 3 CKD over 24 months of follow-up. After excluding prevalent cases of CKD, FGF23 (per 1 SD increase) was associated with incident stage 3 CKD (hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.06, 2.16; P=0.02), low and declining eGFR (HR, 3.69; 95% CI, 1.68, 8.11; P=0.001), and increase in serum creatinine (HR, 5.35; 95%, CI, 1.27, 22.54; P=0.02) in respective multivariable Cox proportional hazards models adjusting for baseline eGFR, age, race, phosphate, 1,25-dihydroxyvitamin D(3), parathyroid hormone, and other potential confounders. Conclusions Elevated FGF23 is an independent risk factor for incident CKD in older, disabled, community-dwelling women. Clin J Am Soc. Nephrol 7: 85-91, 2012. doi:10.2215/CJN.08070811 C1 [Semba, Richard D.; Sun, Kai; Dalal, Mansi; Crasto, Candace] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Fink, Jeffrey C.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Smith Bldg,M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu OI Fink, Jeffrey/0000-0002-5622-5052 FU National Institutes of Health [R01AG027012, R01AG029148, R37AG019905]; National Institute on Aging, National Institutes of Health FX This study was supported by Grants R01AG027012, R01AG029148, and R37AG019905 from the National Institutes of Health, as well as the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 28 TC 19 Z9 19 U1 0 U2 11 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JAN PY 2012 VL 7 IS 1 BP 85 EP 91 DI 10.2215/CJN.08070811 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 877RD UT WOS:000299198700015 PM 22076875 ER PT J AU Shastri, S Tangri, N Tighiouart, H Beck, GJ Vlagopoulos, P Ornt, D Eknoyan, G Kusek, JW Herzog, C Cheung, AK Sarnak, MJ AF Shastri, Shani Tangri, Navdeep Tighiouart, Hocine Beck, Gerald J. Vlagopoulos, Panagiotis Ornt, Daniel Eknoyan, Garabed Kusek, John W. Herzog, Charles Cheung, Alfred K. Sarnak, Mark J. TI Predictors of Sudden Cardiac Death: A Competing Risk Approach in the Hemodialysis Study SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID BODY-MASS INDEX; MAINTENANCE HEMODIALYSIS; DIALYSIS PATIENTS; RENAL-DISEASE; VASCULAR CALCIFICATION; CARDIOVASCULAR-DISEASE; COMORBIDITY ASSESSMENT; ALKALINE-PHOSPHATASE; SERUM CREATININE; MORTALITY RISK AB Background and objectives There are few data on risk factors for sudden cardiac death (SCD) in patients undergoing hemodialysis (HD). The study objective was to identify predictors associated with various causes of death in the Hemodialysis (HEMO) Study and to develop a prediction model for SCD using a competing risk approach. Design, setting, participants, & measurements In this analysis of 1745 HEMO participants, all-cause mortality was classified as SCD, non-SCD, and noncardiac death. Predictors for each cause of death were evaluated using cause-specific Cox proportional hazards models, and a competing risk approach was used to calculate absolute risk predictions for SCD. Results During a median follow-up of 2.5 years, 808 patients died. Rates of SCD, non-SCD, and noncardiac death were 22%, 17%, and 61%, respectively. Predictors of various causes of death differ somewhat in HD patients. Age, diabetes, peripheral vascular disease, ischemic heart disease, serum creatinine, and alkaline phosphatase were independent predictors of SCD. The 3-year C-statistic for SCD was 0.75 (95% confidence interval, 0.70-0.79), and calibration was good (chi(2)=1.1; P=0.89). At years 3 and 5 of follow-up, the standard Cox model overestimated the risk for SCD as compared with the competing risk approach on the relative scale by 25% and 46%, respectively, and on the absolute scale by 2% and 6%, respectively. Conclusions Predictors of various causes of death differ in HD patients. The proposed prediction model for SCD accounts for competing causes of death. External validation of this model is required. Clin J Am Soc Nephrol 7: 123-130, 2012. doi: 10.2215/CJN.06320611 C1 [Shastri, Shani; Tangri, Navdeep; Vlagopoulos, Panagiotis; Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA 02111 USA. [Tighiouart, Hocine] Tufts Med Ctr, Biostat Res Ctr, Boston, MA 02111 USA. [Beck, Gerald J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Ornt, Daniel] Case Western Reserve Sch Med, Cleveland, OH USA. [Eknoyan, Garabed] Baylor Coll Med, Houston, TX 77030 USA. [Kusek, John W.] NIH, Bethesda, MD 20892 USA. [Herzog, Charles] Univ Minnesota, Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Cheung, Alfred K.] Univ Utah, Salt Lake City, UT USA. [Cheung, Alfred K.] Vet Affairs Salt Lake City Healthcare Syst, Salt Lake City, UT USA. RP Sarnak, MJ (reprint author), Tufts Med Ctr, Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. EM msarnak@tuftsmedicalcenter.org OI Tangri, Navdeep/0000-0002-5075-6370 FU National Institutes of Health [T32 DK07777, K24 DK078204]; Johnson Johnson; National Institutes of Diabetes and Digestive and Kidney Diseases/National Institutes of Health FX The study was funded by National Institutes of Health Grants T32 DK07777 and K24 DK078204.; C.H. served as a consultant for Amgen, Abbott, Affymax, and Fibrogen; has an equity interest in Cambridge Heart and Boston Scientific; and has received research support from Johnson & Johnson and the National Institutes of Diabetes and Digestive and Kidney Diseases/National Institutes of Health. NR 41 TC 22 Z9 25 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JAN PY 2012 VL 7 IS 1 BP 123 EP 130 DI 10.2215/CJN.06320611 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 877RD UT WOS:000299198700020 PM 22076880 ER PT J AU Biancotto, A Dagur, PK Fuchs, JC Langweiler, M McCoy, JP AF Biancotto, Angelique Dagur, Pradeep K. Fuchs, J. Chris Langweiler, Marc McCoy, J. Philip, Jr. TI OMIP-004: In-depth characterization of human T regulatory cells SO CYTOMETRY PART A LA English DT Editorial Material DE human; T cells; Treg ID EXPRESSION; DIFFERENTIATION; SUBSETS C1 [Biancotto, Angelique; Dagur, Pradeep K.; Fuchs, J. Chris; Langweiler, Marc; McCoy, J. Philip, Jr.] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. RP McCoy, JP (reprint author), 10 Ctr Dr,MSC 1357,Bldg 10,Rm 8C103D, Bethesda, MD 20892 USA. EM mccoyjp@mail.nih.gov FU Intramural NIH HHS [ZIC HL005905-02] NR 7 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD JAN PY 2012 VL 81A IS 1 BP 15 EP 16 DI 10.1002/cyto.a.21158 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 862KH UT WOS:000298089100007 PM 22052639 ER PT J AU Rajagopalan, S Nepa, J Venkatachalam, S AF Rajagopalan, Sangeetha Nepa, Justin Venkatachalam, Sundaresan TI Chromodomain helicase DNA-binding protein 2 affects the repair of X-ray and UV-Induced DNA damage SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE chromatin remodeling; Chd2; DNA repair; UVC; X-ray ID DOUBLE-STRAND BREAKS; NUCLEOTIDE EXCISION-REPAIR; HISTONE H2A; SACCHAROMYCES-CEREVISIAE; IONIZING-RADIATION; MAMMALIAN-CELLS; ATM; INO80; PHOSPHORYLATION; TRANSCRIPTION AB Eukaryotic cells have evolved a variety of parallel and redundant DNA damage response pathways that function in a coordinated fashion to prevent the fixation of DNA damage as mutations. Despite the wealth of knowledge on DNA damage signaling on downstream cellular events, the mechanisms of DNA damage recognition, DNA repair as well as DNA damage signaling in the context of chromatin is poorly understood. Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. In an effort to understand the physiological role of one of the CHD members in a mammalian model system, we developed a mutant mouse model for the Chd2 gene. The Chd2 mutant mice are highly susceptible to spontaneous lymphoid tumor formation. In this study, we present evidence that the Chd2 mutant cells are defective in their ability to repair DNA damage induced by ionizing and ultraviolet radiation. Consistent with the role of Chd2 in regulating DNA damage responses, the Chd2 mutant cells are also sensitive to DNA damaging agents in clonogenic assays. In summary, our data suggest that the Chd2 protein is involved in regulating the DNA damage responses at the chromatin level. Environ. Mol. Mutagen. 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Rajagopalan, Sangeetha; Nepa, Justin; Venkatachalam, Sundaresan] Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN USA. RP Venkatachalam, S (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM sundar@utk.edu FU NIH [5R03CA133761]; Leukemia Research Foundation; PMERF Foundation FX Grant sponsor: NIH; Grant number: 5R03CA133761; Grant sponsors: Leukemia Research Foundation and PMERF Foundation. NR 39 TC 8 Z9 8 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JAN PY 2012 VL 53 IS 1 BP 44 EP 50 DI 10.1002/em.20674 PG 7 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 872ZK UT WOS:000298849900005 PM 22223433 ER PT J AU Theodore, WH Wiggs, EA Martinez, AR Dustin, IH Khan, OI Appel, S Reeves-Tyer, P Sato, S AF Theodore, William H. Wiggs, Edythe A. Martinez, Ashley R. Dustin, Irene H. Khan, Omar I. Appel, Shmuel Reeves-Tyer, Pat Sato, Susumu TI Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy SO EPILEPSIA LA English DT Article DE Serotonin receptors; Temporal lobe epilepsy; Memory; Depression; PET scanning ID POSITRON-EMISSION-TOMOGRAPHY; ACUTE TRYPTOPHAN DEPLETION; 5-HT1A RECEPTOR; HIPPOCAMPAL VOLUME; MAJOR DEPRESSION; ALZHEIMERS-DISEASE; TREATMENT RESPONSE; BINDING; PET; COGNITION AB Purpose: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study. Methods: We studied 40 patients (24 male; mean age 34.5 +/- 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video- electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1). Key Findings: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 +/- 27.3 vs. 95.4 +/- 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 +/- 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory. Significance: Our study suggests that reduced left hippocampal 5HT1A- receptor binding may play a role in memory impairment in patients with TLE. C1 [Theodore, William H.; Martinez, Ashley R.; Dustin, Irene H.; Khan, Omar I.; Reeves-Tyer, Pat] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Wiggs, Edythe A.] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Appel, Shmuel; Sato, Susumu] NINDS, EEG Lab, NIH, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NINDS, Clin Epilepsy Sect, NIH, Bldg 10 Room 7C-103, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov FU NINDS NIH Division of Intramural Research FX Supported by NINDS NIH Division of Intramural Research. We thank Dr Sungyoung Auh for statistical advice. NR 42 TC 22 Z9 25 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JAN PY 2012 VL 53 IS 1 BP 129 EP 133 DI 10.1111/j.1528-1167.2011.03309.x PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 872DZ UT WOS:000298790100020 PM 22050514 ER PT J AU White, HS Alex, AB Pollock, A Hen, N Shekh-Ahmad, T Wilcox, KS McDonough, JH Stables, JP Kaufmann, D Yagen, B Bialer, M AF White, H. Steve Alex, Anitha B. Pollock, Amanda Hen, Naama Shekh-Ahmad, Tawfeeq Wilcox, Karen S. McDonough, John H. Stables, James P. Kaufmann, Dan Yagen, Boris Bialer, Meir TI A new derivative of valproic acid amide possesses a broad-spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage SO EPILEPSIA LA English DT Article DE New anticonvulsant drug; Status epilepticus; Pilocarpine-induced SE rat model; Soman-induced SE rat model; Pharmacokinetic-pharmacodynamic correlation ID TEMPORAL-LOBE EPILEPSY; PILOCARPINE MODEL; INDUCED NEUROPATHOLOGY; SEIZURES; DIAZEPAM; BRAIN; SOMAN; RATS; EPILEPTOGENESIS; LEVETIRACETAM AB Purpose: sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death. Methods: The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s. c.) metrazol-, s. c. picrotoxin, s. c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i. p.) administration in the soman SE rat model. Key Findings: SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD50/ED50]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED50 for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpineinduced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e. g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED50 values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/ L (40 min after the onset of soman-induced seizures). The time to peak (tmax) pharmacodynamic effect (PD-tmax) occurred after the PK-tmax, suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD. Significance: The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement. C1 [Hen, Naama; Shekh-Ahmad, Tawfeeq; Kaufmann, Dan; Yagen, Boris; Bialer, Meir] Hebrew Univ Jerusalem, Sch Pharm, Inst Drug Res, Fac Med, IL-91120 Jerusalem, Israel. [White, H. Steve; Alex, Anitha B.; Pollock, Amanda; Wilcox, Karen S.] Univ Utah, Coll Pharm, Dept Pharmacol & Toxicol, Anticonvulsant Drug Dev Program, Salt Lake City, UT 84112 USA. [McDonough, John H.] USA, Med Res Inst Chem Def, Pharmacol Branch, Div Res, Aberdeen Proving Ground, MD 21010 USA. [Stables, James P.] NINDS, ASP, Off Translat Res, NIH, Bethesda, MD 20892 USA. [Yagen, Boris; Bialer, Meir] Hebrew Univ Jerusalem, David R Bloom Ctr Pharm, IL-91120 Jerusalem, Israel. RP Bialer, M (reprint author), Hebrew Univ Jerusalem, Sch Pharm, Inst Drug Res, Fac Med, IL-91120 Jerusalem, Israel. EM bialer@md.huji.ac.il FU NINDS, NIH [NO1-NS-4-2359]; NIH/NINDS [Y1-O6-9613-01]; USAMRICD [A120-B.P2009-2]; Defense Threat Reduction Agency - Joint Science and Technology Office, Medical ST Division FX Studies conducted at the University of Utah were supported by NINDS, NIH Contract No. NO1-NS-4-2359 (HSW, ABA, KSW, ALP). The studies conducted at MRICD were supported by an Inter-Agency Agreement between NIH/NINDS (Y1-O6-9613-01) and USAMRICD (A120-B.P2009-2) and the Defense Threat Reduction Agency - Joint Science and Technology Office, Medical S&T Division. The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. NR 44 TC 35 Z9 35 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JAN PY 2012 VL 53 IS 1 BP 134 EP 146 DI 10.1111/j.1528-1167.2011.03338.x PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 872DZ UT WOS:000298790100021 PM 22150444 ER PT J AU Gugger, OS Hartmann, J Birnbaumer, L Kapfhammer, JP AF Gugger, Olivia S. Hartmann, Jana Birnbaumer, Lutz Kapfhammer, Josef P. TI P/Q-type and T-type calcium channels, but not type 3 transient receptor potential cation channels, are involved in inhibition of dendritic growth after chronic metabotropic glutamate receptor type 1 and protein kinase C activation in cerebellar Purkinje cells SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebellar organotypic slice cultures; dendritic development; dendritic growth; mouse ID ORGANOTYPIC SLICE CULTURES; CA2+ CHANNELS; PERIPHERAL NEURONS; PHOSPHOLIPASE-C; TRPC3 CHANNELS; EXPRESSION; CURRENTS; MICE; ANTAGONIST; MUTATION AB The development of a neuronal dendritic tree is modulated both by signals from afferent fibers and by an intrinsic program. We have previously shown that chronic activation of either type 1 metabotropic glutamate receptors (mGluR1s) or protein kinase C (PKC) in organotypic cerebellar slice cultures of mice and rats severely inhibits the growth and development of the Purkinje cell dendritic tree. The signaling events linking receptor activation to the regulation of dendritic growth remain largely unknown. We have studied whether channels allowing the entry of Ca2+ into Purkinje cells, in particular the type 3 transient receptor potential cation channels (TRPC3s), P/Q-type Ca2+ channels, and T-type Ca2+ channels, might be involved in signaling after mGluR1 or PKC stimulation. We show that the inhibition of dendritic growth seen after mGluR1 or PKC stimulation is partially rescued by pharmacological blockade of P/Q-type and T-type Ca2+ channels, indicating that activation of these channels mediating Ca2+ influx contributes to the inhibition of dendritic growth. In contrast, the absence of Ca2+ -permeable TRPC3s in TRPC3-deficient mice or pharmacological blockade had no effect on mGluR1-mediated and PKC-mediated inhibition of Purkinje cell dendritic growth. Similarly, blockade of Ca2+ influx through glutamate receptor d2 or R-type Ca2+ channels or inhibition of release from intracellular stores did not influence mGluR1-mediated and PKC-mediated inhibition of Purkinje cell dendritic growth. These findings suggest that both T-type and P/Q-type Ca2+ channels, but not TRPC3 or other Ca2+-permeable channels, are involved in mGluR1 and PKC signaling leading to the inhibition of dendritic growth in cerebellar Purkinje cells. C1 [Gugger, Olivia S.; Kapfhammer, Josef P.] Univ Basel, Inst Anat, Dept Biomed Basel, CH-4056 Basel, Switzerland. [Hartmann, Jana] Tech Univ Munich, Inst Neurosci, Munich, Germany. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Kapfhammer, JP (reprint author), Univ Basel, Inst Anat, Dept Biomed Basel, Pestalozzistr 20, CH-4056 Basel, Switzerland. EM Josef.Kapfhammer@unibas.ch RI Hartmann, Jana/C-1024-2008 FU University of Basel; Swiss National Science Foundation [31003A-116624] FX We thank Markus Saxer for technical assistance. This work was supported by the University of Basel and the Swiss National Science Foundation (31003A-116624). NR 45 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JAN PY 2012 VL 35 IS 1 BP 20 EP 33 DI 10.1111/j.1460-9568.2011.07942.x PG 14 WC Neurosciences SC Neurosciences & Neurology GA 871KR UT WOS:000298737500003 PM 22188405 ER PT J AU Vivar, C Traub, RD Gutierrez, R AF Vivar, Carmen Traub, Roger D. Gutierrez, Rafael TI Mixed electrical-chemical transmission between hippocampal mossy fibers and pyramidal cells SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE CA3; electrical communication; mixed transmission; mossy fibers; rat; spikelets ID LONG-TERM POTENTIATION; RAT DENTATE GYRUS; SYNAPTIC-TRANSMISSION; GRANULE CELLS; IN-VITRO; SYNAPSES; NEURONS; INTERNEURONS; OSCILLATIONS; NETWORK AB Morphological and electrophysiological studies have shown that granule cell axons, the mossy fibers (MFs), establish gap junctions and therefore electrical communication among them. That granule cells express gap junctional proteins in their axons suggests the possibility that their terminals also express them. If this were to be the case, mixed electricalchemical communication could be supported, as MF terminals normally use glutamate for fast communication with their target cells. Here we present electrophysiological studies in the rat and modeling studies consistent with this hypothesis. We show that MF activation produced fast spikelets followed by excitatory postsynaptic potentials in pyramidal cells (PCs), which, unlike the spikelets, underwent frequency potentiation and were strongly depressed by activation of metabotropic glutamate receptors, as expected from transmission of MF origin. The spikelets, which persisted during blockade of chemical transmission, were potentiated by dopamine and suppressed by the gap junction blocker carbenoxolone. The various waveforms evoked by MF stimulation were replicated in a multi-compartment model of a PC by brief current-pulse injections into the proximal apical dendritic compartment, where MFs are known to contact PCs. Mixed electrical and glutamatergic communication between granule cells and some PCs in CA3 may ensure the activation of sets of PCs, bypassing the strong action of concurrent feed-forward inhibition that granule cells activate. Importantly, MF-to-PC electrical coupling may allow bidirectional, possibly graded, communication that can be faster than chemical synapses and subject to different forms of modulation. C1 [Vivar, Carmen] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Physiol Biophys & Neurosci, Mexico City, DF, Mexico. [Traub, Roger D.] IBM TJ Watson Res Ctr, Yorktown Hts, NY USA. [Gutierrez, Rafael] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Pharmacobiol, Mexico City 14330, DF, Mexico. RP Gutierrez, R (reprint author), NIA, NIH, Biomed Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. EM rafagut@cinvestav.mx OI Gutierrez, Rafael/0000-0002-6566-3900 FU Consejo Nacional de Ciencia y Tecnologia [45754, I020/193/10FON.INST.-29-10]; NINDS/NIH [RO1NS44133] FX We thank D. Schmitz and A. Draguhn for valuable comments during the execution of this project. The postdoctoral fellowship to C. V. and this study were supported by grants to R. G. (45754 and I020/193/10FON.INST.-29-10 from Consejo Nacional de Ciencia y Tecnologia). R. D. T. was supported by NINDS/NIH RO1NS44133. Part of this investigation was conducted while R. G. was a member of the Department of Physiology, Biophysics and Neurosciences. NR 44 TC 19 Z9 19 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JAN PY 2012 VL 35 IS 1 BP 76 EP 82 DI 10.1111/j.1460-9568.2011.07930.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 871KR UT WOS:000298737500008 PM 22151275 ER PT J AU Bang, SJ Jensen, P Dymecki, SM Commons, KG AF Bang, Sun Jung Jensen, Patricia Dymecki, Susan M. Commons, Kathryn G. TI Projections and interconnections of genetically defined serotonin neurons in mice SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE dorsal raphe; feedback inhibition; median raphe; rhombomere; serotonin; serotonin1A receptor ID DORSAL RAPHE NUCLEUS; AXON TERMINALS; SUPRACHIASMATIC NUCLEUS; CEREBRAL-CORTEX; RAT; SYSTEM; ORGANIZATION; STIMULATION; INNERVATION; ACTIVATION AB Brain serotonin neurons are heterogeneous and can be distinguished by several anatomical and physiological characteristics. Toward resolving this heterogeneity into classes of functional relevance, subtypes of mature serotonin neurons were previously identified based on gene expression differences initiated during development in different rhombomeric (r) segments of the hindbrain. This redefinition of mature serotonin neuron subtypes based on the criteria of genetic lineage, along with the enabling genetic fate mapping tools, now allows various functional properties, such as axonal projections, to be allocated onto these identified subtypes. Furthermore, our approach uniquely enables interconnections between the different serotonin neuron subtypes to be determined; this is especially relevant because serotonin neuron activity is regulated by several feedback mechanisms. We used intersectional and subtractive genetic fate mapping tools to generate three independent lines of mice in which serotonin neurons arising in different rhombomeric segments, either r1, r2 or both r3 and r5, were uniquely distinguished from all other serotonin neurons by their expression of enhanced green fluorescent protein. Each of these subgroups of serotonergic neurons had a unique combination of forebrain projection targets. Typically more than one subgroup innervated an individual target area. Unique patterns of interconnections between the different groups of serotonin neurons were also observed and these pathways could subserve feedback regulatory circuits. Overall, the current findings suggest that activation of subsets of serotonin neurons could result in topographic serotonin release in the forebrain coupled with feedback inhibition of serotonin neurons with alternative projection targets. C1 [Bang, Sun Jung; Commons, Kathryn G.] Childrens Hosp, Dept Anesthesia Perioperat & Pain Med, Boston, MA 02115 USA. [Bang, Sun Jung; Commons, Kathryn G.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Jensen, Patricia] NIEHS, Neurobiol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Dymecki, Susan M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Commons, KG (reprint author), Childrens Hosp, Dept Anesthesia Perioperat & Pain Med, 300 Longwood Ave, Boston, MA 02115 USA. EM kathryn.commons@childrens.harvard.edu FU NIH [P01-HD036379, R21-DA023643, R01-DA021801]; Charles H. Hood Foundation (Boston, MA); William Randolph Hearst Fund; NIH, National Institute of Environmental Health Sciences FX This work was supported by grants from NIH P01-HD036379, R21-DA023643, R01-DA021801, Charles H. Hood Foundation (Boston, MA), William Randolph Hearst Fund and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 38 TC 51 Z9 51 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JAN PY 2012 VL 35 IS 1 BP 85 EP 96 DI 10.1111/j.1460-9568.2011.07936.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 871KR UT WOS:000298737500010 PM 22151329 ER PT J AU Harris, PJ Speranza, G Ullmann, CD AF Harris, Pamela Jo Speranza, Giovanna Ullmann, Claudio Dansky TI Targeting embryonic signaling pathways in cancer therapy SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE cancer; cancer stem cells; developmental pathways; embryonic signaling pathways; Hedgehog; Notch; Wnt ID SMALL-MOLECULE ANTAGONISTS; INHIBITS TUMOR-GROWTH; BASAL-CELL CARCINOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GAMMA-SECRETASE INHIBITORS; HUMAN BREAST-CANCER; HEDGEHOG PATHWAY; LUNG-CANCER; STEM-CELLS; BETA-CATENIN AB Introduction: The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. Areas covered: This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. Expert opinion: CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established. C1 [Ullmann, Claudio Dansky] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Harris, Pamela Jo] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Speranza, Giovanna] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Ullmann, CD (reprint author), NCI, Clin Invest Branch, Canc Therapy Evaluat Program, 6130 Execut Blvd,Execut Plaza N,Suite 7030, Bethesda, MD 20892 USA. EM danskyullc@mail.nih.gov NR 112 TC 19 Z9 19 U1 0 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JAN PY 2012 VL 16 IS 1 BP 131 EP 145 DI 10.1517/14728222.2011.645808 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 876FH UT WOS:000299092400011 PM 22239436 ER PT J AU Gahl, WA Markello, TC Toro, C Fajardo, KF Sincan, M Gill, F Carlson-Donohoe, H Gropman, A Pierson, TM Golas, G Wolfe, L Groden, C Godfrey, R Nehrebecky, M Wahl, C Landis, DMD Yang, S Madeo, A Mullikin, JC Boerkoel, CF Tifft, CJ Adams, D AF Gahl, William A. Markello, Thomas C. Toro, Camilo Fajardo, Karin Fuentes Sincan, Murat Gill, Fred Carlson-Donohoe, Hannah Gropman, Andrea Pierson, Tyler Mark Golas, Gretchen Wolfe, Lynne Groden, Catherine Godfrey, Rena Nehrebecky, Michele Wahl, Colleen Landis, Dennis M. D. Yang, Sandra Madeo, Anne Mullikin, James C. Boerkoel, Cornelius F. Tifft, Cynthia J. Adams, David CA NISC Comparative Sequencing Progr TI The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases SO GENETICS IN MEDICINE LA English DT Article DE neurological disorders; rare disease; SNP arrays; undiagnosed disease; whole exome sequencing ID PARAPLEGIN MUTATIONS; GENE AB Purpose: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. Methods: Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. Results: Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. Conclusion: The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup. C1 [Gahl, William A.; Toro, Camilo; Fajardo, Karin Fuentes; Pierson, Tyler Mark; Wolfe, Lynne; Groden, Catherine; Godfrey, Rena; Nehrebecky, Michele; Wahl, Colleen; Landis, Dennis M. D.; Yang, Sandra; Boerkoel, Cornelius F.; Tifft, Cynthia J.; Adams, David] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Gahl, William A.; Markello, Thomas C.; Gropman, Andrea; Golas, Gretchen; Groden, Catherine; Yang, Sandra; Tifft, Cynthia J.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Gahl, William A.; Sincan, Murat; Carlson-Donohoe, Hannah; Adams, David] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Gill, Fred] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Pierson, Tyler Mark] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD USA. [Madeo, Anne] NIH, Social & Behav Res Branch, Off Rare Dis Res, Off Director, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Adams, D (reprint author), NIH, Undiagnosed Dis Program, Bldg 10, Bethesda, MD 20892 USA. EM david.adams@nih.gov RI Madeo, Anne/K-2880-2012 FU Intramural Division of the National Human Genome Research Institute; National Institute of Neurological Disorders and Stroke; NIH Clinical Center; NIH Office of the Director; Office of Rare Diseases Research; National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Division of the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke, the NIH Clinical Center, the NIH Office of the Director, the Office of Rare Diseases Research (Dr Stephen Groft), the NIH Clinical Center (Dr John Gallin), and the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke. The authors thank the NIH UDP patients, their families, and their physicians for making this enterprise a truly united effort; Roxanne Fischer and Richard Hess for their excellent technical assistance and the entire UDP staff for their dedicated service; and the NIH Intramural Sequencing Center for performing the whole exome and whole genome sequencing and analysis. The NHGRI Genomics Core provided superb SNP array results. NR 31 TC 95 Z9 95 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JAN PY 2012 VL 14 IS 1 BP 51 EP 59 DI 10.1038/gim.0b013e318232a005 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 873NI UT WOS:000298889600005 PM 22237431 ER PT J AU Hsu, AP Dowdell, KC Davis, J Niemela, JE Anderson, SM Shaw, PA Rao, VK Puck, JM AF Hsu, Amy P. Dowdell, Kennichi C. Davis, Joie Niemela, Julie E. Anderson, Stacie M. Shaw, Pamela A. Rao, V. Koneti Puck, Jennifer M. TI Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance SO GENETICS IN MEDICINE LA English DT Article DE autoimmune lymphoproliferative syndrome; FAS; genotype-phenotype correlation; haploinsufficiency; penetrance ID CELL-DEATH; MESSENGER-RNA; SYNDROME ALPS; CD95; APOPTOSIS; DOMINANT; GENE; COMPLEX; SITE; TRANSPLANTATION AB Purpose: Autoimmune lymphoproliferative syndrome is a disorder of lymphocyte apoptosis. Although FAS molecules bearing mutations in the signal-transducing intracellular death domain exhibit dominant-negative interference with FAS-mediated apoptosis, mechanisms for pathology of non-death domain FAS mutations causing autoimmune lymphoproliferative syndrome are poorly defined. Methods: RNA stability, protein expression, ligand binding, and ability to transmit apoptosis signals by anti-FAS antibody or FAS ligand were determined for a cohort of 39 patients with non-death domain autoimmune lymphoproliferative syndrome. Correlations between mutation type and disease penetrance were established in mutation-positive family members. Results: Frameshifts or transcriptional stop mutations before exon 7 resulted in messenger RNA haploinsufficiency, whereas an amino-terminal signal sequence mutation and certain intracellular truncations prevented cell surface localization of FAS. All resulted in decreased FAS localization, inability to bind FAS ligand, and reduced FAS ligand-induced apoptosis. Extracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis. Mutation-positive relatives with haploinsufficient or extracellular mutations had lower penetrance of autoimmune lymphoproliferative syndrome clinical phenotypes than did relatives with death domain mutations. Conclusion: We have defined molecular mechanisms by which non-death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with autoimmune lymphoproliferative syndrome, and demonstrated that FAS haploinsufficiency can lead to autoimmune lymphoproliferative syndrome. C1 [Hsu, Amy P.; Davis, Joie; Rao, V. Koneti] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dowdell, Kennichi C.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Niemela, Julie E.] NIH, Warren Grant Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. [Anderson, Stacie M.] NHGRI, Bethesda, MD 20892 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. RP Hsu, AP (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twins@niaid.nih.gov OI Niemela, Julie/0000-0003-4197-3792 FU National Institutes of Health, National Human Genome Research Institute, and National Institute of Allergy and Infectious Disease, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Human Genome Research Institute, and National Institute of Allergy and Infectious Disease, Bethesda, MD 20892. The authors thank the patients and their families, Roxanne E. Fischer for her valuable contributions related to sample processing, Tom Fleisher and Janet Dale for phenotypic delineation, and Mike Lenardo and the late Stephen Straus for their helpful discussions. NR 36 TC 9 Z9 12 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JAN PY 2012 VL 14 IS 1 BP 81 EP 89 DI 10.1038/gim.0b013e3182310b7d PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 873NI UT WOS:000298889600009 PM 22237435 ER PT J AU Bellcross, CA Bedrosian, SR Daniels, E Duquette, D Hampel, H Jasperson, K Joseph, DA Kaye, C Lubin, I Meyer, LJ Reyes, M Scheuner, MT Schully, SD Senter, L Stewart, SL St Pierre, J Westman, J Wise, P Yang, VW Khoury, MJ AF Bellcross, Cecelia A. Bedrosian, Sara R. Daniels, Elvan Duquette, Debra Hampel, Heather Jasperson, Kory Joseph, Djenaba A. Kaye, Celia Lubin, Ira Meyer, Laurence J. Reyes, Michele Scheuner, Maren T. Schully, Sheri D. Senter, Leigha Stewart, Sherri L. St Pierre, Jeanette Westman, Judith Wise, Paul Yang, Vincent W. Khoury, Muin J. TI Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting SO GENETICS IN MEDICINE LA English DT Article DE colorectal cancer; genetic screening; genetic testing; HNPCC; Lynch syndrome ID CUMULATIVE LIFETIME INCIDENCE; GENETIC TESTING STRATEGIES; MISMATCH REPAIR PROTEINS; EGAPP WORKING GROUP; MICROSATELLITE INSTABILITY; ENDOMETRIAL CANCER; REDUCING MORBIDITY; MUTATION CARRIERS; PROVEN MUTATIONS; MLH1 PROMOTER AB Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships. C1 [Bellcross, Cecelia A.; Bedrosian, Sara R.; Reyes, Michele; St Pierre, Jeanette; Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Bellcross, Cecelia A.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Daniels, Elvan] Morehouse Sch Med, Natl Ctr Primary Care, Atlanta, GA 30310 USA. [Duquette, Debra] Michigan Dept Community Hlth, Lansing, MI USA. [Hampel, Heather; Senter, Leigha; Westman, Judith] Ohio State Univ, Dept Internal Med, Div Human Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Jasperson, Kory] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Joseph, Djenaba A.; Stewart, Sherri L.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Kaye, Celia] Univ Colorado, Off Educ Dev & Res, Sch Med, Aurora, CO USA. [Lubin, Ira] Ctr Dis Control & Prevent, Lab Res & Evaluat Branch, Atlanta, GA USA. [Meyer, Laurence J.] Salt Lake City Hlth Care Syst, Dept Vet Affairs, Salt Lake City, UT USA. [Scheuner, Maren T.] Greater Los Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Scheuner, Maren T.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Schully, Sheri D.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Wise, Paul] Vanderbilt Univ, Dept Surg, Med Ctr, Nashville, TN 37240 USA. [Yang, Vincent W.] Emory Univ, Sch Med, Div Digest Dis, Atlanta, GA USA. RP Bellcross, CA (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. EM cbellcr@emory.edu OI Wise, Paul/0000-0003-3798-7913 FU NCI NIH HHS [R01 CA084197]; NIDDK NIH HHS [R01 DK052230] NR 62 TC 32 Z9 33 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JAN PY 2012 VL 14 IS 1 BP 152 EP 162 DI 10.1038/gim.0b013e31823375ea PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 873NI UT WOS:000298889600019 PM 22237445 ER PT J AU Schully, SD Benedicto, CB Khoury, MJ AF Schully, Sheri D. Benedicto, Camilla B. Khoury, Muin J. TI How can we stimulate translational research in cancer genomics beyond bench to bedside? SO GENETICS IN MEDICINE LA English DT Letter C1 [Schully, Sheri D.; Benedicto, Camilla B.; Khoury, Muin J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Khoury, Muin J.] CDC, Off Publ Hlth Genom, Atlanta, GA 30333 USA. RP Schully, SD (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM schullys@mail.nih.gov NR 6 TC 12 Z9 12 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JAN PY 2012 VL 14 IS 1 BP 169 EP 170 DI 10.1038/gim.2011.12 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 873NI UT WOS:000298889600022 PM 22237448 ER PT J AU Fradkin, JE AF Fradkin, Judith E. TI Confronting The Urgent Challenge Of Diabetes: An Overview SO HEALTH AFFAIRS LA English DT Article ID LIFE-STYLE INTERVENTION; 10-YEAR FOLLOW-UP; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; PREVENTION PROGRAM; MELLITUS; PREVALENCE; OBESITY; YOUTH; HYPERGLYCEMIA AB The rising tide of diabetes has an unacceptable human and societal toll. Rates of all major forms of diabetes are increasing at enormous individual and societal cost: 8.3 percent of the US population is afflicted today, and financial costs reached $174 billion for 2007. A major cause of blindness, renal failure, amputation, and cardiovascular disease, diabetes also increases the risk of cancer and dementia and more than doubles individual health care costs. Control of glucose, blood pressure, and lipids improves outcomes. Yet diabetes management is nonetheless suboptimal, particularly in disproportionately affected poor and minority populations. Safer, less burdensome, and more personalized approaches to therapy are needed. People at high risk for type 2 diabetes must be identified if society is to realize the benefits of therapies proven to delay or prevent the disease. We have many of the tools we need to address this challenge, and we must apply them now. C1 NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Fradkin, JE (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. EM jf58s@nih.gov NR 35 TC 11 Z9 11 U1 0 U2 4 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JAN PY 2012 VL 31 IS 1 BP 12 EP 19 DI 10.1377/hlthaff.2011.1150 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 879DD UT WOS:000299309000003 PM 22232089 ER PT J AU Briassoulis, G Quezado, M Lee, CCR Xekouki, P Keil, M Stratakis, CA AF Briassoulis, George Quezado, Martha Lee, Chyi-Chia Richard Xekouki, Paraskevi Keil, Meg Stratakis, Constantine A. TI Myxoma of the ear lobe in a 23-month-old girl with Carney complex SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article DE Carney complex; ear tumors; pediatrics; PRKAR1A mutation; protein kinase A ID TUMORS AB Myxomas of the ear are extremely uncommon, especially in young children. A 23-month-old girl born to a family with known Carney complex, a condition that predisposes to multiple myxomas, presented with a large, cauliflower-like mass located on the back of her right ear. Histopathologically, the lesion was composed of scattered spindle-shaped or stellate cells with abundant associated mucin and a very sparse inflammatory infiltrate containing lymphocytes and neutrophils. The patient was a carrier of a protein kinase A regulatory subunit 1A (PRKAR1A) mutation; PRKAR1A mutations cause Carney complex in most patients with this rare disorder. This is the earliest presentation of an ear lobe myxoma reported in the literature. C1 [Briassoulis, George; Xekouki, Paraskevi; Keil, Meg; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Briassoulis, George] Univ Crete, Dept Pediat, Iraklion, Crete, Greece. [Quezado, Martha; Lee, Chyi-Chia Richard] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Keil, Meg; Stratakis, Constantine A.] NIH, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,CRC, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Crete, Heraklion, Crete, Greece FX This study was supported by the Intramural Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and, in part, by a sabbatical to Dr G. Briassoulis by the University of Crete, Heraklion, Crete, Greece. NR 10 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD JAN PY 2012 VL 39 IS 1 BP 68 EP 71 DI 10.1111/j.1600-0560.2011.01786.x PG 4 WC Dermatology; Pathology SC Dermatology; Pathology GA 869HF UT WOS:000298588100015 PM 21880053 ER PT J AU Harazim, SM Xi, W Schmidt, CK Sanchez, S Schmidt, OG AF Harazim, Stefan M. Xi, Wang Schmidt, Christine K. Sanchez, Samuel Schmidt, Oliver G. TI Fabrication and applications of large arrays of multifunctional rolled-up SiO/SiO2 microtubes SO JOURNAL OF MATERIALS CHEMISTRY LA English DT Article ID FLUIDIC RING-RESONATOR; CELLS; NANOTUBES; FILMS; NANOTECHNOLOGY; SCAFFOLDS; ENGINES; TUBES AB Biocompatible, multifunctional large arrays of transparent SiO/SiO2 microtubes are fabricated by rolled-up nanotech. The outer tubular diameter as a function of thicknesses of SiO and SiO2 has been systematically studied and the roll-up parameters have been optimized to deterministically achieve a yield of nearly 100%. A macroscopic continuum mechanical model is in good agreement with the experimental data. The relative ease in functionalization of the "glass'' microtubes with different biomaterials renders rolled-up nanotech an excellent option for various on- and off-chip applications, including optofluidic sensors, micro-engines and pre-patterned 3D scaffolds for cell culturing. C1 [Harazim, Stefan M.; Xi, Wang; Sanchez, Samuel; Schmidt, Oliver G.] IFW Dresden, Inst Integrat Nanosci, D-01069 Dresden, Germany. [Schmidt, Christine K.] NCI, NIH, Bethesda, MD 20892 USA. [Schmidt, Oliver G.] Tech Univ Chemnitz, D-09107 Chemnitz, Germany. RP Sanchez, S (reprint author), IFW Dresden, Inst Integrat Nanosci, Helmholtzstr 20, D-01069 Dresden, Germany. EM s.sanchez@ifw-dresden.de RI Sanchez, Samuel/B-6803-2015; OI Sanchez, Samuel/0000-0002-5845-8941; Schmidt, Christine/0000-0002-8363-7933 FU Volkswagen Foundation [I/84 072]; DFG Research Unit [1713]; U. S. Air Force Office of Scientific Research (AFOSR) [FA9550-09-0550]; EMBO FX This work was financially supported by the Volkswagen Foundation I/84 072, DFG Research Unit 1713 "Sensoric Micro- and Nanosystems and a Multidisciplinary University Research Initiative (MURI) sponsored by the U. S. Air Force Office of Scientific Research (AFOSR) (FA9550-09-0550) and an EMBO long-term fellowship to CKS. Authors thank S. Kiravittaya for supporting the calculation, B. Eichler for AFM scanning, R. Engelhard and E. J. Smith for support in eBeam evaporation and discussions and Dr Daniel Gerlich for supplying the HeLa Kyoto cell line, stably expressing mEGFP-alpha-tubulin and H2B-mcherry. Dr Tom Misteli is acknowledged for supporting the biological studies. NR 54 TC 37 Z9 38 U1 1 U2 36 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0959-9428 J9 J MATER CHEM JI J. Mater. Chem. PY 2012 VL 22 IS 7 BP 2878 EP 2884 DI 10.1039/c1jm14800a PG 7 WC Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 881RI UT WOS:000299504200012 ER PT J AU Kandiah, E Watts, NR Cheng, NG Cardone, G Stahl, SJ Heller, T Liang, TJ Wingfield, PT Steven, AC AF Kandiah, Eaazhisai Watts, Norman R. Cheng, Naigian Cardone, Giovanni Stahl, Stephen J. Heller, Theo Liang, T. Jake Wingfield, Paul T. Steven, Alasdair C. TI Cryo-EM study of Hepatitis B virus core antigen capsids decorated with antibodies from a human patient SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Polyclonal antibodies; Antibody labeling; Molecular modeling; Immunodominant epitopes; Conformational epitopes ID CRYOELECTRON MICROSCOPY; MONOCLONAL-ANTIBODIES; ELECTRON-MICROGRAPHS; ESCHERICHIA-COLI; PROTEINS; BINDING; FAB; EPITOPES; SURFACE; COCRYSTALLIZATION AB The capsid (core antigen, HBcAg) is one of three major antigens present in patients infected with Hepatitis B virus. The capsids are icosahedral particles, whose most prominent features are spikes that extend 25 angstrom out from the contiguous "floor". At the spike tip are two copies of the "immunodominant loop". Previously, the epitopes of seven murine monoclonal antibodies have been identified by cryo-EM analysis of Fab-labeled capsids. All but one are conformational and all but one map around the spike tip. The exception, which is also the tightest-binder, straddles an inter-molecular interface on the floor. Seeking to relate these observations to the immunological response of infected humans, we isolated anti-cAg antibodies from a patient, prepared Fabs, and analyzed their binding to capsids. A priori, one possibility was that many different Fabs would give an undifferentiated continuum of Fab-related density. In fact, the density observed was highly differentiated and could be reproduced by modeling with just five Fabs, three binding to the spike and two to the floor. These results show that epitopes on the floor, far (similar to 30 angstrom) from the immunodominant loop, are clinically relevant and that murine anti-cAg antibodies afford a good model for the human system. Published by Elsevier Inc. C1 [Kandiah, Eaazhisai; Cheng, Naigian; Cardone, Giovanni; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Watts, Norman R.; Stahl, Stephen J.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Heller, Theo; Liang, T. Jake] Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, 50 S Dr,Rm 1517, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov FU NIAMS; NIDDK FX This research was supported by the Intramural Research Programs of NIAMS and NIDDK. NR 41 TC 8 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD JAN PY 2012 VL 177 IS 1 SI SI BP 145 EP 151 DI 10.1016/j.jsb.2011.10.003 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 880ZK UT WOS:000299448900019 PM 22056468 ER PT J AU Hartge, P Speyer, JL AF Hartge, Patricia Speyer, James L. TI Finding Ovarian Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BREAST-CANCER; TUMOR SIZE; MORTALITY; PROSTATE; TRIAL; LUNG C1 [Hartge, Patricia] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Speyer, James L.] NYU, Dept Med, Langone Med Ctr, Ctr Clin Canc,Canc Inst, New York, NY 10016 USA. RP Hartge, P (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8090, Bethesda, MD 20892 USA. EM hartgep@mail.nih.gov FU Intramural NIH HHS NR 10 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN PY 2012 VL 104 IS 2 BP 82 EP 83 DI 10.1093/jnci/djr518 PG 2 WC Oncology SC Oncology GA 879QF UT WOS:000299346200001 PM 22247023 ER PT J AU Andriole, GL Crawford, ED Grubb, RL Buys, SS Chia, D Church, TR Fouad, MN Isaacs, C Kvale, PA Reding, DJ Weissfeld, JL Yokochi, LA O'Brien, B Ragard, LR Clapp, JD Rathmell, JM Riley, TL Hsing, AW Izmirlian, G Pinsky, PF Kramer, BS Miller, AB Gohagan, JK Prorok, PC AF Andriole, Gerald L. Crawford, E. David Grubb, Robert L., III Buys, Saundra S. Chia, David Church, Timothy R. Fouad, Mona N. Isaacs, Claudine Kvale, Paul A. Reding, Douglas J. Weissfeld, Joel L. Yokochi, Lance A. O'Brien, Barbara Ragard, Lawrence R. Clapp, Jonathan D. Rathmell, Joshua M. Riley, Thomas L. Hsing, Ann W. Izmirlian, Grant Pinsky, Paul F. Kramer, Barnett S. Miller, Anthony B. Gohagan, John K. Prorok, Philip C. CA PLCO Project Team TI Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COMORBIDITY AB Background The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial. Methods A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided. Results Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68). Conclusions After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing. C1 [Izmirlian, Grant; Prorok, Philip C.] NCI, Biometry Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Pinsky, Paul F.] NCI, Early Detect Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Gohagan, John K.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Andriole, Gerald L.; Grubb, Robert L., III] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Crawford, E. David] Univ Colorado, Denver, CO 80202 USA. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Chia, David] Univ Calif Los Angeles, Immunogenet Ctr, Los Angeles, CA USA. [Church, Timothy R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Fouad, Mona N.] Univ Alabama, Sch Med, Birmingham, AL USA. [Isaacs, Claudine] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Kvale, Paul A.] Henry Ford Hlth Syst, Detroit, MI USA. [Reding, Douglas J.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Weissfeld, Joel L.] Univ Pittsburgh, Med Ctr Canc Pavil, Pittsburgh, PA USA. [Yokochi, Lance A.] Pacific Hlth Res Inst, Honolulu, HI USA. [O'Brien, Barbara; Ragard, Lawrence R.] Westat Corp, Rockville, MD USA. [Clapp, Jonathan D.; Rathmell, Joshua M.; Riley, Thomas L.] Informat Management Serv Inc, Rockville, MD USA. [Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Prorok, PC (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, NIH, 6130 Execut Blvd,Ste 3132, Bethesda, MD 20892 USA. EM prorokp@mail.nih.gov OI Church, Timothy R./0000-0003-3292-5035 FU National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases; GlaxoSmithKline; Human Genome Sciences, Inc; National Cancer Institute at the National Institutes of Health [N01-CN-25514, N01-CN-25522, N01-CN-25515, N01-CN-25512, N01-CN-25513, N01-CN-25511, N01-CN-25524, N01-CN-25518, N01-CN-25516, N01-CN-75022, N01-CN-25404, N01-CN-25476] FX This work was supported by contracts from the National Cancer Institute at the National Institutes of Health (N01-CN-25514 to E.D.C.; N01-CN-25522 to C.I.; N01-CN-25515 to L.A.Y.; N01-CN-25512 to P.A.K.; N01-CN-25513 to T.R.C.; N01-CN-25511 to J.L.W.; N01-CN-25524 to S.S.B.; N01-CN-25518 to D.J.R.; N01-CN-25516 to G.L.A. and R.L.G.; N01-CN-75022 to M.N.F.; N01-CN-25404 to D.C.; and N01-CN-25476 to B.O'B and L.R.R.).; G. L. Andriole serves as a Consultant/Advisor for Amgen, Augmenix, Bayer, Cambridge Endo, Caris, France Foundation, GenProbe, GlaxoSmithKline, Myriad Genetics, Steba Biotech, and Ortho Clinical Diagnostics. He serves as Medical Director of Envisioneering Medical and Viking Medical. He is the recipient of grant support from the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. R. L. Grubb conducts research sponsored by GlaxoSmithKline. J. D. Clapp has a financial interest in Human Genome Sciences, Inc, which conducts research and development in the treatment of hepatitis, lupus, and cancer. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial is a federally funded registered clinical trial (ClinicalTrials.gov identifier NCT00002540). We thank the study participants for their contributions in making this study possible. The authors are solely responsible for the study design, data collection, analysis and interpretation of the data, writing the article, and decision to submit the article for publication. NR 22 TC 425 Z9 440 U1 5 U2 51 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 JAN PY 2012 VL 104 IS 2 BP 125 EP 132 DI 10.1093/jnci/djr500 PG 8 WC Oncology SC Oncology GA 879QF UT WOS:000299346200008 PM 22228146 ER PT J AU Sitas, F Egger, S Urban, MI Taylor, PR Abnet, CC Boffetta, P O'Connell, DL Whiteman, DC Brennan, P Malekzadeh, R Pawlita, M Dawsey, SM Waterboer, T AF Sitas, Freddy Egger, Sam Urban, Margaret I. Taylor, Philip R. Abnet, Christian C. Boffetta, Paolo O'Connell, Dianne L. Whiteman, David C. Brennan, Paul Malekzadeh, Reza Pawlita, Michael Dawsey, Sanford M. Waterboer, Tim CA InterSCOPE Collaboration TI InterSCOPE Study: Associations Between Esophageal Squamous Cell Carcinoma and Human Papillomavirus Serological Markers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HIGH-RISK AREA; GLUTATHIONE-S-TRANSFERASE; UPPER AERODIGESTIVE TRACT; INVASIVE CERVICAL-CANCER; GASTRIC CANCERS; TYPE-16 INFECTION; ALCOHOL-USE; VIRUS HPV; TOBACCO; CHINA AB Background The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case-control studies conducted in regions with differing background risks of esophageal cancer. Methods We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case-control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided. Results We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036). Conclusions We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers. C1 [Sitas, Freddy; Egger, Sam; O'Connell, Dianne L.] NSW Canc Council, Canc Epidemiol Res Unit, Sydney, NSW, Australia. German Canc Res Ctr, Genome Modificat & Carcinogenesis Div, Infect & Canc Program, D-6900 Heidelberg, Germany. [Taylor, Philip R.; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Natl Hlth Lab Serv, NHLS MRC Canc Epidemiol Res Grp, Johannesburg, South Africa. [Urban, Margaret I.] Univ Witwatersrand, Johannesburg, South Africa. Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Whiteman, David C.] Queensland Inst Med Res, Populat Hlth Dept, Brisbane, Qld 4006, Australia. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. RP Sitas, F (reprint author), NSW Canc Council, Canc Epidemiol Res Unit, POB 572, Kings Cross, NSW 1340, Australia. EM freddys@nswcc.org.au RI Abnet, Christian/C-4111-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Whiteman, David/P-2728-2014; Waterboer, Tim/G-1252-2010; Pawlita, Labor/C-9720-2011; Curado, Maria Paula/M-6200-2013; Zaridze, David/K-5605-2013; hayward, nicholas/C-1367-2015 OI Pawlita, Michael/0000-0002-4720-8306; Abnet, Christian/0000-0002-3008-7843; Whiteman, David/0000-0003-2563-9559; Curado, Maria Paula/0000-0001-8172-2483; mates, dana/0000-0002-6219-9807; Malekzadeh, Reza/0000-0003-1043-3814; Sitas, Freddy/0000-0001-9679-1481; hayward, nicholas/0000-0003-4760-1033 FU US National Cancer Institute; German Cancer Research Center; Cancer Council New South Wales, Australia; Deutsche Krebshilfe; European Commission [IC18-CT97-0222] FX The InterSCOPE collaboration was partially funded by the intramural research programs of the US National Cancer Institute; the German Cancer Research Center; and Cancer Council New South Wales, Australia; and by grants from the Deutsche Krebshilfe. Institutions who funded the field work of the original studies were Brazilian Multicentric Case-Control Study: European Commission (grant no IC18-CT97-0222); Central and Eastern European Case-Control Study: World Cancer Research Fund, European Commission (Contract No. IC15-CT98-0332); The Golestan Case-Control Study: Digestive Disease Research Center, Tehran University of Medical Sciences (Grant Number 82-603); The Australian Cancer Study: National Health and Medical Research Council (Program Grant No. 199600) (Australia); Johannesburg Cancer Case-Control Study: South African National Health Laboratory Service and Medical Research Council; University of the Witwatersrand; Cancer Research UK; Shanxi Case-Control Study: the US National Cancer Institute (Contract NO2-SC-66211). NR 62 TC 31 Z9 32 U1 1 U2 5 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 JAN PY 2012 VL 104 IS 2 BP 147 EP 158 DI 10.1093/jnci/djr499 PG 12 WC Oncology SC Oncology GA 879QF UT WOS:000299346200010 PM 22228147 ER PT J AU Safaeian, M Wacholder, S Hildesheim, A AF Safaeian, Mahboobeh Wacholder, Sholom Hildesheim, Allan TI Re: Epidemiological Study of Anti-HPV16/18 Seropositivity and Subsequent Risk of HPV16 and-18 Infections Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID HUMAN-PAPILLOMAVIRUS TYPE; COSTA-RICA; SEROPREVALENCE; WOMEN C1 [Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, Rockville, MD 20852 USA. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, 6120 Execut Blvd,Ste 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 NR 4 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN PY 2012 VL 104 IS 2 BP 163 EP 164 DI 10.1093/jnci/djr519 PG 2 WC Oncology SC Oncology GA 879QF UT WOS:000299346200013 ER PT J AU Magadan, JG Bonifacino, JS AF Magadan, Javier G. Bonifacino, Juan S. TI Transmembrane Domain Determinants of CD4 Downregulation by HIV-1 Vpu SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS TYPE-1 NEF; CHIMERIC ENVELOPE GLYCOPROTEINS; PROTEIN-U VPU; ENDOPLASMIC-RETICULUM; CYTOPLASMIC DOMAIN; 3-DIMENSIONAL STRUCTURE; MEMBRANE INTERFACES; RETRO-TRANSLOCATION; INDUCED DEGRADATION; SURFACE EXPRESSION AB The transmembrane domains (TMDs) of integral membrane proteins do not merely function as membrane anchors but play active roles in many important biological processes. The downregulation of the CD4 coreceptor by the Vpu protein of HIV-1 is a prime example of a process that is dependent on specific properties of TMDs. Here we report the identification of Trp22 in the Vpu TMD and Gly415 in the CD4 TMD as critical determinants of Vpu-induced targeting of CD4 to endoplasmic reticulum (ER)-associated degradation (ERAD). The two residues participate in different aspects of ERAD targeting. Vpu Trp22 is required to prevent assembly of Vpu into an inactive, oligomeric form and to promote CD4 polyubiquitination and subsequent recruitment of the VCP-UFD1L-NPL4 dislocase complex. In the presence of a Vpu Trp22 mutant, CD4 remains integrally associated with the ER membrane, suggesting that dislocation from the ER into the cytosol is impaired. CD4 Gly415, on the other hand, contributes to CD4-Vpu interactions. We also identify two residues, Val20 and Ser23, in the Vpu TMD that mediate retention of Vpu and, by extension, CD4 in the ER. These findings highlight the exploitation of several TMD-mediated mechanisms by HIV-1 Vpu in order to downregulate CD4 and thus promote viral pathogenesis. C1 [Magadan, Javier G.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU NIH; NICHD; Pew Charitable Trusts FX This work was supported by the NIH Intramural AIDS Targeted Antiviral Program (IATAP) and the Intramural Program of the NICHD. J.G.M. is the recipient of a fellowship from The Pew Charitable Trusts. NR 87 TC 30 Z9 33 U1 4 U2 6 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 JAN PY 2012 VL 86 IS 2 BP 757 EP 772 DI 10.1128/JVI.05933-11 PG 16 WC Virology SC Virology GA 870MW UT WOS:000298674600011 PM 22090097 ER PT J AU Thai, KTD Henn, MR Zody, MC Tricou, V Nguyet, NM Charlebois, P Lennon, NJ Green, L de Vries, PJ Hien, TT Farrar, J van Doorn, HR de Jong, MD Birren, BW Holmes, EC Simmons, CP AF Thai, Khoa T. D. Henn, Matthew R. Zody, Michael C. Tricou, Vianney Nguyen Minh Nguyet Charlebois, Patrick Lennon, Niall J. Green, Lisa de Vries, Peter J. Tran Tinh Hien Farrar, Jeremy van Doorn, H. Rogier de Jong, Menno D. Birren, Bruce W. Holmes, Edward C. Simmons, Cameron P. TI High-Resolution Analysis of Intrahost Genetic Diversity in Dengue Virus Serotype 1 Infection Identifies Mixed Infections SO JOURNAL OF VIROLOGY LA English DT Article ID EVOLUTIONARY GENETICS; MAXIMUM-LIKELIHOOD; FRENCH-POLYNESIA; TYPE-3 VIRUS; IN-VIVO; RNA; EMERGENCE; HOST; RECOMBINATION; TRANSMISSION AB Little is known about the rate at which genetic variation is generated within intrahost populations of dengue virus (DENV) and what implications this diversity has for dengue pathogenesis, disease severity, and host immunity. Previous studies of intrahost DENV variation have used a low frequency of sampling and/or experimental methods that do not fully account for errors generated through amplification and sequencing of viral RNAs. We investigated the extent and pattern of genetic diversity in sequence data in domain III (DIII) of the envelope (E) gene in serial plasma samples (n = 49) taken from 17 patients infected with DENV type 1 (DENV-1), totaling some 8,458 clones. Statistically rigorous approaches were employed to account for artifactual variants resulting from amplification and sequencing, which we suggest have played a major role in previous studies of intrahost genetic variation. Accordingly, nucleotide sequence diversities of viral populations were very low, with conservative estimates of the average levels of genetic diversity ranging from 0 to 0.0013. Despite such sequence conservation, we observed clear evidence for mixed infection, with the presence of multiple phylogenetically distinct lineages present within the same host, while the presence of stop codon mutations in some samples suggests the action of complementation. In contrast to some previous studies we observed no relationship between the extent and pattern of DENV-1 genetic diversity and disease severity, immune status, or level of viremia. C1 [Thai, Khoa T. D.; Tricou, Vianney; Nguyen Minh Nguyet; Tran Tinh Hien; Farrar, Jeremy; van Doorn, H. Rogier; Simmons, Cameron P.] Hosp Trop Dis, Oxford Univ Clin Res Unit, Ho Chi Minh City, Vietnam. [Farrar, Jeremy; van Doorn, H. Rogier; Simmons, Cameron P.] Univ Oxford, Nuffield Dept Clin Med, Ctr Clin Vaccinol & Trop Med, Ctr Trop Med, Oxford, England. [Thai, Khoa T. D.; de Vries, Peter J.] Univ Amsterdam, Acad Med Ctr, Trop Med & AIDS, Div Infect Dis, NL-1105 AZ Amsterdam, Netherlands. [Thai, Khoa T. D.; de Vries, Peter J.; de Jong, Menno D.] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Inflammat Res, NL-1105 AZ Amsterdam, Netherlands. [de Jong, Menno D.] Univ Amsterdam, Acad Med Ctr, Div Clin Virol, NL-1105 AZ Amsterdam, Netherlands. [Henn, Matthew R.; Zody, Michael C.; Charlebois, Patrick; Lennon, Niall J.; Green, Lisa; Birren, Bruce W.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Thai, KTD (reprint author), Hosp Trop Dis, Oxford Univ Clin Res Unit, Ho Chi Minh City, Vietnam. EM khoat@oucru.org OI van Doorn, H Rogier/0000-0002-9807-1821; Simmons, Cameron P./0000-0002-9039-7392; Tricou, Vianney/0000-0002-5465-8647; Farrar, Jeremy/0000-0002-2700-623X; Holmes, Edward/0000-0001-9596-3552 FU Wellcome Trust; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900006C, HHSN272200900018C]; Netherlands Organization for Scientific Research (NWO) [017.004.074] FX This study was funded by the Wellcome Trust (C. P. S.) and in part with U.S. Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200900006C (B. W. B.) and HHSN272200900018C (B. W. B.). Khoa T. D. Thai is supported by a "Mosaic" fellowship from the Netherlands Organization for Scientific Research (NWO) (grant 017.004.074). NR 39 TC 37 Z9 37 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 2 BP 835 EP 843 DI 10.1128/JVI.05985-11 PG 9 WC Virology SC Virology GA 870MW UT WOS:000298674600017 PM 22090119 ER PT J AU Allison, AB Harbison, CE Pagan, I Stucker, KM Kaelber, JT Brown, JD Ruder, MG Keel, MK Dubovi, EJ Holmes, EC Parrish, CR AF Allison, Andrew B. Harbison, Carole E. Pagan, Israel Stucker, Karla M. Kaelber, Jason T. Brown, Justin D. Ruder, Mark G. Keel, M. Kevin Dubovi, Edward J. Holmes, Edward C. Parrish, Colin R. TI Role of Multiple Hosts in the Cross-Species Transmission and Emergence of a Pandemic Parvovirus SO JOURNAL OF VIROLOGY LA English DT Article ID FELINE PANLEUKOPENIA VIRUS; MINK ENTERITIS VIRUS; CANINE PARVOVIRUS; TRANSFERRIN RECEPTORS; CAPSID STRUCTURE; IN-VIVO; RANGE; EVOLUTION; BINDING; CELLS AB Understanding the mechanisms of cross-species virus transmission is critical to anticipating emerging infectious diseases. Canine parvovirus type 2 (CPV-2) emerged as a variant of a feline parvovirus when it acquired mutations that allowed binding to the canine transferrin receptor type 1 (TfR). However, CPV-2 was soon replaced by a variant virus (CPV-2a) that differed in antigenicity and receptor binding. Here we show that the emergence of CPV involved an additional host range variant virus that has circulated undetected in raccoons for at least 24 years, with transfers to and from dogs. Raccoon virus capsids showed little binding to the canine TfR, showed little infection of canine cells, and had altered antigenic structures. Remarkably, in capsid protein (VP2) phylogenies, most raccoon viruses fell as evolutionary intermediates between the CPV-2 and CPV-2a strains, suggesting that passage through raccoons assisted in the evolution of CPV-2a. This highlights the potential role of alternative hosts in viral emergence. C1 [Allison, Andrew B.; Harbison, Carole E.; Stucker, Karla M.; Kaelber, Jason T.; Parrish, Colin R.] Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, James A Baker Inst Anim Hlth, Ithaca, NY 14853 USA. [Allison, Andrew B.; Brown, Justin D.; Ruder, Mark G.; Keel, M. Kevin] Univ Georgia, Coll Vet Med, SE Cooperat Wildlife Dis Study, Athens, GA USA. [Pagan, Israel; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Kaelber, Jason T.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Dubovi, Edward J.] Cornell Univ, Coll Vet Med, Dept Populat Med, Ithaca, NY 14853 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Parrish, CR (reprint author), Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, James A Baker Inst Anim Hlth, Ithaca, NY 14853 USA. EM crp3@cornell.edu RI Pagan, Israel/H-1843-2015; OI Pagan, Israel/0000-0001-8876-1194; Kaelber, Jason/0000-0001-9426-1030; Allison, Andrew B./0000-0003-0971-1215; Holmes, Edward/0000-0001-9596-3552 FU Southeastern Cooperative Wildlife Disease Study (SCWDS); Marie Curie fellowship [PIOF-GA-2009-236470]; NIH [GM080533-05, AI028385, AI092571] FX A.B.A., J.D.B., M. G. R., and M. K. K. were supported by funds obtained through sponsorship by the fish and wildlife agencies of the member states of the Southeastern Cooperative Wildlife Disease Study (SCWDS). A. B. A. thanks Jeremiah Saliki at the University of Georgia for graciously allowing the use of his laboratory space. I. P. was supported by Marie Curie fellowship PIOF-GA-2009-236470. This work was also supported by NIH grants GM080533-05 (to E. C. H. and C. R. P.), AI028385, and AI092571 (to C.R.P.). NR 35 TC 34 Z9 34 U1 1 U2 32 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 JAN PY 2012 VL 86 IS 2 BP 865 EP 872 DI 10.1128/JVI.06187-11 PG 8 WC Virology SC Virology GA 870MW UT WOS:000298674600020 PM 22072763 ER PT J AU Frieman, M Yount, B Agnihothram, S Page, C Donaldson, E Roberts, A Vogel, L Woodruff, B Scorpio, D Subbarao, K Baric, RS AF Frieman, Matthew Yount, Boyd Agnihothram, Sudhakar Page, Carly Donaldson, Eric Roberts, Anjeanette Vogel, Leatrice Woodruff, Becky Scorpio, Diana Subbarao, Kanta Baric, Ralph S. TI Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease SO JOURNAL OF VIROLOGY LA English DT Article ID PAPAIN-LIKE PROTEASE; ANGIOTENSIN-CONVERTING ENZYME-2; SARS-CORONAVIRUS; VIRUS-INFECTION; HEPATITIS-VIRUS; SPIKE PROTEIN; I INTERFERON; FEVER VIRUS; BALB/C MICE; RECEPTOR AB SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease. C1 [Frieman, Matthew; Page, Carly] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Yount, Boyd; Agnihothram, Sudhakar; Donaldson, Eric; Woodruff, Becky; Baric, Ralph S.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Roberts, Anjeanette; Vogel, Leatrice; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Scorpio, Diana] Johns Hopkins Univ, Dept Mol & Comparat Pathol, Baltimore, MD USA. RP Frieman, M (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM mfrieman@som.umaryland.edu RI Scorpio, Diana/C-4839-2012 FU NIH [AI075297, F32 AI066542]; NIAID, NIH FX This work was generously supported by NIH grant AI075297 to R. S. Baric, and M. Frieman was supported by NIH training grant F32 AI066542. This research was supported in part by the Intramural Research Program of the NIAID, NIH. NR 75 TC 23 Z9 25 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 JAN PY 2012 VL 86 IS 2 BP 884 EP 897 DI 10.1128/JVI.05957-11 PG 14 WC Virology SC Virology GA 870MW UT WOS:000298674600022 PM 22072787 ER PT J AU Kong, R Li, H Bibollet-Ruche, F Decker, JM Zheng, NN Gottlieb, GS Kiviat, NB Sow, PS Georgiev, I Hahn, BH Kwong, PD Robinson, JE Shaw, GM AF Kong, Rui Li, Hui Bibollet-Ruche, Frederic Decker, Julie M. Zheng, Natalie N. Gottlieb, Geoffrey S. Kiviat, Nancy B. Sow, Papa Salif Georgiev, Ivelin Hahn, Beatrice H. Kwong, Peter D. Robinson, James E. Shaw, George M. TI Broad and Potent Neutralizing Antibody Responses Elicited in Natural HIV-2 Infection SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RHESUS MONOCLONAL-ANTIBODIES; BLOOD MONONUCLEAR-CELLS; FUSION INHIBITOR T-20; HIV-2-INFECTED INDIVIDUALS; MEDIATED NEUTRALIZATION; V3-SPECIFIC ANTIBODIES; ENVELOPE GLYCOPROTEINS; WEST-AFRICA; VIRAL LOAD AB Compared with human immunodeficiency virus type 1 (HIV-1), little is known about the susceptibility of HIV-2 to antibody neutralization. We characterized the potency and breadth of neutralizing antibody (NAb) responses in 64 subjects chronically infected with HIV-2 against three primary HIV-2 strains: HIV-2(7312A), HIV-2(ST), and HIV-2(UC1). Surprisingly, we observed in a single-cycle JC53bl-13/TZM-bl virus entry assay median reciprocal 50% inhibitory concentration (IC(50)) NAb titers of 1.7 x 10(5), 2.8 x 10(4), and 3.3 x 10(4), respectively. A subset of 5 patient plasma samples tested against a larger panel of 17 HIV-2 strains where the extracellular gp160 domain was substituted into the HIV-2(7312A) proviral backbone showed potent neutralization of all but 4 viruses. The specificity of antibody neutralization was confirmed using IgG purified from patient plasma, HIV-2 Envs cloned by single-genome amplification, viruses grown in human CD4(+) T cells and tested for neutralization sensitivity on human CD4(+) T target cells, and, as negative controls, env-minus viruses pseudotyped with HIV-1, vesicular stomatitis virus, or murine leukemia virus Env glycoproteins. Human monoclonal antibodies (MAbs) specific for HIV-2 V3 (6.10F), V4 (1.7A), CD4 binding site (CD4bs; 6.10B), CD4 induced (CD4i; 1.4H), and membrane-proximal external region (MPER; 4E10) epitopes potently neutralized the majority of 32 HIV-2 strains bearing Envs from 13 subjects. Patient antibodies competed with V3, V4, and CD4bs MAbs for binding to monomeric HIV-2 gp120 at titers that correlated significantly with NAb titers. HIV-2 MPER antibodies did not contribute to neutralization breadth or potency. These findings indicate that HIV-2 Env is highly immunogenic in natural infection, that high-titer broadly neutralizing antibodies are commonly elicited, and that unlike HIV-1, native HIV-2 Env trimers expose multiple broadly cross-reactive epitopes readily accessible to NAbs. C1 [Li, Hui; Bibollet-Ruche, Frederic; Hahn, Beatrice H.; Shaw, George M.] Univ Penn, Sch Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kong, Rui; Decker, Julie M.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Kong, Rui; Decker, Julie M.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Zheng, Natalie N.; Gottlieb, Geoffrey S.; Kiviat, Nancy B.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Zheng, Natalie N.; Gottlieb, Geoffrey S.; Kiviat, Nancy B.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Sow, Papa Salif] Univ Cheikh Anta Diop Dakar, Ctr Hosp Univ Fann, Clin Malad Infect Ibrahima DIOP Mar, Dakar, Senegal. [Georgiev, Ivelin; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Robinson, James E.] Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70118 USA. RP Shaw, GM (reprint author), Univ Penn, Sch Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM shawg@upenn.edu FU NIH [AI67854, AI88564, AI87383] FX This work was supported by grants from the NIH (AI67854, AI88564, and AI87383). NR 66 TC 29 Z9 29 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 JAN PY 2012 VL 86 IS 2 BP 947 EP 960 DI 10.1128/JVI.06155-11 PG 14 WC Virology SC Virology GA 870MW UT WOS:000298674600027 PM 22031948 ER PT J AU Veeranna, RP Haque, M Davis, DA Yang, M Yarchoan, R AF Veeranna, Ravindra P. Haque, Muzammel Davis, David A. Yang, Min Yarchoan, Robert TI Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Induction by Hypoxia and Hypoxia-Inducible Factors SO JOURNAL OF VIROLOGY LA English DT Article ID LYMPHOMA CELL-LINE; EPSTEIN-BARR-VIRUS; PAS DOMAIN PROTEIN-1; ENDOTHELIAL-CELLS; DNA-SEQUENCES; HUMAN-HERPESVIRUS-8 DNA; LYTIC REPLICATION; BINDING PROTEIN; GENE-EXPRESSION; TRANSCRIPTION AB Hypoxia and hypoxia-inducible factors (HIFs) play an important role in the Kaposi's sarcoma-associated herpesvirus (KSHV) life cycle. In particular, hypoxia can activate lytic replication of KSHV and specific lytic genes, including the replication and transcription activator (RTA), while KSHV infection in turn can increase the levels and activity of HIFs. In the present study, we show that hypoxia increases the levels of mRNAs encoding KSHV latency-associated nuclear antigen (LANA) in primary effusion lymphoma (PEL) cell lines and also increases the levels of LANA protein. Luciferase reporter assays in Hep3B cells revealed a moderate activation of the LANA promoter region by hypoxia as well as by cotransfection with degradation-resistant HIF-1 alpha or HIF-2 alpha expression plasmids. Computer analysis of a 1.2-kb sequence upstream of the LANA translational start site identified six potential hypoxia-responsive elements (HRE). Sequential deletion studies revealed that much of this activity was mediated by one of these HREs (HRE 4R) oriented in the 3' to 5' direction and located between the constitutive (LTc) and RTA-inducible (LTi) mRNA start sites. Site-directed mutation of this HRE substantially reduced the response to both HIF-1 alpha and HIF-2 alpha in a luciferase reporter assay. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated binding of both HIF-1 alpha and HIF-2 alpha to this region. Also, HIF-1 alpha was found to associate with RTA, and HIFs enhanced the activation of LTi by RTA. These results provide evidence that hypoxia and HIFs upregulate both latent and lytic KSHV replication and play a central role in the life cycle of this virus. C1 [Veeranna, Ravindra P.; Haque, Muzammel; Davis, David A.; Yang, Min; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM yarchoan@helix.nih.gov OI Ravindra, P V/0000-0003-4228-1843 FU NIH, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 55 TC 11 Z9 11 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 2 BP 1097 EP 1108 DI 10.1128/JVI.05167-11 PG 12 WC Virology SC Virology GA 870MW UT WOS:000298674600041 PM 22090111 ER PT J AU Klatt, NR Canary, LA Vanderford, TH Vinton, CL Engram, JC Dunham, RM Cronise, HE Swerczek, JM Lafont, BAP Picker, LJ Silvestri, G Brenchley, JM AF Klatt, Nichole R. Canary, Lauren A. Vanderford, Thomas H. Vinton, Carol L. Engram, Jessica C. Dunham, Richard M. Cronise, Heather E. Swerczek, Joanna M. Lafont, Bernard A. P. Picker, Louis J. Silvestri, Guido Brenchley, Jason M. TI Dynamics of Simian Immunodeficiency Virus SIVmac239 Infection in Pigtail Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID PIG-TAILED MACAQUES; CD4(+) T-CELLS; ACUTE SIV INFECTION; MACACA-NEMESTRINA; IMMUNE ACTIVATION; HIV-1 INFECTION; IN-VIVO; AFRICAN INDIVIDUALS; TYPE-1 INFECTION; MOLECULAR CLONES AB Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P = 0.0018). However, increased SIV progression was not associated with increased viremia, as both peak and set-point plasma viremias were similar between PTM and RM (P = 0.7953 and P = 0.1006, respectively). Moreover, this increased disease progression was not associated with rapid CD4(+) T cell depletion, as CD4(+) T cell decline resembled other SIV/human immunodeficiency virus (HIV) models. Since immune activation is the best predictor of disease progression during HIV infection, we analyzed immune activation by turnover of T cells by BrdU decay and Ki67 expression. We found increased levels of turnover prior to SIV infection of PTM compared to that observed with RM, which may contribute to their increased disease progression rate. These data evaluate the kinetics of SIVmac239-induced disease progression and highlight PTM as a model for HIV infection and the importance of immune activation in SIV disease progression. C1 [Klatt, Nichole R.; Canary, Lauren A.; Vinton, Carol L.; Lafont, Bernard A. P.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Klatt, Nichole R.; Canary, Lauren A.; Vinton, Carol L.; Lafont, Bernard A. P.; Brenchley, Jason M.] NIAID, Program Barrier Immun & Repair, NIH, Bethesda, MD 20892 USA. [Vanderford, Thomas H.; Engram, Jessica C.; Dunham, Richard M.; Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Cronise, Heather E.; Swerczek, Joanna M.] NIAID, Comparat Med Branch, NIH, Poolesville, MD USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, VGTI, Dept Mol Microbiol, Beaverton, OR USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM jbrenchl@niaid.nih.gov RI Dunham, Richard/B-2012-2009; Lafont, Bernard/B-7236-2014 OI Dunham, Richard/0000-0003-4542-2330; FU National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health; NIH [R01-AI90797, AI054292]; ONPRC [RR00163] FX These studies were supported by the intramural program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, and in part by NIH grants R01-AI90797 to G. Silvestri and AI054292 to L. Picker as well as ONPRC Core grant RR00163. NR 61 TC 22 Z9 25 U1 1 U2 6 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 JAN PY 2012 VL 86 IS 2 BP 1203 EP 1213 DI 10.1128/JVI.06033-11 PG 11 WC Virology SC Virology GA 870MW UT WOS:000298674600050 PM 22090099 ER PT J AU Schiefelbein, EL Mirchandani, GG George, GC Becker, EA Castrucci, BC Hoelscher, DM AF Schiefelbein, Emily L. Mirchandani, Gita G. George, Goldy C. Becker, Emilie A. Castrucci, Brian C. Hoelscher, Deanna M. TI Association Between Depressed Mood and Perceived Weight in Middle and High School Age Students: Texas 2004-2005 SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Adolescent; Body weight; Weight perception; Overweight; Obesity; Depression ID BODY-MASS INDEX; MENTAL-HEALTH OUTCOMES; ADOLESCENT GIRLS; RISK-FACTORS; CLINICAL-IMPLICATIONS; GENDER-DIFFERENCES; YOUNG ADOLESCENTS; PHYSICAL-ACTIVITY; OVERWEIGHT STATUS; UNITED-STATES AB Research exploring the relationship between weight perception and depressed mood among adolescents is limited in the United States. The purpose of this study is to examine the association of perceived versus actual body weight and depressed mood in a representative sample of 8th and 11th grade public school students in Texas. Using data from the 2004-2005 School Physical Activity and Nutrition (SPAN) study, logistic regression analyses were conducted to assess the association of weight perception with depressed mood. Healthy weight students who perceived themselves to be a healthy weight were the reference group for all analyses. A high prevalence of misperception of body weight was observed. Overweight and obese 8th grade girls and boys who perceived themselves to be overweight had increased odds of depressed mood [Girls: OR 1.70 (95% CI: 1.07-2.69), Boys: OR 2.05 (95% CI: 1.16-3.62)]. Healthy weight 8th grade girls who perceived themselves to be overweight had 2.5 times greater odds of depressed mood (OR 2.63, 95% CI: 1.54-4.50). Healthy weight boys who perceived themselves to be underweight had more than twice the odds (OR 2.18, 95% CI: 1.23-3.89) of depressed mood. No weight category was significantly associated with depressed mood in boys or girls in 11th grade. The present study suggests that weight misperceptions are associated with depressed mood in young adolescents. Education about healthy body size is necessary to correct the common weight misperceptions observed. The high prevalence rates of depressed mood suggest a greater need for research into understanding factors that may contribute to depressed mood in adolescents. C1 [Schiefelbein, Emily L.] Ctr Dis Control & Prevent, CDC CSTE Appl Epidemiol Fellowship Program, Div Family & Community Hlth Serv, Council State & Terr Epidemiologists,Texas Dept S, Austin, TX 78714 USA. [George, Goldy C.] NCI, Bethesda, MD 20892 USA. [George, Goldy C.] Univ Texas Sch Publ Hlth, Michael & Susan Dell Ctr Adv Hlth Living, Houston, TX USA. [Becker, Emilie A.] Texas Dept State Hlth Serv, Div Mental Hlth & Subst Abuse, Austin, TX USA. [Castrucci, Brian C.] Georgia Dept Publ Hlth, Maternal & Child Hlth Program, Austin, TX USA. [Hoelscher, Deanna M.] Univ Texas Sch Publ Hlth Austin, Michael & Susan Dell Ctr Adv Hlth Living, Austin, TX USA. RP Schiefelbein, EL (reprint author), Ctr Dis Control & Prevent, CDC CSTE Appl Epidemiol Fellowship Program, Div Family & Community Hlth Serv, Council State & Terr Epidemiologists,Texas Dept S, MC 1922,POB 149347, Austin, TX 78714 USA. EM Emily.schiefelbein@gmail.com; gita.mirchandani@dshs.state.tx.us; goldyjg@yahoo.com; emilie.becker@dshs.state.tx.us; brian.castrucci@gmail.com; deanna.m.hoelscher@uth.tmc.edu FU NCHM CDC HHS [5U38HM000414] NR 49 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD JAN PY 2012 VL 16 IS 1 BP 169 EP 176 DI 10.1007/s10995-010-0733-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 875AL UT WOS:000299001100019 PM 21165762 ER PT J AU Pena, L Franks, J Chapman, KA Gropman, A Mew, NA Chakrapani, A Island, E MacLeod, E Matern, D Smith, B Stagni, K Sutton, VR Ueda, K Urv, T Venditti, C Enns, GM Summar, ML AF Pena, Loren Franks, Jill Chapman, Kimberly A. Gropman, Andrea Mew, Nicholas Ah Chakrapani, Anupam Island, Eddie MacLeod, Erin Matern, Dietrich Smith, Brittany Stagni, Kathy Sutton, V. Reid Ueda, Keiko Urv, Tiina Venditti, Charles Enns, Gregory M. Summar, Marshall L. TI Natural history of propionic acidemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Propionic acidemia; Organic acidemia; Pancreatitis; Cardiomyopathy; Long QT interval; Long-term complications ID METHYLMALONIC ACIDURIA; ACUTE-PANCREATITIS; IDIOPATHIC HYPERGLYCINEMIA; KETOTIC-HYPERGLYCINEMIA; METABOLISM; DISORDERS; CARDIOMYOPATHY; CARBOXYLASE; DEFICIENCY; MANAGEMENT AB Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation. The natural history of the disease is just beginning to be elucidated as individuals reach older ages. Recent studies have identified the genomic mutations in the genes PCCA and PCCB. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications. This article reviews the available literature for the natural history of propionic acidemia. C1 [Pena, Loren] Univ Illinois, Dept Pediat, Div Genet, Coll Med Chicago, Chicago, IL 60612 USA. [Franks, Jill; Smith, Brittany] Propion Acidemia Fdn, Highland Pk, IL USA. [Chapman, Kimberly A.; Gropman, Andrea; Mew, Nicholas Ah; MacLeod, Erin; Summar, Marshall L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Chakrapani, Anupam] Birmingham Childrens Hosp, Birmingham, W Midlands, England. [Island, Eddie] Georgetown Univ, Transplant Program, Washington, DC USA. [Matern, Dietrich] Mayo Clin, Rochester, MN USA. [Stagni, Kathy] Organ Acidemia Assoc, Pinole, CA USA. [Sutton, V. Reid] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Sutton, V. Reid] Texas Childrens Hosp, Houston, TX 77030 USA. [Ueda, Keiko] Tufts Med Ctr, Boston, MA USA. [Urv, Tiina; Venditti, Charles] NIH, Bethesda, MD 20892 USA. [Enns, Gregory M.] Stanford Univ, Palo Alto, CA 94304 USA. RP Pena, L (reprint author), Univ Illinois, Dept Pediat, Div Genet, Coll Med Chicago, 840 S Wood St,12th Floor,MC 856, Chicago, IL 60612 USA. EM lpena@uic.edu NR 60 TC 27 Z9 27 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2012 VL 105 IS 1 BP 5 EP 9 DI 10.1016/j.ymgme.2011.09.022 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 879WO UT WOS:000299363800003 PM 21986446 ER PT J AU Schreiber, J Chapman, KA Summar, ML Mew, NA Sutton, VR MacLeod, E Stagni, K Ueda, K Franks, J Island, E Matern, D Pena, L Smith, B Urv, T Venditti, C Chakarapani, A Gropman, AL AF Schreiber, John Chapman, Kimberly A. Summar, Marshall L. Mew, Nicholas Ah Sutton, V. Reid MacLeod, Erin Stagni, Kathy Ueda, Keiko Franks, Jill Island, Eddie Matern, Dietrich Pena, Loren Smith, Brittany Urv, Tiina Venditti, Charles Chakarapani, Anupam Gropman, Andrea L. TI Neurologic considerations in propionic acidemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Propionic acidemia; Neurological; Seizure; Neuroimaging; Spectroscopy; Inborn error of metabolism ID IN-VITRO PHOSPHORYLATION; RAT CEREBRAL-CORTEX; BRAIN; ONSET; NEUROPATHOLOGY; SPECTROSCOPY; METABOLISM; DISORDERS; ACIDS AB Propionic acidemia (PA) is an organic acidemia which has a broad range of neurological complications, including developmental delay, intellectual disability, structural abnormalities, metabolic stroke-like episodes, seizures, optic neuropathy, and cranial nerve abnormalities. As the PA consensus conference hosted by Children's National Medical Center progressed from January 28 to 30, 2011, it became evident that neurological complications were common and a major component of morbidity, but the role of imaging and the basis for brain pathophysiology were unclear. This paper reviews the hypothesized pathophysiology, presentation and uses the best available evidence to suggest programs for treatment, imaging, and monitoring the neurological complications of PA, C1 [Schreiber, John; Gropman, Andrea L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Chapman, Kimberly A.; Summar, Marshall L.; Mew, Nicholas Ah; MacLeod, Erin] Childrens Natl Med Ctr, Sect Genet & Metab, Washington, DC 20010 USA. [Sutton, V. Reid] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Sutton, V. Reid] Texas Childrens Hosp, Houston, TX 77030 USA. [Stagni, Kathy] Organ Acidemia Assoc, Pinole, CA USA. [Ueda, Keiko] Tufts Med Ctr, Boston, MA USA. [Franks, Jill; Smith, Brittany] Propion Acidemia Fdn, Highland, IL USA. [Island, Eddie] Georgetown Univ, Transplant Program, Washington, DC USA. [Matern, Dietrich] Mayo Clin, Rochester, MN USA. [Pena, Loren] Univ Illinois, Coll Med Chicago, Chicago, IL USA. [Urv, Tiina; Venditti, Charles] NIH, Bethesda, MD 20892 USA. [Chakarapani, Anupam] Birmingham Childrens Hosp, Birmingham, W Midlands, England. RP Gropman, AL (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM agropman@childrensnational.org NR 40 TC 18 Z9 20 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2012 VL 105 IS 1 BP 10 EP 15 DI 10.1016/j.ymgme.2011.10.003 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 879WO UT WOS:000299363800004 PM 22078457 ER PT J AU Chapman, KA Gropman, A MacLeod, E Stagni, K Summar, ML Ueda, K Mew, NA Franks, J Island, E Matern, D Pena, L Smith, B Sutton, VR Urv, T Venditti, C Chakrapani, A AF Chapman, Kimberly A. Gropman, Andrea MacLeod, Erin Stagni, Kathy Summar, Marshall L. Ueda, Keiko Mew, Nicholas Ah Franks, Jill Island, Eddie Matern, Dietrich Pena, Loren Smith, Brittany Sutton, V. Reid Urv, Tiina Venditti, Charles Chakrapani, Anupam TI Acute management of propionic acidemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Propionic acidemia; Inborn error of metabolism; Organic acidemia; Treatment; Acute management ID EMERGENCY CARDIOVASCULAR CARE; RESTING ENERGY-EXPENDITURE; SYRUP-URINE-DISEASE; METHYLMALONIC ACIDEMIA; L-CARNITINE; INBORN-ERRORS; CARDIOPULMONARY-RESUSCITATION; PARENTERAL-NUTRITION; METABOLIC DISEASES; SAUDI-ARABIA AB Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30,2011 in Washington, D.C., Children's National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge. C1 [Chapman, Kimberly A.; Gropman, Andrea; MacLeod, Erin; Summar, Marshall L.; Mew, Nicholas Ah] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Stagni, Kathy] Organ Acidemia Assoc, Pinole, CA USA. [Ueda, Keiko] Tufts Med Ctr, Boston, MA USA. [Franks, Jill; Smith, Brittany] Propion Acidemia Fdn, Highland Pk, IL USA. [Island, Eddie] Georgetown Univ, Transplant Program, Washington, DC USA. [Matern, Dietrich] Mayo Clin, Rochester, MN USA. [Pena, Loren] Univ Illinois, Coll Med Chicago, Chicago, IL USA. [Sutton, V. Reid] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Sutton, V. Reid] Texas Childrens Hosp, Houston, TX 77030 USA. [Urv, Tiina; Venditti, Charles] NIH, Bethesda, MD 20892 USA. [Chakrapani, Anupam] Birmingham Childrens Hosp, Birmingham, W Midlands, England. RP Chapman, KA (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave NW,Suite 4800, Washington, DC 20010 USA. EM kchapman@childrensnational.org FU European Union [E-IMD 2010 12 01] FX Special thanks to Dr. Brendan Lanpher for his critical review and editing of this manuscript. This publication arises from the project 'E-IMD 2010 12 01' which has received funding from the European Union, in the framework of the Health Programme. NR 53 TC 25 Z9 29 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2012 VL 105 IS 1 BP 16 EP 25 DI 10.1016/j.ymgme.2011.09.026 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 879WO UT WOS:000299363800005 PM 22000903 ER PT J AU Sutton, VR Chapman, KA Gropman, AL MacLeod, E Stagni, K Summar, ML Ueda, K Mew, NA Franks, J Island, E Matern, D Pena, L Smith, B Urv, T Venditti, C Chakarapani, A AF Sutton, V. Reid Chapman, Kimberly A. Gropman, Andrea L. MacLeod, Erin Stagni, Kathy Summar, Marshall L. Ueda, Keiko Mew, Nicholas Ah Franks, Jill Island, Eddie Matern, Dietrich Pena, Loren Smith, Brittany Urv, Tina Venditti, Charles Chakarapani, Anupam TI Chronic management and health supervision of individuals with propionic acidemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Propionic acidemia; Organic acidemia; Propionic aciduria; Organic aciduria; Chronic management; Health supervision ID LIVER-TRANSPLANTATION; METHYLMALONIC ACIDEMIA; PARENTERAL-NUTRITION; ACUTE-PANCREATITIS; ORGANIC ACIDURIAS; INBORN-ERRORS; L-CARNITINE; DISORDERS; METABOLISM; CHILDREN AB Propionic acidemia is a relatively rare inborn error of metabolism. Individuals with propionic acidemia often have life-threatening episodes of hyperammonemia and metabolic acidosis, as well as intellectual disability. There are many reports of additional problems, including poor growth, stroke-like episodes of the basal ganglia, seizures, cardiomyopathy, long QTc syndrome, immune defects, pancreatitis and optic neuropathy: however, there is little information about the incidence of these problems in this rare disease. Additionally, there are no clear guidelines for medical or surgical management of individuals with propionic acidemia. Through a comprehensive and systematic review of the current medical literature and survey of expert opinion, we have developed practice guidelines for the chronic management of individuals with propionic acidemia, including dietary therapy, use of medications, laboratory monitoring, chronic health supervision, use of gastrostomy tubes and liver transplantation. C1 [Sutton, V. Reid] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Sutton, V. Reid] Texas Childrens Hosp, Houston, TX 77030 USA. [Chapman, Kimberly A.; Gropman, Andrea L.; MacLeod, Erin; Summar, Marshall L.; Mew, Nicholas Ah] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Stagni, Kathy] Organ Acidemia Assoc, Pinole, CA USA. [Ueda, Keiko] Tufts Med Ctr, Boston, MA USA. [Franks, Jill; Smith, Brittany] Propion Acidemia Fdn, Highland, IL USA. [Island, Eddie] Georgetown Univ, Transplant Program, Washington, DC USA. [Matern, Dietrich] Mayo Clin, Rochester, MN USA. [Pena, Loren] Univ Illinois, Coll Med Chicago, Chicago, IL USA. [Urv, Tina; Venditti, Charles] NIH, Bethesda, MD 20892 USA. [Chakarapani, Anupam] Birmingham Childrens Hosp, Birmingham, W Midlands, England. RP Sutton, VR (reprint author), 6701 Fannin,Suite 1560-10, Houston, TX 77030 USA. EM vrsutton@texaschildrens.org NR 61 TC 29 Z9 29 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2012 VL 105 IS 1 BP 26 EP 33 DI 10.1016/j.ymgme.2011.08.034 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 879WO UT WOS:000299363800006 PM 21963082 ER PT J AU Okugawa, S Moayeri, M Pomerantsev, AP Sastalla, I Crown, D Gupta, PK Leppla, SH AF Okugawa, Shu Moayeri, Mahtab Pomerantsev, Andrei P. Sastalla, Inka Crown, Devorah Gupta, Pradeep K. Leppla, Stephen H. TI Lipoprotein biosynthesis by prolipoprotein diacylglyceryl transferase is required for efficient spore germination and full virulence of Bacillus anthracis SO MOLECULAR MICROBIOLOGY LA English DT Article ID GRAM-POSITIVE BACTERIA; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; STREPTOCOCCUS-PNEUMONIAE; PROTECTIVE ANTIGEN; LIPID MODIFICATION; PROTEIN SECRETION; IN-VITRO; SUBTILIS; IDENTIFICATION AB Bacterial lipoproteins play a crucial role in virulence in some Gram-positive bacteria. However, the role of lipoprotein biosynthesis in Bacillus anthracis is unknown. We created a B. anthracis mutant strain altered in lipoproteins by deleting the lgt gene encoding the enzyme prolipoprotein diacylglyceryl transferase, which attaches the lipid anchor to prolipoproteins. 14C-palmitate labelling confirmed that the mutant strain lacked lipoproteins, and hydrocarbon partitioning showed it to have decreased surface hydrophobicity. The anthrax toxin proteins were secreted from the mutant strain at nearly the same levels as from the wild-type strain. The TLR2-dependent TNF-a response of macrophages to heat-killed lgt mutant bacteria was reduced. Spores of the lgt mutant germinated inefficiently in vitro and in mouse skin. As a result, in a murine subcutaneous infection model, lgt mutant spores had markedly attenuated virulence. In contrast, vegetative cells of the lgt mutant were as virulent as those of the wild-type strain. Thus, lipoprotein biosynthesis in B. anthracis is required for full virulence in a murine infection model. C1 [Okugawa, Shu; Moayeri, Mahtab; Pomerantsev, Andrei P.; Sastalla, Inka; Crown, Devorah; Gupta, Pradeep K.; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Lab Bacterial Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX We thank Alan Sher for kindly providing TLR2-deficient mice and Drs. Akira and Merkel for MyD88 knockout mice. We also thank Mini Varughese for editing the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 60 TC 14 Z9 14 U1 1 U2 7 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 JAN PY 2012 VL 83 IS 1 BP 96 EP 109 DI 10.1111/j.1365-2958.2011.07915.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 869GL UT WOS:000298585600010 PM 22103323 ER PT J AU Wu, PH Hale, CM Chen, WC Lee, JSH Tseng, Y Wirtz, D AF Wu, Pei-Hsun Hale, Christopher M. Chen, Wei-Chiang Lee, Jerry S. H. Tseng, Yiider Wirtz, Denis TI High-throughput ballistic injection nanorheology to measure cell mechanics SO NATURE PROTOCOLS LA English DT Article ID PARTICLE-TRACKING MICRORHEOLOGY; DIFFUSING WAVE SPECTROSCOPY; ACTIN-FILAMENT NETWORKS; ATOMIC-FORCE MICROSCOPY; LIVING CELLS; INTRACELLULAR NANORHEOLOGY; ENDOTHELIAL-CELLS; MATRIX STIFFNESS; MAMMALIAN-CELLS; COMPLEX FLUIDS AB High-throughput ballistic injection nanorheology is a method for the quantitative study of cell mechanics. Cell mechanics are measured by ballistic injection of submicron particles into the cytoplasm of living cells and tracking the spontaneous displacement of the particles at high spatial resolution. The trajectories of the cytoplasm-embedded particles are transformed into mean-squared displacements, which are subsequently transformed into frequency-dependent viscoelastic moduli and time-dependent creep compliance of the cytoplasm. This method allows for the study of a wide range of cellular conditions, including cells inside a 3D matrix, cell subjected to shear flows and biochemical stimuli, and cells in a live animal. Ballistic injection lasts <1 min and is followed by overnight incubation. Multiple particle tracking for one cell lasts <1 min. Forty cells can be examined in <1 h. C1 [Wu, Pei-Hsun; Hale, Christopher M.; Chen, Wei-Chiang; Tseng, Yiider; Wirtz, Denis] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD 21218 USA. [Wu, Pei-Hsun; Hale, Christopher M.; Chen, Wei-Chiang; Lee, Jerry S. H.; Wirtz, Denis] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA. [Lee, Jerry S. H.] NCI, Ctr Strateg Sci Initiat, Off Director, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Tseng, Yiider] Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. RP Tseng, Y (reprint author), Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD 21218 USA. EM ytseng@che.ufl.edu; wirtz@jhu.edu RI Lee, Jerry/A-3189-2008; Lee, Jerry/K-4553-2014; Hale, Christopher/A-6633-2009 OI Lee, Jerry/0000-0003-1515-0952; Hale, Christopher/0000-0002-2360-7759 FU NIH [U54CA143868, R21CA137686, R01GM084204] FX Normal human ovarian epithelial cells (OSE10) and ovarian cancer cells (OVCAR3) were provided by I.-M. Shih (Department of Pathology, Johns Hopkins University School of Medicine). This work was supported in part by NIH grants U54CA143868 and R21CA137686, and R01GM084204. We thank members of the Wirtz and Tseng labs for technical advice and reagents. NR 73 TC 20 Z9 20 U1 2 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD JAN PY 2012 VL 7 IS 1 BP 155 EP 170 DI 10.1038/nprot.2011.436 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 876LL UT WOS:000299108900014 PM 22222790 ER PT J AU Pommier, Y Marchand, C AF Pommier, Yves Marchand, Christophe TI Interfacial inhibitors: targeting macromolecular complexes SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID DNA TOPOISOMERASE-II; BREAKAGE-REUNION REACTION; X-RAY STRUCTURES; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; ANTITUMOR DRUGS; INTEGRASE INHIBITORS; ALLOSTERIC PROTEINS; HUMAN CALCINEURIN; COVALENT COMPLEX AB Interfacial inhibitors belong to a broad class of natural products and synthetic drugs that are commonly used to treat cancers as well as bacterial and HIV infections. They bind selectively to interfaces as macromolecular machines assemble and are set in motion. The bound drugs transiently arrest the targeted molecular machines, which can initiate allosteric effects, or desynchronize macromolecular machines that normally function in concert. Here, we review five archetypical examples of interfacial inhibitors: the camptothecins, etoposide, the quinolone antibiotics, the vinca alkaloids and the novel anti-HIV inhibitor raltegravir. We discuss the common and diverging elements between interfacial and allosteric inhibitors and give a perspective for the rationale and methods used to discover novel interfacial inhibitors. C1 [Pommier, Yves; Marchand, Christophe] NCI, Mol Pharmacol Lab, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research, the National Cancer Institute, US National Institutes of Health FX Our studies are supported by the Center for Cancer Research, the Intramural Program of the National Cancer Institute, US National Institutes of Health. NR 83 TC 90 Z9 90 U1 5 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JAN PY 2012 VL 11 IS 1 BP 25 EP 36 DI 10.1038/nrd3404 PG 12 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 879IO UT WOS:000299323100019 PM 22173432 ER PT J AU Gupta, S Gellert, M Yang, W AF Gupta, Shikha Gellert, Martin Yang, Wei TI Mechanism of mismatch recognition revealed by human MutS beta bound to unpaired DNA loops SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID REPAIR PROTEIN MUTS; SACCHAROMYCES-CEREVISIAE; REPEAT INSTABILITY; COLORECTAL-CANCER; YEAST MSH2-MSH6; ATPASE ACTIVITY; HMUTS-BETA; IN-VIVO; MSH6; BINDING AB DNA mismatch repair corrects replication errors, thus reducing mutation rates and microsatellite instability. Genetic defects in this pathway cause Lynch syndrome and various cancers in humans. Binding of a mispaired or unpaired base by bacterial MutS and eukaryotic MutS alpha is well characterized. We report here crystal structures of human MutS beta in complex with DNA containing insertion-deletion loops (IDL) of two, three, four or six unpaired nucleotides. In contrast to eukaryotic MutS alpha and bacterial MutS, which bind the base of a mismatched nucleotide, MutS beta binds three phosphates in an IDL. DNA is severely bent at the IDL; unpaired bases are flipped out into the major groove and partially exposed to solvent. A normal downstream base pair can become unpaired; a single unpaired base can thereby be converted to an IDL of two nucleotides and recognized by MutS beta. The C-terminal dimerization domains form an integral part of the MutS structure and coordinate asymmetrical ATP hydrolysis by Msh2 and Msh3 with mismatch binding to signal for repair. C1 [Gupta, Shikha; Gellert, Martin; Yang, Wei] NIDDKD, Mol Biol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health FX We thank J. Jiang for collecting X-ray diffraction data of Loop4; A. Howard for help with data processing; T. Kunkel for the term 'isomerization'; R. Kolodner, E. Alani and J. Surtees for vital discussions; and D. Leahy for critical reading of the manuscript. The research of all authors was funded by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health. NR 53 TC 48 Z9 48 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JAN PY 2012 VL 19 IS 1 BP 72 EP U91 DI 10.1038/nsmb.2175 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 875PW UT WOS:000299046000012 PM 22179786 ER PT J AU Leischow, SJ Zeller, M Backinger, CL AF Leischow, Scott J. Zeller, Mitch Backinger, Cathy L. TI Research Priorities and Infrastructure Needs of the Family Smoking Prevention and Tobacco Control Act: Science to Inform FDA Policy SO NICOTINE & TOBACCO RESEARCH LA English DT Editorial Material AB Introduction: A new law in the United States gives the Food and Drug Administration (FDA) wide latitude to regulate tobacco products for the first time. Given the need for science to serve as a foundation for FDA actions, it is critical that a scientific review of the literature relevant to the proposed legislation be undertaken by experts in the field of nicotine and tobacco research in order to develop research priorities. Methods: This paper describes an initiative that was implemented to identify research opportunities under "The Family Smoking Prevention and Tobacco Control Act" and summarizes the conclusions and future directions derived from that initiative. Results: Multiple research and surveillance needs were identified, such as characterization of biomarkers and increased analysis of risk perception. It was also recognized that science will play a critical role in policy determinations such as what constitutes "substantial equivalence" and that there will be considerable infrastructure needs (e. g., laboratories for product testing). Conclusions: Science must drive FDA's decision making regarding tobacco regulation. This article provides a summary of research opportunities identified through literature reviews related to various provisions of the new law. However, the science required by the law requires a transdisciplinary approach because of its complexity, so one of the challenges facing the FDA will be to connect the silos of research in recognition that the "system" of tobacco regulation is greater than the sum of its parts. C1 [Leischow, Scott J.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. [Zeller, Mitch] Pinney Associates, Bethesda, MD USA. [Backinger, Cathy L.] NCI, Bethesda, MD 20892 USA. RP Leischow, SJ (reprint author), Univ Arizona, Arizona Canc Ctr, POB 245024, Tucson, AZ 85724 USA. EM sleischow@azcc.arizona.edu NR 7 TC 13 Z9 13 U1 0 U2 6 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 JAN PY 2012 VL 14 IS 1 BP 1 EP 6 DI 10.1093/ntr/ntr057 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 877YS UT WOS:000299219200001 PM 22184581 ER PT J AU Basel-Vanagaite, L Sprecher, E Gat, A Merlob, P Albin-Kaplanski, A Konen, O Solomon, BD Muenke, M Grzeschik, KH Sirota, L AF Basel-Vanagaite, Lina Sprecher, Eli Gat, Andrea Merlob, Paul Albin-Kaplanski, Adi Konen, Osnat Solomon, Benjamin D. Muenke, Maximilian Grzeschik, Karl H. Sirota, Lea TI New Syndrome of Congenital Circumferential Skin Folds Associated with Multiple Congenital Anomalies SO PEDIATRIC DERMATOLOGY LA English DT Article ID MICHELIN-TIRE BABY; AUTOSOMAL DOMINANT TRAIT; SMOOTH-MUSCLE HAMARTOMA; MCA/MR SYNDROME; CREASES; MUTATIONS; SPECTRUM; NEVUS; GENE AB Congenital circumferential skin folds can be found in individuals with no additional defects, as well as in patients with multiple congenital anomalies and developmental abnormalities. Current data point to etiological heterogeneity of syndromic cases. We describe a 7-month-old girl with a novel combination of symmetrical congenital circumferential skin folds, dysmorphic features, and multiple congenital abnormalities. Examination of the patient revealed symmetrical congenital circumferential skin folds and dysmorphic features, as well as multiple congenital anomalies including nasal pyriform aperture stenosis, ventricular septal defect, absent spleen, camptodactyly, and severe psychomotor retardation. Skin biopsy demonstrated subcutaneous fat extending into the superficial and deep reticular dermis. Sequencing of the CDON, SHH, ZIC2, SIX3, and TGIF genes (associated with holoprosencephaly) did not disclose pathogenic alterations. Extensive review of previously described cases of syndromic congenital circumferential skin folds did not reveal a similar combination of clinical and histopathological findings. C1 [Basel-Vanagaite, Lina] Beilinson Med Ctr, Rabin Med Ctr, Schneider Childrens Med Ctr Israel, IL-49100 Petah Tiqwa, Israel. [Basel-Vanagaite, Lina] Beilinson Med Ctr, Rabin Med Ctr, Raphael Recanati Genet Inst, IL-49100 Petah Tiqwa, Israel. [Basel-Vanagaite, Lina; Sprecher, Eli; Gat, Andrea] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Sprecher, Eli] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Dermatol, IL-69978 Tel Aviv, Israel. [Gat, Andrea] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Pathol, IL-69978 Tel Aviv, Israel. [Sirota, Lea] Rabin Med Ctr, Dept Neonatol, Petah Tiqwa, Israel. [Konen, Osnat] Schneider Childrens Med Ctr Israel, Dept Imaging, Petah Tiqwa, Israel. [Albin-Kaplanski, Adi] Rabin Med Ctr, Raphael Recanati Genet Inst, Petah Tiqwa, Israel. [Grzeschik, Karl H.] Univ Marburg, Dept Human Genet, Marburg, Germany. [Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Basel-Vanagaite, L (reprint author), Beilinson Med Ctr, Rabin Med Ctr, Schneider Childrens Med Ctr Israel, IL-49100 Petah Tiqwa, Israel. EM basel@post.tau.ac.il FU Intramural NIH HHS [ZIA HG000209-12] NR 32 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD JAN-FEB PY 2012 VL 29 IS 1 BP 89 EP 95 DI 10.1111/j.1525-1470.2011.01403.x PG 7 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 877UX UT WOS:000299209300016 PM 21995818 ER PT J AU Komarow, HD Skinner, J Young, M Gaskins, D Nelson, C Gergen, PJ Metcalfe, DD AF Komarow, Hirsh D. Skinner, Jeff Young, Michael Gaskins, Donna Nelson, Celeste Gergen, Peter J. Metcalfe, Dean D. TI A study of the use of impulse oscillometry in the evaluation of children with asthma: Analysis of lung parameters, order effect, and utility compared with spirometry SO PEDIATRIC PULMONOLOGY LA English DT Article DE pediatric asthma; lung function; bronchodilator response; spirometry; impulse oscillometry ID FORCED OSCILLATION TECHNIQUE; REFERENCE VALUES; BRONCHODILATOR RESPONSE; RESPIRATORY RESISTANCE; PRESCHOOL-CHILDREN; YOUNG-CHILDREN; IMPEDANCE; HEALTHY; RISK AB Background The ability to objectively measure lung function in children is critical in the assessment and treatment of asthma in this age group. We thus determined the effectiveness of impulse oscillometry (IOS) as a non-invasive technique to assess lung function in children and in comparison to spirometry for sensitivity and specificity, testing variability, and the order effect of sequential testing of IOS and spirometry.Methods: One hundred seventeen children sequentially evaluated in a pediatric clinic and under medical care for disease, were asked to perform IOS and spirometry. The utility of IOS and spirometry in differentiating children that had asthma versus those children who did not was then analyzed. Results: In the primary analysis (n = 117), bronchodilator response using IOS distinguished asthmatics from non- asthmatics, P = 0.0008 for R10. Receiver- operator characteristic curve (ROC) analysis of R10 bronchodilator response at the best cut- off (-8.6% change) correctly identified 77% of patients with asthma and excluded 76% of non- asthmatics. Amongst those children able to perform spirometry (asthmatics, n = 66; non- asthmatics, n = 16), FEV1 did not reveal a difference between these two groups, while area of reactance (AX) did distinguish these groups (P = 0.0092). Sequential testing of IOS and then spirometry (n = 47) showed a significant decrement in lung function as determined by IOS following performance of spirometry (P = 0.0309). Conclusion: In the diagnosis and management of children with lung disease, IOS is a non- invasive approach that easily and objectively measures lung impedance and should be considered as both an adjunct, and in some situations, an alternative to standard spirometry. Pediatr Pulmonol. 2012; 47: 18- 26. (C) 2011 Wiley Periodicals, Inc. C1 [Komarow, Hirsh D.; Young, Michael; Gaskins, Donna; Nelson, Celeste; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Skinner, Jeff] NIAID, BCBB, NIH, Bethesda, MD 20892 USA. [Gergen, Peter J.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Komarow, HD (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 1C129A1,10 Ctr Dr, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov OI Skinner, Jeff/0000-0001-5697-0442 FU Division of Intramural Research of NIAID, NIH FX Division of Intramural Research of NIAID, NIH. NR 30 TC 23 Z9 28 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 8755-6863 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD JAN PY 2012 VL 47 IS 1 BP 18 EP 26 DI 10.1002/ppul.21507 PG 9 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA 869IE UT WOS:000298590800003 PM 22170806 ER PT J AU Kinsinger, CR Apffel, J Baker, M Bian, XP Borchers, CH Bradshaw, R Brusniak, MY Chan, DW Deutsch, EW Domon, B Gorman, J Grimm, R Hancock, W Hermjakob, H Horn, D Hunter, C Kolar, P Kraus, HJ Langen, H Linding, R Moritz, RL Omenn, GS Orlando, R Pandey, A Ping, PP Rahbar, A Rivers, R Seymour, SL Simpson, RJ Slotta, D Smith, RD Stein, SE Tabb, DL Tagle, D Yates, JR Rodriguez, H AF Kinsinger, Christopher R. Apffel, James Baker, Mark Bian, Xiaopeng Borchers, Christoph H. Bradshaw, Ralph Brusniak, Mi-Youn Chan, Daniel W. Deutsch, Eric W. Domon, Bruno Gorman, Jeff Grimm, Rudolf Hancock, William Hermjakob, Henning Horn, David Hunter, Christie Kolar, Patrik Kraus, Hans-Joachim Langen, Hanno Linding, Rune Moritz, Robert L. Omenn, Gilbert S. Orlando, Ron Pandey, Akhilesh Ping, Peipei Rahbar, Amir Rivers, Robert Seymour, Sean L. Simpson, Richard J. Slotta, Douglas Smith, Richard D. Stein, Stephen E. Tabb, David L. Tagle, Danilo Yates, John R. Rodriguez, Henry TI Recommendations for mass spectrometry data quality metrics for open access data (corollary to the Amsterdam principles) SO PROTEOMICS LA English DT Article DE Amsterdam principles; Bioinformatics; Data quality; Metrics; Open access; Selected reaction monitoring; Standards ID PROTEIN IDENTIFICATION DATA; SHOTGUN PROTEOMICS; PEPTIDE IDENTIFICATION; CLINICAL PROTEOMICS; MINIMUM INFORMATION; STATISTICAL-MODEL; GUIDELINES; RESOURCE; SPECTRA; REPRODUCIBILITY AB Policies supporting the rapid and open sharing of proteomic data are being implemented by the leading journals in the field. The proteomics community is taking steps to ensure that data are made publicly accessible and are of high quality, a challenging task that requires the development and deployment of methods for measuring and documenting data quality metrics. On September 18, 2010, the U.S. National Cancer Institute (NCI) convened the International Workshop on Proteomic Data Quality Metrics in Sydney, Australia, to identify and address issues facing the development and use of such methods for open access proteomics data. The stakeholders at the workshop enumerated the key principles underlying a framework for data quality assessment in mass spectrometry data that will meet the needs of the research community, journals, funding agencies, and data repositories. Attendees discussed and agreed upon two primary needs for the wide use of quality metrics: (i) an evolving list of comprehensive quality metrics and (ii) standards accompanied by software analytics. Attendees stressed the importance of increased education and training programs to promote reliable protocols in proteomics. This workshop report explores the historic precedents, key discussions, and necessary next steps to enhance the quality of open access data. By agreement, this article is published simultaneously in Proteomics, Proteomics Clinical Applications, Journal of Proteome Research, and Molecular and Cellular Proteomics, as a public service to the research community. The peer review process was a coordinated effort conducted by a panel of referees selected by the journals. C1 [Kinsinger, Christopher R.; Rahbar, Amir; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA. [Apffel, James] Agilent Res Labs, Santa Clara, CA USA. [Baker, Mark] Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. [Bian, Xiaopeng] NCI, Ctr Bioinformat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Borchers, Christoph H.] Univ Victoria, Genome BC Prote Ctr, Victoria, BC, Canada. [Bradshaw, Ralph] Univ Calif San Francisco, Mass Spectrometry Facil, San Francisco, CA 94143 USA. [Chan, Daniel W.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Domon, Bruno] CRP Sante, Luxembourg Clin Prote Ctr, Luxembourg, Luxembourg. [Gorman, Jeff] Queensland Inst Med Res, Prot Discovery Ctr, Herston, Qld 4006, Australia. [Grimm, Rudolf] Agilent Technol, Santa Clara, CA USA. [Hancock, William] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Hermjakob, Henning] European Bioinformat Inst, Prote Serv, Cambridge, England. [Horn, David] Thermo Fisher Sci, Prote Software Strateg Mkt, San Jose, CA USA. [Hunter, Christie; Rivers, Robert] AB SCIEX, Foster City, AB, Canada. [Kolar, Patrik] European Commiss, Directorate Gen Res, Brussels, Belgium. [Kraus, Hans-Joachim] Wiley VCH, Weinheim, Germany. [Langen, Hanno] Hoffmann La Roche Ag, Exploratory Biomarkers, CH-4002 Basel, Switzerland. [Linding, Rune] Tech Univ Denmark DTU, Cellular Signal Integrat Grp C SIG, Ctr Biol Sequence Anal CBS, Dept Syst Biol, Lyngby, Denmark. [Moritz, Robert L.] Inst Syst Biol, Cellular & Mol Logic Unit, Seattle, WA USA. [Omenn, Gilbert S.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Orlando, Ron] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. [Pandey, Akhilesh] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Seymour, Sean L.] NCI, Small Business Dev Ctr, NIH, Bethesda, MD 20892 USA. [Simpson, Richard J.] La Trobe Univ, La Trobe Inst Mol Sci, Bundoora, Vic, Australia. [Slotta, Douglas] NIH, Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Smith, Richard D.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Stein, Stephen E.] NIST, Chem Reference Data Grp, Gaithersburg, MD 20899 USA. [Tabb, David L.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Tagle, Danilo] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Yates, John R.] Scripps Res Inst, La Jolla, CA 92037 USA. RP Kinsinger, CR (reprint author), NCI, Off Canc Clin Prote Res, NIH, 31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. EM kinsingc@mail.nih.gov RI Pandey, Akhilesh/B-4127-2009; Smith, Richard/J-3664-2012; Bradshaw, Ralph/K-1515-2013; OI Hermjakob, Henning/0000-0001-8479-0262; Baker, Mark/0000-0001-5858-4035; Pandey, Akhilesh/0000-0001-9943-6127; Smith, Richard/0000-0002-2381-2349; Ping, Peipei/0000-0003-3583-3881; Omenn, Gilbert S./0000-0002-8976-6074 NR 51 TC 18 Z9 18 U1 1 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD JAN PY 2012 VL 12 IS 1 BP 11 EP 20 DI 10.1002/pmic.201100562 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 872WL UT WOS:000298841000004 PM 22069307 ER PT J AU Bacigalupo, A Chien, J Barisione, G Pavletic, S AF Bacigalupo, Andrea Chien, Jason Barisione, Giovanni Pavletic, Steven TI Late Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation: Diagnosis, Monitoring, Prevention, and Treatment SO SEMINARS IN HEMATOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; BRONCHIOLITIS OBLITERANS SYNDROME; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; BONE-MARROW TRANSPLANTATION; CHRONIC MYELOGENOUS LEUKEMIA; UNRELATED DONORS; RANDOMIZED-TRIAL; CLINICAL-TRIALS; ANTITHYMOCYTE GLOBULIN AB Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication that occurs among recipients of allogeneic lung and hematopoietic stem cell transplantation (allo-HSCT). BOS usually occurs within the first 2 years but may develop as late as 5 years after allo-HSCT. Recent prevalence estimates suggest that BOS is likely underdiagnosed in the clinical setting and that 14% of all long-term survivors with chronic graft-versus-host disease (GVHD) may develop BOS. It is difficult to diagnose and once respiratory symptoms appear, most allo-HSCT recipients show severe airflow obstruction. This may be due, at least in part, to the low sensitivity of standard spirometry in detecting small airways obstruction and lack of formal recommendations for screening for this complication. The prognosis of BOS is poor with reported 5-year survival of about 15%. A key obstacle in advancing clinical research in BOS is the lack of diagnostic and therapeutic response standards, making interpretation of survival and treatment results between studies difficult. This situation has significantly improved due to the introduction of the National Institutes of Health (NIH) criteria, which provide investigators with common definitions for studying BOS and for assessing the effects of therapeutic interventions. Future advances in the therapy of BOS may need to include development of better early intervention strategies based on identification of reliable early biological markers of the disease. It would be also important to improve understanding of the biological heterogeneity of this devastating complication after allo-HSCT. Semin Hematol 49:15-24. (C) 2012 Published by Elsevier Inc. C1 [Bacigalupo, Andrea] Azienda Osped Univ San Martino, Unita Operat Ematol 2, I-16132 Genoa, Italy. [Chien, Jason] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Barisione, Giovanni] Azienda Osped Univ San Martino, Unita Operat Med Prevent & Lavoro, Lab Fisiopatol Resp, I-16132 Genoa, Italy. [Pavletic, Steven] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Bacigalupo, A (reprint author), Azienda Osped Univ San Martino, Unita Operat Ematol 2, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. EM andrea.bacigalupo@hsanmartino.it FU Associazione Italiana Ricerca contro il Cancro (A.I.R.C.), Milano; Fondazione Ricerca Trapianto di Midollo Osseo (FA-RI.T.M.O.), Genova, Italy FX This work was supported by Associazione Italiana Ricerca contro il Cancro (A.I.R.C.), Milano, and Fondazione Ricerca Trapianto di Midollo Osseo (FA-RI.T.M.O.), Genova, Italy NR 53 TC 21 Z9 21 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 JAN PY 2012 VL 49 IS 1 BP 15 EP 24 DI 10.1053/j.seminhematol.2011.10.005 PG 10 WC Hematology SC Hematology GA 880JE UT WOS:000299402600004 PM 22221781 ER PT J AU Shanis, D Merideth, M Pulanic, TK Savani, BN Battiwalla, M Stratton, P AF Shanis, Dana Merideth, Melissa Pulanic, Tajana Klepac Savani, Bipin N. Battiwalla, Minoo Stratton, Pamela TI Female Long-Term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation: Evaluation and Management SO SEMINARS IN HEMATOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; TOTAL-BODY IRRADIATION; PREMATURE OVARIAN FAILURE; QUALITY-OF-LIFE; CONSENSUS DEVELOPMENT PROJECT; HUMAN-PAPILLOMAVIRUS HPV; VIRUS-LIKE PARTICLES; WORKING GROUP-REPORT; CHRONIC GRAFT AB Female long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) incur a significant burden of late effects. Genital graft-versus-host disease (GVHD), human papillomavinis (HPV) reactivation, ovarian failure and infertility, sexual dysfunction, and osteoporosis are concerns that can significantly impact quality of life. This review examines the risk, pathogenesis, clinical presentation, and implications of these common complications. Recommendations are provided for evaluation and management of these late effects and other obstetric and gynecologic issues that may arise in this patient population. Semin Hematol 49:83-93. Published by Elsevier Inc. C1 [Stratton, Pamela] Eunice Kennedy Schriver NICHD, Head Gynecol Consult Serv, Program Reprod & Adult Endocrinol, CRC,NIH, Bethesda, MD 20892 USA. [Merideth, Melissa] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Merideth, Melissa] Intramural Off Rare Dis, NIH, Bethesda, MD USA. [Pulanic, Tajana Klepac] Community Hlth Ctr E, Zagreb, Croatia. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplantat Sect, Nashville, TN USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), Eunice Kennedy Schriver NICHD, Head Gynecol Consult Serv, Program Reprod & Adult Endocrinol, CRC,NIH, Bldg 10,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM strattop@mail.nih.gov FU NIH Clinical Center; NHLBI; NICHD; NHGRI; NIH; American College of Obstetricians and Gynecologists FX This work was supported in part by the Intramural Research Program of the NIH Clinical Center, NHLBI, NICHD, and NHGRI; 2008 NIH Intramural bench to bedside award to NICHD, NHLBI, and NCI: women's health category and 2011-2012 American College of Obstetricians and Gynecologists/Hologic Research Award on Cervical Cancer Prevention. NR 82 TC 19 Z9 19 U1 0 U2 3 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 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2012 VL 49 IS 1 BP 83 EP 93 DI 10.1053/j.seminhematol.2011.10.002 PG 11 WC Hematology SC Hematology GA 880JE UT WOS:000299402600011 PM 22221788 ER PT J AU Than, NG Romero, R Kim, CJ McGowen, MR Papp, Z Wildman, DE AF Than, Nandor Gabor Romero, Roberto Kim, Chong Jai McGowen, Michael R. Papp, Zoltan Wildman, Derek E. TI Galectins: guardians of eutherian pregnancy at the maternal-fetal interface SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID GALACTOSIDE-BINDING LECTINS; LEYDEN CRYSTAL PROTEIN; NATURAL-KILLER-CELLS; REGULATORY T-CELLS; PHYLOGENETIC ANALYSIS; PLACENTAL EXPRESSION; SEVERE PREECLAMPSIA; PROTEOMIC ANALYSIS; IMMUNE TOLERANCE; ANIMAL LECTINS AB Galectins are multifunctional regulators of fundamental cellular processes. They are also involved in innate and adaptive immune responses, and play a functional role in immune-endocrine crosstalk. Some galectins have attracted attention in the reproductive sciences because they are highly expressed at the maternal-fetal interface, their functional significance in eutherian pregnancies has been documented, and their dysregulated expression is observed in the 'great obstetrical syndromes'. The evolution of these galectins has been linked to the emergence of eutherian mammals. Based on published evidence, galectins expressed at the maternal-fetal interface may serve as important proteins involved in maternal-fetal interactions, and the study of these galectins may facilitate the prediction, prevention, diagnosis, and treatment of pregnancy complications. C1 [Than, Nandor Gabor; Romero, Roberto; Kim, Chong Jai; Wildman, Derek E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Than, Nandor Gabor; Papp, Zoltan] Semmelweis Univ, Dept Obstet & Gynecol 1, Budapest, Hungary. [McGowen, Michael R.; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Than, NG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. EM nthan@med.wayne.edu; prbchiefstaff@med.wayne.edu; dwildman@wayne.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; National Science Foundation [BCS-0827546]; European Union [037244] FX We thank Prof Dr Peter Zavodszky and Dr Andras Szilagyi (Hungarian Academy of Sciences) for constructing Figures 3c and 3d and for their permission to re-use these images; Dr Adi Tarca and Gaurav Bhatti (Wayne State University) for their assistance in computations; Pat Schoff (Wayne State University) and Valerie Richardson for art work; and Maureen McGerty and Sara Tipton (Wayne State University) for their critical readings of the manuscript. This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; the National Science Foundation (BCS-0827546); and the European Union FP6 Program (Pregenesys; 037244). NR 84 TC 36 Z9 36 U1 1 U2 18 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD JAN PY 2012 VL 23 IS 1 BP 23 EP 31 DI 10.1016/j.tem.2011.09.003 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 881AE UT WOS:000299450900004 PM 22036528 ER PT J AU Muthana, SM Campbell, CT Gildersleeve, JC AF Muthana, Saddam M. Campbell, Christopher T. Gildersleeve, Jeffrey C. TI Modifications of Glycans: Biological Significance and Therapeutic Opportunities SO ACS CHEMICAL BIOLOGY LA English DT Article DE Carbohydrate; Glycan; Post-glycosylational modification; Sulfation; Phosphorylation; Acylation; Methylation ID CHONDROITIN SULFATE PROTEOGLYCANS; MUCOID PSEUDOMONAS-AERUGINOSA; ACETYLATED SIALIC ACIDS; DE-ORTHO-ACETYLATION; WALL TEICHOIC-ACID; N-LINKED GLYCANS; O-ACETYLATION; STAPHYLOCOCCUS-AUREUS; HEPARAN-SULFATE; L-SELECTIN AB Carbohydrates play a central role in a wide range of biological processes. As with nucleic acids and proteins, modifications of specific sites within the glycan chain can modulate a carbohydrate's overall biological function. For example, acylation, methylation, sulfation, epimerization, and phosphorylation can occur at various positions within a carbohydrate to modulate bioactivity. Therefore, there is significant interest in identifying discrete carbohydrate modifications and understanding,their biological effects. Additionally, enzymes that catalyze those modifications and proteins that bind modified glycans provide numerous targets for therapeutic intervention. This review will focus on modifications of glycans that occur after the oligomer/polymer has been assembled, generally referred to as post-glycosylational modifications. C1 [Muthana, Saddam M.; Campbell, Christopher T.; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Gildersleeve, JC (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU National Institutes of Health, NCI; Pharmacology Research Associate (PRAT) of the NIGMS FX This research was supported by the Intramural Research Program of the National Institutes of Health, NCI. C.T.C. received fellowship support from the Pharmacology Research Associate (PRAT) program of the NIGMS. NR 144 TC 36 Z9 36 U1 5 U2 44 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 JAN PY 2012 VL 7 IS 1 BP 31 EP 43 DI 10.1021/cb2004466 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 878FQ UT WOS:000299241300005 PM 22195988 ER PT J AU Chandran, PL Horkay, F AF Chandran, Preethi L. Horkay, Ferenc TI Aggrecan, an unusual polyelectrolyte: Review of solution behavior and physiological implications SO ACTA BIOMATERIALIA LA English DT Review DE Cartilage; Osmotic pressure; ECM; Light scattering; Viscoelasticity ID ATOMIC-FORCE MICROSCOPY; CONNECTIVE-TISSUE POLYSACCHARIDES; CONFOCAL FLUORESCENCE RECOVERY; SULFATE TRANSPORTER GENE; BOVINE NASAL CARTILAGE; ARTICULAR-CARTILAGE; HYDRODYNAMIC PROPERTIES; VISCOELASTIC PROPERTIES; PROTEOGLYCAN SOLUTIONS; IONIC-STRENGTH AB Aggrecan is a high-molecular-weight, bottlebrush-shaped, negatively charged biopolymer that forms supermolecular complexes with hyaluronic acid. In the extracellular matrix of cartilage, aggrecan-hyaluronic acid complexes are interspersed in a collagen meshwork and provide the osmotic properties required to resist deswelling under compressive load. In this review we compile aggrecan solution behavior from different experimental techniques, and discuss them in the context of concentration regimes that were identified in osmotic pressure experiments. At low concentrations, aggrecan exhibits microgel-like behavior. With increasing concentration, the bottlebrushes self-assemble into large complexes. In the physiological concentration range (2 < c(aggrecan) < 8% w/w), the physical properties of the solution are dominated by repulsive electrostatic interactions between aggrecan complexes. We discuss the consequences of the bottlebrush architecture on the polyelectrolyte characteristics of the aggrecan molecule, and its implications for cartilage properties and function. Published by Elsevier Ltd. on behalf of Acta Materialia Inc. C1 [Chandran, Preethi L.; Horkay, Ferenc] NICHD, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Chandran, Preethi L.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Chandran, PL (reprint author), NICHD, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bldg 13,13 South Dr, Bethesda, MD 20892 USA. EM chandranlp@mail.nih.gov; horkay@helix.nih.gov FU NICHD, NIH FX This work was supported by the Intramural Research Program of the NICHD, NIH. The authors are grateful to Dr. Peter Basser (NIH) and Dr. Jack Douglas (NIST) for their thoughtful comments and suggestions. NR 81 TC 22 Z9 22 U1 2 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 J9 ACTA BIOMATER JI Acta Biomater. PD JAN PY 2012 VL 8 IS 1 BP 3 EP 12 DI 10.1016/j.actbio.2011.08.011 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 871UP UT WOS:000298763500001 PM 21884828 ER PT J AU Acosta, MT Munashinge, J Zhang, L Guerron, DA Vortmeyer, A Theodore, WH AF Acosta, M. T. Munashinge, J. Zhang, L. Guerron, Daniel A. Vortmeyer, Alexander Theodore, W. H. TI Isolated seizures in rats do not cause neuronal injury SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE seizures; neuroimaging; epilepsy ID TEMPORAL-LOBE EPILEPSY; EXPERIMENTAL FEBRILE SEIZURES; MAGNETIC-RESONANCE; STATUS-EPILEPTICUS; STRUCTURAL ALTERATIONS; HIPPOCAMPAL DAMAGE; RECURRENT SEIZURES; ADULT RATS; MODEL; MRI AB Background - Previous studies have shown that status epilepticus can lead to neuronal injury. However, the effect of a small number of isolated seizures is uncertain. Methods - We used structural MRI and neuropathology to study the effects of isolated seizures induced by kainic acid (KA), (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid (ATPA), and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate in rats. A group of animals received normal saline. After seizure induction, animals were followed for 12 weeks. Results - ATPA and KA led to small but significant increases in ADC. There were no changes in T2 signal intensity or hippocampal volume. Blinded pathological examination showed no differences between animals receiving saline or glutamatergic agents. Conclusion - Our study suggests that isolated seizures cause minimal neuronal injury in rats. C1 [Acosta, M. T.; Theodore, W. H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Acosta, M. T.; Guerron, Daniel A.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Munashinge, J.; Zhang, L.; Guerron, Daniel A.] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Vortmeyer, Alexander] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NINDS, Clin Epilepsy Sect, NIH, Bldg 10,Room 5N-250, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov FU NIH NINDS Division of Intramural Research FX This study was supported by the NIH NINDS Division of Intramural Research. NR 37 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD JAN PY 2012 VL 125 IS 1 BP 30 EP 37 DI 10.1111/j.1600-0404.2011.01521.x PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 867TN UT WOS:000298477600008 PM 21615350 ER PT J AU Kovalchik, SA AF Kovalchik, Stephanie A. TI Mother's CD4(+) Count Moderates the Risk Associated with Higher Parity for Late Postnatal HIV-Free Survival of Breastfed Children: An Individual Patient Data Meta-Analysis of Randomized Controlled Trials SO AIDS AND BEHAVIOR LA English DT Article DE Gravidity; Human Immunodeficiency Virus; Meta-analysis; Parity; Prevention of maternal to child transmission of HIV; Risk factors ID DAR-ES-SALAAM; ANTIRETROVIRAL THERAPY; POOLED ANALYSIS; INFANTS BORN; TRANSMISSION; WOMEN; VIRUS; MILK; CHALLENGES; PREVENTION AB Risk association studies of late postnatal outcomes for children breastfed by HIV-1 positive mothers have had inconsistent findings and have not explored interactions among risk factors. This study addresses these limitations through an individual patient data (IPD) meta-analysis of HIV-free survival outcomes of nine randomized controlled trials to prevent early mother-to-child transmission of HIV-1. The pooled sample consisted of 3,324 African children in resource-limited settings who survived to age 28 days and were at-risk of acquiring HIV through breast milk. Based on a proportional hazards mixed effects meta-analysis, the composite endpoint of HIV-1 infection and all-cause mortality was found to be significantly associated with maternal immune status (CD4(+) a parts per thousand yen350 cells/mm(3), HR 0.59 95% CI (0.39, 0.87)), infant preterm delivery (gestational age < 37 weeks, 1.40 (1.03, 1.89)), infant oral candidiasis infection (1.87, (1.53, 2.29)), and occurrence of breast abnormality before breastfeeding cessation (2.56 (1.90, 3.46)). A significant interaction between mother's parity (any previous pregnancy) and CD4(+) count a parts per thousand yen350 (HR 0.63 (0.40, 0.99), P-value = 0.045) suggested that higher CD4(+) count offsets the risk associated with higher parity. Further research is needed to elucidate the moderating effect of immune status on the risk associated with high parity and adverse late postnatal outcomes for infants breastfed by HIV-infected mothers in the absence of antiretroviral treatment. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. RP Kovalchik, SA (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, 6120 Execut Blvd,EPS 8044, Rockville, MD 20852 USA. EM kovalchiksa@mail.nih.gov FU NIAID NIH HHS [N01-AI-35173, U01 AI069530, T32-AI007370] NR 30 TC 1 Z9 1 U1 0 U2 1 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 JAN PY 2012 VL 16 IS 1 BP 79 EP 85 DI 10.1007/s10461-011-9989-8 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 875SI UT WOS:000299054700011 PM 21739289 ER PT J AU Muniyappa, R Sachdev, V Sidenko, S Ricks, M Castillo, DC Courville, AB Sumner, AE AF Muniyappa, Ranganath Sachdev, Vandana Sidenko, Stanislav Ricks, Madia Castillo, Darleen C. Courville, Amber B. Sumner, Anne E. TI Postprandial endothelial function does not differ in women by race: an insulin resistance paradox? SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE African Americans; endothelial function ID AFRICAN-AMERICAN PATIENTS; FLOW-MEDIATED DILATION; HIGH-FAT MEAL; VASCULAR REACTIVITY; RACIAL-DIFFERENCES; METABOLIC SYNDROME; OXIDATIVE STRESS; BRACHIAL-ARTERY; ETHNIC-DIFFERENCES; DIABETES-MELLITUS AB Muniyappa R, Sachdev V, Sidenko S, Ricks M, Castillo DC, Courville AB, Sumner AE. Postprandial endothelial function does not differ in women by race: an insulin resistance paradox? Am J Physiol Endocrinol Metab 302: E218-E225, 2012. First published November 1, 2011; doi: 10.1152/ajpendo.00434.2011.-Insulin resistance is associated with endothelial dysfunction. Because African-American women are more insulin-resistant than white women, it is assumed that African-American women have impaired endothelial function. However, racial differences in postprandial endothelial function have not been examined. In this study, we test the hypothesis that African-American women have impaired postprandial endothelial function compared with white women. Postprandial endothelial function following a breakfast (20% protein, 40% fat, and 40% carbohydrate) was evaluated in 36 (18 AfricanAmerican women, 18 white women) age-and body mass index (BMI)-matched (age: 37 +/- 11 yr; BMI: 30 +/- 6 kg/m(2)) women. Endothelial function, defined by percent change in brachial artery flow-mediated dilation (FMD), was measured at 0, 2, 4, and 6 h following a meal. There were no significant differences between the groups in baseline FMD, total body fat, abdominal visceral fat, and fasting levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, or serum estradiol. Although AfricanAmerican women were less insulin-sensitive [insulin sensitivity index (mean +/- SD): 3.6 +/- 1.5 vs. 5.2 +/- 2.6, P = 0.02], both fasting triglyceride (TG: 56 +/- 37 vs. 97 +/- 49 mg/dl, P = 0.007) and incremental TG area under the curve (AUC(0-6hr): 279 +/- 190 vs. 492 +/- 255 mg.dl(-1).min(-1).10(-2), P = 0.008) were lower in African-American than white women. Breakfast was associated with a significant increase in FMD in whites and African-Americans, and there was no significant difference in postprandial FMD between the groups (P > 0.1 for group x time interactions). Despite being insulin-resistant, postprandial endothelial function in African-American women was comparable to white women. These results imply that insulin sensitivity may not be an important determinant of racial differences in endothelial function. C1 [Muniyappa, Ranganath] NIDDK, Diabet Endocrinol & Obes Branch, Intramural Program, Bethesda, MD 20892 USA. [Sachdev, Vandana; Sidenko, Stanislav] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. RP Muniyappa, R (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, Intramural Program, 10 Ctr Dr,Bldg 10,Rm 4-1730,MSC 1302, Bethesda, MD 20892 USA. EM muniyapr@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Programs of National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute, National Institutes of Health. NR 54 TC 6 Z9 6 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JAN PY 2012 VL 302 IS 2 BP E218 EP E225 DI 10.1152/ajpendo.00434.2011 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 876MX UT WOS:000299112700007 PM 22045315 ER PT J AU Motabar, O Goldin, E Leister, W Liu, K Southall, N Huang, WW Marugan, JJ Sidransky, E Zheng, W AF Motabar, Omid Goldin, Ehud Leister, William Liu, Ke Southall, Noel Huang, Wenwei Marugan, Juan J. Sidransky, Ellen Zheng, Wei TI A high throughput glucocerebrosidase assay using the natural substrate glucosylceramide SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Glucocerebrosidase; Natural substrate; Gaucher disease; Enzyme substrate; Inhibitor ID LYSOSOMAL STORAGE DISORDERS; GAUCHER-DISEASE; BETA-GLUCOSIDASE; POMPE DISEASE; THERAPY; LIVER; STRATEGIES; DIAGNOSIS; ACID AB Glucocerebrosidase is a lysosomal enzyme that catalyzes the hydrolysis of glucosylceramide to form ceramide and glucose. A deficiency of lysosomal glucocerebrosidase due to genetic mutations results in Gaucher disease, in which glucosylceramide accumulates in the lysosomes of certain cell types. Although enzyme replacement therapy is currently available for the treatment of type 1 Gaucher disease, the neuronopathic forms of Gaucher disease are still not treatable. Small molecule drugs that can penetrate the blood-brain barrier, such as pharmacological chaperones and enzyme activators, are new therapeutic approaches for Gaucher disease. Enzyme assays for glucocerebrosidase are used to screen compound libraries to identify new lead compounds for drug development for the treatment of Gaucher disease. But the current assays use artificial substrates that are not physiologically relevant. We developed a glucocerebrosidase assay using the natural substrate glucosylceramide coupled to an Amplex-red enzyme reporting system. This assay is in a homogenous assay format and has been miniaturized in a 1,536-well plate format for high throughput screening. The assay sensitivity and robustness is similar to those seen with other glucocerebrosidase fluorescence assays. Therefore, this new glucocerebrosidase assay is an alternative approach for high throughput screening. C1 [Motabar, Omid; Leister, William; Liu, Ke; Southall, Noel; Huang, Wenwei; Marugan, Juan J.; Zheng, Wei] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Motabar, Omid; Goldin, Ehud; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Zheng, W (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute; National Institutes of Health FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. NR 24 TC 12 Z9 12 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 JAN PY 2012 VL 402 IS 2 BP 731 EP 739 DI 10.1007/s00216-011-5496-z PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 870BY UT WOS:000298645300015 PM 22033823 ER PT J AU Orbach, Y Lamb, ME La Rooy, D Pipe, ME AF Orbach, Yael Lamb, Michael E. La Rooy, David Pipe, Margaret-Ellen TI A Case Study of Witness Consistency and Memory Recovery Across Multiple Investigative Interviews SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article ID CHILDRENS EVENT REPORTS; EYEWITNESS MEMORY; SEXUAL-ABUSE; QUESTION TYPE; ALLEGED VICTIMS; RECALL; HYPERMNESIA; PRESCHOOLERS; REMINISCENCE; DELAY AB Access to audio recordings of five interviews (Interviews 26), and to the interviewer's contemporaneous notes during an initial unrecorded interview, made it possible to assess consistency across repeated attempts by a 9-year-old to describe her older sister's abduction from their shared bedroom. Information provided in each of the interviews was systematically analysed to determine whether each unit of information was new, consistent (repeated) or contradictory in relation to earlier reported information and whether any informative detail provided in the witness' initial interview was subsequently omitted. In addition, the witness' accounts were compared with details provided by the victim upon her rescue. This case analysis is particularly informative in light of widespread professional concerns about the effects of repeated interviewing on the quality and accuracy of children's accounts of experienced events. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Lamb, Michael E.] Univ Cambridge, Dept Social & Dev Psychol, Cambridge CB2 3RQ, England. [Orbach, Yael] NICHHD, Bethesda, MD 20892 USA. [La Rooy, David] Scottish Inst Policing Res, Dundee, Scotland. [La Rooy, David] Univ Abertay Dundee, Dundee, Scotland. [Pipe, Margaret-Ellen] CUNY Brooklyn Coll, New York, NY USA. RP Lamb, ME (reprint author), Univ Cambridge, Dept Social & Dev Psychol, Free Sch Lane, Cambridge CB2 3RQ, England. EM Mel37@cam.ac.uk NR 77 TC 10 Z9 11 U1 3 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD JAN-FEB PY 2012 VL 26 IS 1 BP 118 EP 129 DI 10.1002/acp.1803 PG 12 WC Psychology, Experimental SC Psychology GA 877SU UT WOS:000299203800012 ER PT J AU Bhaumik, P Gustchina, A Wlodawer, A AF Bhaumik, Prasenjit Gustchina, Alla Wlodawer, Alexander TI Structural studies of vacuolar plasmepsins SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Review DE Aspartic protease; Malaria; Crystal structure; Plasmepsin; Inhibitors ID HYDROXYMETHYLCARBONYL HMC ISOSTERE; PARASITE PLASMODIUM-FALCIPARUM; ASPARTIC PROTEASE PLASMEPSIN; ACTIVE-SITE; CRYSTAL-STRUCTURES; FOOD VACUOLE; POTENT INHIBITORS; ENZYMATIC CHARACTERIZATION; HISTOASPARTIC PROTEASE; ANTIMALARIAL ACTIVITY AB Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium spp. (P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes 10 PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), 4 of which (PM!, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50-79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium spp.. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV. PMI, and HAP resulted in a more complete picture of the structure-function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15 years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. Published by Elsevier B.V. C1 [Bhaumik, Prasenjit; Gustchina, Alla; Wlodawer, Alexander] NCI, Prot Struct Sect, MCL, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, MCL, Bldg 536,Rm 5, Frederick, MD 21702 USA. EM wlodawer@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We are grateful to Professor Ben Dunn for constructive criticism of a draft of this manuscript. This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 83 TC 14 Z9 14 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD JAN PY 2012 VL 1824 IS 1 SI SI BP 207 EP 223 DI 10.1016/j.bbapap.2011.04.008 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 871CS UT WOS:000298715900021 PM 21540129 ER PT J AU Kawamoto, EM Gleichmann, M Yshii, LM Lima, LD Mattson, MP Scavone, C AF Kawamoto, E. M. Gleichmann, M. Yshii, L. M. de Sa Lima, L. Mattson, M. P. Scavone, C. TI Effect of activation of canonical Wnt signaling by the Wnt-3a protein on the susceptibility of PC12 cells to oxidative and apoptotic insults SO BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH LA English DT Article DE Wnt-3a; PC12 cells; Beta-catenin; NF-kappa B ID GLYCOGEN-SYNTHASE KINASE-3-BETA; FACTOR-KAPPA-B; HIPPOCAMPAL-NEURONS; CYTO-TOXICITY; BETA-CATENIN; PATHWAY; DISEASE; EXPRESSION; KINASE; GENES AB Wnt proteins are involved in tissue development and their signaling pathways play an important role during embryogenesis. Wnt signaling can promote cell survival, which is beneficial for neurons, but could also lead to tumor development in different tissues. The present study investigated the effects of a Wnt protein on the susceptibility of a neural tumor cell line (PC12 cells) to the cytotoxic compounds ferrous sulfate (10 mM), staurosporine (100 and 500 nM), 3-nitropropionic acid (5 mM), and amyloid beta-peptide (A beta(25-35); 50 mu M). Cells (1 x 10(6) cells/mL) were treated with the Wnt-3a recombinant peptide (200 ng/mL) for 24 h before exposure to toxic insults. The Wnt-3a protein partially protected PC12 cells, with a 6-15% increase in cell viability in the presence of toxic agents, similar to the effect measured using the MTT and lactate dehydrogenase cell viability assays. The Wnt-3a protein increased protein expression of beta-catenin by 52% compared to control. These findings suggest that Wnt signaling can protect neural cells against apoptosis induced by toxic agents, which are relevant to the pathogenesis of Alzheimer's and Huntington's diseases. C1 [Kawamoto, E. M.; Yshii, L. M.; de Sa Lima, L.; Scavone, C.] Univ Sao Paulo, Dept Farmacol, Inst Ciencias Biomed, BR-05508900 Sao Paulo, Brazil. [Kawamoto, E. M.; Gleichmann, M.; Mattson, M. P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Scavone, C (reprint author), Univ Sao Paulo, Dept Farmacol, Inst Ciencias Biomed, Ave Lineu Prestes 1524, BR-05508900 Sao Paulo, Brazil. EM cristoforo.scavone@gmail.com RI Mattson, Mark/F-6038-2012; Kawamoto, Elisa/E-3485-2012; YSHII, Lidia/I-6039-2013; OI Kawamoto, Elisa/0000-0001-8637-414X; YSHII, Lidia/0000-0002-1988-6855; Scavone, Cristoforo/0000-0002-1206-0882 FU FAPESP [06/59722-1]; CNPq [0668-05-2]; CAPES; Sumitomo Bank; National Institute on Aging of the NIH FX We thank Maria Aparecida G.S. Fernandes for technical assistance. Research supported by FAPESP (#06/59722-1 to C. Scavone), CNPq (#0668-05-2), CAPES, Bunka Fund - Sumitomo Bank, and the National Institute on Aging Intramural Research Program of the NIH. E.M. Kawamoto and C. Scavone were recipients of fellowships from FAPESP and CNPq, respectively. NR 40 TC 10 Z9 10 U1 1 U2 14 PU ASSOC BRAS DIVULG CIENTIFICA PI SAO PAULO PA FACULDADE MEDICINA, SALA 21, 14049 RIBEIRAO PRETO, SAO PAULO, 00, BRAZIL SN 0100-879X J9 BRAZ J MED BIOL RES JI Brazilian J. Med. Biol. Res. PD JAN PY 2012 VL 45 IS 1 BP 58 EP 67 DI 10.1590/S0100-879X2011007500157 PG 10 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA 875RU UT WOS:000299053200010 PM 22124704 ER PT J AU Marcus, L Murphy, R Fox, E McCully, C Cruz, R Warren, KE Meyer, T McNiff, E Balis, FM Widemann, BC AF Marcus, Leigh Murphy, Robert Fox, Elizabeth McCully, Cynthia Cruz, Raphael Warren, Katherine E. Meyer, Thorsten McNiff, Edward Balis, Frank M. Widemann, Brigitte C. TI The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pharmocology; Non-human primate; Satraplatin; Pharmacokinetics ID HIGH-GRADE ASTROCYTOMA; CELL LUNG-CANCER; PHASE-I; ACQUIRED-RESISTANCE; RHESUS-MONKEY; CISPLATIN; CHILDREN; OXALIPLATIN; CARBOPLATIN; CHEMOTHERAPY AB Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. Satraplatin (120 mg/m(2)) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 mu M in UF and 0.006 mu M after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC(0-48h) : plasma UF AUC(0-48h). Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C (max)) 8.3 mu M (5.7-10.6), area under the curve (AUC(0-48h)) 29.2 mu M h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t (1/2) 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C (max) 0.07 mu M (0.02-0.12), AUC(0-48h) 1.2 mu M h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress. C1 [Marcus, Leigh; Murphy, Robert; McCully, Cynthia; Cruz, Raphael; Warren, Katherine E.; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Meyer, Thorsten; McNiff, Edward] Agennix, Munich, Germany. [Meyer, Thorsten; McNiff, Edward] Agennix, Princeton, NJ USA. RP Marcus, L (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 1-5742, Bethesda, MD 20892 USA. EM marculei@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 2 Z9 2 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JAN PY 2012 VL 69 IS 1 BP 247 EP 252 DI 10.1007/s00280-011-1659-z PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 870EO UT WOS:000298652100028 PM 21706317 ER PT J AU Camargo, MC Goto, Y Zabaleta, J Morgan, DR Correa, P Rabkin, CS AF Camargo, M. Constanza Goto, Yasuyuki Zabaleta, Jovanny Morgan, Douglas R. Correa, Pelayo Rabkin, Charles S. TI Sex Hormones, Hormonal Interventions, and Gastric Cancer Risk: A Meta-Analysis SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID HELICOBACTER-PYLORI INFECTION; ADJUVANT TAMOXIFEN THERAPY; POPULATION-BASED COHORT; POSITIVE BREAST-CANCER; INS-GAS MICE; REPRODUCTIVE FACTORS; REPLACEMENT THERAPY; 2ND CANCERS; POSTMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES AB Estrogens may influence gastric cancer risk, but published studies are inconclusive. We therefore carried out a meta-analysis addressing the associations of gastric cancer in women with menstrual and reproductive factors and with use of estrogen-and antiestrogen-related therapies. Searches of PubMed up to June, 2011 and review of citations yielded a total of 28 independent studies, including at least one exposure of interest. Random effects pooled estimates of relative risk (RR) and corresponding 95% CIs were calculated for eight exposures reported in at least five studies, including: age at menarche, age at menopause, years of fertility, parity, age at first birth, oral contraceptive use, hormone replacement therapy (HRT), and tamoxifen treatment. Longer years of fertility (RR 0.74, 95% CI: 0.63-0.86) and HRT (RR = 0.77; 95% CI: 0.64-0.92) were each associated with decreased gastric cancer risk. Conversely, tamoxifen treatment was associated with increased risk (RR = 1.82; 95% CI: 1.39-2.38). The other five exposures were not significantly associated. Our analysis supports the hypothesis that longer exposure to estrogen effects of either ovarian or exogenous origin may decrease risk of gastric cancer. Additional studies are warranted to extend this finding and to identify the underlying mechanisms. Cancer Epidemiol Biomarkers Prev; 21(1); 20-38. (C) 2011 AACR. C1 [Camargo, M. Constanza] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Goto, Yasuyuki] Nagoya Univ, Grad Sch Med, Dept Prevent Med, Nagoya, Aichi 4648601, Japan. [Zabaleta, Jovanny] Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA USA. [Zabaleta, Jovanny] Louisiana State Univ, Hlth Sci Ctr, Stanley S Scott Canc Ctr, New Orleans, LA USA. [Morgan, Douglas R.] Univ N Carolina, Sch Med, Dept Gastroenterol & Hepatol, Chapel Hill, NC USA. [Correa, Pelayo] Vanderbilt Univ, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37212 USA. RP Camargo, MC (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-6116, Rockville, MD 20852 USA. EM camargomc@mail.nih.gov RI Camargo, M. Constanza/R-9891-2016 FU U.S. National Cancer Institute, NIH FX This study was funded by the Intramural Research Program of the U.S. National Cancer Institute, NIH. NR 105 TC 53 Z9 58 U1 0 U2 3 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 JAN PY 2012 VL 21 IS 1 BP 20 EP 38 DI 10.1158/1055-9965.EPI-11-0834 PG 19 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500002 PM 22028402 ER PT J AU Veiga, LHS Bhatti, P Ronckers, CM Sigurdson, AJ Stovall, M Smith, SA Weathers, R Leisenring, W Mertens, AC Hammond, S Neglia, JP Meadows, AT Donaldson, SS Sklar, CA Friedman, DL Robison, LL Inskip, PD AF Veiga, Lene H. S. Bhatti, Parveen Ronckers, Cecile M. Sigurdson, Alice J. Stovall, Marilyn Smith, Susan A. Weathers, Rita Leisenring, Wendy Mertens, Ann C. Hammond, Sue Neglia, Joseph P. Meadows, Anna T. Donaldson, Sarah S. Sklar, Charles A. Friedman, Debra L. Robison, Leslie L. Inskip, Peter D. TI Chemotherapy and Thyroid Cancer Risk: a Report from the Childhood Cancer Survivor Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID 2ND MALIGNANT NEOPLASMS; ALKYLATING-AGENTS; SOLID TUMORS; RADIATION; RADIOTHERAPY; EXPERIENCE; LEUKEMIA; THERAPY; DISEASE; COHORT AB Background: Although ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors and the possible joint effects of chemotherapy and radiotherapy. Methods: The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated with life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose. Results: Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0-1.6) for females and 0.6% (0.4-0.8) for males. Among patients with thyroid radiation doses of 20 Gy or less, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3-4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P(trend) = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses more than 20 Gy. Conclusions: Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing. Impact: Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy. Cancer Epidemiol Biomarkers Prev; 21(1); 92-101. (C) 2011 AACR. C1 [Veiga, Lene H. S.; Bhatti, Parveen; Ronckers, Cecile M.; Sigurdson, Alice J.; Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Veiga, Lene H. S.] Brazilian Nucl Energy Commiss, Inst Radiat Protect & Dosimetry, Rio De Janeiro, Brazil. [Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Leisenring, Wendy] Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98104 USA. [Ronckers, Cecile M.] Dutch Childhood Oncol Grp, Late Effects Childhood Canc Registry LATER, The Hague, Netherlands. [Stovall, Marilyn; Smith, Susan A.; Weathers, Rita] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Mertens, Ann C.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Hammond, Sue] Childrens Hosp, Dept Lab Med & Pathol, Columbus, OH 43205 USA. [Hammond, Sue] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Neglia, Joseph P.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. [Meadows, Anna T.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Donaldson, Sarah S.] Stanford Canc Ctr, Dept Radiat Oncol, Stanford, CA USA. [Sklar, Charles A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Friedman, Debra L.] Vanderbilt Ingram Canc Ctr, Canc Control & Prevent Program, Nashville, TN USA. [Robison, Leslie L.] St Jude Childrens Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. RP Veiga, LHS (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7051,MSC 7238, Bethesda, MD 20892 USA. EM veigal@mail.nih.gov FU Department of Health and Human Services [5U01-CA-55727]; Lance Armstrong Foundation [147149] FX This work was supported by the Department of Health and Human Services (grant number 5U01-CA-55727) to L.L. Robison. Additional support was provided by the American Lebanese-Syrian Associated Charities (ALSAC), the Lance Armstrong Foundation (grant number 147149), and the Intramural Research Program of the National Cancer Institute, NIH. NR 27 TC 37 Z9 37 U1 0 U2 5 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 JAN PY 2012 VL 21 IS 1 BP 92 EP 101 DI 10.1158/1055-9965.EPI-11-0576 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500010 PM 22028399 ER PT J AU Mavaddat, N Barrowdale, D Andrulis, IL Domchek, SM Eccles, D Nevanlinna, H Ramus, SJ Spurdle, A Robson, M Sherman, M Mulligan, AM Couch, FJ Engel, C McGuffog, L Healey, S Sinilnikova, OM Southey, MC Terry, MB Goldgar, D O'Malley, F John, EM Janavicius, R Tihomirova, L Hansen, TVO Nielsen, FC Osorio, A Stavropoulou, A Benitez, J Manoukian, S Peissel, B Barile, M Volorio, S Pasini, B Dolcetti, R Putignano, AL Ottini, L Radice, P Hamann, U Rashid, MU Hogervorst, FB Kriege, M van der Luijt, RB Peock, S Frost, D Evans, DG Brewer, C Walker, L Rogers, MT Side, LE Houghton, C Weaver, J Godwin, AK Schmutzler, RK Wappenschmidt, B Meindl, A Kast, K Arnold, N Niederacher, D Sutter, C Deissler, H Gadzicki, D Preisler-Adams, S Varon-Mateeva, R Schonbuchner, I Gevensleben, H Stoppa-Lyonnet, D Belotti, M Barjhoux, L Isaacs, C Peshkin, BN Caldes, T de la Hoya, M Canadas, C Heikkinen, T Heikkila, P Aittomaki, K Blanco, I Lazaro, C Brunet, J Agnarsson, BA Arason, A Barkardottir, RB Dumont, M Simard, J Montagna, M Agata, S D'Andrea, E Yan, M Fox, S Rebbeck, TR Rubinstein, W Tung, N Garber, JE Wang, XS Fredericksen, Z Pankratz, VS Lindor, NM Szabo, C Offit, K Sakr, R Gaudet, MM Singer, CF Tea, MK Rappaport, C Mai, PL Greene, MH Sokolenko, A Imyanitov, E Toland, AE Senter, L Sweet, K Thomassen, M Gerdes, AM Kruse, T Caligo, M Aretini, P Rantala, J von Wachenfeld, A Henriksson, K Steele, L Neuhausen, SL Nussbaum, R Beattie, M Odunsi, K Sucheston, L Gayther, SA Nathanson, K Gross, J Walsh, C Karlan, B Chenevix-Trench, G Easton, DF Antoniou, AC AF Mavaddat, Nasim Barrowdale, Daniel Andrulis, Irene L. Domchek, Susan M. Eccles, Diana Nevanlinna, Heli Ramus, Susan J. Spurdle, Amanda Robson, Mark Sherman, Mark Mulligan, Anna Marie Couch, Fergus J. Engel, Christoph McGuffog, Lesley Healey, Sue Sinilnikova, Olga M. Southey, Melissa C. Terry, Mary Beth Goldgar, David O'Malley, Frances John, Esther M. Janavicius, Ramunas Tihomirova, Laima Hansen, Thomas V. O. Nielsen, Finn C. Osorio, Ana Stavropoulou, Alexandra Benitez, Javier Manoukian, Siranoush Peissel, Bernard Barile, Monica Volorio, Sara Pasini, Barbara Dolcetti, Riccardo Putignano, Anna Laura Ottini, Laura Radice, Paolo Hamann, Ute Rashid, Muhammad U. Hogervorst, Frans B. Kriege, Mieke van der Luijt, Rob B. Peock, Susan Frost, Debra Evans, D. Gareth Brewer, Carole Walker, Lisa Rogers, Mark T. Side, Lucy E. Houghton, Catherine Weaver, JoEllen Godwin, Andrew K. Schmutzler, Rita K. Wappenschmidt, Barbara Meindl, Alfons Kast, Karin Arnold, Norbert Niederacher, Dieter Sutter, Christian Deissler, Helmut Gadzicki, Doroteha Preisler-Adams, Sabine Varon-Mateeva, Raymonda Schoenbuchner, Ines Gevensleben, Heidrun Stoppa-Lyonnet, Dominique Belotti, Muriel Barjhoux, Laure Isaacs, Claudine Peshkin, Beth N. Caldes, Trinidad de la Hoya, Miguel Canadas, Carmen Heikkinen, Tuomas Heikkila, Paivi Aittomaki, Kristiina Blanco, Ignacio Lazaro, Conxi Brunet, Joan Agnarsson, Bjarni A. Arason, Adalgeir Barkardottir, Rosa B. Dumont, Martine Simard, Jacques Montagna, Marco Agata, Simona D'Andrea, Emma Yan, Max Fox, Stephen Rebbeck, Timothy R. Rubinstein, Wendy Tung, Nadine Garber, Judy E. Wang, Xianshu Fredericksen, Zachary Pankratz, Vernon S. Lindor, Noralane M. Szabo, Csilla Offit, Kenneth Sakr, Rita Gaudet, Mia M. Singer, Christian F. Tea, Muy-Kheng Rappaport, Christine Mai, Phuong L. Greene, Mark H. Sokolenko, Anna Imyanitov, Evgeny Toland, Amanda Ewart Senter, Leigha Sweet, Kevin Thomassen, Mads Gerdes, Anne-Marie Kruse, Torben Caligo, Maria Aretini, Paolo Rantala, Johanna von Wachenfeld, Anna Henriksson, Karin Steele, Linda Neuhausen, Susan L. Nussbaum, Robert Beattie, Mary Odunsi, Kunle Sucheston, Lara Gayther, Simon A. Nathanson, Kate Gross, Jenny Walsh, Christine Karlan, Beth Chenevix-Trench, Georgia Easton, Douglas F. Antoniou, Antonis C. CA HEBON EMBRACE GEMO Study Collaborators kConFab Investigators SWE-BRCA Collaborators Consortium Investigators Modifiers TI Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ESTROGEN-RECEPTOR STATUS; IMMUNOHISTOCHEMICAL MARKERS; GERMLINE MUTATIONS; TUMOR SUBTYPES; FEATURES; RISK; PHENOTYPE; WOMEN; PREDICTION; CARCINOMA AB Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 x 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend 6.8 x 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 x 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 x 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 x 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 21(1); 134-47. (C) 2011 AACR. C1 [Mavaddat, Nasim; Barrowdale, Daniel; McGuffog, Lesley; Peock, Susan; Frost, Debra; Easton, Douglas F.; Antoniou, Antonis C.; EMBRACE] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Andrulis, Irene L.; O'Malley, Frances] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Samuel Lunenfeld Res Inst, Toronto, ON, Canada. [Robson, Mark; Offit, Kenneth; Sakr, Rita] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA. [Robson, Mark; Offit, Kenneth; Sakr, Rita] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY USA. [Robson, Mark; Offit, Kenneth; Sakr, Rita] Mem Sloan Kettering Canc Ctr, Dept Epidemiol Biostat, New York, NY USA. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Andrulis, Irene L.; O'Malley, Frances] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A1, Canada. [Mulligan, Anna Marie] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Rebbeck, Timothy R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Weaver, JoEllen] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, NHS Trust, Southampton SO9 5NH, Hants, England. [Nevanlinna, Heli; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Heikkila, Paivi] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Ramus, Susan J.; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Gross, Jenny; Walsh, Christine; Karlan, Beth] Cedars Sinai Med Ctr, Samuel Oschin Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Gross, Jenny; Walsh, Christine; Karlan, Beth] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Los Angeles, CA 90048 USA. [Spurdle, Amanda; Healey, Sue; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Sherman, Mark] NCI, Hormonal & Reprod Epidemiol Branch, Rockville, MD USA. [Mai, Phuong L.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Couch, Fergus J.; Fredericksen, Zachary; Pankratz, Vernon S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lindor, Noralane M.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Sinilnikova, Olga M.] Ctr Hosp Univ Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, Olga M.; Barjhoux, Laure] Univ Lyon 1, Canc Res Ctr Lyon, CNRS, INSERM,U1052,UMR5286, F-69622 Villeurbanne, France. [GEMO Study Collaborators] Federat Natl Ctr Lutte Canc, Canc Genet Network Grp Genet & Canc, Lyon, France. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia. [Fox, Stephen; kConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Goldgar, David] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Dept Mol & Regenerat Med, Hematol Oncol & Transfus Med Ctr, Vilnius, Lithuania. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Hansen, Thomas V. O.; Nielsen, Finn C.] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Gerdes, Anne-Marie] Univ Copenhagen, Rigshosp, Dept Clin Genet, DK-1168 Copenhagen, Denmark. [Caldes, Trinidad; de la Hoya, Miguel; Canadas, Carmen] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Stavropoulou, Alexandra] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, IRRP, Athens, Greece. [Manoukian, Siranoush; Peissel, Bernard] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, San Giovanni Rotondo, Italy. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, San Giovanni Rotondo, Italy. [Volorio, Sara; Radice, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Pasini, Barbara] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Dolcetti, Riccardo] IRCCS, Ctr Riferimento Oncol, Canc Bioimmunotherapy Unit, Aviano, PN, Italy. [Putignano, Anna Laura] Univ Florence, Dept Clin Physiopathol, I-50121 Florence, Italy. [Ottini, Laura] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy. [Sutter, Christian] Univ Heidelberg Hosp, Dept Human Genet, Inst Human Genet, Heidelberg, Germany. [Rashid, Muhammad U.] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan. [Hogervorst, Frans B.] Family Canc Clin, Amsterdam, Netherlands. [HEBON] Netherlands Canc Inst, Amsterdam, Netherlands. [Kriege, Mieke] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Rogers, Mark T.] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam, Wales. [Side, Lucy E.] Great Ormond St Hosp Sick Children, NE Thames Reg Genet Serv, London WC1N 3JH, England. [Houghton, Catherine] Liverpool Womens NHS Fdn Trust, Cheshire & Merseyside Clin Genet Serv, Liverpool, Merseyside, England. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-8000 Munich, Germany. [Kast, Karin] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Obstet & Gynaecol, D-01062 Dresden, Germany. [Arnold, Norbert] Univ Kiel, Inst Human Genet, Univ Hosp Schleswig Holstein, Kiel, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dept Obstet & Gynaecol, Univ Hosp Dusseldorf, D-40225 Dusseldorf, Germany. [Deissler, Helmut] Univ Hosp Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Gadzicki, Doroteha] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany. [Preisler-Adams, Sabine] Univ Munster, Inst Human Genet, D-4400 Munster, Germany. [Varon-Mateeva, Raymonda] Charite, Inst Human Genet, Campus Virchov Klinikum, Berlin, Germany. Univ Wurzburg, Dept Med Genet, Inst Human Genet, Ctr Familial Breast & Ovarian Canc, Wurzburg, Germany. [Stoppa-Lyonnet, Dominique; Belotti, Muriel] Inst Curie, Serv Genet Oncol, F-75231 Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM, Unite U830, F-75231 Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Fac Med, Paris, France. [Isaacs, Claudine; Peshkin, Beth N.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. Germans Trias & Pujol Biopmed Res Inst IGTP, Inst Catala Oncol, Hereditary Canc Program, Badalona, Spain. [Blanco, Ignacio; Lazaro, Conxi] Hosp Duran i Reynals, Inst Catala Oncol, Hereditary Canc Program, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain. [Brunet, Joan] Hosp Josp Trueta, Inst Catala Oncol, Hereditary Canc Program, Girona Biomed Res Inst IdiBGi, Girona, Spain. [Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.] Univ Iceland, Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Simard, Jacques] Ctr Hosp Univ Quebec, Canc Genom Lab, Canada Res Chair Oncogenet, Quebec City, PQ, Canada. [Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Montagna, Marco; Agata, Simona] IRCCS, Ist Oncol Veneto, Immunol & Mol Oncol Unit, Padua, Italy. [D'Andrea, Emma] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. [Yan, Max] Prince Wales Hosp, Dept Anat Pathol, Randwick, NSW 2031, Australia. [Rubinstein, Wendy] N Shore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Szabo, Csilla] Univ Delaware, Newark, DE USA. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine] Med Univ Vienna, Dept OB GYN, Vienna, Austria. [Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Sokolenko, Anna; Imyanitov, Evgeny] St Petersburg Pediat Med Acad, Mol Oncol Lab, NN Petrov Inst Oncol, St Petersburg, Russia. [Sokolenko, Anna; Imyanitov, Evgeny] St Petersburg Pediat Med Acad, Dept Med Genet, St Petersburg, Russia. [Toland, Amanda Ewart] Ohio State Univ, Med Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Senter, Leigha; Sweet, Kevin] Ohio State Univ, Med Ctr, Dept Internal Med, Div Human Genet,Comprehens Canc Ctr, Columbus, OH 43210 USA. [Thomassen, Mads; Kruse, Torben] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Caligo, Maria; Aretini, Paolo] Univ Pisa, Sect Genet Oncol, Dept Lab Med, Pisa, Italy. [Caligo, Maria; Aretini, Paolo] Univ Hosp Pisa, Pisa, Italy. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [von Wachenfeld, Anna] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [SWE-BRCA Collaborators] Karolinska Univ, Stockholm, Sweden. [Henriksson, Karin] Univ Lund Hosp, Ctr Oncol, S-22185 Lund, Sweden. [Steele, Linda; Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Nussbaum, Robert] Univ Calif San Francisco, Dept Med, Div Med Genet, San Francisco, CA USA. [Beattie, Mary] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Beattie, Mary] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. RP Antoniou, AC (reprint author), Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England. EM antonis@srl.cam.ac.uk RI Oosterwijk, Jan C./G-5770-2011; Lester, Jenny/B-5933-2012; Toland, Amanda/E-4202-2011; Arnold, Norbert/E-3012-2010; Osorio, Ana/I-4324-2014; GLADIEFF, Laurence/O-5129-2014; Dolcetti, Riccardo/O-3832-2015; montagna, marco/E-2225-2012; D'Andrea, Emma/B-4374-2013; Sweet, Kevin/E-4172-2011; Andrulis, Irene/E-7267-2013; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Spurdle, Amanda/A-4978-2011; Ligtenberg, Marjolijn/N-9666-2013; Sokolenko, Anna/G-3123-2013; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; OI Arnold, Norbert/0000-0003-4523-8808; Osorio, Ana/0000-0001-8124-3984; GLADIEFF, Laurence/0000-0002-6980-9719; Dolcetti, Riccardo/0000-0003-1625-9853; montagna, marco/0000-0002-4929-2150; Blanco, Ignacio/0000-0002-7414-7481; Ramus, Susan/0000-0003-0005-7798; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; PUTIGNANO, Anna Laura/0000-0001-9434-1612; Brunet, Joan/0000-0003-1945-3512; Nevanlinna, Heli/0000-0002-0916-2976; Fox, Stephen/0000-0002-7648-8896; Ligtenberg, Marjolijn/0000-0003-1290-1474; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Janavicius, Ramunas/0000-0002-3773-8485; Rappaport-Fuerhauser, Christine/0000-0002-6820-0020; Robson, Mark/0000-0002-3109-1692; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Jacobs, Chris/0000-0002-9557-9080; Evans, Gareth/0000-0002-8482-5784 FU University of Kansas Cancer Center; Kansas Bioscience Authority Eminent Scholar Program; Cancer Research UK [C12292/A11174, C1287/A10118, C1287/A11990, C5047/A8385]; European Community [223175, HEALTH-F2-2009-223175]; Medical Research Council; National Cancer Institute, NIH, [RFA-CA-06-503]; Breast Cancer Family Registry and Principal Investigators, including Cancer Care Ontario [U01 CA69467]; Columbia University [U01 CA69398]; Fox Chase Cancer Center [U01 CA69631]; Huntsman Cancer Institute [U01 CA69446]; Cancer Prevention Institute of California [U01 CA69417]; University of Melbourne [U01 CA69638]; Research Triangle Institute Informatics Support Center (RFP) [N02PC45022-46]; Cancer Care Ontario; U.S. National Cancer Institute, NIH under RFA [CA-06-503]; Research Council of Lithuania [LIG-19/2010]; LSC [05.0023.04., 10.0010.08]; NEYE Foundation; Fundacion Mutua Madrilena; Asociacion Espanola Contra el Cancer; Spanish Ministry of Science and Innovation [FIS PI08 1120]; Basque Foundation for Health Innovation and Research (BIOEF) [BIO07/CA/006]; DKFZ; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; ZonMW [91109024]; NIHR; Royal Marsden NHS Foundation Trust; Eileen Stein Jacoby Fund [U01CA69631, 5U01CA113916]; Centre of Molecular Medicine Cologne (CMMC) [109076]; Ligue National Contre le Cancer and The Association; National Cancer Institute [NCI P30 CA51008-12]; Fisher Center for Familial Cancer Research; Helsinki University Central Hospital; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital; Canadian Breast Cancer Research [019511]; Ministero della Salute [RFPS 2006-5-341353, ACC2/R6.9]; Progetto Tumori Femminili; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC) [145684, 288704, 454508]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; NIH [CA116167, CA128978, CA74415]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Komen Foundation for the Cure; Breast Cancer Research Foundation; U.S. National Cancer Institute; Westat, Inc. [NO2-CP-11019-50, N02-CP-65504]; Russian Federation for Basic Research [10-04-92601, 11-04-00250, 11-04-00227]; Federal Agency for Science and Innovations [02.740.11.0780]; Commission of the European Communities [PITN-GA-2009-238132]; OSU Comprehensive Cancer Center; ITT (Tuscany Institute for Tumors) [2010-2012]; NCI Bay Area Breast Cancer SPORE [P50-CA058207]; Avon Foundation; UCSF Helen Diller Family Comprehensive Cancer Center; CRUK; Cancer Genetics Network and Marjorie Cohen Foundation; American Cancer Society [SIOP-06-258-01-CCE] FX The author, A.K. Godwin, thanks the support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin is the Chancellors Distinguished Chair in Biomedical Sciences-endowed Professor.; This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175). NM was funded by a scholarship from the Medical Research Council. ACA is a CR-UK Senior Cancer Research Fellow. DFE is a CR-UK Principal Research Fellow.; This work was supported by the National Cancer Institute, NIH, under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46).; This work was supported by Cancer Care Ontario and the U.S. National Cancer Institute, NIH, under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators.; Lithuania: This work is financially supported by the Research Council of Lithuania grant LIG-19/2010 to R. Janavicius.; Latvia: L. Tihomirova was financially supported by LSC grants 05.0023.04. and 10.0010.08.; The authors thank NEYE Foundation for financial support; This study was partially supported financially by the Fundacion Mutua Madrilena, Asociacion Espanola Contra el Cancer and the Spanish Ministry of Science and Innovation (FIS PI08 1120). This was funded, in part, by the Basque Foundation for Health Innovation and Research (BIOEF): BIO07/CA/006.; The DKFZ study was supported by the DKFZ.; The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, and NKI2007-3756 and the ZonMW grant 91109024.; EMBRACE is financially supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. G. Evans and F. Lalloo are financially supported by an NIHR grant to the Biomedical Research Centre, Manchester, UK. The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are financially supported by an NIHR grant to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. R. Eeles, E. Bancroft, and L. D'Mello are also financially supported by a Cancer Research UK grant C5047/A8385.; A.K. Godwinwas funded by U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund.; GC-HBOC is financially supported by a grant of the German Cancer Aid (grant 109076) the Centre of Molecular Medicine Cologne (CMMC).; This study was supported by The Ligue National Contre le Cancer and The Association "Le cancer du sein, parlons-en!" Award.; C. Isaacs and B.N. Peshkin are supported by National Cancer Institute Grant (NCI P30 CA51008-12) and by the Fisher Center for Familial Cancer Research.; The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.; The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund.; This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and by the Canadian Breast Cancer Research Alliance-grant #019511.; This study was supported by "Ministero della Salute" (grant numbers RFPS 2006-5-341353, ACC2/R6.9 and "Progetto Tumori Femminili").; kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia (funded by NHMRC grants 145684, 288704, and 454508).; The MAYO study was supported by NIH grants CA116167, CA128978, a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and awards from the Komen Foundation for the Cure and the Breast Cancer Research Foundation.; The research of Drs. P. L. Mai and M. H. Greene was supported by the Intramural Research Program of the U.S. National Cancer Institute and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc.; This work has been supported by the Russian Federation for Basic Research (grants 10-04-92601, 11-04-00250, 11-04-00227), the Federal Agency for Science and Innovations (contract 02.740.11.0780), and the Commission of the European Communities (grant PITN-GA-2009-238132).; This work was supported by the OSU Comprehensive Cancer Center. Caroline Craven and Michelle O'Connor were responsible for patient accrual and data management.; M. Caligo was supported by an ITT (Tuscany Institute for Tumors) grant 2010-2012.; S. L. Neuhausen was partially supported by NIH CA74415 and the Morris and Horowitz Families Endowed Professorship.; The grant funding was obtained from the NIH, NCI Bay Area Breast Cancer SPORE (P50-CA058207), and the Avon Foundation. Support was also provided from the UCSF Helen Diller Family Comprehensive Cancer Center.; UKFOCR was supported by a project grant from CRUK to Paul Pharoah.; The funding was obtained from Breast Cancer Research Foundation (to K.L. Nathanson); and Cancer Genetics Network and Marjorie Cohen Foundation (to S.M. Domchek).; WCRI acknowledges support from the American Cancer Society, SIOP-06-258-01-CCE. NR 47 TC 110 Z9 112 U1 6 U2 43 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 JAN PY 2012 VL 21 IS 1 BP 134 EP 147 DI 10.1158/1055-9965.EPI-11-0775 PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500014 PM 22144499 ER PT J AU Simard, EP Shiels, MS Bhatia, K Engels, EA AF Simard, Edgar P. Shiels, Meredith S. Bhatia, Kishor Engels, Eric A. TI Long-term Cancer Risk among People Diagnosed with AIDS during Childhood SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTIOUS-DISEASES SOCIETY; HIV MEDICINE ASSOCIATION; INSTITUTES-OF-HEALTH; UNITED-STATES; OPPORTUNISTIC INFECTIONS; CHILDREN; HIV/AIDS; TRENDS; HUMAN-HERPESVIRUS-8 AB Background: Highly active antiretroviral therapy (HAART) results in partial immune restoration for people with AIDS, but its impact on cancer risk among children is unknown. Methods: Data from the U. S. HIV/AIDS Cancer Match Study were used to evaluate cancer risk for people diagnosed with AIDS as children (diagnosed with AIDS at ages 0-14 years, during 1980-2007, followed for up to 10 years; N = 5,850). We calculated standardized incidence ratios (SIR) to compare cancer risk to the general population. Poisson regression evaluated changes in cancer incidence between the pre-HAART (1980-1995) and HAART eras (1996-2007). Results: There were 106 cancers observed with significantly elevated risks for the two major AIDS-defining cancers: Kaposi sarcoma [KS; N = 20, SIR 1,694; 95% confidence interval (CI), 986-2,712 and SIR 1,146; 95% CI, 236-3,349] during the pre-HAART and HAART eras, respectively, and non-Hodgkin lymphoma (NHL; N = 64, SIR 338; 95% CI, 242-458 and SIR = 116; 95% CI, 74-175). Incidence of both cancers declined 87% and 60%, respectively, in the HAART era (P < 0.05). Of non-AIDS-defining cancers, leiomyosarcoma risk (N = 9) was elevated during both time periods (SIR 863; 95% CI, 235-2,211 and SIR 533; 95% CI, 173-1,243). Conclusion: People diagnosed with AIDS during childhood remain at elevated risk for KS, NHL, and leiomyosarcoma in the HAART era. Incidence of KS and NHL declined relative to widespread HAART use, but there was no change in the incidence of other cancers. Impact: People diagnosed with AIDS during childhood remain at elevated risk for certain cancers. Continued monitoring is warranted as this immunosuppressed population ages into adulthood where cancer risks generally increase. Cancer Epidemiol Biomarkers Prev; 21(1); 148-54. (C) 2011 AACR. C1 [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Simard, Edgar P.] Amer Canc Soc, Surveillance Res Program, Atlanta, GA 30329 USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7076, Rockville, MD 20892 USA. EM engelse@mail.nih.gov FU National Cancer Institute FX This study was funded by the Intramural Research Program of the National Cancer Institute. NR 37 TC 11 Z9 14 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2012 VL 21 IS 1 BP 148 EP 154 DI 10.1158/1055-9965.EPI-11-0823 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500015 PM 22068287 ER PT J AU Schlichting, JA Soliman, AS Schairer, C Banerjee, M Rozek, LS Schottenfeld, D Harford, JB Merajver, SD AF Schlichting, Jennifer A. Soliman, Amr S. Schairer, Catherine Banerjee, Mousumi Rozek, Laura S. Schottenfeld, David Harford, Joe B. Merajver, Sofia D. TI Association of Inflammatory and Noninflammatory Breast Cancer with Socioeconomic Characteristics in the Surveillance, Epidemiology, and End Results Database, 2000-2007 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HORMONE-RECEPTOR STATUS; DIFFERENT HISTOPATHOLOGIC TYPES; CENSUS-BASED METHODOLOGY; AGE-SPECIFIC INCIDENCE; UNITED-STATES; CARCINOMA INCIDENCE; RISK-FACTORS; MOLECULAR DETERMINANTS; INCIDENCE RATES; RESULTS PROGRAM AB Background: Inflammatory breast cancer (IBC) is a rare and highly aggressive form of primary breast cancer. Little is known about the risk factors for IBC, specifically the association with socioeconomic position (SEP). Methods: The association between breast cancer type (IBC vs. non-IBC) with county-level SEP in the Surveillance, Epidemiology, and End Results database for cases diagnosed from 2000 to 2007 was examined. County-level SEP characteristics included metropolitan versus non-metropolitan residence, percentage below the poverty level, percentage less than high-school graduate, and an index combining the poverty and high-school variables. IBC and non-IBC age-adjusted incidence rates were calculated, stratified on SEP and race/ethnicity. The odds of IBC versus non-IBC given a particular SEP characteristic, adjusting for age and race/ethnicity, was examined through fitting of hierarchical logistic regression models (HLM). Results: Incidence rates for IBC generally increased as SEP decreased, whereas the opposite was found for non-IBC. HLM results showed that low SEP is associated with higher odds of IBC: highest (>= 20%) versus lowest (<10%) persons below the poverty level [OR (95% confidence interval, CI) 1.25 (1.09-1.43)]; highest (>28.76%) versus lowest (<= 15.99%) persons less than high-school graduate [OR (95% CI) = 1.25 (1.10-1.42)]; and low SEP as measured by poverty-high school index versus high SEP [OR (95% CI) = 1.26 (1.11-1.44)]. Conclusion: Overall breast cancer has been found to be positively associated with SEP, whereas in this analysis, IBC was associated with decreasing SEP. Impact: Studies focused on understanding the disparity in IBC incidence, as well as interventions to eliminate these differences are needed. Cancer Epidemiol Biomarkers Prev; 21(1); 155-65. (C) 2011 AACR. C1 [Schlichting, Jennifer A.; Soliman, Amr S.; Schottenfeld, David; Merajver, Sofia D.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Banerjee, Mousumi] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Rozek, Laura S.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Schottenfeld, David; Merajver, Sofia D.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Merajver, Sofia D.] Univ Michigan, Ctr Global Hlth, Ann Arbor, MI 48109 USA. [Schairer, Catherine] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. NCI, Office Int Affairs, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Schlichting, JA (reprint author), Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. EM jschlic@umich.edu FU University of Michigan [CA R25 112383]; Avon Foundation; Breast Cancer Research Foundation; Debbie Strange-Browne Inflammatory Breast Cancer Foundation FX This work was supported by a Rackham Merit Fellowship (J.A. Schlichting) from the University of Michigan and the Cancer Epidemiology Education in Special Populations Program of the University of Michigan (CA R25 112383). Additional funding was received from the Avon Foundation (A.S. Soliman and S.D. Merajver), the Breast Cancer Research Foundation (S.D. Merajver), and the Debbie Strange-Browne Inflammatory Breast Cancer Foundation (S.D. Merajver). NR 82 TC 8 Z9 8 U1 1 U2 3 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 JAN PY 2012 VL 21 IS 1 BP 155 EP 165 DI 10.1158/1055-9965.EPI-11-0833 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500016 PM 22028401 ER PT J AU Southard, EB Roff, A Fortugno, T Richie, JP Kaag, M Chinchilli, VM Virtamo, J Albanes, D Weinstein, S Wilson, RT AF Southard, Emily B. Roff, Alanna Fortugno, Tracey Richie, John P., Jr. Kaag, Matthew Chinchilli, Vernon M. Virtamo, Jarmo Albanes, Demetrius Weinstein, Stephanie Wilson, Robin Taylor TI Lead, Calcium Uptake, and Related Genetic Variants in Association with Renal Cell Carcinoma Risk in a Cohort of Male Finnish Smokers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AMINOLEVULINIC-ACID DEHYDRATASE; VITAMIN-D-RECEPTOR; ACTIVE CA2+ REABSORPTION; BLOOD LEAD; 25-HYDROXYVITAMIN D; D SUPPLEMENTATION; TARGETED THERAPY; UNITED-STATES; KIDNEY CANCER; NHANES-III AB Background: Lead is classified as a probable human carcinogen. However, its role in renal cell cancer (RCC) has not been established. Calcium and vitamin D may off-set toxicity in vivo. Methods: In this nested case-control study, whole blood lead, total serum calcium, and serum 25-hydroxyvitamin D levels were measured in blood drawn prior to diagnosis among male smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Single-nucleotide polymorphisms (SNP) in five genes (CALB1, TRPV5, TRPV6, VDR, and ALAD) related to lead toxicity or calcium transport were genotyped. Logistic and linear regressions were used to determine RCC risk and time to diagnosis (respectively), adjusting for other risk factors. Results: Among 154 newly diagnosed cases and 308 matched controls, RCC was associated with higher whole blood lead [OR = 2.0; 95% confidence interval (CI), 1.0-3.9; quartile 4 (Q4) vs. Q1, P-trend = 0.022] and CALB1 rs1800645 (P-trend = 0.025, minor 'T' allele frequency = 0.34). Higher total serum calcium (P-trend <= 0.001) was associated with reduced RCC risk. Total serum calcium and 25-hydroxyvitamin D levels did not alter the association observed with lead. Time from enrollment to RCC diagnosis was positively associated with serum calcium (P-trend = 0.002) and 25-hydroxyvitamin D (P-trend = 0.054) among cases. Conclusions: Higher blood lead concentrations, below the 10 mu g/dL level of concern, were associated with RCC, independent from serum calcium and CALB1 promoter polymorphism. Impact: Increased risk of RCC is associated with lower serum calcium and higher whole blood lead in smokers. The clinical prognostic value of serum calcium and vitamin D in RCC should be further investigated. Cancer Epidemiol Biomarkers Prev; 21(1); 191-201. (C) 2011 AACR. C1 [Southard, Emily B.; Roff, Alanna; Fortugno, Tracey; Richie, John P., Jr.; Chinchilli, Vernon M.; Wilson, Robin Taylor] Penn State Univ, Dept Publ Hlth Sci, Div Urol, Coll Med, Hershey, PA USA. [Kaag, Matthew] Penn State Univ, Dept Surg, Div Urol, Coll Med, Hershey, PA USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. [Albanes, Demetrius; Weinstein, Stephanie] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wilson, RT (reprint author), Penn State Coll Med, Dept Publ Hlth Sci, Div Epidemiol, Penn State Canc Inst, 500 Univ Dr,Mail Code CH69, Hershey, PA 17033 USA. EM rwilson@psu.edu RI Albanes, Demetrius/B-9749-2015 FU American Institute for Cancer Research [200810] FX The study was supported by American Institute for Cancer Research, grant no. 200810 awarded to R.T. Wilson. NR 68 TC 7 Z9 8 U1 0 U2 5 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 JAN PY 2012 VL 21 IS 1 BP 191 EP 201 DI 10.1158/1055-9965.EPI-11-0670 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500020 PM 22086884 ER PT J AU Lindstrom, S Schumacher, FR Campa, D Albanes, D Andriole, G Berndt, SI Bueno-de-Mesquita, HB Chanock, SJ Diver, WR Ganziano, JM Gapstur, SM Giovannucci, E Haiman, CA Henderson, B Hunter, DJ Johansson, M Kolonel, LN Le Marchand, L Ma, J Stampfer, M Stevens, VL Trichopoulos, D Virtamo, J Willett, WC Yeager, M Hsing, AW Kraft, P AF Lindstroem, Sara Schumacher, Fredrick R. Campa, Daniele Albanes, Demetrius Andriole, Gerald Berndt, Sonja I. Bueno-de-Mesquita, H. Bas Chanock, Stephen J. Diver, W. Ryan Ganziano, J. Michael Gapstur, Susan M. Giovannucci, Edward Haiman, Christopher A. Henderson, Brian Hunter, David J. Johansson, Mattias Kolonel, Laurence N. Le Marchand, Loic Ma, Jing Stampfer, Meir Stevens, Victoria L. Trichopoulos, Dimitrios Virtamo, Jarmo Willett, Walter C. Yeager, Meredith Hsing, Ann W. Kraft, Peter TI Replication of Five Prostate Cancer Loci Identified in an Asian Population-Results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GROWTH-FACTOR-I; GENOME-WIDE ASSOCIATION; BINDING PROTEIN-3; PREDICTORS; GENES; RISK; MEN AB Background: A recent genome-wide association study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry. Methods: We genotyped five single-nucleotide polymorphism (SNP): rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22), and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the National cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed whether associations differed with respect to disease severity and age of onset. Results: Four SNPs (rs13385191, rs12653946, rs1983891, and rs339331) were significantly associated with prostate cancer risk (P values ranging from 0.01 to 1.1 x 10(-5)). Allele frequencies and ORs were overall lower in our population of European descent than in the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (P = 0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (P = 0.62). Conclusions: Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent. Impact: This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups. Cancer Epidemiol Biomarkers Prev; 21(1); 212-16. (C) 2011 AACR. C1 [Lindstroem, Sara; Hunter, David J.; Stampfer, Meir; Trichopoulos, Dimitrios; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lindstroem, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ganziano, J. Michael] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr MA, Boston, MA USA. [Ganziano, J. Michael] Boston Vet Affairs Healthcare Syst, GRECC, Boston, MA USA. [Ganziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Hunter, David J.; Ma, Jing; Stampfer, Meir; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Haiman, Christopher A.; Henderson, Brian] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Albanes, Demetrius; Berndt, Sonja I.; Chanock, Stephen J.; Yeager, Meredith; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Andriole, Gerald] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] UMCU, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Diver, W. Ryan; Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Johansson, Mattias] Int Agcy Res Canc, F-69372 Lyon, France. [Johansson, Mattias] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Lindstrom, S (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 655 Huntington Ave,Bldg 2,Room 249B, Boston, MA 02115 USA. EM slindstr@hsph.harvard.edu RI Albanes, Demetrius/B-9749-2015; Campa, Daniele/K-1617-2016 OI Campa, Daniele/0000-0003-3220-9944 FU U.S. NIH, National Cancer Institute [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the U.S. NIH, National Cancer Institute (cooperative agreements U01-CA98233-07 to D.J. Hunter, U01-CA98710-06 to S.M. Gapstur, U01-CA98216-06 to Elio Riboli and Rudolf Kaaks, and U01-CA98758-07 to B. Henderson, and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). NR 16 TC 16 Z9 17 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2012 VL 21 IS 1 BP 212 EP 216 DI 10.1158/1055-9965.EPI-11-0870-T PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500022 PM 22056501 ER PT J AU Meng, SS Song, FJ Chen, HL Gao, X Amos, CI Lee, JE Wei, QY Qureshi, AA Han, JL AF Meng, Shasha Song, Fengju Chen, Honglei Gao, Xiang Amos, Christopher I. Lee, Jeffrey E. Wei, Qingyi Qureshi, Abrar A. Han, Jiali TI No Association between Parkinson Disease Alleles and the Risk of Melanoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SKIN-CANCER AB Background: Recent data showed that melanoma was more common among patients with Parkinson disease than individuals without Parkinson disease and vice versa. It has been hypothesized that these two diseases may share common genetic and environmental risk factors. Methods: We evaluated the association between single-nucleotide polymorphisms (SNP) selected on the basis of recent genome-wide association studies (GWAS) on Parkinson disease risk and the risk of melanoma using 2,297 melanoma cases and 6,651 controls. Results: The Parkinson disease SNPrs156429 in the chromosome 7p15 region was nominally associated with melanoma risk with P value of 0.04, which was not significant after the Bonferroni correction for multiple comparisons. No association was observed between the remaining 31 Parkinson disease SNPs and the risk of melanoma. The genetic score based on the number of Parkinson disease risk allele was not associated with melanoma risk [ OR for the highest genetic score quartile (30-35) vs. the lowest (15-20), 1.13, 95% confidence interval (CI), 0.47-2.70]. Conclusion: The Parkinson disease SNPs identified in published GWAS do not seem to play an important role in melanoma development. Impact: The Parkinson disease susceptibility loci discovered by GWAS contribute little to the observed epidemiologic association between the Parkinson disease and melanoma. Cancer Epidemiol Biomarkers Prev; 21(1); 243-5. (C)2011 AACR. C1 [Meng, Shasha; Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gao, Xiang] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. [Gao, Xiang; Qureshi, Abrar A.; Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Song, Fengju; Qureshi, Abrar A.; Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Amos, Christopher I.; Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. RP Han, JL (reprint author), Brigham & Womens Hosp, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM jiali.han@channing.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU NIH [CA87969, CA49449, CA055075, CA093459, CA122838]; National Institute of Environmental Health Sciences [Z01-ES-101986] FX This work was supported by NIH CA87969, CA49449, CA055075, CA093459, and CA122838. This study was also in part supported by the intramural research program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986). NR 8 TC 12 Z9 12 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2012 VL 21 IS 1 BP 243 EP 245 DI 10.1158/1055-9965.EPI-11-0905 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500026 PM 22086882 ER PT J AU Albanes, D Weinstein, SJ Mondul, AM Virtamo, J AF Albanes, Demetrius Weinstein, Stephanie J. Mondul, Alison M. Virtamo, Jarmo TI Circulating Vitamin D and Risk of Prostate Cancer-Response SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 [Albanes, Demetrius; Weinstein, Stephanie J.; Mondul, Alison M.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20982 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Albanes, D (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Bethesda, MD 20982 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015 NR 1 TC 0 Z9 0 U1 0 U2 3 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 JAN PY 2012 VL 21 IS 1 BP 247 EP 247 DI 10.1158/1055-9965.EPI-11-1003 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500028 ER PT J AU Hock, JM Nealley, A Morrison, D Farah, C Hosgood, HD Zahm, S AF Hock, Janet M. Nealley, Amelia Morrison, Deborah Farah, Christopher Hosgood, H. Dean Zahm, Sheila TI Unmet Challenges in Cancer Disparities-Letter SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 [Hock, Janet M.; Nealley, Amelia; Morrison, Deborah; Farah, Christopher] Maine Inst Human Genet & Hlth, Bangor, ME USA. [Hosgood, H. Dean; Zahm, Sheila] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hock, JM (reprint author), Maine Inst Human Genet & Hlth, Bangor, ME USA. EM jhock@emh.org RI Zahm, Shelia/B-5025-2015; OI Hock, Janet/0000-0001-8873-2545 FU Intramural NIH HHS [Z99 CA999999] NR 4 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JAN PY 2012 VL 21 IS 1 BP 248 EP 249 DI 10.1158/1055-9965.EPI-11-1039 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 875RH UT WOS:000299051500029 PM 22144498 ER PT J AU Sahasrabuddhe, VV Parham, GP Mwanahamuntu, MH Vermund, SH AF Sahasrabuddhe, Vikrant V. Parham, Groesbeck P. Mwanahamuntu, Mulindi H. Vermund, Sten H. TI Cervical Cancer Prevention in Low- and Middle-Income Countries: Feasible, Affordable, Essential SO CANCER PREVENTION RESEARCH LA English DT Review ID HIV-INFECTED WOMEN; HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN-PAPILLOMAVIRUS; ANTIRETROVIRAL THERAPY; RANDOMIZED-TRIAL; HPV DETECTION; ZAMBIA; INDIA; TREAT; CRYOTHERAPY AB The annual worldwide burden of the preventable disease cervical cancer is more than 530,000 new cases and 275,000 deaths, with the majority occurring in low-and middle-income countries (LMIC), where cervical cancer screening and early treatment are uncommon. Widely used in high-income countries, Pap smear (cytology based) screening is expensive and challenging for implementation in LMICs, where lower-cost, effective alternatives such as visual inspection with acetic acid (VIA) and rapid human papillomavirus (HPV)-based screening tests offer promise for scaling up prevention services. Integrating HPV screening with VIA in "screen-and-treat-or-refer" programs offers the dual benefits of HPV screening to maximize detection and using VIA to triage for advanced lesions/cancer, as well as a pelvic exam to address other gynecologic issues. A major issue in LMICs is coinfection with human immunodeficiency virus (HIV) and HPV, which further increases the risk for cervical cancer and marks a population with perhaps the greatest need of cervical cancer prevention. Public-private partnerships to enhance the availability of cervical cancer prevention services within HIV/AIDS care delivery platforms through initiatives such as Pink Ribbon Red Ribbon present an historic opportunity to expand cervical cancer screening in LMICs. Cancer Prev Res; 5(1); 11-17. (C)2011 AACR. C1 [Sahasrabuddhe, Vikrant V.; Vermund, Sten H.] Vanderbilt Univ, Vanderbilt Inst Global Hlth, Sch Med, Nashville, TN 37203 USA. [Sahasrabuddhe, Vikrant V.; Vermund, Sten H.] Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN 37203 USA. [Sahasrabuddhe, Vikrant V.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Parham, Groesbeck P.] Univ Alabama Birmingham, Sch Med, Ctr Infect Dis Res Zambia, Birmingham, AL USA. [Parham, Groesbeck P.] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL USA. [Parham, Groesbeck P.; Mwanahamuntu, Mulindi H.] Univ Teaching Hosp, Lusaka, Zambia. [Parham, Groesbeck P.; Mwanahamuntu, Mulindi H.] Univ Zambia, Sch Med, Lusaka, Zambia. RP Vermund, SH (reprint author), Vanderbilt Univ, Vanderbilt Inst Global Hlth, Sch Med, 2525 W End Ave,Suite 750, Nashville, TN 37203 USA. EM sten.vermund@vanderbilt.edu OI Vermund, Sten/0000-0001-7289-8698 FU FIC NIH HHS [D43 TW001035]; Intramural NIH HHS [Z01 CP010124-13, Z99 CA999999]; NCI NIH HHS [R21 CA113465] NR 65 TC 30 Z9 30 U1 2 U2 10 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 JAN PY 2012 VL 5 IS 1 BP 11 EP 17 DI 10.1158/1940-6207.CAPR-11-0540 PG 7 WC Oncology SC Oncology GA 877RT UT WOS:000299200500003 PM 22158053 ER PT J AU Lowy, DR Schiller, JT AF Lowy, Douglas R. Schiller, John T. TI Reducing HPV-Associated Cancer Globally SO CANCER PREVENTION RESEARCH LA English DT Article ID INVASIVE CERVICAL-CANCER; HUMAN-PAPILLOMAVIRUS; PARTICLE VACCINE; UNITED-STATES; PREVENTION; INFECTION; WOMEN; L1; IMPACT; ADOLESCENTS AB Human papillomavirus (HPV)-related cancers are a major worldwide public health concern. Virtually all cervical cancer is HPV related, with 70% caused by HPV16 and -18. Variable proportions of certain noncervical cancers (e. g., anal, vulvar, and oropharyngeal) are HPV related; more than 90% of the HPV-related ones are caused by HPV16, -18. The HPV-related cancers are dominated by cervical cancer in the developing world, where cervical cancer screening is limited. In this setting, widespread uptake of current HPV vaccines by adolescent girls could reduce this cancer's incidence and mortality by approximately two-thirds, with cost-effective screening programs of adult women having the potential to reduce mortality more rapidly. In the industrialized world, some noncervical HPV-related cancers, especially oropharyngeal, are rapidly increasing, and now rival the incidence of cervical cancer, whose rates continue to decline thanks to established cervical screening programs. Therefore, reducing HPV-associated noncervical cancers with HPV vaccination has greater importance in the industrialized world, especially because there are no approved screening programs for these cancers. Preventing the substantial number of noncervical HPV cancers in men will require either "herd" immunity through high-vaccination rates in females or male vaccination. Current HPV vaccination can complement cervical screening in protecting against cervical cancer and may permit the safe reduction of screening intensity in industrialized countries. Second-generation HPV vaccines (active against a broader array of cervical cancer-related HPV types) could prevent an even higher proportion of cervical precancer and cancer and might permit further reductions in screening intensity. Cancer Prev Res; 5(1); 18-23. (C)2012 AACR. C1 [Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, 37 Convent Dr,MSC 4263,Bldg 37,Rm 4106, Bethesda, MD 20892 USA. EM lowyd@mail.nih.gov FU NIH, National Cancer Institute, and Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. NR 35 TC 57 Z9 61 U1 0 U2 10 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 JAN PY 2012 VL 5 IS 1 BP 18 EP 23 DI 10.1158/1940-6207.CAPR-11-0542 PG 6 WC Oncology SC Oncology GA 877RT UT WOS:000299200500004 PM 22219162 ER PT J AU Yuan, HY Upadhyay, G Yin, YZ Kopelovich, L Glazer, RI AF Yuan, Hongyan Upadhyay, Geeta Yin, Yuzhi Kopelovich, Levy Glazer, Robert I. TI Stem Cell Antigen-1 Deficiency Enhances the Chemopreventive Effect of Peroxisome Proliferator-Activated Receptor gamma Activation SO CANCER PREVENTION RESEARCH LA English DT Article ID MEDIATES RADIATION-RESISTANCE; DMBA-INDUCED MAMMARY; PPAR-GAMMA; BREAST-CANCER; PROGENITOR CELLS; GENETIC DISRUPTION; TUMOR-SUPPRESSOR; TRANSGENIC MICE; SCA-1; EXPRESSION AB Stem cell antigen-1 (Sca-1, Ly6A) is a glycerophosphatidylinositol (GPI)-anchored protein that was identified as a murine marker of bone marrow stem cells. Although Sca-1 is widely used to enrich for stem and progenitor cells in various tissues, little is known about its function and associated signaling pathways in normal and malignant cells. Here, we report that the absence of Sca-1 in the mammary gland resulted in higher levels of PPAR gamma and PTEN, and a reduction of pSer84PPAR gamma, pERK1/2, and PPAR delta. This phenotype correlated with markedly increased sensitivity of Sca-1 null mice to PPAR gamma agonist GW7845 and insensitivity to PPAR delta agonist GW501516. Reduction of Sca-1 expression in mammary tumor cells by RNA interference resulted in a phenotype similar to the Sca-1 deficient mammary gland, as evidenced by increased PPAR gamma expression and transcriptional activity, resulting in part from a lesser susceptibility to proteasomal degradation. These data implicate Sca-1 as a negative regulator of the tumor suppressor effects of PPAR gamma. Cancer Prev Res; 5(1); 51-60. (C)2011 AACR. C1 [Yuan, Hongyan; Upadhyay, Geeta; Yin, Yuzhi; Glazer, Robert I.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Yuan, Hongyan; Upadhyay, Geeta; Yin, Yuzhi; Glazer, Robert I.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Kopelovich, Levy] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Glazer, RI (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. EM glazerr@georgetown.edu FU NIH [1NO1 CN43302-WA19, 1G20RR025828-01]; National Cancer Institute, NIH [P30CA051008] FX The work was supported by NIH grant 1NO1 CN43302-WA19 (R. I. Glazer). This study was supported by Award P30CA051008 from the National Cancer Institute, NIH, and by Grant 1G20RR025828-01 from the NIH for Rodent Barrier Facility Equipment. NR 66 TC 5 Z9 6 U1 0 U2 1 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 JAN PY 2012 VL 5 IS 1 BP 51 EP 60 DI 10.1158/1940-6207.CAPR-11-0256 PG 10 WC Oncology SC Oncology GA 877RT UT WOS:000299200500009 PM 21955520 ER PT J AU Kim, EH Deng, CX Sporn, MB Royce, DB Risingsong, R Williams, CR Liby, KT AF Kim, Eun-Hee Deng, Chuxia Sporn, Michael B. Royce, Darlene B. Risingsong, Renee Williams, Charlotte R. Liby, Karen T. TI CDDO-Methyl Ester Delays Breast Cancer Development in Brca1-Mutated Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID FATTY-ACID SYNTHASE; NITRIC-OXIDE PRODUCTION; ESTROGEN-RECEPTOR; IRREVERSIBLE INHIBITOR; MAMMARY TUMORIGENESIS; TYROSINE KINASE; TUMOR-FORMATION; PREVENTION; CHEMOPREVENTION; BRCA1 AB The breast cancer-associated gene 1 (BRCA1) is the most frequently mutated tumor suppressor gene in familial breast cancers. Mutations in BRCA1 also predispose to other types of cancers, pointing to a fundamental role of this pathway in tumor suppression and emphasizing the need for effective chemoprevention in these high-risk patients. Because the methyl ester of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) is a potent chemopreventive agent, we tested its efficacy in a highly relevant mouse model of BRCA1-mutated breast cancer. Beginning at 12 weeks of age, Brca1(Co/Co); MMTV-Cre;p53(+/-) mice were fed powdered control diet or diet containing CDDO-Me (50 mg/kg diet). CDDO-Me significantly (P < 0.05) delayed tumor development in the Brca1-mutated mice by an average of 5.2 weeks. We also observed that levels of ErbB2, p-ErbB2, and cyclin D1 increased in a time-dependent manner in the mammary glands in Brca1-deficient mice, and CDDO-Me inhibited the constitutive phosphorylation of ErbB2 in tumor tissues from these mice. In BRCA1-deficient cell lines, the triterpenoids directly interacted with ErbB2, decreased constitutive phosphorylation of ErbB2, inhibited proliferation, and induced G(0)-G(1) arrest. These results suggest that CDDO-Me has the potential to prevent BRCA1-mutated breast cancer. Cancer Prev Res; 5(1); 89-97. (C)2011 AACR. C1 [Liby, Karen T.] Dartmouth Med Sch, Dept Med, Hanover, NH 03755 USA. [Kim, Eun-Hee; Sporn, Michael B.; Royce, Darlene B.; Risingsong, Renee; Williams, Charlotte R.] Dartmouth Med Sch, Dept Pharmacol, Hanover, NH 03755 USA. [Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Liby, KT (reprint author), Dartmouth Med Sch, Dept Med, Remsen 524,HB 7650, Hanover, NH 03755 USA. EM Karen.T.Liby@Dartmouth.Edu RI deng, chuxia/N-6713-2016 FU Breast Cancer Research Foundation; NIH [RO1 CA78814]; Reata Pharmaceuticals, Inc. FX These studies were supported by the Breast Cancer Research Foundation and the NIH (RO1 CA78814).; M. B. Sporn has commercial research grant in Reata Pharmaceuticals, Inc.; M. B. Sporn and K. Liby have patent interest in synthetic triterpenoids. No potential conflicts of interest were disclosed by other authors. NR 43 TC 22 Z9 23 U1 1 U2 1 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 JAN PY 2012 VL 5 IS 1 BP 89 EP 97 DI 10.1158/1940-6207.CAPR-11-0359 PG 9 WC Oncology SC Oncology GA 877RT UT WOS:000299200500013 PM 21933912 ER PT J AU Do, JS Foucras, G Kamada, N Schenk, AF Shaw, M Nunez, G Paul, WE Min, B AF Do, Jeong-su Foucras, Gilles Kamada, Nobuhiko Schenk, Austin F. Shaw, Michael Nunez, Gabriel Paul, William E. Min, Booki TI Both exogenous commensal and endogenous self antigens stimulate T cell proliferation under lymphopenic conditions SO CELLULAR IMMUNOLOGY LA English DT Article DE Homeostasis; T cell; Commensal antigen; FTY720; Self antigen; Lymphopenia ID HOMEOSTATIC PROLIFERATION; IN-VIVO; AUTOIMMUNITY; SEQUESTRATION; EXPRESSION; INDUCTION; SURVIVAL AB Within lymphopenic recipients, naive T cells undergo proliferation that is induced by homeostatic mechanisms. Earlier studies have demonstrated that commensal antigens play a key role in inducing the proliferation. However, a relative contribution of endogenous self antigens in this process has not been formally investigated. In this study, we utilized a pharmacologic inhibitor that blocks T cell egress from the lymphoid tissues, antibiotics, and germ-free animals to examine the role of commensal and self antigens. The results suggest that T cell proliferation under lymphopenic conditions is a heterogeneous process triggered by both exogenous commensal and endogenous self antigens. (C) 2011 Elsevier Inc. All rights reserved. C1 [Do, Jeong-su; Schenk, Austin F.; Min, Booki] Cleveland Clin Fdn, Dept Immunol, Lerner Res Inst, Cleveland, OH 44195 USA. [Foucras, Gilles; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kamada, Nobuhiko; Shaw, Michael; Nunez, Gabriel] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Kamada, Nobuhiko; Shaw, Michael; Nunez, Gabriel] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Min, B (reprint author), Cleveland Clin Fdn, Dept Immunol NB30, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM minb@ccf.org RI Do, Jeong su/G-9483-2014; OI Kamada, Nobuhiko/0000-0002-1980-4178 FU NIH [A1074932]; NIAID/NIH FX This study was supported by NIH grant A1074932 (B.M.) and the intramural research program of the NIAID/NIH. NR 28 TC 5 Z9 5 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PY 2012 VL 272 IS 2 BP 117 EP 123 DI 10.1016/j.cellimm.2011.11.002 PG 7 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 879AP UT WOS:000299302400003 PM 22169530 ER PT J AU Tsourkas, PK Liu, WL Das, SC Pierce, SK Raychaudhuri, S AF Tsourkas, Philippos K. Liu, Wanli Das, Somkanya C. Pierce, Susan K. Raychaudhuri, Subhadip TI Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE computational modeling; Monte Carlo; lymphocyte signaling; Lyn; Syk ID RESPONSES IN-VIVO; SYNAPSE FORMATION; LYMPH-NODE; SUBCAPSULAR SINUS; DENDRITIC CELLS; LIVING CELLS; MONTE-CARLO; T-CELLS; ACTIVATION; ADHESION AB B-cell receptor signaling in response to membrane-bound antigen increases with antigen affinity, a process known as affinity discrimination. We use computational modeling to show that B-cell affinity discrimination requires that kinetic proofreading predominate over serial engagement. We find that if B-cell receptors become signaling-capable immediately upon antigen binding, which results in decreasing serial engagement as affinity increases, then increasing affinity can lead to weaker signaling. Rather, antigen must stay bound to B-cell receptors for a threshold time of several seconds before becoming signaling-capable, a process similar to kinetic proofreading. This process overcomes the loss in serial engagement due to increasing antigen affinity, and replicates the monotonic increase in B-cell signaling with increasing affinity that has been observed in B-cell activation experiments. This finding matches well with the experimentally observed time (similar to 20 s) required for the B-cell receptor signaling domains to undergo antigen and lipid raft-mediated conformational changes that lead to Src-family kinase recruitment. We hypothesize that the physical basis for a threshold time of antigen binding might lie in the formation timescale of B-cell receptor dimers. The time required for dimer formation decreases with increasing antigen affinity, thereby resulting in shorter threshold antigen binding times as affinity increases. Such an affinity-dependent kinetic proofreading requirement results in affinity discrimination very similar to that observed in biological experiments. B-cell affinity discrimination is critical to the process of affinity maturation and the production of high-affinity antibodies, and thus our results have important implications in applications such as vaccine design. Cellular & Molecular Immunology (2012) 9, 62-74; doi: 10.1038/cmi.2011.29; published online 12 September 2011 C1 [Tsourkas, Philippos K.; Das, Somkanya C.; Raychaudhuri, Subhadip] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Liu, Wanli; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Raychaudhuri, S (reprint author), Univ Calif Davis, Dept Biomed Engn, 1 Shields Ave, Davis, CA 95616 USA. EM raychaudhuri@ucdavis.edu RI liu, wanli/H-5690-2011; Tsourkas, Philippos/G-4026-2014; OI liu, wanli/0000-0003-2624-6802; Raychaudhuri, Subhadip/0000-0002-9873-6475 FU NIH [AI074022] FX The authors thank Dr Emanual Maverakis, Dr Aaron Dinner and Dr Stephen Kaattari for proofreading the manuscript and offering valuable advice. PT and SR are supported by NIH grant AI074022. NR 44 TC 9 Z9 9 U1 2 U2 6 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD JAN PY 2012 VL 9 IS 1 SI SI BP 62 EP 74 DI 10.1038/cmi.2011.29 PG 13 WC Immunology SC Immunology GA 877RX UT WOS:000299201200012 PM 21909127 ER PT J AU O'Connor, CM Whellan, DJ Wojdyla, D Leifer, E Clare, RM Ellis, SJ Fine, LJ Fleg, JL Zannad, F Keteyian, SJ Kitzman, DW Kraus, WE Rendall, D Pina, IL Cooper, LS Fiuzat, M Lee, KL AF O'Connor, Christopher M. Whellan, David J. Wojdyla, Daniel Leifer, Eric Clare, Robert M. Ellis, Stephen J. Fine, Lawrence J. Fleg, Jerome L. Zannad, Faiez Keteyian, Steven J. Kitzman, Dalane W. Kraus, William E. Rendall, David Pina, Ileana L. Cooper, Lawton S. Fiuzat, Mona Lee, Kerry L. TI Factors Related to Morbidity and Mortality in Patients With Chronic Heart Failure With Systolic Dysfunction The HF-ACTION Predictive Risk Score Model SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; systolic heart failure; risk assessment; Cox proportional hazards models; exercise ID CITY CARDIOMYOPATHY QUESTIONNAIRE; INITIATE LIFESAVING TREATMENT; LEFT-VENTRICULAR DYSFUNCTION; RANDOMIZED CONTROLLED-TRIAL; WORSENING RENAL-FUNCTION; CORONARY-ARTERY DISEASE; PEAK OXYGEN-CONSUMPTION; CLINICAL CHARACTERISTICS; MYOCARDIAL-INFARCTION; HOSPITALIZED-PATIENTS AB Background-We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results-In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II-IV, left ventricular ejection fraction <= 0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). Conclusions-Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. C1 [O'Connor, Christopher M.; Wojdyla, Daniel; Clare, Robert M.; Ellis, Stephen J.; Rendall, David; Fiuzat, Mona; Lee, Kerry L.] Duke Clin Res Inst, Durham, NC USA. [Whellan, David J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Leifer, Eric; Fine, Lawrence J.; Fleg, Jerome L.; Cooper, Lawton S.] NHLBI, Bethesda, MD 20892 USA. [Zannad, Faiez] Nancy Univ, Nancy, France. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Kitzman, Dalane W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Kraus, William E.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Kraus, William E.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Pina, Ileana L.] Montefiore Med Ctr, New York, NY USA. RP O'Connor, CM (reprint author), DUMC Box 3356, Durham, NC 27710 USA. EM Oconn002@mc.duke.edu OI Kraus, William E/0000-0003-1930-9684 FU National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD FX The HF-ACTION trial was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD. NR 36 TC 67 Z9 71 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JAN PY 2012 VL 5 IS 1 BP 63 EP 71 DI 10.1161/CIRCHEARTFAILURE.111.963462 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 879IY UT WOS:000299324100015 PM 22114101 ER PT J AU Zhang, MC Tavora, F Oliveira, JB Li, L Franco, M Fowler, D Zhao, ZQ Burke, A AF Zhang, Mingchang Tavora, Fabio Oliveira, Joao Bosco Li, Ling Franco, Marcello Fowler, David Zhao, Ziqin Burke, Allen TI PKP2 Mutations in Sudden Death From Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and Sudden Unexpected Death With Negative Autopsy (SUDNA) SO CIRCULATION JOURNAL LA English DT Article DE Arrhythmia; Arrhythmogenic right ventricular cardiomyopathy; Desmosome; Negative autopsy; Sudden death ID CARDIAC DEATH; PLAKOPHILIN-2 MUTATIONS; MOLECULAR AUTOPSY; EPITHELIAL-CELLS; DYSPLASIA/CARDIOMYOPATHY; EXPRESSION; DESMOSOMES; PROTEIN; GENE; DESMOCOLLIN-2 AB Background: Plakophilin2 (PKP2) is a desmosome-related protein with numerous armadillo repeats and has been linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy, and have been linked to ion channel mutations in a subset of cases, but so far not to PKP2. Methods and Results: We sequenced all 14 exons of PKP2 in DNA extracted from postmortem heart tissues of 25 patients dying from ARVC and 25 from sudden unexpected death with negative autopsy (SUDNA). The primers were designed using the Primer Express 3.0 software. Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130XL Genetic Analyzer. Mutation damage prediction was made using Mutation Taster, Polyphen and SIFT software. In 6 of the 25 ARVC samples, 6 PKP2 mutations were identified, 4 of which were likely significant, and 3 of which were novel (p.N641del, p.L64PfsX22, p.G269R). In 6 of the 25 cases of SUDNA samples, 6 PKP2 mutations were identified, 3 of which were likely significant, and 4 of which were not previously described (p.P665S, p.Y217TfsX45, p.E540, p.S615T). Conclusions: PKP2 mutations are not specific for ARVC and may result in SUDNA. The link between ARVC and desmosomal mutations may not be causal but related to an association between defective desmosomal proteins and arrhythmias. (Circ J 2012; 76: 189-194) C1 [Zhang, Mingchang; Li, Ling; Fowler, David; Zhao, Ziqin; Burke, Allen] Fudan Univ, Shanghai Med Coll, Dept Forens Med, Shanghai 200433, Peoples R China. [Zhang, Mingchang; Oliveira, Joao Bosco] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Tavora, Fabio] Messejana Heart & Lung Hosp, Fortaleza, Ceara, Brazil. [Li, Ling; Fowler, David] China Univ Polit Sci & Law, Div Forens Med, Key Lab Evidence Sci, Beijing, Peoples R China. [Zhang, Mingchang; Li, Ling; Fowler, David; Burke, Allen] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Tavora, Fabio; Franco, Marcello] Escola Paulista Med, BR-04023 Sao Paulo, Brazil. RP Burke, A (reprint author), UMMS, 21 S Greene St, Baltimore, MD 21201 USA. EM aburke@umm.edu OI Oliveira, Joao/0000-0001-9388-8173 NR 38 TC 19 Z9 19 U1 2 U2 5 PU JAPANESE CIRCULATION SOC PI KYOTO PA KINKI INVENTION CENTER, 14 YOSHIDA KAWAHARACHO, SAKYO-KU, KYOTO, 606-8305, JAPAN SN 1346-9843 J9 CIRC J JI Circ. J. PD JAN PY 2012 VL 76 IS 1 BP 189 EP 194 DI 10.1253/circj.CJ-11-0747 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 871XN UT WOS:000298771100032 PM 22019812 ER PT J AU Bates, SE AF Bates, Susan E. TI On Drug Development, Chance, and the Prepared Mind SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bldg 10,Room 12N226,900 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2012 VL 18 IS 1 BP 22 EP 22 DI 10.1158/1078-0432.CCR-11-2908 PG 1 WC Oncology SC Oncology GA 871SV UT WOS:000298758900005 PM 22215902 ER PT J AU Bates, SE Amiri-Kordestani, L Giaccone, G AF Bates, Susan E. Amiri-Kordestani, Laleh Giaccone, Giuseppe TI Drug Development: Portals of Discovery SO CLINICAL CANCER RESEARCH LA English DT Article ID REFRACTORY PROSTATE-CANCER; GROWTH-FACTOR RECEPTOR; RENAL-CELL CARCINOMA; METASTATIC COLORECTAL-CANCER; RECURRENT OVARIAN-CANCER; ACUTE MYELOID-LEUKEMIA; PHASE-III TRIAL; BREAST-CANCER; SOLID TUMORS; LUNG-CANCER AB A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer. Clin Cancer Res; 18(1); 23-32. (C) 2012 AACR. C1 [Bates, Susan E.; Amiri-Kordestani, Laleh; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Bldg 10,Room 12N226,900 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 71 TC 23 Z9 23 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2012 VL 18 IS 1 BP 23 EP 32 DI 10.1158/1078-0432.CCR-11-1001 PG 10 WC Oncology SC Oncology GA 871SV UT WOS:000298758900006 PM 22215903 ER PT J AU Komlodi-Pasztor, E Sackett, DL Fojo, AT AF Komlodi-Pasztor, Edina Sackett, Dan L. Fojo, Antonio Tito TI Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale SO CLINICAL CANCER RESEARCH LA English DT Article ID AURORA-B KINASE; TUMOR DOUBLING TIME; POLO-LIKE KINASE; ADVANCED SOLID TUMORS; BREAST-CANCER GROWTH; RENAL-CELL CARCINOMA; LUNG-CANCER; NATURAL-HISTORY; SELECTIVE INHIBITOR; IN-VIVO AB Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise. Clin Cancer Res; 18(1); 51-63. (C) 2012 AACR. C1 [Komlodi-Pasztor, Edina; Fojo, Antonio Tito] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Fojo, AT (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 10 Ctr Dr,MSC 1906,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 121 TC 81 Z9 82 U1 2 U2 10 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 JAN 1 PY 2012 VL 18 IS 1 BP 51 EP 63 DI 10.1158/1078-0432.CCR-11-0999 PG 13 WC Oncology SC Oncology GA 871SV UT WOS:000298758900009 PM 22215906 ER PT J AU Neckers, L Workman, P AF Neckers, Len Workman, Paul TI Hsp90 Molecular Chaperone Inhibitors: Are We There Yet? SO CLINICAL CANCER RESEARCH LA English DT Article ID HEAT-SHOCK-PROTEIN; BREAST-CANCER CELLS; PHASE-II TRIAL; MULTIPLE-MYELOMA; TANESPIMYCIN 17-AAG; ACQUIRED-RESISTANCE; SIGNALING PATHWAYS; CRYSTAL-STRUCTURE; TARGETING HSP90; DOSE-ESCALATION AB Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Investigators established Hsp90's druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (especially multiple myeloma) in which buffering of proteotoxic stress is critical for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70. Clin Cancer Res; 18(1); 64-76. (C) 2012 AACR. C1 [Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Workman, Paul] Inst Canc Res, Haddow Labs, Div Canc Therapeut,Canc Res UK Canc Therapeut Uni, Signal Transduct & Mol Pharmacol Team, Sutton SM2 5NG, Surrey, England. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10-CRC,Room 1-5940, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov; paul.workman@icr.ac.uk FU National Cancer Institute; Cancer Research UK [C309/A8274]; National Health Service (NIHR Biomedical Research Centre) FX Intramural Research Program of the National Cancer Institute (L. Neckers); Cancer Research UK (program grant C309/A8274 to P. Workman); National Health Service (NIHR Biomedical Research Centre; P. Workman). P. Workman is a Cancer Research UK Life Fellow. NR 115 TC 355 Z9 366 U1 14 U2 76 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 JAN 1 PY 2012 VL 18 IS 1 BP 64 EP 76 DI 10.1158/1078-0432.CCR-11-1000 PG 13 WC Oncology SC Oncology GA 871SV UT WOS:000298758900010 PM 22215907 ER PT J AU Kemp, CD Rao, M Xi, SC Inchauste, S Mani, H Fetsch, P Filie, A Zhang, M Hong, JA Walker, RL Zhu, YLJ Ripley, RT Mathur, A Liu, F Yang, MC Meltzer, PA Marquez, VE De Rienzo, A Bueno, R Schrump, DS AF Kemp, Clinton D. Rao, Mahadev Xi, Sichuan Inchauste, Suzanne Mani, Haresh Fetsch, Patricia Filie, Armando Zhang, Mary Hong, Julie A. Walker, Robert L. Zhu, Yuelin J. Ripley, R. Taylor Mathur, Aarti Liu, Fang Yang, Maocheng Meltzer, Paul A. Marquez, Victor E. De Rienzo, Assunta Bueno, Raphael Schrump, David S. TI Polycomb Repressor Complex-2 Is a Novel Target for Mesothelioma Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID MALIGNANT PLEURAL MESOTHELIOMA; GROUP PROTEIN EED; STEM-CELLS; HISTONE METHYLATION; X-CHROMOSOME; CANCER-CELLS; EZH2; EXPRESSION; GENE; CARCINOMA AB Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 or EED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy. Clin Cancer Res; 18(1); 77-90. (C) 2011 AACR. C1 [Kemp, Clinton D.; Rao, Mahadev; Xi, Sichuan; Inchauste, Suzanne; Zhang, Mary; Hong, Julie A.; Ripley, R. Taylor; Mathur, Aarti; Liu, Fang; Yang, Maocheng; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mani, Haresh; Fetsch, Patricia; Filie, Armando] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Walker, Robert L.; Zhu, Yuelin J.; Meltzer, Paul A.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Marquez, Victor E.] NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. [De Rienzo, Assunta; Bueno, Raphael] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02115 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Room 4-3942,MSC 1201, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov NR 49 TC 38 Z9 41 U1 1 U2 8 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 JAN 1 PY 2012 VL 18 IS 1 BP 77 EP 90 DI 10.1158/1078-0432.CCR-11-0962 PG 14 WC Oncology SC Oncology GA 871SV UT WOS:000298758900011 PM 22028491 ER PT J AU Welsh, AW Lannin, DR Young, GS Sherman, ME Figueroa, JD Henry, NL Ryden, L Kim, C Love, RR Schiff, R Rimm, DL AF Welsh, Allison W. Lannin, Donald R. Young, Gregory S. Sherman, Mark E. Figueroa, Jonine D. Henry, N. Lynn Ryden, Lisa Kim, Chungyeul Love, Richard R. Schiff, Rachel Rimm, David L. TI Cytoplasmic Estrogen Receptor in Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; AUTOMATED QUANTITATIVE-ANALYSIS; RETRACTED ARTICLE. SEE; PLASMA-MEMBRANE; MONOCLONAL-ANTIBODIES; ENDOCRINE RESISTANCE; TAMOXIFEN RESISTANCE; ADJUVANT TAMOXIFEN; ALPHA; CELLS AB Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-alpha (ER alpha) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens. Experimental Design: A panel of ER alpha-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world. Results: Four of the antibodies specifically recognized ER by Western and QIF analysis, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with Pearson correlations (r(2) values) ranging from 0.87 to 0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other four antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%. Conclusions: Our data show ER alpha is present in the cytoplasm in a number of cases using multiple antibodies while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. Clin Cancer Res; 18(1); 118-26. (C) 2011 AACR. C1 [Welsh, Allison W.; Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Lannin, Donald R.] Yale Univ, Sch Med, Dept Surg & Oncol, New Haven, CT 06520 USA. [Young, Gregory S.] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Sherman, Mark E.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Henry, N. Lynn] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Ryden, Lisa] Lund Univ, Dept Surg, Lund, Sweden. [Kim, Chungyeul] Natl Surg Adjuvant Breast & Bowel Project Fdn, Div Pathol, Pittsburgh, PA USA. [Love, Richard R.] Int Breast Canc Fdn, Madison, WI USA. [Schiff, Rachel] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Schiff, Rachel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Schiff, Rachel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. RP Rimm, DL (reprint author), Yale Univ, Sch Med, Dept Pathol, BML 116,310 Cedar St, New Haven, CT 06520 USA. EM david.rimm@yale.edu OI kim, chungyeul/0000-0002-9636-5228 FU National Cancer Institute; NIH [R33 CA 106709]; US Army CDMRP; American Society of Clinical Oncology FX The study was supported by additional grants from the Intramural Research Program of the National Cancer Institute to M.E. Sherman and J.D. Figueroa, and an American Society of Clinical Oncology Young Investigator award to N.L. Henry. The support for this research comes from NIH R33 CA 106709 (to D.L. Rimm) and a US Army CDMRP pre-doctoral fellowship (A.W. Welsh). NR 49 TC 25 Z9 25 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2012 VL 18 IS 1 BP 118 EP 126 DI 10.1158/1078-0432.CCR-11-1236 PG 9 WC Oncology SC Oncology GA 871SV UT WOS:000298758900014 PM 21980134 ER PT J AU Singh, R Zhang, YJ Pastan, I Kreitman, RJ AF Singh, Rajat Zhang, Yujian Pastan, Ira Kreitman, Robert J. TI Synergistic Antitumor Activity of Anti-CD25 Recombinant Immunotoxin LMB-2 with Chemotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID HAIRY-CELL LEUKEMIA; ANTI-MESOTHELIN IMMUNOTOXIN; NUDE-MICE BEARING; PHASE-I TRIAL; RFB4(DSFV)-PE38 BL22; PSEUDOMONAS EXOTOXIN; HUMAN CARCINOMA; ANTI-B4-BLOCKED RICIN; MULTIDRUG-RESISTANT; CYTOTOXIC ACTIVITY AB Purpose: Although anti-CD25 recombinant immunotoxin LMB-2 is effective against CD25(+) hairy cell leukemia, activity against more aggressive diseases such as adult T-cell leukemia (ATL) is limited by rapid disease progression between treatment cycles. Our goal was to determine in vivo whether rapid growth of CD25(+) tumor is associated with high levels of tumor interstitial soluble CD25 (sCD25) and whether chemotherapy can reduce tumor sCD25 and synergize with LMB-2. Experimental Design: Tumor xenografts expressing human CD25 were grown in mice, which were then treated with LMB-2 and chemotherapy either alone or in combination, and sCD25 level and antitumor activity were measured. Results: CD25(+) human xenografts growing rapidly in nude mice had intratumoral sCD25 at levels that were between 21- and 2,200 (median 118)-fold higher than in serum, indicating that interstitial sCD25 interacts with LMB-2 in tumors. Intratumoral sCD25 levels were in the range 21 to 157 (median 54) ng/mL without treatment and 0.95 to 6.1 (median 2.6) ng/mL (P < 0.0001) 1 day after gemcitabine administration. CD25(+) xenografts that were too large to regress with LMB-2 alone were minimally responsive to gemcitabine alone but completely regressed with the combination. Ex vivo, different ratios of gemcitabine and LMB-2 were cytotoxic to the CD25(+) tumor cells in an additive, but not synergistic, manner. Conclusions: Gemcitabine is synergistic with LMB-2 in vivo unrelated to improved cytotoxicity. Synergism, therefore, appears to be related to improved distribution of LMB-2 to CD25(+) tumors, and is preceded by decreased sCD25 within the tumor because of chemotherapy. To test the concept of combined treatment clinically, patients with relapsed/refractory ATL are being treated with fludarabine plus cyclophosphamide before LMB-2. Clin Cancer Res; 18(1); 152-60. (C) 2011 AACR. C1 [Singh, Rajat; Zhang, Yujian; Pastan, Ira; Kreitman, Robert J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov OI Singh, Rajat/0000-0002-9542-1929 FU National Cancer Institute, NIH FX This work was supported by the intramural research program from National Cancer Institute, NIH. NR 49 TC 14 Z9 15 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2012 VL 18 IS 1 BP 152 EP 160 DI 10.1158/1078-0432.CCR-11-1839 PG 9 WC Oncology SC Oncology GA 871SV UT WOS:000298758900017 PM 22068660 ER PT J AU Qayum, N Im, J Stratford, MR Bernhard, EJ McKenna, WG Muschel, RJ AF Qayum, Naseer Im, Jaehong Stratford, Michael R. Bernhard, Eric J. McKenna, W. Gillies Muschel, Ruth J. TI Modulation of the Tumor Microvasculature by Phosphoinositide-3 Kinase Inhibition Increases Doxorubicin Delivery In Vivo SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; BLOOD-VESSELS; VASCULAR NORMALIZATION; SIGNALING PATHWAY; NECK-CANCER; NUDE-MICE; ANGIOGENESIS; HYPOXIA; MICROENVIRONMENT; ABNORMALITIES AB Purpose: Because effective drug delivery is often limited by inadequate vasculature within the tumor, the ability to modulate the tumor microenvironment is one strategy that may achieve better drug distribution. We have previously shown that treatment of mice bearing tumors with phosphoinositide-3 kinase (PI3K) inhibitors alters vascular structure in a manner analogous to vascular normalization and results in increased perfusion of the tumor. On the basis of that result, we asked whether inhibition of PI3K would improve chemotherapy delivery. Experimental Design: Mice with xenografts using the cell line SQ20B bearing a hypoxia marker or MMTV-neu transgenic mice with spontaneous breast tumors were treated with the class I PI3K inhibitor GDC-0941. The tumor vasculature was evaluated by Doppler ultrasound, and histology. The delivery of doxorubicin was assessed using whole animal fluorescence, distribution on histologic sections, high-performance liquid chromatography on tumor lysates, and tumor growth delay. Results: Treatment with GDC-0941 led to approximately three-fold increases in perfusion, substantially reduced hypoxia and vascular normalization by histology. Significantly increased amounts of doxorubicin were delivered to the tumors correlating with synergistic tumor growth delay. The GDC-0941 itself had no effect on tumor growth. Conclusion: Inhibition of PI3K led to vascular normalization and improved delivery of a chemotherapeutic agent. This study highlights the importance of the microvascular effects of some novel oncogenic signaling inhibitors and the need to take those changes into account in the design of clinical trials many of which use combinations of chemotherapeutic agents. Clin Cancer Res; 18(1); 161-9. (C) 2011 AACR. C1 [Qayum, Naseer; Im, Jaehong; Stratford, Michael R.; McKenna, W. Gillies; Muschel, Ruth J.] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. [Bernhard, Eric J.] NCI, Radiotherapy Dev Branch, Radiat Res Program, Div Canc Treatment & Diag,NIH, Rockville, MD USA. RP Muschel, RJ (reprint author), Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. EM ruth.muschel@rob.ox.ac.uk FU Medical Research Council-Cancer Research UK; CRUK/EPSRC [NIH RO1 CA73820, NIH PO1 CA75138]; U.S. Department of Defense BCCOE; Cancer Research UK; NIH [RO1 CA73820, PO1 CA75138] FX The study was supported by Medical Research Council-Cancer Research UK grant-in-aid. Oxford Cancer Imaging Centre was supported by CRUK/EPSRC (N. Qayum, J. Im, M.R. Stratford, E. J. Bernhard, W.G. McKenna, and R.J. Muschel), NIH RO1 CA73820 (E.J. Bernhard), and NIH PO1 CA75138 (W.G. McKenna, E.J. Bernhard) and U.S. Department of Defense BCCOE grant (R.J. Muschel). N. Qayum was supported by a Cancer Research UK studentship. NR 39 TC 23 Z9 23 U1 0 U2 8 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 JAN 1 PY 2012 VL 18 IS 1 BP 161 EP 169 DI 10.1158/1078-0432.CCR-11-1413 PG 9 WC Oncology SC Oncology GA 871SV UT WOS:000298758900018 PM 22065081 ER PT J AU Wright, LN Ryscavage, A Merlino, G Yuspa, SH AF Wright, Lisa Nolan Ryscavage, Andrew Merlino, Glenn Yuspa, Stuart H. TI Modeling the Transcriptional Consequences of Epidermal Growth Factor Receptor Ablation in Ras-Initiated Squamous Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; TYROSINE KINASE INHIBITORS; GENE-EXPRESSION PATTERNS; CARCINOMA-CELLS; BREAST-CANCER; IN-VIVO; ERLOTINIB; EGFR; KRAS AB Purpose: Epidermal growth factor receptor (EGFR)-targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. RAS mutations in these tumors are a negative prognostic factor for response, and skin inflammation is an adverse reaction to therapy. We investigated transcriptional and biochemical changes that could account for the confounding effects of RAS activation and inflammation in a squamous tissue. Experimental Design: We carried out gene expression profiling on oncogenic Ras-transformed and wildtype mouse and human keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment and followed leads provided by pathway analysis with biochemical studies. Results: We identified a 25-gene signature specific to the Ras-EGFR ablation interaction and a distinct 19-gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wild-type Ras reduces ontologies favoring cell-cycle control and transcription, whereas oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. Ontologies between chronic EGFR ablation and acute pharmacologic ablation were unique, both with and without Ras activation. p38 alpha is activated in response to abrogation of EGFR signaling under conditions of Ras activation in both mouse and human keratinocytes and in RAS-transformed tumor orthografts of EGFR-ablated mouse keratinocytes. EGFR ablation in the absence of oncogenic Ras revealed Erk and interleukin-1 beta-related pathways. Conclusion: These findings reveal unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy. Clin Cancer Res; 18(1); 170-83. (C) 2011 AACR. C1 [Wright, Lisa Nolan; Ryscavage, Andrew; Merlino, Glenn; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bldg 37,Room 4068, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov FU Center for Cancer Research, National Cancer Institute FX This work was supported by the intramural program of the Center for Cancer Research, National Cancer Institute. NR 49 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2012 VL 18 IS 1 BP 170 EP 183 DI 10.1158/1078-0432.CCR-11-1349 PG 14 WC Oncology SC Oncology GA 871SV UT WOS:000298758900019 PM 22068661 ER PT J AU Schnabel, RB Baccarelli, A Lin, HH Ellinor, PT Benjamin, EJ AF Schnabel, Renate B. Baccarelli, Andrea Lin, Honghuang Ellinor, Patrick T. Benjamin, Emelia J. TI Next Steps in Cardiovascular Disease Genomic Research-Sequencing, Epigenetics, and Transcriptomics SO CLINICAL CHEMISTRY LA English DT Review ID CORONARY-ARTERY-DISEASE; SINGLE-NUCLEOTIDE POLYMORPHISMS; COPY NUMBER VARIANTS; DNA METHYLATION; GENE-EXPRESSION; MYOCARDIAL-INFARCTION; WIDE ASSOCIATION; HEART-FAILURE; CHROMATIN MODIFICATIONS; CARDIAC-HYPERTROPHY AB BACKGROUND: Genomic research in cardiovascular disease (CVD) has progressed rapidly over the last 5 years. In most cases, however, these groundbreaking observations have not yet been accompanied by clinically applicable tools for risk prediction, diagnosis, or therapeutic interventions. CONTENT: We reviewed the scientific literature published in English for novel methods and promising genomic targets that would permit large-scale screening and follow-up of recent genomic findings for CVD. We anticipate that advances in 3 key areas will be critical for the success of these projects. First, exome-centered and whole-genome next-generation sequencing will identify rare and novel genetic variants associated with CVD and its risk factors. Improvements in methods will also greatly advance the field of epigenetics and gene expression in humans. Second, research is increasingly acknowledging that static DNA sequence variation explains only a fraction of the inherited phenotype. Therefore, we expect that multiple epigenetic and gene expression signatures will be related to CVD in experimental and clinical settings. Lever-aging existing large-scale consortia and clinical biobanks in combination with electronic health records holds promise for integrating epidemiological and clinical genomics data. Finally, a systems biology approach will be needed to integrate the accumulated multidimensional data. SUMMARY: Novel methods in sequencing, epigenetics, and transcriptomics, plus unprecedented large-scale cooperative efforts, promise to generate insights into the complexity of CVD. The rapid accumulation and integration of knowledge will shed light on a considerable proportion of the missing heritability for CVD. (C) 2011 American Association for Clinical Chemistry C1 [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Lab Environm Epigenet, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. [Lin, Honghuang; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Lin, Honghuang; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. RP Schnabel, RB (reprint author), Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany. EM schnabelr@gmx.de RI Schnabel, Renate/F-6527-2014; OI Lin, Honghuang/0000-0003-3043-3942; Baccarelli, Andrea/0000-0002-3436-0640; Benjamin, Emelia/0000-0003-4076-2336 FU Evans Center for Interdisciplinary Biomedical Research ARC on "Atrial Fibrillation at Boston University"; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/3-1]; National Institute of Environmental Health Sciences [P30ES000002, R21ES019773, R01ES015172]; NIH [1R01HL092577, 5R21DA027021, 5R01HL104156, 1K24HL105780, 1RC1HL101056, 1R01HL102214, 1R01AG028321] FX Evans Center for Interdisciplinary Biomedical Research ARC on "Atrial Fibrillation at Boston University" (http://www.bumc.bu.edu/evanscenteribr/). R. Schnabel, Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program SCHN 1149/3-1; A. Baccarelli, National Institute of Environmental Health Sciences grants P30ES000002, R21ES019773, and R01ES015172; P. Ellinor, NIH grants 1R01HL092577, 5R21DA027021, 5R01HL104156, and 1K24HL105780; E. Benjamin, NIH grants 1R01HL092577, 1RC1HL101056, 1R01HL102214, and 1R01AG028321. NR 100 TC 28 Z9 29 U1 1 U2 18 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JAN PY 2012 VL 58 IS 1 BP 113 EP 126 DI 10.1373/clinchem.2011.170423 PG 14 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 875RQ UT WOS:000299052700020 PM 22100807 ER PT J AU Kwong, PD Mascola, JR Nabel, GJ AF Kwong, Peter D. Mascola, John R. Nabel, Gary J. TI Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1 SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; RECOMBINANT GLYCOPROTEIN-120 VACCINE; GP120 ENVELOPE GLYCOPROTEIN; CROSS-CLADE NEUTRALIZATION; CORECEPTOR BINDING-SITE; STRUCTURAL BASIS; POTENT NEUTRALIZATION; INFECTED INDIVIDUALS; CRYSTAL-STRUCTURE AB The development of a highly effective AIDS vaccine will likely depend on success in designing immunogens that elicit broadly neutralizing antibodies to naturally circulating strains of HIV-1. Although the antibodies induced after natural infection with HIV-1 are often directed to strain-specific or nonneutralizing determinants, it is now evident that 10%-25% of HIV-infected individuals generate neutralizing antibody responses of considerable breadth. In the past, only four broadly neutralizing monoclonal antibodies had been defined, but more than a dozen monoclonal antibodies of substantial breadth have more recently been isolated. An understanding of their recognition sites, the structural basis of their interaction with the HIV Env, and their development pathways provides new opportunities to design vaccine candidates that will elicit broadly protective antibodies against this virus. C1 [Kwong, Peter D.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov NR 102 TC 1 Z9 1 U1 0 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD JAN PY 2012 VL 4 IS 1 AR a007278 DI 10.1101/cshperspect.a007278 PG 16 WC Cell Biology SC Cell Biology GA 877GO UT WOS:000299165700005 ER PT J AU Shui, GH Bendt, AK Jappar, IA Lim, HM Laneelle, M Herve, M Via, LE Chua, GH Bratschi, MW Rahim, SZZ Michelle, ALT Hwang, SH Lee, JS Eum, SY Kwak, HK Daffe, M Dartois, V Michel, G Barry, CE Wenk, MR AF Shui, Guanghou Bendt, Anne K. Jappar, Ignasius A. Lim, Hui Ming Laneelle, Marie Herve, Maxime Via, Laura E. Chua, Gek Huey Bratschi, Martin W. Rahim, Siti Zarina Zainul Michelle, Ang Lay Teng Hwang, Soo-Hee Lee, Jong-Soek Eum, Seok-Yong Kwak, Hyun-Kyung Daffe, Mamadou Dartois, Veronique Michel, Gerd Barry, Clifton E., III Wenk, Markus R. TI Mycolic acids as diagnostic markers for tuberculosis case detection in humans and drug efficacy in mice SO EMBO MOLECULAR MEDICINE LA English DT Article DE diagnostic marker; lipidomics; mass spectrometry; Mycobacterium tuberculosis; mycolic acids ID REAL-TIME PCR; MYCOBACTERIUM-TUBERCULOSIS; LIPIDS; IDENTIFICATION; CHEMOTHERAPY; VIRULENCE; SAMPLES AB Mycolic acids are attractive diagnostic markers for tuberculosis (TB) infection because they are bacteria-derived, contain information about bacterial species, modulate hostpathogen interactions and are chemically inert. Here, we present a novel approach based on mass spectrometry. Quantification of specific precursor fragment transitions of approximately 2000 individual mycolic acids (MAs) resulted in high analytical sensitivity and specificity. We next used this tool in a retrospective casecontrol study of patients with pulmonary TB with varying disease burdens from South Korea, Vietnam, Uganda and South Africa. MAs were extracted from small volume sputum (200 mu l) and analysed without the requirement for derivatization. Infected patients (70, 19 of whom were HIV+) could be separated from controls (40, 20 of whom were HIV+) with a sensitivity and specificity of 94 and 93%, respectively. Furthermore, we quantified MA species in lung tissue of TB-infected mice and demonstrated effective clearance of MA levels following curative rifampicin treatment. Thus, our results demonstrate for the first time the feasibility and clinical relevance of direct detection of mycobacterial lipids as biomarkers of TB infection. C1 [Shui, Guanghou; Bendt, Anne K.; Jappar, Ignasius A.; Lim, Hui Ming; Chua, Gek Huey; Bratschi, Martin W.; Wenk, Markus R.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117595, Singapore. [Laneelle, Marie; Daffe, Mamadou] IPBS UMR, Dept Mecanismes Mol Infect Mycobacteriennes, Toulouse, France. [Herve, Maxime; Dartois, Veronique] Novartis Inst Trop Dis, Singapore, Singapore. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bratschi, Martin W.; Wenk, Markus R.] Univ Basel, Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Rahim, Siti Zarina Zainul; Michelle, Ang Lay Teng] Natl Univ Singapore, Dept Microbiol, Singapore 117595, Singapore. [Hwang, Soo-Hee] Natl Masan TB Hosp, Masan, South Korea. [Lee, Jong-Soek; Eum, Seok-Yong; Kwak, Hyun-Kyung] Int TB Res Ctr, Masan, South Korea. [Dartois, Veronique; Wenk, Markus R.] Natl Univ Singapore, Dept Biol Sci, Singapore 117595, Singapore. [Michel, Gerd] Fdn Innovat New Diagnost FIND, Geneva, Switzerland. RP Shui, GH (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117595, Singapore. EM guanghou_shui@nuhs.edu.sg; markus_wenk@nuhs.edu.sg RI Barry, III, Clifton/H-3839-2012; Bratschi, Martin/A-4386-2013; Wenk, Markus/D-1441-2014; OI Bratschi, Martin/0000-0003-0825-1587; Via, Laura/0000-0001-6074-9521 FU National Research Foundation [2007-04]; Academic Research Fund [R-183-000-160-112]; Biomedical Research Council of Singapore [R-183-000-211-305]; National Medical Research Council [R-183-000-224-213]; NIH, NIAID; European Community [HEALTH-F4-2010-241587] FX We thank Sindhu Ravindranand and Hui Chien Tay (NITD) for help with animal experiments and Xueli Guan (NUS) for technical assistance with figures. We are grateful to Kenneth Olivier (NIH) for providing NTM specimens. Special thanks are also due to Eloise Valli and Catharina Boehme (FIND) for their excellent help in managing the clinical samples from the FIND repository. This work was supported by the National Research Foundation (under CRP Award No. 2007-04), the Academic Research Fund (R-183-000-160-112), the Biomedical Research Council of Singapore (R-183-000-211-305), the National Medical Research Council (R-183-000-224-213) and partly by the Intramural Research Program of the NIH, NIAID. Work in the laboratory of MD was supported in part by a grant (SysteMTb HEALTH-F4-2010-241587) from the European Community. NR 23 TC 18 Z9 18 U1 2 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-4676 J9 EMBO MOL MED JI EMBO Mol. Med. PD JAN PY 2012 VL 4 IS 1 BP 27 EP 37 DI 10.1002/emmm.201100185 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 870MB UT WOS:000298672300004 PM 22147526 ER PT J AU Grallert, H Dupuis, J Bis, JC Dehghan, A Barbalic, M Baumert, J Lu, C Smith, NL Uitterlinden, AG Roberts, R Khuseyinova, N Schnabel, RB Rice, KM Rivadeneira, F Hoogeveen, RC Fontes, JD Meisinger, C Keaney, JF Lemaitre, R Aulchenko, YS Vasan, RS Ellis, S Hazen, SL van Duijn, CM Nelson, JJ Marz, W Schunkert, H McPherson, RM Stirnadel-Farrant, HA Psaty, BM Gieger, C Siscovick, D Hofman, A Illig, T Cushman, M Yamamoto, JF Rotter, JI Larson, MG Stewart, AFR Boerwinkle, E Witteman, JCM Tracy, RP Koenig, W Benjamin, EJ Ballantyne, CM AF Grallert, Harald Dupuis, Josee Bis, Joshua C. Dehghan, Abbas Barbalic, Maja Baumert, Jens Lu, Chen Smith, Nicholas L. Uitterlinden, Andre G. Roberts, Robert Khuseyinova, Natalie Schnabel, Renate B. Rice, Kenneth M. Rivadeneira, Fernando Hoogeveen, Ron C. Fontes, Joao Daniel Meisinger, Christa Keaney, John F., Jr. Lemaitre, Rozenn Aulchenko, Yurii S. Vasan, Ramachandran S. Ellis, Stephen Hazen, Stanley L. van Duijn, Cornelia M. Nelson, Jeanenne J. Maerz, Winfried Schunkert, Heribert McPherson, Ruth M. Stirnadel-Farrant, Heide A. Psaty, Bruce M. Gieger, Christian Siscovick, David Hofman, Albert Illig, Thomas Cushman, Mary Yamamoto, Jennifer F. Rotter, Jerome I. Larson, Martin G. Stewart, Alexandre F. R. Boerwinkle, Eric Witteman, Jacqueline C. M. Tracy, Russell P. Koenig, Wolfgang Benjamin, Emelia J. Ballantyne, Christie M. TI Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies SO EUROPEAN HEART JOURNAL LA English DT Article DE Genome-wide association; Inflammation; Lipoprotein-associated phospholipase A2 ID ACTIVATING-FACTOR-ACETYLHYDROLASE; ARTERY-DISEASE; ATHEROSCLEROTIC PLAQUE; CARDIOVASCULAR-DISEASE; A(2); RISK; CHOLESTEROL; VARIANTS; RECEPTOR; EPIDEMIOLOGY AB Aims Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Methods and results In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 x 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 x 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. Conclusion Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels. C1 [Grallert, Harald; Baumert, Jens; Meisinger, Christa; Gieger, Christian; Illig, Thomas] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Dupuis, Josee; Schnabel, Renate B.; Fontes, Joao Daniel; Vasan, Ramachandran S.; Yamamoto, Jennifer F.; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Dupuis, Josee; Lu, Chen] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bis, Joshua C.; Lemaitre, Rozenn] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Lemaitre, Rozenn; Psaty, Bruce M.; Siscovick, David] Univ Washington, Dept Med, Seattle, WA USA. [Dehghan, Abbas; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; van Duijn, Cornelia M.; Hofman, Albert; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Smith, Nicholas L.; Psaty, Bruce M.; Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Roberts, Robert; McPherson, Ruth M.; Stewart, Alexandre F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Khuseyinova, Natalie; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hoogeveen, Ron C.; Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Div Atherosclerosis & Vasc Med, Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Fontes, Joao Daniel; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Cardiol, Boston, MA 02118 USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA USA. [Ellis, Stephen; Hazen, Stanley L.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Nelson, Jeanenne J.] GlaxoSmithKline Inc, Worldwide Epidemiol, Res Triangle Pk, NC USA. [Maerz, Winfried] Synlab Ctr Lab Diagnost Heidelberg, Heidelberg, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Maerz, Winfried] Univ Heidelberg, Med Fac Mannheim, Inst Publ Hlth Social & Prevent Med, Heidelberg, Germany. [Schunkert, Heribert] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Stirnadel-Farrant, Heide A.] GlaxoSmithKline Inc, Worldwide Epidemiol, Harlow, Essex, England. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Illig, Thomas] Univ Munich, Inst Med Data Management Biometr & Epidemiol, Chair Epidemiol, Munich, Germany. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Dupuis, Josee; Schnabel, Renate B.; Fontes, Joao Daniel; Vasan, Ramachandran S.; Yamamoto, Jennifer F.; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. RP Koenig, W (reprint author), German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. EM wolfgang.koenig@uniklinik-ulm.de; cmb@bcm.tmc.edu RI Stewart, Alexandre/A-5677-2011; Rice, Kenneth/A-4150-2013; Grallert, Harald/B-3424-2013; Aulchenko, Yurii/M-8270-2013; Meisinger, Christine/B-5358-2014; Schnabel, Renate/F-6527-2014; Lu, Chen/D-8514-2015; Rivadeneira, Fernando/O-5385-2015; OI Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336; Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Dehghan, Abbas/0000-0001-6403-016X; Rice, Kenneth/0000-0001-5779-4495; Aulchenko, Yurii/0000-0002-7899-1575; Rivadeneira, Fernando/0000-0001-9435-9441; Larson, Martin/0000-0002-9631-1254; Stewart, Alexandre/0000-0003-2673-9164; Ramachandran, Vasan/0000-0001-7357-5970 FU Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research; National Institute of Neurological Disorders and Stroke; Cedars-Sinai Board of Governors' Chair in Medical Genetics; National Center for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; GlaxoSmithKline; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc., for genotyping services [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/1-1]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly; Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organization for Scientific Research (NWO) [175.010.2005.011, 911.03.012, 918-76-619]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/NWO [050-060-810]; Helmholtz Zentrum Munchen; German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFNPlus) [01GS0834]; University of Ulm; Munich Center of Health Sciences (MC Health); diaDexus; NGFN; CADnet BMBF; [HL64753]; [HL076784]; [AG028321] FX The authors thank the staff and participants of the individual studies for their important contributions, and acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in the development and support of this manuscript. CHARGE members include NHLBI's ARIC Study, Cardiovascular Health Study, and Framingham Heart Study; NIA's Iceland Age, Gene/Environment Susceptibility (AGES) Study; and the Netherland's Rotterdam Study.; The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, 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 contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by the Cedars-Sinai Board of Governors' Chair in Medical Genetics (J.L.R.), 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. Lp-PLA2 measurements were funded by a grant from GlaxoSmithKline. The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract number N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract number N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project; grants HL64753, HL076784, and AG028321 (E.J.B.); and Deutsche Forschungsgemeinschaft (German Research Foundation) Research Fellowship SCHN 1149/1-1 (R.B.S.). Lp-PLA2 activity measurements were provided by GlaxoSmithKline and mass measurements by diaDexus at no cost to the FHS. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE2) (014-93-015). This study was supported by the Netherlands Genomics Initiative (NGI)/NWO project number 050-060-810. Abbas Dehghan is supported by a grant from NWO (Vici, 918-76-619). The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF).; Part of this work was financed bythe German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of LMU innovative.; Lp-PLA2 activity measurements were provided by GlaxoSmithKline and mass measurements by diaDexus at no cost to the FHS. R.R. has been consultant to Cumberland Pharmaceuticals and Celera. R.C.H. has received research/grant support from diaDexus for Lp-PLA2 work in ARIC. J.J.N. is an employee of GlaxoSmithKline. H. S. has received research grants from the EU, project Cardiogenics; NGFN, project Atherogenomics; and CADnet BMBF. H.A.S.-F. is an employee of GlaxoSmithKline. B.M.P. serves on a data and safety monitoring board for a device clinical trial funded by Zoll Lifecor. M. C. has been consultant for GlaxoSmithKline in relation to Lp-PLA2 and had grant funding from them for same. R.P.T.'s laboratory has received support from GlaxoSmithKline in the form of free assay kits for Lp-PLA2 measurements. W.K. has received honoraria for lectures from diaDexus and GlaxoSmithKline, and is a member of the Steering Committee of the GlaxoSmithKline-sponsored STABILITY and SOLID trials. C.M.B. has received research/grant support from GlaxoSmithKline and diaDexus, and consulting honoraria from GlaxoSmithKline. All other authors have no conflict of interest to declare. NR 37 TC 47 Z9 51 U1 0 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JAN PY 2012 VL 33 IS 2 BP 238 EP 251 DI 10.1093/eurheartj/ehr372 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 879RU UT WOS:000299350500020 PM 22003152 ER PT J AU Semba, RD Ang, A Talegawkar, S Crasto, C Dalal, M Jardack, P Traber, MG Ferrucci, L Arab, L AF Semba, R. D. Ang, A. Talegawkar, S. Crasto, C. Dalal, M. Jardack, P. Traber, M. G. Ferrucci, L. Arab, L. TI Dietary intake associated with serum versus urinary carboxymethyl-lysine, a major advanced glycation end product, in adults: the Energetics Study SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE advanced glycation end products; carboxymethyl-lysine; diet; 24-h dietary recall; food ID CARDIOVASCULAR-DISEASE MORTALITY; LIQUID-CHROMATOGRAPHY; MAILLARD REACTION; HUMAN HEALTH; ENDPRODUCTS; WOMEN; FOOD; GLYCOTOXINS; SYSTEMS; OBESE AB Background/Objectives: Advanced glycation end products (AGEs) are implicated in the pathogenesis of atherosclerosis, diabetes and kidney disease. The objective was to describe dietary intake, the dominant source of exposure to AGEs, with carboxymethyl-lysine (CML), a major AGE, in serum and urine, respectively. Subjects/Methods: Serum and urinary CML were measured in 261 adults, aged 21-69 years, and compared with diet as assessed by six separate 24-h dietary recalls. Results: Median (25th, 75th percentile) serum and urinary CML concentrations were 686 (598, 803) mu g/l and 1023 (812, 1238) mu g/gm creatinine. There was no correlation between serum and urinary CML (r = -0.02, P = 0.78). Serum CML was positively correlated with intake of soy, fruit juice, cold breakfast cereal, non-fat milk, whole grains, fruit, non-starchy vegetables and legumes, and negatively correlated with intake of red meat. Intake of fast food was not significantly correlated with serum CML. Urinary CML was positively correlated with intake of starchy vegetables, whole grains, sweets, nuts/seeds and chicken, and negatively correlated with intake of fast foods. Intake of AGE-rich foods such as fried chicken, French fries, bacon/sausage and crispy snacks were not significantly correlated with serum or urinary CML, except for a significant negative correlation between fried chicken and serum CML. Conclusions: These findings suggest that the high consumption of foods considered high in CML is not a major determinant of either serum or urinary CML. Further work is needed to understand the relationship of AGEs in blood and urine with the metabolism of dietary AGEs. European Journal of Clinical Nutrition (2012) 66, 3-9; doi:10.1038/ejcn.2011.139; published online 27 July 2011 C1 [Semba, R. D.; Crasto, C.; Dalal, M.] Johns Hopkins Univ, Dept Ophthalmol, Sch Med, Baltimore, MD 21287 USA. [Ang, A.; Jardack, P.; Arab, L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Epidemiol, Los Angeles, CA 90095 USA. [Ang, A.; Jardack, P.; Arab, L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Talegawkar, S.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, Baltimore, MD USA. [Traber, M. G.] Oregon State Univ, Dept Nutr & Exercise Sci, Linus Pauling Inst, Corvallis, OR 97331 USA. [Ferrucci, L.] NIA, Longitudinal Studies Branch, Div Clin Res, NIH, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Dept Ophthalmol, Sch Med, Smith Bldg,M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu OI Traber, Maret/0000-0002-2892-4024 FU National Institutes of Health [R01 CA105048, R01 AG027012, R01 AG029148, R01 HL094507, R37 AG019905]; National Institute on Aging, NIH FX This study was supported by the National Institutes of Health Grants R01 CA105048, R01 AG027012, R01 AG029148, R01 HL094507 and R37 AG019905, and the Intramural Research Program, National Institute on Aging, NIH. NR 28 TC 20 Z9 20 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JAN PY 2012 VL 66 IS 1 BP 3 EP 9 DI 10.1038/ejcn.2011.139 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 876GE UT WOS:000299094800002 PM 21792213 ER PT J AU Anderson, AL Harris, TB Tylavsky, FA Perry, SE Houston, DK Lee, JS Kanaya, AM Sahyoun, NR AF Anderson, A. L. Harris, T. B. Tylavsky, F. A. Perry, S. E. Houston, D. K. Lee, J. S. Kanaya, A. M. Sahyoun, N. R. CA Hlth ABC Study TI Dietary patterns, insulin sensitivity and inflammation in older adults SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE diet; dietary patterns; insulin sensitivity; inflammation; older adults ID LIFE-STYLE INTERVENTION; WAIST CIRCUMFERENCE; METABOLIC SYNDROME; BODY-MASS; RESISTANCE; GENE; GLUCOSE; MARKERS; INDEX; WOMEN AB Background/Objectives: Several studies have linked dietary patterns to insulin sensitivity and systemic inflammation, which affect risk of multiple chronic diseases. The purpose of this study was to investigate the dietary patterns of a cohort of older adults, and to examine relationships of dietary patterns with markers of insulin sensitivity and systemic inflammation. Subjects/Methods: The Health, Aging and Body Composition (Health ABC) Study is a prospective cohort study of 3075 older adults. In Health ABC, multiple indicators of glucose metabolism and systemic inflammation were assessed. Food intake was estimated with a modified Block food frequency questionnaire. In this study, dietary patterns of 1751 participants with complete data were derived by cluster analysis. Results: Six clusters were identified, including a 'healthy foods' cluster, characterized by higher intake of low-fat dairy products, fruit, whole grains, poultry, fish and vegetables. In the main analysis, the 'healthy foods' cluster had significantly lower fasting insulin and homeostasis model assessment of insulin resistance values than the 'breakfast cereal' and 'high-fat dairy products' clusters, and lower fasting glucose than the 'high-fat dairy products' cluster (p <= 0.05). No differences were found in 2-h glucose. With respect to inflammation, the 'healthy foods' cluster had lower interleukin-6 than the 'sweets and desserts' and 'high-fat dairy products' clusters, and no differences were seen in C-reactive protein or tumor necrosis factor-a. Conclusions: A dietary pattern high in low-fat dairy products, fruit, whole grains, poultry, fish and vegetables may be associated with greater insulin sensitivity and lower systemic inflammation in older adults. European Journal of Clinical Nutrition (2012) 66, 18-24; doi:10.1038/ejcn.2011.162; published online 14 September 2011 C1 [Anderson, A. L.; Sahyoun, N. R.] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Harris, T. B.] NIA, NIH, Bethesda, MD 20892 USA. [Tylavsky, F. A.] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Perry, S. E.] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Houston, D. K.] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Lee, J. S.] Univ Georgia, Dept Foods & Nutr, Athens, GA 30602 USA. [Kanaya, A. M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Anderson, AL (reprint author), Univ Maryland, Dept Nutr & Food Sci, 0112 Skinner Bldg, College Pk, MD 20742 USA. EM amylouiseanderson@yahoo.com RI Sahyoun, Nadine/G-2608-2011 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA/NIH FX The Health ABC Study was supported by the National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103 and N01-AG-6-2106. This research was supported in part by the Intramural Research Program of NIA/NIH. NR 21 TC 28 Z9 29 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JAN PY 2012 VL 66 IS 1 BP 18 EP 24 DI 10.1038/ejcn.2011.162 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 876GE UT WOS:000299094800004 PM 21915138 ER PT J AU Satyanarayana, A Klarmann, KD Gavrilova, O Keller, JR AF Satyanarayana, Ande Klarmann, Kimberly D. Gavrilova, Oksana Keller, Jonathan R. TI Ablation of the transcriptional regulator Id1 enhances energy expenditure, increases insulin sensitivity, and protects against age and diet induced insulin resistance, and hepatosteatosis SO FASEB JOURNAL LA English DT Article DE PGC1a; UCP1; adipogenesis; brown adipose tissue; thermogenesis ID WHITE ADIPOSE-TISSUE; ADIPOCYTE DIFFERENTIATION; IN-VIVO; MELANOCORTIN SYSTEM; HEPATIC STEATOSIS; INDUCED OBESITY; LEAN PHENOTYPE; DEFICIENT MICE; KNOCKOUT MICE; BROWN FAT AB Obesity is a major health concern that contributes to the development of diabetes, hyperlipidemia, coronary artery disease, and cancer. Id proteins are helix-loop-helix transcription factors that regulate the proliferation and differentiation of cells from multiple tissues, including adipocytes. We screened mouse tissues for the expression of Id1 and found that Id1 protein is highly expressed in brown adipose tissue (BAT) and white adipose tissue (WAT), suggesting a role for Id1 in adipogenesis and cell metabolism. Id1(-/-) mice are viable but show a significant reduction in fat mass (P<0.005) over the life of the animal that was not due to decreased number of adipocytes. Analysis of Id1(-/-) mice revealed higher energy expenditure, increased lipolysis, and fatty acid oxidation, resulting in reduced triglyceride accumulation in WAT compared to Id1(+/+) mice. Serum levels of triglycerides (193.9 +/- 32.2 vs. 86.5 +/- 33.8, P<0.0005), cholesterol (189.4 +/- 33.8 vs. 110.6 +/- 8.23, P<0.0005) and leptin (1263 +/- 835 vs. 222 +/- 260, P<0.005) were significantly lower in aged Id1(-/-) mice compared to Id1(+/+) mice. Id1-deficient mice have higher resting (P<0.005) and total (P<0.05) O-2 consumption and lower respiratory exchange ratio (P<0.005), confirming that Id1(-/-) mice use a higher proportion of lipid as an energy source for the increased energy expenditure. The expression of PGC1 alpha and UCP1 were 2- to 3-fold up-regulated in Id1(-/-) BAT, suggesting that loss of Id1 increases thermogenesis. As a consequence of higher energy expenditure and reduced fat mass, Id1(-/-) mice displayed enhanced insulin sensitivity. Id1 deficiency protected mice against age-and high-fat-diet-induced adiposity, insulin resistance, and hepatosteatosis. Our findings suggest that Id1 plays a critical role in the regulation of energy homeostasis and could be a potential target in the treatment of insulin resistance and fatty liver disease.-Satyanarayana, A., Klarmann, K. D., Gavrilova, 1 O., Keller, J. R. Ablation of the transcriptional regulator Id1 enhances energy expenditure, increases insulin sensitivity, and protects against age and diet-induced insulin resistance and hepatosteatosis. FASEB J. 26, 309-323 (2012). www.fasebj.org C1 [Satyanarayana, Ande; Klarmann, Kimberly D.; Keller, Jonathan R.] NCI, Basic Res Program, SAIC Frederick, Ctr Canc Res, Frederick, MD 21701 USA. [Gavrilova, Oksana] Natl Inst Diabet Digest & Kidney Dis, Mouse Metab Core Lab, NIH, Bethesda, MD USA. RP Keller, JR (reprint author), Inst Frederick, Basic Res Program, SAIC Frederick, Ctr Canc Res, Bldg 560-12-03,1050 Boyles St, Frederick, MD 21702 USA. EM kellerjo@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors thank Dr. Robert Benezra (Memorial Sloan-Kettering Cancer Center, New York, NY, USA) for providing the Id1-knockout mice. The authors thank Steven Stull and Juanita Mercado for animal care; Tatyana Chanturiya and William Jou for technical help; and Roberta Smith and the Pathology/Histotechnology Laboratory, NCI-Frederick, for tissue sectioning and staining. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The authors declare no competing financial interests. NR 75 TC 17 Z9 17 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JAN PY 2012 VL 26 IS 1 BP 309 EP 323 DI 10.1096/fj.11-190892 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 877SF UT WOS:000299202200031 PM 21990377 ER PT J AU Csoka, B Selmeczy, Z Koscso, B Nemeth, ZH Pacher, P Murray, PJ Kepka-Lenhart, D Morris, SM Gause, WC Leibovich, SJ Hasko, G AF Csoka, Balazs Selmeczy, Zsolt Koscso, Balazs Nemeth, Zoltan H. Pacher, Pal Murray, Peter J. Kepka-Lenhart, Diane Morris, Sidney M., Jr. Gause, William C. Leibovich, S. Joseph Hasko, Gyoergy TI Adenosine promotes alternative macrophage activation via A(2A) and A(2B) receptors SO FASEB JOURNAL LA English DT Article DE cancer; helminth infection; inflammation; wound healing; obesity ID HUMAN MAST-CELLS; C/EBP-BETA; IL-10 PRODUCTION; GENE-EXPRESSION; IFN-GAMMA; TNF-ALPHA; ARGINASE; MECHANISM; INFLAMMATION; INFECTIONS AB Adenosine has been implicated in suppressing the proinflammatory responses of classically activated macrophages induced by Th1 cytokines. Alternative macrophage activation is induced by the Th2 cytokines interleukin (IL)-4 and IL-13; however, the role of adenosine in governing alternative macrophage activation is unknown. We show here that adenosine treatment of IL-4- or IL-13-activated macrophages augments the expression of alternative macrophage markers arginase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and macrophage galactose-type C-type lectin-1. The stimulatory effect of adenosine required primarily A(2B) receptors because the nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased both arginase activity (EC50 = 261.8 nM) and TIMP-1 production (EC50 = 80.67 nM), and both pharmacologic and genetic blockade of A(2B) receptors prevented the effect of NECA. A(2A) receptors also contributed to the adenosine augmentation of IL-4-induced TIMP-1 release, as both adenosine and NECA were less efficacious in augmenting TIMP-1 release by A(2A) receptor-deficient than control macrophages. Of the transcription factors known to drive alternative macrophage activation, CCAAT-enhancer-binding protein beta was required, while cAMP response element-binding protein and signal transducer and activator of transcription 6 were dispensable in mediating the effect of adenosine. We propose that adenosine receptor activation suppresses inflammation and promotes tissue restitution, in part, by promoting alternative macrophage activation.-Csoka, B., Selmeczy, Z., Koscso, B., Nemeth, Z. H., Pacher, P., Murray, P. J., Kepka-Lenhart, D., Morris S. M., Jr., Gause, W. C., Leibovich, S. J., Hasko, G. Adenosine promotes alternative macrophage activation via A(2A) and A(2B) receptors. FASEB J. 26, 376-386 (2012). www.fasebj.org C1 [Csoka, Balazs; Selmeczy, Zsolt; Koscso, Balazs; Nemeth, Zoltan H.; Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Gause, William C.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Newark, NJ 07103 USA. [Gause, William C.] Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ 07103 USA. [Leibovich, S. Joseph] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. [Nemeth, Zoltan H.] Morristown Mem Hosp, Dept Surg, Morristown, NJ USA. [Pacher, Pal] NIAAA, Bethesda, MD 90034 USA. [Murray, Peter J.] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Murray, Peter J.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Kepka-Lenhart, Diane; Morris, Sidney M., Jr.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Hasko, Gyoergy] Univ Debrecen, Dept Med Chem, Med & Hlth Sci Ctr, Debrecen, Hungary. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008; Morris, Sidney/I-3440-2015; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU U.S. National Institutes of Health (NIH) [R01GM66189, R01GM57384]; NIH, National Institute on Alcohol Abuse and Alcoholism; Hungarian Research Fund [CK 78275] FX This work was supported by U.S. National Institutes of Health (NIH) grants R01GM66189 and R01GM57384, and the NIH Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, as well as the Hungarian Research Fund (CK 78275). The authors declare no competing financial interests. NR 57 TC 76 Z9 78 U1 1 U2 13 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JAN PY 2012 VL 26 IS 1 BP 376 EP 386 DI 10.1096/fj.11-190934 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 877SF UT WOS:000299202200037 PM 21926236 ER PT J AU Shi, J Ju, M Abramowitz, J Large, WA Birnbaumer, L Albert, AP AF Shi, Jian Ju, Min Abramowitz, Joel Large, William A. Birnbaumer, Lutz Albert, Anthony P. TI TRPC1 proteins confer PKC and phosphoinositol activation on native heteromeric TRPC1/C5 channels in vascular smooth muscle: comparative study of wild-type and TRPC1(-/-) mice SO FASEB JOURNAL LA English DT Article DE Ca2+; signaling; hypertension; transgenic ID OPERATED CA2+ CHANNELS; CA2+-PERMEABLE CATION CHANNEL; GLOMERULAR MESANGIAL CELLS; CORONARY-ARTERY MYOCYTES; KINASE-C; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; ANGIOTENSIN-II; CALCIUM-ENTRY; DESENSITIZATION; DIACYLGLYCEROL AB Ca2+-permeable cation channels consisting of canonical transient receptor potential 1 (TRPC1) proteins mediate Ca2+ influx pathways in vascular smooth muscle cells (VSMCs), which regulate physiological and pathological functions. We investigated properties conferred by TRPC1 proteins to native single TRPC channels in acutely isolated mesenteric artery VSMCs from wildtype (WT) and TRPC1-deficient (TRPC1(-/-)) mice using patch-clamp techniques. In WT VSMCs, the intracellular Ca2+ store-depleting agents cyclopiazonic acid (CPA) and 1,2-bis-(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM) both evoked channel currents, which had unitary conductances of similar to 2 pS. In TRPC1(-/-) VSMCs, CPA-induced channel currents had 3 subconductance states of 14, 32, and 53 pS. Passive depletion of intracellular Ca2+ stores activated whole-cell cation currents in WT but not TRPC1(-/-) VSMCs. Differential blocking actions of anti-TRPC antibodies and coimmunoprecipitation studies revealed that CPA induced heteromeric TRPC1/C5 channels in WT VSMCs and TRPC5 channels in TRPC1(-/-) VSMCs. CPA-evoked TRPC1/C5 channel activity was prevented by the protein kinase C (PKC) inhibitor chelerythrine. In addition, the PKC activator phorbol 12,13-dibutyrate (PDBu), a PKC catalytic subunit, and phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidylinositol-3,4,5-trisphosphate (PIP3) activated TRPC1/C5 channel activity, which was prevented by chelerythrine. In contrast, CPA-evoked TRPC5 channel activity was potentiated by chelerythrine, and inhibited by PDBu, PIP2, and PIP3. TRPC5 channels in TRPC1(-/-) VSMCs were activated by increasing intracellular Ca2+ concentrations ([Ca2+](i)), whereas increasing [Ca2+](i) had no effect in WT VSMCs. We conclude that agents that deplete intracellular Ca2+ stores activate native heteromeric TRPC1/C5 channels in VSMCs, and that TRPC1 subunits are important in determining unitary conductance and conferring channel activation by PKC, PIP2, and PIP3.-Shi, J., Ju, M., Abramowitz, J., Large, W. A., Birnbaumer, L., Albert, A. P. TRPC1 proteins confer PKC and phosphoinositol activation on native heteromeric TRPC1/C5 channels in vascular smooth muscle: comparative study of wild-type and TRPC1(-/-) mice. FASEB J. 26, 409-419 (2012). www.fasebj.org C1 [Shi, Jian; Ju, Min; Large, William A.; Albert, Anthony P.] Univ London, Div Biomed Sci, London SW17 0RE, England. [Abramowitz, Joel; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC USA. RP Albert, AP (reprint author), Univ London, Div Biomed Sci, London SW17 0RE, England. EM aalbert@sgul.ac.uk RI Abramowitz, Joel/A-2620-2015 FU British Heart Foundation FX This work was supported by the British Heart Foundation. NR 47 TC 23 Z9 28 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JAN PY 2012 VL 26 IS 1 BP 409 EP 419 DI 10.1096/fj.11-185611 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 877SF UT WOS:000299202200040 PM 21968068 ER PT J AU He, AB Shen, XH Ma, Q Cao, JJ von Gise, A Zhou, PZ Wang, G Marquez, VE Orkin, SH Pu, WT AF He, Aibin Shen, Xiaohua Ma, Qing Cao, Jingjing von Gise, Alexander Zhou, Pingzhu Wang, Gang Marquez, Victor E. Orkin, Stuart H. Pu, William T. TI PRC2 directly methylates GATA4 and represses its transcriptional activity SO GENES & DEVELOPMENT LA English DT Article DE epigenetics; heart development; polycomb complex; transcriptional regulation ID HISTONE METHYLTRANSFERASE ACTIVITY; H3 LYSINE-27 METHYLATION; STEM-CELLS; POLYCOMB; EZH2; DIFFERENTIATION; ACETYLATION; PROTEIN; GENOME; HEART AB Polycomb-repressive complex 2 (PRC2) promotes tissue-specific differentiation by depositing trimethylated histone H3 Lys 27 (H3K27me3) epigenetic marks to silence ectopic gene expression programs. Here, we show that EZH2, the catalytic subunit of PRC2, is required for cardiac morphogenesis. Both in vitro and in fetal hearts, EZH2 interacted with cardiac transcription factor GATA4 and directly methylated it at Lys 299. PRC2 methylation of GATA4 attenuated its transcriptional activity by reducing its interaction with and acetylation by p300. Our results reveal a new mechanism of PRC2-mediated transcriptional repression in which PRC2 methylates a transcription factor to inhibit its transcriptional activity. C1 [He, Aibin; Ma, Qing; Cao, Jingjing; von Gise, Alexander; Zhou, Pingzhu; Wang, Gang; Pu, William T.] Harvard Univ, Sch Med, Dept Cardiol, Childrens Hosp Boston, Boston, MA 02115 USA. [He, Aibin; Shen, Xiaohua; Ma, Qing; Cao, Jingjing; von Gise, Alexander; Zhou, Pingzhu; Wang, Gang; Orkin, Stuart H.; Pu, William T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Shen, Xiaohua; Orkin, Stuart H.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst,Childrens Hosp Boston, Boston, MA 02115 USA. [Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Pu, WT (reprint author), Harvard Univ, Sch Med, Dept Cardiol, Childrens Hosp Boston, Boston, MA 02115 USA. EM wpu@enders.tch.harvard.edu RI Zhou, Pingzhu/J-2809-2014 FU National Institutes of Health (NIH) [U01HL098166, R01HL095712]; American Heart Association; NIDDK; NIH, National Cancer Institute, and Center for Cancer Research FX This work was supported by funding from the National Institutes of Health (NIH) (U01HL098166 and R01HL095712 to W.T.P.) and the American Heart Association (post-doctoral fellowship to A. H.); by charitable donations from Edward Marram, Karen Carpenter, and Gail Federici Smith; and by a Center of Excellence Award in Molecular Hematology from the NIDDK to S.H.O., an Investigator of the HHMI. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. Mass spectrometry analysis was performed by the Proteomics Center at Children's Hospital Boston. NR 34 TC 72 Z9 78 U1 4 U2 24 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JAN 1 PY 2012 VL 26 IS 1 BP 37 EP 42 DI 10.1101/gad.173930.111 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 877RI UT WOS:000299199200006 PM 22215809 ER PT J AU Edwards, DRV Baird, DD Hasan, R Savitz, DA Hartmann, KE AF Edwards, D. R. Velez Baird, D. D. Hasan, R. Savitz, D. A. Hartmann, K. E. TI First-trimester bleeding characteristics associate with increased risk of preterm birth: data from a prospective pregnancy cohort SO HUMAN REPRODUCTION LA English DT Article DE epidemiology; first-trimester; pregnancy; preterm birth; vaginal bleeding ID BACTERIAL VAGINOSIS; 1ST TRIMESTER; DELIVERY; WOMEN; METAANALYSIS; POPULATION; BIAS AB BACKGROUND: Prior evidence linking first-trimester bleeding with preterm birth (PTB, <37 weeks gestation) risk has been inconsistent and may be biased by subject selection and/or incomplete documentation of bleeding episodes for all participants. Prior studies have not carefully examined the role of bleeding characteristics in PTB risk. In the present study, we estimate the association between first-trimester bleeding and PTB in a non-clinical prospective cohort and test whether bleeding characteristics better predict risk. METHODS: Women were enrolled in Right from the Start (2000-2009), a prospective pregnancy cohort. Data about bleeding and bleeding characteristics were examined with logistic regression to assess association with PTB. RESULTS: Among 3978 pregnancies 344 were PTB and 3634 term. Bleeding was reported by 986 (26%) participants. After screening candidate confounders, only multiple gestations remained in the model. Bleeding associated with PTB [odds ratio (OR)(adjusted) = 1.40, 95% confidence interval (CI) 1.09-1.80]. Risk did not vary by race/ethnicity. Compared with non-bleeders, PTB risk was higher for bleeding with red color (OR(adjusted) = 1.92, 95% CI, 1.32-2.82), for heavy episodes (OR(adjusted) = 2.40, 95% CI 1.18-4.88) and long duration (OR(adjusted) = 1.67, 95% CI 1.17-2.38). CONCLUSIONS: Bleeding associated with PTB was not confounded by common risk factors for bleeding or PTB. PTB risk was greatest for women with heavy bleeding episodes with long duration and red color and would suggest that combining women with different bleeding characteristics may affect the accuracy of risk assessment. These data suggest a candidate etiologic pathway for PTB and warrant further investigation of the biologic mechanisms. C1 [Edwards, D. R. Velez; Hartmann, K. E.] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Dept Obstet & Gynecol, Nashville, TN 37203 USA. [Edwards, D. R. Velez] Ctr Human Genet Res, Nashville, TN 37232 USA. [Baird, D. D.] NIEHS, Epidemiol Branch, NIH, Durham, NC 27707 USA. [Hasan, R.] Univ N Carolina Gillings, Dept Epidemiol, Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Savitz, D. A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Savitz, D. A.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. RP Edwards, DRV (reprint author), Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Dept Obstet & Gynecol, Nashville, TN 37203 USA. EM digna.r.velez.edwards@vanderbilt.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU National Institute of Child and Human Development [R01HD043883, R01HD049675]; American Water Association Research Foundation [2579]; Building Interdisciplinary Research Careers in Women's Health career development program [K12HD4383]; National Institute of Environmental Health Sciences, NIH FX The authors acknowledge the field research was supported by grants from the National Institute of Child and Human Development (R01HD043883 and R01HD049675) and the American Water Association Research Foundation (2579). Additional funds were provided by the Building Interdisciplinary Research Careers in Women's Health career development program (K12HD4383). This research was funded in part (DD Baird salary) by the National Institute of Environmental Health Sciences, NIH. NR 39 TC 5 Z9 5 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JAN PY 2012 VL 27 IS 1 BP 54 EP 60 DI 10.1093/humrep/der354 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 877ZG UT WOS:000299220600009 ER PT J AU Amarnath, S Fowler, DH AF Amarnath, Shoba Fowler, Daniel H. TI Harnessing autophagy for adoptive T-cell therapy SO IMMUNOTHERAPY LA English DT Editorial Material DE autophagy; immunology; rapamycin; Th1; Th2; transplantation; tumor ID DONOR TH2 CELLS; MAMMALIAN TARGET; IN-VIVO; DISEASE; APOPTOSIS; SURVIVAL; TH1/TC1; COMPLEX; PREVENT; MEMORY C1 [Amarnath, Shoba; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. RP Amarnath, S (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Clin Res Ctr, 3 E Labs,3-3224, Bethesda, MD 20892 USA. EM samarnath@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 26 TC 5 Z9 5 U1 0 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-743X J9 IMMUNOTHERAPY-UK JI Immunotherapy PD JAN PY 2012 VL 4 IS 1 BP 1 EP 4 DI 10.2217/IMT.11.144 PG 4 WC Immunology SC Immunology GA 878EH UT WOS:000299236700001 PM 22149992 ER PT J AU Goncalves, AN Meschiari, CA Stetler-Stevenson, WG Nonato, MC Alves, CP Espreafico, EM Gerlach, RF AF Goncalves, Andrezza N. Meschiari, Cesar A. Stetler-Stevenson, William G. Nonato, M. Cristina Alves, Cleidson P. Espreafico, Enilza M. Gerlach, Raquel F. TI Expression of soluble and functional full-length human matrix metalloproteinase-2 in Escherichia coli SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE Matrix metalloproteinase-2; Gelatinase A; Bacteria; Protein expression; Escherichia coli ID GELATINASE-A; IV COLLAGENASE; TISSUE INHIBITOR; MMP-2; ACTIVATION; BINDING; DOMAIN; PURIFICATION; FIBROBLASTS; DYSFUNCTION AB Characterization of the matrix metalloproteinase-2 (MMP-2) substrates and understanding of its function remain difficult because up to date preparations containing minor amounts of other eukaryotic proteins that are co-purified with MMP-2 are still used. In this work, the expression of a soluble and functional full-length recombinant human MMP-2 (rhMMP-2) in the cytoplasm of Escherichia coli is reported, and the purification of this metalloproteinase is described. Culture of this bacterium at 18 degrees C culminated in maintenance of the soluble and functional rhMMP-2 in the soluble fraction of the E. coli lysate and its purification by affinity with gelatin-sepharose yielded approximately 0.12 mg/L of medium. Western Blotting and zymographic analysis revealed that the most abundant form was the 72-kDa MMP-2, but some gelatinolytic bands corresponding to proteins with lower molecular weight were also detected. The obtained rhMMP-2 was demonstrated to be functional in a gelatinolytic fluorimetric assay, suggesting that the purified rhMMP-2 was correctly folded. The method described here involves fewer steps, is less expensive, and is less prone to contamination with other proteinases and MMP inhibitors as compared to expression of rhMMP-2 in eukaryotic tissue culture. This protocol will facilitate the use of the full-length rhMMP-2 expressed in bacteria and will certainly help researchers to acquire new knowledge about the substrates and biological activities of this important proteinase. (C) 2011 Elsevier B.V. All rights reserved. C1 [Goncalves, Andrezza N.] Univ Sao Paulo, Dept Pharmaceut Sci, Fac Pharmaceut Sci Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Meschiari, Cesar A.] Univ Sao Paulo, Dept Pharmacol, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Stetler-Stevenson, William G.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Nonato, M. Cristina] Univ Sao Paulo, Dept Chem & Phys, Fac Pharmaceut Sci Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Alves, Cleidson P.; Espreafico, Enilza M.] Univ Sao Paulo, Dept Mol & Cellular Biol, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Gerlach, Raquel F.] Univ Sao Paulo, Dept Morphol Stomatol & Physiol, Dent Sch Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. RP Gerlach, RF (reprint author), FORP USP, Fac Odontol Ribeirao Preto, Avenida Cafe S-N, BR-14040904 Ribeirao Preto, SP, Brazil. EM rfgerlach@forp.usp.br RI Nonato, Maria/C-5659-2012; Gerlach, Raquel/D-7883-2012; Stetler-Stevenson, William/H-6956-2012; Espreafico, Enilza/O-3053-2016 OI Stetler-Stevenson, William/0000-0002-5500-5808; FU State of Sao Paulo Research Foundation (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, FAPESP) FX This study was funded by the State of Sao Paulo Research Foundation (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, FAPESP). We thank Dr. Jose Moacyr Marin for allocation of equipment and technical discussions. NR 32 TC 11 Z9 12 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 J9 J BIOTECHNOL JI J. Biotechnol. PD JAN PY 2012 VL 157 IS 1 BP 20 EP 24 DI 10.1016/j.jbiotec.2011.09.030 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 869YB UT WOS:000298635200004 PM 22001844 ER PT J AU Valenzuela, MS Hu, L Lueders, J Walker, R Meltzer, PS AF Valenzuela, Manuel S. Hu, Lan Lueders, John Walker, Robert Meltzer, Paul S. TI Broader utilization of origins of DNA replication in cancer cell lines along a 78?kb region of human chromosome 2q34 SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE DNA replication origins; Nascent DNA; Real-time PCR; Human cell lines; RPE gene ID TRANSFORMED MAMMALIAN-CELLS; INITIATION POINTS; S PHASE; SITES; IDENTIFICATION; SUBUNITS; STRESS; CHOICE AB Human DNA replication depends on the activation of thousands of origins distributed within the genome. The actual distribution of origins is not known, nor whether this distribution is unique to a cell type, or if it changes with the proliferative state of the cell. In this study, we have employed a real-time PCR-based nascent strand DNA abundance assay, to determine the location of origins along a 78 kb region on Chr2q34. Preliminary studies using nascent DNA strands isolated from either HeLa and normal skin fibroblast cells showed that in both cell lines peaks of high origin activity mapped in similar locations. However, the overall origin profile in HeLa cells corresponded to broad origin activation zones, whereas in fibroblasts a more punctuated profile of origin activation was observed. To investigate the relevance of this differential origin profile, we compared the origin distribution profiles in breast cancer cell lines MDA-MB-231, BT-474, and MCF-7, to their normal counterpart MCF-10A. In addition, the CRL7250 cell line was also used as a normal control. Our results validated our earlier observation and showed that the origin profile in normal cell lines exhibited a punctuated pattern, in contrast to broader zone profiles observed in the cancer cell lines. A quantitative analysis of origin peaks revealed that the number of activated origins in cancer cells is statistically larger than that obtained in normal cells, suggesting that the flexibility of origin usage is significantly increased in cancer cells compared to their normal counterparts. J. Cell. Biochem. 113: 132140, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Valenzuela, Manuel S.; Hu, Lan] Meharry Med Coll, Sch Med, Dept Biochem & Canc Biol, Nashville, TN 37208 USA. [Lueders, John; Walker, Robert; Meltzer, Paul S.] NCI, Genet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Valenzuela, MS (reprint author), Meharry Med Coll, Sch Med, Dept Biochem & Canc Biol, 1005 DB Todd Jr,Blvd, Nashville, TN 37208 USA. EM mvalenzuela@mmc.edu FU National Institute for Human Genome Research; National Institutes of Health (NIH) [CA138180] FX We would like to thank S. Anderson, and M. Kirby, for assistance with the flow cytometry studies, and to Nicole Green and Yidong Chen for help with the figures. MSV wishes to thank the Health Disparities Visiting Faculty Program at the National Institute for Human Genome Research for support during the initial phase of this study. This research was funded in part by the intramural program of the National Institutes of Health (NIH), and by NIH grant CA138180 to MSV. NR 24 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JAN PY 2012 VL 113 IS 1 BP 132 EP 140 DI 10.1002/jcb.23336 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 869LB UT WOS:000298598300015 PM 21898540 ER PT J AU O'Shea, TM Allred, EN Kuban, KCK Hirtz, D Specter, B Durfee, S Paneth, N Leviton, A AF O'Shea, T. Michael Allred, Elizabeth N. Kuban, Karl C. K. Hirtz, Deborah Specter, Barbara Durfee, Sara Paneth, Nigel Leviton, Alan CA ELGAN Study Investigators TI Intraventricular Hemorrhage and Developmental Outcomes at 24 Months of Age in Extremely Preterm Infants SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE cerebral palsy; vision impairment; developmental delay; disability; prematurity; Bayley Scales of Infant Development; neurodevelopmental outcome; intraventricular hemorrhage ID LOW-BIRTH-WEIGHT; ULTRASOUND ABNORMALITIES; CEREBRAL-PALSY; CHILDREN; DISORDERS; BRAIN; PREMATURITY; DISABILITY; COHORT AB Whether intraventricular hemorrhage increases the risk of adverse developmental outcome among premature infants is controversial. Using brain ultrasound, we identified intraventricular hemorrhage and white matter abnormalities among 1064 infants born before 28 weeks' gestation. We identified adverse developmental outcomes at 24 months of age using a standardized neurologic examination and the Bayley Scales of Infant Development Mental and Motor Scales. In logistic regression models that adjusted for gestational age, sex, and public insurance, isolated intraventricular hemorrhage was associated with visual fixation difficulty but no other adverse outcome. Infants who had a white matter lesion unaccompanied by intraventricular hemorrhage were at increased risk of cerebral palsy, low Mental and Motor Scores, and visual and hearing impairments. Except when accompanied or followed by a white matter lesion, intraventricular hemorrhage is associated with no more than a modest increase (and possibly no increase) in the risk of adverse developmental outcome during infancy. C1 [O'Shea, T. Michael; Specter, Barbara] Wake Forest Sch Med, Winston Salem, NC USA. [Allred, Elizabeth N.; Durfee, Sara; Leviton, Alan] Harvard Univ, Sch Med, Boston, MA USA. [Allred, Elizabeth N.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Allred, Elizabeth N.; Leviton, Alan] Childrens Hosp, Boston, MA 02115 USA. [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Hirtz, Deborah] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Paneth, Nigel] Michigan State Univ, E Lansing, MI 48824 USA. RP O'Shea, TM (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. EM moshea@wfubmc.edu OI Kuban, Karl/0000-0001-5299-3567 FU National Institute of Neurological Diseases and Stroke [5U01NS040069-05]; National Institute of Child Health and Human Development [5P30HD018655-28] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a cooperative agreement with the National Institute of Neurological Diseases and Stroke (5U01NS040069-05) and a program project grant from the National Institute of Child Health and Human Development (5P30HD018655-28). NR 29 TC 28 Z9 33 U1 2 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD JAN PY 2012 VL 27 IS 1 BP 22 EP 29 DI 10.1177/0883073811424462 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 873LP UT WOS:000298885100004 PM 22232137 ER PT J AU Nakamura, EF Cui, LH Lateef, T Nelson, KB Merikangas, KR AF Nakamura, Erin F. Cui, Lihong Lateef, Tarannum Nelson, Karin B. Merikangas, Kathleen R. TI Parent-Child Agreement in the Reporting of Headaches in a National Sample of Adolescents SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE headache; migraine; concordance; National Comorbidity Survey-Adolescent Supplement ID SUPPLEMENT NCS-A; UNITED-STATES; YOUNG-ADULTS; MIGRAINE; COMORBIDITY; IMPACT; PREVALENCE; HEALTH; SCHOOLCHILDREN; ASSOCIATION AB The aim of this article is to assess the concordance between parent and adolescent headache ratings in a representative sample of 6483 US adolescents (aged 13-18 years). Headaches were assessed using modified criteria from the International Headache Society's International Classification of Headache Disorders, Second Edition. Caregiver report was based on a self-administered questionnaire. Overall concordance between caregivers and adolescents on the presence or absence of headaches was quite low (kappa = 0.39). Female caregivers were twice as likely as male caregivers to report headaches in their offspring. Positive endorsement of headaches in offspring by caregivers was associated with adolescent-reported chronic headaches, longer headache duration, and photophobia or phonophobia. These findings suggest that relying solely on parent report may result in an underestimate of the true prevalence of headaches in the general population. In addition, collecting information from both parents and adolescents could be critical to effective treatment and prevention of the severe consequences of migraine. C1 [Nakamura, Erin F.; Cui, Lihong; Lateef, Tarannum; Merikangas, Kathleen R.] NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20814 USA. [Lateef, Tarannum; Nelson, Karin B.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Nelson, Karin B.] NINDS, Intramural Res Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Nakamura, EF (reprint author), NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bldg 35,Room 1A112,35 Convent Dr,MSC 3720, Bethesda, MD 20814 USA. EM nakamurae@mail.nih.gov FU National Institute of Mental Health [Z01 MH002808-08, U01-MH60220]; National Comorbidity Survey-Adolescent Supplement FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: This work was supported by the Intramural Research Program of the National Institute of Mental Health (Z01 MH002808-08), the National Comorbidity Survey-Adolescent Supplement, and the larger program of related National Combordity Surveys by the National Institute of Mental Health (U01-MH60220). NR 48 TC 11 Z9 11 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD JAN PY 2012 VL 27 IS 1 BP 61 EP 67 DI 10.1177/0883073811413580 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 873LP UT WOS:000298885100009 PM 21832254 ER PT J AU Betancourt, L Rada, P Paredes, D Hernandez, L AF Betancourt, Luis Rada, Pedro Paredes, Daniel Hernandez, Luis TI In vivo monitoring of cerebral agmatine by microdialysis and capillary electrophoresis SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Capillary electrophoresis; Neurotransmission; Chemical messengers; Bioamines; Probe recovery ID CLONIDINE-DISPLACING SUBSTANCE; PERFORMANCE LIQUID-CHROMATOGRAPHY; INDUCED FLUORESCENCE DETECTION; BIOGENIC-AMINES; IMIDAZOLINE RECEPTORS; RAT-BRAIN; EXTRACELLULAR GLUTAMATE; DECARBOXYLATED ARGININE; HIPPOCAMPAL-NEURONS; BIOLOGICAL SAMPLES AB Agmatine is a putative neurotransmitter in the brain. Current analytical techniques do not allow the detection of agmatine in extracellular fluid, making it difficult to study its physiological role. However, a new method for in vivo monitoring agmatine in the brain was developed. Capillary zone electrophoresis and laser induced fluorescence detection (CZE-LIFD) was used to measure nanomolar concentrations of agmatine in submicroliter sample volumes. This analytical technique proved to detect 0.49 attomole of agmatine improving the sensitivity of previous analytical techniques. On the other hand, the hippocampus is a brain region well known for having a population of agmatine containing neurons. Therefore, intracerebral microdialysis was performed in the hippocampus and agmatine was extracted from the extracellular environment. Detectable amounts of agmatine were found in dialysates from probes located in the hippocampus but not from the probes located in the lateral ventricle. Furthermore, extracellular agmatine was calcium and impulse dependent and depolarization of hippocampal neurons increased extracellular agmatine concentration. The methods reported here are sensitive enough to study the physiological role of brain agmatine in freely moving animals. (C) 2011 Elsevier B.V. All rights reserved. C1 [Betancourt, Luis] Univ Los Andes, Fac Med, Dept Morphol Sci, Sch Med, Merida 5101, Venezuela. [Betancourt, Luis; Rada, Pedro; Hernandez, Luis] Univ Los Andes, Dept Physiol, Sch Med, Merida 5101, Venezuela. [Paredes, Daniel] Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Betancourt, L (reprint author), Univ Los Andes, Fac Med, Dept Morphol Sci, Sch Med, Ave Don Tulio, Merida 5101, Venezuela. EM betahitcher@gmail.com RI Paredes , Daniel/L-6610-2013 FU CDCHT [M-1000-10-03-B, M-967-080-7-F] FX This research was supported by Grants M-1000-10-03-B and M-967-080-7-F from the CDCHT. NR 64 TC 4 Z9 5 U1 9 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 1 PY 2012 VL 880 BP 58 EP 65 DI 10.1016/j.jchromb.2011.11.016 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 877QS UT WOS:000299197600009 PM 22134038 ER PT J AU Peer, CJ Spencer, SD VanDenBerg, DAH Pacanowski, MA Horenstein, RB Figg, WD AF Peer, Cody J. Spencer, Shawn D. VanDenBerg, Dustin A. H. Pacanowski, Michael A. Horenstein, Richard B. Figg, William D. TI A sensitive and rapid ultra HPLC-MS/MS method for the simultaneous detection of clopidogrel and its derivatized active thiol metabolite in human plasma SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Clopidogrel; Active metabolite; Ultra HPLC-MS/MS ID CARBOXYLIC-ACID METABOLITE; CHROMATOGRAPHY/TANDEM MASS-SPECTROMETRY; LC-MS/MS; PHARMACOKINETICS; QUANTIFICATION; POLYMORPHISMS; VALIDATION; PRASUGREL; MS AB A sensitive, selective, and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (uHPLC-MS/MS) was developed for the simultaneous quantification of clopidogrel (Plavix (R)) and its derivatized active metabolite (CAMD) in human plasma. Derivatization of the active metabolite in blood with 2-bromo-3'-methoxy acetophenone (MPB) immediately after collection ensured metabolite stability during sample handling and storage. Following addition of ticlopidine as an internal standard and simple protein precipitation, the analytes were separated on a Waters Acquity UPLC (TM) sub-2 mu m-C(18) column via gradient elution before detection on a triple-quadrupole MS with multiple-reaction-monitoring via electrospray ionization. The method was validated across the clinically relevant concentration range of 0.01-50 ng/mL for parent clopidogrel and 0.1-150 ng/mL (r(2) =0.99) for CAMD, with a fast run time of 1.5 min to support pharmacokinetic studies using 75, 150, or 300 mg oral doses of clopidogrel. The analytical method measured concentrations of clopidogrel and CAMD with accuracy (%DEV) <+/- 12% and precision (%CV) of <+/- 6%. The method was successfully applied to measure the plasma concentrations of clopidogrel and CAMD in three subjects administered single oral doses of 75, 150, and 300 mg clopidogrel. It was further demonstrated that the derivatizing agent (MPB) does not affect clopidogrel levels, thus from one aliquot of blood drawn clinically, this method can simultaneously quantify both clopidogrel and CAMD with sensitivity in the picogram per mL range. Published by Elsevier B.V. C1 [Peer, Cody J.; VanDenBerg, Dustin A. H.; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, Bethesda, MD 20892 USA. [Spencer, Shawn D.] SAIC Frederick Inc, Appl & Dev Res, NCI, Frederick, MD USA. [Pacanowski, Michael A.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Horenstein, Richard B.] Univ Maryland, Div Endocrinol Diabet & Nutr, Sch Med, Baltimore, MD 21201 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Off Clin Director, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wf13e@nih.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health [128475]; National Institute of General Medicine Science [U01GM074518-05S1]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This study was funded by the Bench to Bedside Program of the National Institutes of Health (128475) and the National Institute of General Medicine Science (U01GM074518-05S1).; 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. NR 24 TC 28 Z9 32 U1 2 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 1 PY 2012 VL 880 BP 132 EP 139 DI 10.1016/j.jchromb.2011.11.029 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 877QS UT WOS:000299197600019 PM 22169056 ER PT J AU Moody, TW Leyton, J Jensen, RT AF Moody, Terry W. Leyton, Julius Jensen, Robert T. TI Pituitary Adenylate Cyclase-Activating Polypeptide Causes Increased Tyrosine Phosphorylation of Focal Adhesion Kinase and Paxillin SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE PACAP; Signal transduction; Tyrosine phosphorylation; FAK; Paxillin; Lung cancer ID CELL LUNG-CANCER; VASOACTIVE-INTESTINAL-PEPTIDE; GASTRIN-RELEASING-PEPTIDE; FUNCTIONAL EXPRESSION; SIGNAL-TRANSDUCTION; SPLICE VARIANTS; MESSENGER-RNAS; PROTEIN-KINASE; GROWTH-FACTORS; STRESS FIBERS AB The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin were investigated using lung cancer cells. Addition of PACAP-27 or PACAP-38 but not vasoactive intestinal peptide to NCI-H838 or NCI-H1299 human lung cancer cells significantly increased the tyrosine phosphorylation of FAK or paxillin. The increase in FAK or paxillin tyrosine phosphorylation caused by addition of PACAP-27 to NCI-H838 cells was inhibited by PACAP(6-38), a PAC1-receptor (R) antagonist. The increase in FAK or paxillin tyrosine phosphorylation caused by 100 nM PACAP-27 was maximal 2 min after addition to NCI-H838 cells. The effects of PACAP at stimulating FAK and paxillin tyrosine phosphorylation were reversed by cytochalasin D and genistein which inhibit actin polymerization and tyrosine kinase activity, respectively. The effects of PACAP at stimulating FAK and paxillin tyrosine phosphorylation were reversed by U-73122 but not H89 which inhibit phospholipase C and protein kinase A, respectively. The results show that PAC1-R regulates FAK and paxillin tyrosine phosphorylation in lung cancer cells as a result of increased phosphatidylinositol turnover but not adenylyl cylase stimulation. C1 [Moody, Terry W.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Leyton, Julius; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, Ctr Canc Res, 31 Ctr Dr,Bldg 31,Rm 4A48, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov FU NCI; NIDDK of NIH FX This research is supported in part by intramural funds of the NCI and NIDDK of NIH. NR 51 TC 3 Z9 3 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JAN PY 2012 VL 46 IS 1 BP 68 EP 74 DI 10.1007/s12031-011-9639-7 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 879MA UT WOS:000299332200008 PM 21898124 ER PT J AU Holighaus, Y Weihe, E Eiden, LE AF Holighaus, Yvonne Weihe, Eberhard Eiden, Lee E. TI STC1 Induction by PACAP is Mediated Through cAMP and ERK1/2 but not PKA in Cultured Cortical Neurons SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE PACAP; cAMP; PKA; ERK; STC1 gene induction; Signaling ID CYCLASE-ACTIVATING POLYPEPTIDE; CEREBELLAR GRANULE NEURONS; VASOACTIVE-INTESTINAL-PEPTIDE; PROTEIN-KINASE-A; INDEPENDENT SIGNALING PATHWAY; FOCAL CEREBRAL-ISCHEMIA; IN-SITU HYBRIDIZATION; ADENYLATE-CYCLASE; SPLICE VARIANTS; CYCLIC-AMP AB The neuroprotective actions of PACAP (pituitary adenylate cyclase-activating polypeptide) in vitro and in vivo suggest that activation of its cognate G protein-coupled receptor PAC1 or downstream signaling molecules, and thus activation of PACAP target genes, could be of therapeutic benefit. Here, we show that cultured rat cortical neurons predominantly expressed the PAC1hop and null variants. PACAP receptor activation resulted in the elevation of the two second messengers cAMP and Ca2+ and expression of the putative neuroprotectant stanniocalcin 1 (STC1). PACAP signaling to the STC1 gene proceeded through the extracellular signal-regulated kinases 1 and 2 (ERK1/2), but not through the cAMP-dependent protein kinase (PKA), and was mimicked by the adenylate cyclase activator forskolin. PACAP- and forskolin-mediated activation of ERK1/2 occurred through cAMP, but not PKA. These results suggest that STC1 gene induction proceeds through cAMP and ERK1/2, independently of PKA, the canonical cAMP effector. In contrast, PACAP signaling to the BDNF gene proceeded through PKA, suggesting that two different neuroprotective cAMP pathways co-exist in differentiated cortical neurons. The selective activation of a potentially neuroprotective cAMP-dependent pathway different from the canonical cAMP pathway used in many physiological processes, such as memory storage, has implications for pharmacological activation of neuroprotection in vivo. C1 [Holighaus, Yvonne; Eiden, Lee E.] Lab Cellular & Mol Regulat, Sect Mol Neurosci, Natl Inst Mental Hlth, Bethesda, MD 20892 USA. [Weihe, Eberhard] Univ Marburg, Inst Anat & Cell Biol, Marburg, Germany. RP Eiden, LE (reprint author), Lab Cellular & Mol Regulat, Sect Mol Neurosci, Natl Inst Mental Hlth, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU NIMH [Z01 MH002386-22] FX We would like to thank Chang-Mei Hsu and Charisse Winston for the expert technical assistance with the preparation of rat cortical cultures. This work was supported by NIMH Intramural Research Program Project Z01 MH002386-22. NR 101 TC 7 Z9 7 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JAN PY 2012 VL 46 IS 1 BP 75 EP 87 DI 10.1007/s12031-011-9653-9 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 879MA UT WOS:000299332200009 PM 21975601 ER PT J AU Choi, SH Aid, S Kim, HW Jackson, SH Bosetti, F AF Choi, Sang-Ho Aid, Saba Kim, Hyung-Wook Jackson, Sharon H. Bosetti, Francesca TI Inhibition of NADPH oxidase promotes alternative and anti-inflammatory microglial activation during neuroinflammation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE alternative activation; Alzheimer's disease; microglia; NADPH oxidase; neuroinflammation ID ALZHEIMERS-DISEASE; INFLAMMATORY RESPONSE; OXIDATIVE STRESS; GENE-EXPRESSION; BRAIN; MICE; LIPOPOLYSACCHARIDE; HIPPOCAMPUS; INJURY; MODEL AB Like macrophages, microglia are functionally polarized into different phenotypic activation states, referred as classical and alternative. The balance of the two phenotypes may be critical to ensure proper brain homeostasis, and may be altered in brain pathological states, such as Alzheimers disease. We investigated the role of NADPH oxidase in microglial activation state using p47phox and gp91phox-deficient mice as well as apocynin, a NADPH oxidase inhibitor during neuroinflammation induced by an intracerebroventricular injection of LPS or A beta 142. We showed that NADPH oxidase plays a critical role in the modulation of microglial phenotype and subsequent inflammatory response. We demonstrated that inhibition of NADPH oxidase or gene deletion of its functional p47phox subunit switched microglial activation from a classical to an alternative state in response to an inflammatory challenge. Moreover, we showed a shift in redox state towards an oxidized milieu and that subpopulations of microglia retain their detrimental phenotype in Alzheimers disease brains. Microglia can change their activation phenotype depending on NADPH oxidase-dependent redox state of microenvironment. Inhibition of NADPH oxidase represents a promising neuroprotective approach to reduce oxidative stress and modulate microglial phenotype towards an alternative state. C1 [Bosetti, Francesca] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Jackson, Sharon H.] NIAID, Monocyte Trafficking Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM sjackson@niaid.nih.gov; frances@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX We acknowledge the Harvard Brain Tissue Resource Center (McLean Hospital, Belmont, MA) and Dr J.S. Rao (NIA, NIH) for providing human tissue samples, and Dr S.H. Park (NINDS, NIH) for assistance with confocal microscopy. This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 33 TC 76 Z9 79 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JAN PY 2012 VL 120 IS 2 BP 292 EP 301 DI 10.1111/j.1471-4159.2011.07572.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 869ME UT WOS:000298601400011 PM 22050439 ER PT J AU Kong, H Lee, Y Kim, H Hong, S Kim, DD Yoon, JH Jung, Y Kim, YM AF Kong, Hyesik Lee, Yonghyun Kim, Hyunjeong Hong, Sungchae Kim, Dae-Duk Yoon, Jeong-Hyun Jung, Yunjin Kim, Young Mi TI Susceptibility of glucocorticoids to colonic metabolism and pharmacologic intervention in the metabolism: implication for therapeutic activity of colon-specific glucocorticoid 21-sulfate sodium at the target site SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE colon-specific drug delivery; glucocorticoid; inflammatory bowel disease; sulfated glucocorticoid ID INFLAMMATORY BOWEL-DISEASE; POTENTIAL PRODRUGS; DRUG-DELIVERY; RAT AB Objectives The systemic side effects of glucocorticoids have prevented their long-term use for treatment of inflammatory bowel disease. Colon-specific delivery of glucocorticoids has been adopted as a strategy to circumvent the toxicological trouble. Glucocorticoids delivered to the large intestine might undergo metabolisms by colonic microflora, which should affect therapeutic availability at the target site. It was investigated whether the susceptibility of glucocorticoids to the colonic metabolisms and pharmacologic intervention in the metabolism could modulate the therapeutic availability of colon-targeted glucocorticoids. Methods Various glucocorticoids and their derivatives, glucocorticoid 21-sulfate sodium compounds, were incubated in the cecal contents in the presence or absence of reduction inhibitors and the change in the levels of the drugs was monitored. Key findings The accumulation profiles of the corresponding glucocorticoids liberated from glucocorticoid 21-sulfate sodium compounds vary, depending on the metabolic susceptibility of glucocorticoids. Reduction inhibitors prevented the cecal metabolisms of glucocorticoids, which was most prominent for prednisolone (PD) and methylprednisolone (MP). Moreover, reduction inhibitors increased the accumulated amount of MP and PD released from PD- and MP-21-sulfate sodium in the cecal contents. Conclusions Our data provide information useful for selection of a glucocorticoid and a pharmacologic strategy for the design of an efficient colon-specific glucocorticoid prodrug. C1 [Lee, Yonghyun; Kim, Hyunjeong; Hong, Sungchae; Yoon, Jeong-Hyun; Jung, Yunjin; Kim, Young Mi] Pusan Natl Univ, Coll Pharm, Lab Biomed Med Chem, Pusan 609735, South Korea. [Kim, Dae-Duk] Seoul Natl Univ, Coll Pharm, Seoul, South Korea. [Kim, Dae-Duk] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul, South Korea. [Kong, Hyesik] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Jung, Y (reprint author), Pusan Natl Univ, Coll Pharm, Lab Biomed Med Chem, Pusan 609735, South Korea. EM jungy@pusan.ac.kr; ymikim@pusan.ac.kr RI Kim, Dae Duk/D-8864-2013 FU Korea Research Foundation (KRF); Korean government (MEST) [KRF-2007-314-E00245, KRF-2008-314-E00315] FX This work was supported by Korea Research Foundation (KRF) grants funded by the Korean government (MEST) (KRF-2007-314-E00245 and KRF-2008-314-E00315). NR 19 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3573 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD JAN PY 2012 VL 64 IS 1 BP 128 EP 138 DI 10.1111/j.2042-7158.2011.01386.x PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 861ID UT WOS:000298011700015 PM 22150680 ER PT J AU Gelber, RP Petrovitch, H Masaki, KH Abbott, RD Ross, GW Launer, LJ White, LR AF Gelber, Rebecca P. Petrovitch, Helen Masaki, Kamal H. Abbott, Robert D. Ross, George Webster Launer, Lenore J. White, Lon R. TI Lifestyle and the Risk of Dementia in Japanese-American Men SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE dementia; lifestyle; risk ID HONOLULU HEART PROGRAM; ALZHEIMERS-DISEASE; PHYSICAL-ACTIVITY; DIET; DIAGNOSIS; ANCESTRY; CRITERIA; SMOKING; HAWAII AB OBJECTIVES: To determine whether adhering to a healthy lifestyle in midlife may reduce the risk of dementia. DESIGN: Case-control study nested in a prospective cohort. SETTING: The Honolulu-Asia Aging Study, Oahu, Hawaii. PARTICIPANTS: Three thousand four hundred sixty-eight Japanese-American men (mean age 52 in 1965-1968) examined for dementia 25 years later. MEASUREMENTS: Men at low risk were defined as those with the following midlife characteristics: nonsmoking, body mass index (BMI) less than 25.0 kg/m(2), physically active, and having a healthy diet (based on alcohol, dairy, meat, fish, fruits, vegetables, cereals, and ratio of monounsaturated to saturated fat). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for developing overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD), adjusting for potential confounders. RESULTS: Dementia was diagnosed in 6.4% of men (52.5% with AD, 35.0% with VaD). Examining the risk factors individually, BMI was most strongly associated with greater risk of overall dementia (OR = 1.87, 95% CI = 1.26-2.77; BMI > 25.0 vs <22.6 kg/m(2)). All of the individual risk factors except diet score were significantly associated with VaD, whereas none were significantly associated with AD alone. Men with all four low-risk characteristics (7.2% of the cohort) had the lowest OR for overall dementia (OR = 0.36, 95% CI = 0.15-0.84). There were no significant associations between the combined low-risk characteristics and the risk of AD alone. CONCLUSION: Among Japanese-American men, having a healthy lifestyle in midlife is associated with a lower risk of dementia in late life. J Am Geriatr Soc 60:118-123, 2012. C1 [Gelber, Rebecca P.; Petrovitch, Helen; Masaki, Kamal H.; Abbott, Robert D.; Ross, George Webster; White, Lon R.] Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu, HI USA. [Gelber, Rebecca P.; Petrovitch, Helen; Ross, George Webster] Vet Affairs Pacific Isl Healthcare Syst, Honolulu, HI USA. [Gelber, Rebecca P.] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Petrovitch, Helen; Masaki, Kamal H.; Ross, George Webster; White, Lon R.] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Abbott, Robert D.] Univ Virginia, Sch Med, Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Gelber, RP (reprint author), Kuakini Phys Tower,405 N Kuakini St,Ste 1111, Honolulu, HI 96817 USA. EM rpgelber@gmail.com FU National Institute on Aging [N01-AG-4-2149, 1-R01-AG17155-01A1]; National Heart, Lung, and Blood Institute [N01-HC-05102]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs FX Supported by Contract N01-AG-4-2149 and Grant 1-R01-AG17155-01A1 from the National Institute on Aging; contract N01-HC-05102 from the National Heart, Lung, and Blood Institute; and by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The information contained in this article does not necessarily reflect the position or the policy of the United States government, and no official endorsement should be inferred. NR 24 TC 18 Z9 18 U1 2 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2012 VL 60 IS 1 BP 118 EP 123 DI 10.1111/j.1532-5415.2011.03768.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 875PN UT WOS:000299044100016 PM 22211390 ER PT J AU Grouls, S Iglesias, DM Wentzensen, N Moeller, MJ Bouchard, M Kemler, R Goodyer, P Niggli, F Grone, HJ Kriz, W Koesters, R AF Grouls, Stephan Iglesias, Diana Margarita Wentzensen, Nicolas Moeller, Marcus Johannes Bouchard, Maxime Kemler, Rolf Goodyer, Paul Niggli, Felix Groene, Hermann-Josef Kriz, Wilhelm Koesters, Robert TI Lineage Specification of Parietal Epithelial Cells Requires beta-Catenin/Wnt Signaling SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID KIDNEY DEVELOPMENT; METANEPHRIC MESENCHYME; WNT; TRANSFORMATION; EXPRESSION; GENE AB beta-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target beta-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional beta-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplastic with a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional beta-catenin knockout mice revealed that these "parietal podocytes" derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that beta-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells. C1 [Grouls, Stephan] Univ Heidelberg, Dept Nephrol, D-69120 Heidelberg, Baden Wurttembe, Germany. [Grouls, Stephan] Univ Heidelberg, Inst Human Genet, D-69120 Heidelberg, Baden Wurttembe, Germany. [Iglesias, Diana Margarita; Goodyer, Paul] McGill Univ, Montreal Childrens Hosp, Res Inst, Dept Pediat,Hlth Ctr, Montreal, PQ H3H 1P3, Canada. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Moeller, Marcus Johannes] Rhein Westfael TH Aachen Univ, Univ Hosp, Dept Nephrol & Clin Immunol, Aachen, Germany. [Bouchard, Maxime] McGill Univ, Dept Biochem, Goodman Canc Ctr, Montreal, PQ, Canada. [Kemler, Rolf] Max Planck Inst Immunobiol, Dept Mol Embryol, Freiburg, Germany. [Niggli, Felix] Univ Zurich, Childrens Hosp, Zurich, Switzerland. [Groene, Hermann-Josef] Deutsch Krebsforschungszentrum, Div Cellular & Mol Pathol, D-6900 Heidelberg, Germany. [Kriz, Wilhelm] Univ Heidelberg, Med Fac Mannheim, D-6800 Mannheim, Germany. [Koesters, Robert] Univ Paris 06, Hosp Tenon, INSERM, Unit 702, Paris, France. RP Grouls, S (reprint author), Univ Heidelberg, Dept Nephrol, Neuenheimer Feld 162, D-69120 Heidelberg, Baden Wurttembe, Germany. EM stephan1.grouls@med.uni-heidelberg.de RI Moeller, Marcus/L-1836-2015 FU Nikon Imaging Center at the University of Heidelberg FX We thank Jeanette Weis, Hiltraud Hosser, Brunhilde Hahnel, Claudia Schmidt, and Charlotte Holler for technical assistance and the Nikon Imaging Center at the University of Heidelberg for their support. Ellen Krautkramer contributed valuable critique. NR 25 TC 29 Z9 30 U1 0 U2 3 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 JAN PY 2012 VL 23 IS 1 BP 63 EP 72 DI 10.1681/ASN.2010121257 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 877BK UT WOS:000299151300012 PM 22021707 ER PT J AU Yu, BB Zhou, C AF Yu, Binbing Zhou, Chuan TI Assessing the accuracy of a multiphase diagnosis procedure for dementia SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Dementia; Multiphase design; Receiver operating characteristic curve; Screening; Verification bias ID CHARACTERISTIC ROC CURVES; ALZHEIMERS-DISEASE; VERIFICATION BIAS; TESTS; PREVALENCE; MARKERS; MODEL AB . Multiphase (stage) designs that involve more than two phases are increasingly used by clinicians and psychologists for diagnosis and screening of dementia and many other diseases, e.g. colorectal or breast cancer. The multiphase design is an extension of the commonly used two-phase design, where an inexpensive initial screening test is followed by a gold standard. In a typical three-phase design, the screening test in phase 1 usually has high sensitivity but relatively low specificity. Phase 2 consists of a repeated application of the initial screening test and/or a more confirmatory test and then the gold standard test is used in phase 3. In such designs, both the verification process and the accuracy of each screening test may depend on patients characteristics. In addition, multiple-screening tests are correlated and composite decision rules may be used. However, no estimation methods exist for assessing the accuracy of a multiphase diagnosis procedure. To address these problems, we develop a method of estimating the diagnostic accuracy for each individual test and for the whole diagnostic procedure in a multiphase design in the presence of verification bias. Simulation studies are carried out to evaluate the performance of the method proposed and to compare different strategies of combining sequential tests. The method proposed is applied to data from a multiphase study of dementia. C1 [Yu, Binbing] NIA, Bethesda, MD 20892 USA. [Zhou, Chuan] Univ Washington, Seattle, WA 98195 USA. [Zhou, Chuan] Childrens Hosp, Seattle, WA USA. RP Yu, BB (reprint author), Suite 3C309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU National Institute on Aging FX This research was supported in part by the Intramural Research Program of the National Institute on Aging. We thank Caroline Phillips for editorial help. NR 25 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PY 2012 VL 61 BP 67 EP 81 DI 10.1111/j.1467-9876.2011.00771.x PN 1 PG 15 WC Statistics & Probability SC Mathematics GA 877UH UT WOS:000299207700004 ER PT J AU Dauer, LT Thornton, RH Miller, DL Damilakis, J Dixon, RG Marx, V Schueler, BA Vano, E Venkatesan, A Bartal, G Tsetis, D Cardella, JF AF Dauer, Lawrence T. Thornton, Raymond H. Miller, Donald L. Damilakis, John Dixon, Robert G. Marx, Victoria Schueler, Beth A. Vano, Eliseo Venkatesan, Aradhana Bartal, Gabriel Tsetis, Dimitrios Cardella, John F. CA Soc Interventional Radiology Cardiovasc Interventional TI Radiation Management for Interventions Using Fluoroscopic or Computed Tomographic Guidance during Pregnancy: A Joint Guideline of the Society of Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe with Endorsement by the Canadian Interventional Radiology Association SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID EXPOSED IN-UTERO; CT PULMONARY ANGIOGRAPHY; SEVERE MENTAL-RETARDATION; MONTE-CARLO SIMULATIONS; BOMB SURVIVORS; X-RAY; IONIZING-RADIATION; CHILDHOOD-CANCER; MULTIDETECTOR CT; RADIOGRAPHIC EXAMINATIONS C1 [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Thornton, Raymond H.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, F Edward Hebert Sch Med, Bethesda, MD USA. [Venkatesan, Aradhana] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Damilakis, John] Univ Crete, Dept Med Phys, Fac Med, Iraklion, Greece. [Tsetis, Dimitrios] Univ Crete, Dept Radiol, Fac Med, Iraklion, Greece. [Tsetis, Dimitrios] Univ Hosp Herakl, Dept Radiol, Iraklion, Greece. [Dixon, Robert G.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Los Angeles Cty, Dept Radiol, Los Angeles, CA USA. Univ So Calif, Med Ctr, Los Angeles, CA USA. [Schueler, Beth A.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Vano, Eliseo] Univ Complutense, Dept Radiol, E-28040 Madrid, Spain. [Bartal, Gabriel] Meir Med Ctr, Dept Diagnost & Intervent Radiol, Kefar Sava, Israel. [Cardella, John F.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. RP Dauer, LT (reprint author), Care of Katsarelis D, SIR, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM dauerl@mskcc.org OI Dauer, Lawrence/0000-0002-5629-8462 NR 119 TC 21 Z9 22 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JAN PY 2012 VL 23 IS 1 BP 19 EP 32 DI 10.1016/j.jvir.2011.09.007 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 877BL UT WOS:000299151400004 PM 22112899 ER PT J AU Katki, HA Wentzensen, N AF Katki, Hormuzd A. Wentzensen, Nicolas TI How might HPV testing be integrated into cervical screening? SO LANCET ONCOLOGY LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS; CANCER; CYTOLOGY; RISK C1 [Katki, Hormuzd A.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM katkih@mail.nih.gov RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010217-01] NR 11 TC 9 Z9 10 U1 0 U2 3 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 JAN PY 2012 VL 13 IS 1 BP 8 EP 10 DI 10.1016/S1470-2045(11)70334-5 PG 4 WC Oncology SC Oncology GA 875EZ UT WOS:000299014500030 PM 22177578 ER PT J AU Schiffman, M Wacholder, S AF Schiffman, Mark Wacholder, Sholom TI Success of HPV vaccination is now a matter of coverage SO LANCET ONCOLOGY LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS; EFFICACY; INFECTION; TRIAL C1 [Schiffman, Mark; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM schiffmm@mail.nih.gov FU Intramural NIH HHS NR 10 TC 24 Z9 24 U1 0 U2 10 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 JAN PY 2012 VL 13 IS 1 BP 10 EP 12 DI 10.1016/S1470-2045(11)70324-2 PG 4 WC Oncology SC Oncology GA 875EZ UT WOS:000299014500031 PM 22075169 ER PT J AU Garimella, SV Rocca, A Lipkowitz, S AF Garimella, Sireesha V. Rocca, Andrea Lipkowitz, Stanley TI WEE1 Inhibition Sensitizes Basal Breast Cancer Cells to TRAIL-Induced Apoptosis SO MOLECULAR CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; IN-VIVO; CHEMOTHERAPEUTIC DRUGS; IONIZING-RADIATION; MEDIATED APOPTOSIS; ANTITUMOR EFFICACY; KINASE; LIGAND; THERAPY; DEATH AB TRAIL is a member of the TNF super family and has been shown to induce apoptosis in many cancer cell lines but not in normal cells. Breast cancers can be divided into different subgroups on the basis of the expression of estrogen and progesterone receptors, HER-2 amplification, or the lack of these three markers (known as triple-negative or basal-type breast cancer). Our group and others have shown previously that triple-negative breast cancer cell lines are sensitive to TRAIL whereas others are relatively resistant. In an earlier study, we reported that inhibition of WEE1, a cell-cycle checkpoint regulator, causes increased cell death in breast cancer cell lines. In this study, we tested the effects of WEE1 inhibition on TRAIL-mediated apoptosis in breast cancer cell lines. Pretreatment with WEE1 inhibitor or knockdown of WEE1 increased the toxicity of TRAIL in the basal/triple-negative breast cancer cell lines compared with WEE1 inhibitor or TRAIL treatment alone. The enhanced cell death is attributed to increased surface expression of death receptors, increased caspase activation which could be blocked by the pan-caspase inhibitor, Z-VAD-FMK, thereby rescuing cells from caspase-mediated apoptosis. The cell death was initiated primarily by caspase-8 because knockdown of caspase-8 and not of any other initiator caspases (i.e., caspase-2, -9, or -10) rescued cells from WEE1 inhibitor-sensitized TRAIL-induced cell death. Taken together, the data suggest that the combination of WEE1 inhibitor and TRAIL could provide a novel combination for the treatment of basal/triple-negative breast cancer. Mol Cancer Res; 10(1); 75-85. (C) 2011 AACR. C1 [Garimella, Sireesha V.; Lipkowitz, Stanley] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rocca, Andrea] Study & Treatment Canc IRST Ltd, Dept Med Oncol, Sci Inst Romagna, Meldola, FC, Italy. RP Lipkowitz, S (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM lipkowis@mail.nih.gov RI Rocca, Andrea/M-3930-2015 OI Rocca, Andrea/0000-0003-4613-8884 FU National Cancer Institute, Center for Cancer Research, NIH FX This research was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 50 TC 11 Z9 12 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JAN PY 2012 VL 10 IS 1 BP 75 EP 85 DI 10.1158/1541-7786.MCR-11-0500 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 879JJ UT WOS:000299325200008 PM 22112940 ER PT J AU Vo, DT Abdelmohsen, K Martindale, JL Qiao, M Tominaga, K Burton, TL Gelfond, JAL Brenner, AJ Patel, V Trageser, D Scheffler, B Gorospe, M Penalva, LOF AF Vo, Dat T. Abdelmohsen, Kotb Martindale, Jennifer L. Qiao, Mei Tominaga, Kumiko Burton, Tarea L. Gelfond, Jonathan A. L. Brenner, Andrew J. Patel, Vyomesh Trageser, Daniel Scheffler, Bjoern Gorospe, Myriam Penalva, Luiz O. F. TI The Oncogenic RNA-Binding Protein Musashi1 Is Regulated by HuR via mRNA Translation and Stability in Glioblastoma Cells SO MOLECULAR CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; POSTTRANSCRIPTIONAL GENE-REGULATION; NEURAL STEM-CELLS; AU-RICH ELEMENTS; GLIOMA-CELLS; GENOMIC ANALYSES; LUNG-CANCER; EXPRESSION; STABILIZATION; TARGET AB Musashi1 (Msi1) is an evolutionarily conserved RNA-binding protein (RBP) that has profound implications in cellular processes such as stem cell maintenance, nervous system development, and tumorigenesis. Msi1 is highly expressed in many cancers, including glioblastoma, whereas in normal tissues, its expression is restricted to stem cells. Unfortunately, the factors that modulate Msi1 expression and trigger high levels in tumors are largely unknown. The Msi1 mRNA has a long 30 untranslated region (UTR) containing several AU- and U-rich sequences. This type of sequence motif is often targeted by HuR, another important RBP known to be highly expressed in tumor tissue such as glioblastoma and to regulate a variety of cancer-related genes. In this report, we show an interaction between HuR and the Msi1 3'-UTR, resulting in a positive regulation of Msi1 expression. We show that HuR increased MSI1 mRNA stability and promoted its translation. We also present evidence that expression of HuR and Msi1 correlate positively in clinical glioblastoma samples. Finally, we show that inhibition of cell proliferation, increased apoptosis, and changes in cell-cycle profile as a result of silencing HuR are partially rescued when Msi1 is ectopically expressed. In summary, our results suggest that HuR is an important regulator of Msi1 in glioblastoma and that this regulation has important biological consequences during gliomagenesis. Mol Cancer Res; 10(1); 143-55. (C) 2012 AACR. C1 [Penalva, Luiz O. F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Gelfond, Jonathan A. L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Brenner, Andrew J.] Univ Texas Hlth Sci Ctr San Antonio, Div Hematol & Med Oncol, Dept Med, San Antonio, TX 78229 USA. [Brenner, Andrew J.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Abdelmohsen, Kotb; Martindale, Jennifer L.; Tominaga, Kumiko; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Patel, Vyomesh] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Trageser, Daniel; Scheffler, Bjoern] Univ Bonn, Med Ctr, Inst Reconstruct Neurobiol, Bonn, Germany. RP Penalva, LOF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, Greehey Childrens Canc Res Inst, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM penalva@uthscsa.edu OI abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging, NIH; National Institute of Dental and Craniofacial Research, NIH; Children's Brain Tumor Foundation; Association for Research of Childhood Cancer; The Max and Minnie Tomerlin Voelcker Fund; Cancer Therapy & Research Center P30 Cancer Center from the National Cancer Institute [CA054174] FX K. Abdelmohsen, J.L. Martindale, K. Tominaga, and M. Gorospe are supported by the Intramural Research Program of the National Institute on Aging, NIH. V. Patel is supported by the Intramural Research Program at the National Institute of Dental and Craniofacial Research, NIH. D.T. Vo, M. Qiao, T.L. Burton, and L.O.F. Penalva are supported by grants from the Children's Brain Tumor Foundation, Association for Research of Childhood Cancer, and The Max and Minnie Tomerlin Voelcker Fund. A. J. Brenner is supported by the Cancer Therapy & Research Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174). NR 64 TC 24 Z9 24 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD JAN PY 2012 VL 10 IS 1 BP 143 EP 155 DI 10.1158/1541-7786.MCR-11-0208 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 879JJ UT WOS:000299325200014 PM 22258704 ER PT J AU Kretschmannova, K Kucka, M Gonzalez-Iglesias, AE Stojilkovic, SS AF Kretschmannova, Karla Kucka, Marek Gonzalez-Iglesias, Arturo E. Stojilkovic, Stanko S. TI The Expression and Role of Hyperpolarization-Activated and Cyclic Nucleotide-Gated Channels in Endocrine Anterior Pituitary Cells SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BACKGROUND SODIUM CONDUCTANCE; HORMONE-RELEASING-HORMONE; NITRIC-OXIDE SYNTHASE; CATION CHANNELS; CALCIUM INFLUX; HCN CHANNELS; PROLACTIN-RELEASE; CA2+ OSCILLATIONS; GENE-EXPRESSION; ION CHANNELS AB Pituitary cells fire action potentials independently of external stimuli, and such spontaneous electrical activity is modulated by a large variety of hypothalamic and intrapituitary agonists. Here, we focused on the potential role of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in electrical activity of cultured rat anterior pituitary cells. Quantitative RT-PCR analysis showed higher level of expression of mRNA transcripts for HCN2 and HCN3 subunits and lower expression of HCN1 and HCN4 subunits in these cells. Western immunoblot analysis of lysates from normal and GH(3) immortalized pituitary cells showed bands with appropriate molecular weights for HCN2, HCN3, and HCN4. Electrophysiological experiments showed the presence of a slowly developing hyperpolarization-activated inward current, which was blocked by Cs+ and ZD7288, in gonadotrophs, thyrotrophs, somatotrophs, and a fraction of lactotrophs, as well as in other unidentified pituitary cell types. Stimulation of adenylyl cyclase and addition of 8-Br-cAMP enhanced this current and depolarized the cell membrane, whereas 8-Br-cGMP did not alter the current and hyperpolarized the cell membrane. Both inhibition of basal adenylyl cyclase activity and stimulation of phospholipase C signaling pathway inhibited this current. Inhibition of HCN channels affected the frequency of firing but did not abolish spontaneous electrical activity. These experiments indicate that cAMP and cGMP have opposite effects on the excitability of endocrine pituitary cells, that basal cAMP production in cultured cells is sufficient to integrate the majority of HCN channels in electrical activity, and that depletion of phosphatidylinositol 4,5-bisphosphate caused by activation of phospholipase C silences them. (Molecular Endocrinology 26: 153-164, 2012) C1 [Kretschmannova, Karla; Kucka, Marek; Gonzalez-Iglesias, Arturo E.; Stojilkovic, Stanko S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHD, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov FU NICHD, NIH FX This work was supported by the Intramural Research Program of the NICHD, NIH. NR 58 TC 8 Z9 8 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JAN PY 2012 VL 26 IS 1 BP 153 EP 164 DI 10.1210/me.2011-1207 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 877RO UT WOS:000299199800014 PM 22135067 ER PT J AU Misteli, T AF Misteli, Tom TI Parallel genome universes SO NATURE BIOTECHNOLOGY LA English DT Editorial Material C1 NCI, US NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, US NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov NR 7 TC 4 Z9 4 U1 0 U2 2 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 JAN PY 2012 VL 30 IS 1 BP 55 EP 56 DI 10.1038/nbt.2085 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 876MC UT WOS:000299110600018 PM 22231096 ER PT J AU Jiang, ML Wang, JW Fu, JR Du, L Jeong, H West, T Xiang, L Peng, Q Hou, ZP Cai, H Seredenina, T Arbez, N Zhu, SS Sommers, K Qian, J Zhang, JY Mori, S Yang, XW Tamashiro, KLK Aja, S Moran, TH Luthi-Carter, R Martin, B Maudsley, S Mattson, MP Cichewicz, RH Ross, CA Holtzman, DM Krainc, D Duan, WZ AF Jiang, Mali Wang, Jiawei Fu, Jinrong Du, Lin Jeong, Hyunkyung West, Tim Xiang, Lan Peng, Qi Hou, Zhipeng Cai, Huan Seredenina, Tamara Arbez, Nicolas Zhu, Shanshan Sommers, Katherine Qian, Jennifer Zhang, Jiangyang Mori, Susumu Yang, X. William Tamashiro, Kellie L. K. Aja, Susan Moran, Timothy H. Luthi-Carter, Ruth Martin, Bronwen Maudsley, Stuart Mattson, Mark P. Cichewicz, Robert H. Ross, Christopher A. Holtzman, David M. Krainc, Dimitri Duan, Wenzhen TI Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets SO NATURE MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR FOXO3A; TRANSGENIC MOUSE MODEL; NEUROTROPHIC FACTOR; MUTANT HUNTINGTIN; IN-VITRO; NEURODEGENERATION; MICE; PGC-1-ALPHA; METABOLISM; FORKHEAD AB Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HIT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice)'. We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HIT toxicity, whereas reduction of Sirt1 exacerbates mutant HIT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutantHIT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HIT interacts with Sirt1 and inhibits Sirti deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HIT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease. C1 [Jiang, Mali; Wang, Jiawei; Fu, Jinrong; Xiang, Lan; Peng, Qi; Arbez, Nicolas; Zhu, Shanshan; Sommers, Katherine; Qian, Jennifer; Ross, Christopher A.; Duan, Wenzhen] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Neurobiol, Baltimore, MD 21205 USA. [Wang, Jiawei] Capital Med Univ, Beijing Friendship Hosp, Beijing, Peoples R China. [Du, Lin; Cichewicz, Robert H.] Univ Oklahoma, Dept Chem & Biochem, Nat Prod Discovery Grp, Norman, OK 73019 USA. [Jeong, Hyunkyung; Krainc, Dimitri] Harvard Univ, Sch Med, Dept Neurol, MassGen Inst Neurodegenerat Dis,Massachusetts Gen, Boston, MA 02115 USA. [West, Tim; Holtzman, David M.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [West, Tim; Holtzman, David M.] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA. [Hou, Zhipeng; Zhang, Jiangyang; Mori, Susumu] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Cai, Huan; Martin, Bronwen] NIA, Metab Unit, Lab Clin Invest, US Natl Inst Hlth NIH, Baltimore, MD 21224 USA. [Seredenina, Tamara; Luthi-Carter, Ruth] Ecole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland. [Yang, X. William] Univ Calif Los Angeles, Brain Res Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Aja, Susan] Johns Hopkins Univ, Sch Med, Ctr Metab & Obes Res, Baltimore, MD USA. [Maudsley, Stuart; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21205 USA. [Ross, Christopher A.; Duan, Wenzhen] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA. RP Duan, WZ (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Neurobiol, Baltimore, MD 21205 USA. EM wduan2@jhmi.edu RI Jiang, Mali/B-2631-2012; Du, Lin/G-7889-2011; Mattson, Mark/F-6038-2012; Ross, Christopher/H-8395-2013; Cai, Huan/B-6578-2016; OI Cai, Huan/0000-0001-7731-8891; Cichewicz, Robert/0000-0003-0744-4117 FU Hereditary Disease Foundation; CHDI Foundation [A-2120]; NIH [NS 16375, NS35902, ROINS051303, EB003543, ES012665, NS065306]; NIA FX We thank L. Tsai at Massachusetts Institute of Technology for providing Sirt1 and H363Y retrovirus constructs, S. Imai at Washington University for providing Sir2 complementary DNAs (cDNAs), M. Macdonald at Harvard Medical School for providing STHdhQ7/Q7 and STHdhQ111/Q111 cells, S. Li and X. Li at Emory University for providing antibodies to EM48 and E. Waldron, C. Berlinicke, Y. Chen and J. Jin at Johns Hopkins University School of Medicine for their technical assistance. This work was supported by the Hereditary Disease Foundation (W.D.), CHDI Foundation grant A-2120 (W.D.), NIH grant NS 16375 (C.A.R.), NIH grant NS35902 (D.M.H.), the NIA Intramural Research Program (B.M., H.C., S. Maudesley and M.P.M.), NIH grant ROINS051303 (D.K.), NIH grant EB003543 and ES012665 (S. Mori) and NIH grant NS065306 (J.Z.). NR 41 TC 89 Z9 93 U1 4 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JAN PY 2012 VL 18 IS 1 BP 153 EP 158 DI 10.1038/nm.2558 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 875GO UT WOS:000299018600042 ER PT J AU Resnick, SM Scheltens, P AF Resnick, Susan M. Scheltens, Philip TI MRI-based biomarkers of preclinical AD An Alzheimer signature SO NEUROLOGY LA English DT Editorial Material ID ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; COGNITIVE IMPAIRMENT; DISEASE; RECOMMENDATIONS C1 [Resnick, Susan M.] NIA, Baltimore, MD 21224 USA. [Scheltens, Philip] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Alzheimer Ctr, Amsterdam, Netherlands. RP Resnick, SM (reprint author), NIA, Baltimore, MD 21224 USA. EM susan.resnick@nih.gov FU Intramural NIH HHS [ZIA AG000191-15] NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN PY 2012 VL 78 IS 2 BP 80 EP 81 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 877EL UT WOS:000299159700005 PM 22189450 ER PT J AU Heremans, E Nieuwboer, A Feys, P Vercruysse, S Vandenberghe, W Sharma, N Helsen, WF AF Heremans, Elke Nieuwboer, Alice Feys, Peter Vercruysse, Sarah Vandenberghe, Wim Sharma, Nikhil Helsen, Werner F. TI External Cueing Improves Motor Imagery Quality in Patients With Parkinson Disease SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE mental practice; motor imagery; cueing; Parkinson disease; rehabilitation ID MENTAL MOVEMENT TIMES; HAND MOVEMENTS; MULTIPLE-SCLEROSIS; INTENTION TREMOR; VISUAL FEEDBACK; BASAL GANGLIA; ARM MOVEMENTS; GRAPHIC TASKS; STROKE; GAIT AB Background. Patients with Parkinson disease (PD) are often profoundly slow in their performance of physical tasks, as well as in motor imagery (MI). This may limit the implementation and potential benefits of MI practice during rehabilitation. Objective. The authors investigated whether the quality of MI could be improved by external cueing. Methods. Fourteen patients with PD and 14 healthy controls physically executed and visually imagined a goal-directed aiming task and a box-and-block task, both in the presence and absence of visual and auditory cues. Mental chronometry and eye movement recording allowed objective evaluation of the temporal and spatial characteristics of MI when compared with physical execution. Visual analogue scales were used to assess imagery vividness. Results. The presence of visual cues significantly reduced the patients' bradykinesia during MI and increased their imagery vividness. Conclusions. Visual cueing optimizes MI quality for PD patients and is a potential tool to increase the efficacy of MI practice in PD rehabilitation. C1 [Helsen, Werner F.] Katholieke Univ Leuven, Dept Biomed Kinesiol, Percept & Performance Lab, B-3001 Louvain, Belgium. [Feys, Peter] PHL Univ Coll, Hasselt, Belgium. [Feys, Peter] Univ Hasselt, Hasselt, Belgium. [Vandenberghe, Wim] Univ Hosp Leuven, Louvain, Belgium. [Sharma, Nikhil] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Helsen, WF (reprint author), Katholieke Univ Leuven, Dept Biomed Kinesiol, Percept & Performance Lab, Tervuursevest 101, B-3001 Louvain, Belgium. EM werner.helsen@faber.kuleuven.be RI Nieuwboer, Alice/F-5643-2013; OI Nieuwboer, Alice/0000-0003-1193-6229; Sharma, Nikhil/0000-0001-8903-2938 FU Belgian Charcot Foundation FX Elke Heremans is a research assistant and Wim Vandenberghe a senior clinical investigator at the Research Foundation Flanders (FWO). The authors also acknowledge the support of the Belgian Charcot Foundation to obtain eye movement recording equipment. NR 61 TC 25 Z9 25 U1 1 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD JAN PY 2012 VL 26 IS 1 BP 27 EP 35 DI 10.1177/1545968311411055 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 876BQ UT WOS:000299082400004 PM 21778409 ER PT J AU Lai, JS Nowinski, C Victorson, D Bode, R Podrabsky, T McKinney, N Straube, D Holmes, GL McDonald, CM Henricson, E Abresch, RT Moy, CS Cella, D AF Lai, Jin-Shei Nowinski, Cindy Victorson, David Bode, Rita Podrabsky, Tracy McKinney, Natalie Straube, Don Holmes, Gregory L. McDonald, Craig M. Henricson, Erik Abresch, R. Ted Moy, Claudia S. Cella, David TI Quality-of-Life Measures in Children With Neurological Conditions: Pediatric Neuro-QOL SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE health-related quality of life; children; neurological disorders; item bank; item response theory ID PARKINSONS-DISEASE; MULTIPLE-SCLEROSIS; OUTCOMES; VALIDATION; EPILEPSY; STROKE; SCALE; REHABILITATION; INSTRUMENT; DISABILITY AB Background. A comprehensive, reliable, and valid measurement system is needed to monitor changes in children with neurological conditions who experience lifelong functional limitations. Objective. This article describes the development and psychometric properties of the pediatric version of the Quality of Life in Neurological Disorders (Neuro-QOL) measurement system. Methods. The pediatric Neuro-QOL consists of generic and targeted measures. Literature review, focus groups, individual interviews, cognitive interviews of children and consensus meetings were used to identify and finalize relevant domains and item content. Testing was conducted on 1018 children aged 10 to 17 years drawn from the US general population for generic measures and 171 similarly aged children with muscular dystrophy or epilepsy for targeted measures. Dimensionality was evaluated using factor analytic methods. For unidimensional domains, item parameters were estimated using item response theory models. Measures with acceptable fit indices were calibrated as item banks; those without acceptable fit indices were treated as summary scales. Results. Ten measures were developed: 8 generic or targeted banks (anxiety, depression, anger, interaction with peers, fatigue, pain, applied cognition, and stigma) and 2 generic scales (upper and lower extremity function). The banks reliably (r > 0.90) measured 63.2% to 100% of the children tested. Conclusions. The pediatric Neuro-QOL is a comprehensive measurement system with acceptable psychometric properties that could be used in computerized adaptive testing. The next step is to validate these measures in various clinical populations. C1 [Lai, Jin-Shei] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Straube, Don] Univ Illinois, Chicago, IL USA. [Holmes, Gregory L.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [McDonald, Craig M.; Henricson, Erik; Abresch, R. Ted] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Lai, JS (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, 710 N Lake Shore Dr,724, Chicago, IL 60611 USA. EM js-lai@northwestern.edu OI McDonald, Craig/0000-0002-8779-3220 FU National Institute of Neurological Disorders and Stroke [HHSN265200423601C] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project is supported by the National Institute of Neurological Disorders and Stroke (HHSN265200423601C; Principal Investigator: David Cella). NR 36 TC 14 Z9 14 U1 0 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD JAN PY 2012 VL 26 IS 1 BP 36 EP 47 DI 10.1177/1545968311412054 PG 12 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 876BQ UT WOS:000299082400001 PM 21788436 ER PT J AU Ndongwe, TP Adedeji, AO Michailidis, E Ong, YT Hachiya, A Marchand, B Ryan, EM Rai, DK Kirby, KA Whatley, AS Burke, DH Johnson, M Ding, SL Zheng, YM Liu, SL Kodama, EI Delviks-Frankenberry, KA Pathak, VK Mitsuya, H Parniak, MA Singh, K Sarafianos, SG AF Ndongwe, Tanyaradzwa P. Adedeji, Adeyemi O. Michailidis, Eleftherios Ong, Yee Tsuey Hachiya, Atsuko Marchand, Bruno Ryan, Emily M. Rai, Devendra K. Kirby, Karen A. Whatley, Angela S. Burke, Donald H. Johnson, Marc Ding, Shilei Zheng, Yi-Min Liu, Shan-Lu Kodama, Ei-Ichi Delviks-Frankenberry, Krista A. Pathak, Vinay K. Mitsuya, Hiroaki Parniak, Michael A. Singh, Kamalendra Sarafianos, Stefan G. TI Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CHRONIC-FATIGUE-SYNDROME; HUMAN RETROVIRUS XMRV; CRYSTAL-STRUCTURE; DRUG-RESISTANCE; DNA-SYNTHESIS; PROSTATE-CANCER; IN-VITRO; INFECTIOUS RETROVIRUS; POLYMERASE FIDELITY; ANGSTROM RESOLUTION AB We report key mechanistic differences between the reverse transcriptases (RT) of human immunodeficiency virus type-1 (HIV-1) and of xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus that can infect human cells. Steady and pre-steady state kinetics demonstrated that XMRV RT is significantly less efficient in DNA synthesis and in unblocking chain-terminated primers. Surface plasmon resonance experiments showed that the gammaretroviral enzyme has a remarkably higher dissociation rate (k(off)) from DNA, which also results in lower processivity than HIV-1 RT. Transient kinetics of mismatch incorporation revealed that XMRV RT has higher fidelity than HIV-1 RT. We identified RNA aptamers that potently inhibit XMRV, but not HIV-1 RT. XMRV RT is highly susceptible to some nucleoside RT inhibitors, including Translocation Deficient RT inhibitors, but not to non-nucleoside RT inhibitors. We demonstrated that XMRV RT mutants K103R and Q190M, which are equivalent to HIV-1 mutants that are resistant to tenofovir (K65R) and AZT (Q151M), are also resistant to the respective drugs, suggesting that XMRV can acquire resistance to these compounds through the decreased incorporation mechanism reported in HIV-1. C1 [Ndongwe, Tanyaradzwa P.; Adedeji, Adeyemi O.; Michailidis, Eleftherios; Ong, Yee Tsuey; Hachiya, Atsuko; Marchand, Bruno; Ryan, Emily M.; Rai, Devendra K.; Kirby, Karen A.; Whatley, Angela S.; Burke, Donald H.; Johnson, Marc; Zheng, Yi-Min; Liu, Shan-Lu; Singh, Kamalendra; Sarafianos, Stefan G.] Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Sch Med, Columbia, MO 65211 USA. [Burke, Donald H.; Sarafianos, Stefan G.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Ding, Shilei; Liu, Shan-Lu] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Kodama, Ei-Ichi] Tohoku Univ, Sch Med, Dept Internal Med, Div Emerging Infect Dis, Sendai, Miyagi 980, Japan. [Delviks-Frankenberry, Krista A.; Pathak, Vinay K.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Internal Med, Kumamoto 860, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Parniak, Michael A.] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. RP Sarafianos, SG (reprint author), Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Sch Med, Columbia, MO 65211 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; Rai, Devendra/J-3857-2013; Delviks-Frankenberry, Krista/M-4822-2013; Liu, Shan-Lu/L-5923-2016; OI Kirby, Karen A./0000-0003-2468-4796; Kodama, Eiichi /0000-0002-6622-2752; Rai, Devendra/0000-0001-9035-685X; Liu, Shan-Lu/0000-0003-1620-3817; Sarafianos, Stefan G/0000-0002-5840-154X FU NIH [AI076119, AI079801, AI094715, AI074389]; NIH, National Cancer Institute, Center for Cancer Research; Ministry of Knowledge and Economy, Republic of Korea; Canadian Institutes of Health Research (CIHR); University of Missouri FX NIH grants (AI076119, AI079801, and AI094715, to S. G. S.), (AI074389, to D. H. B.), (AI079801 to M. A. P.); NIH Bench-to-Bedside Award and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to V. K. P); Ministry of Knowledge and Economy, Bilateral International Collaborative R&D Program, Republic of Korea; Canadian Institutes of Health Research (CIHR) and University of Missouri (to S-L. L.); amfAR Mathilde Krim Fellowship and a CIHR Fellowship (to B. M.). Funding for open access charge: NIH grants (AI076119, AI094715, AI074389, AI079801). NR 84 TC 7 Z9 7 U1 1 U2 14 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 JAN PY 2012 VL 40 IS 1 BP 345 EP 359 DI 10.1093/nar/gkr694 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 871JG UT WOS:000298733500038 PM 21908397 ER PT J AU Asagoshi, K Lehmann, W Braithwaite, EK Santana-Santos, L Prasad, R Freedman, JH Van Houten, B Wilson, SH AF Asagoshi, Kenjiro Lehmann, Wade Braithwaite, Elena K. Santana-Santos, Lucas Prasad, Rajendra Freedman, Jonathan H. Van Houten, Bennett Wilson, Samuel H. TI Single-nucleotide base excision repair DNA polymerase activity in C. elegans in the absence of DNA polymerase beta SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NEMATODE CAENORHABDITIS-ELEGANS; X-FAMILY; IDENTIFICATION; HOMOLOG; GENES; SITE; PURIFICATION; GLYCOSYLASE; RESISTANCE; LONGEVITY AB The base excision DNA repair (BER) pathway known to occur in Caenorhabditis elegans has not been well characterized. Even less is known about the DNA polymerase (pol) requirement for the gap-filling step during BER. We now report on characterization of in vitro uracil-DNA initiated BER in C. elegans. The results revealed single-nucleotide (SN) gap-filling DNA polymerase activity and complete BER. The gap-filling polymerase activity was not due to a DNA polymerase beta (pol beta) homolog, or to another X-family polymerase, since computer-based sequence analyses of the C. elegans genome failed to show a match for a pol beta-like gene or other X-family polymerases. Activity gel analysis confirmed the absence of pol beta in the C. elegans extract. BER gap-filling polymerase activity was partially inhibited by both dideoxy-nucleotide and aphidicolin. The results are consistent with a combination of both replicative polymerase(s) and lesion bypass/BER polymerase pol theta contributing to the BER gap-filling synthesis. Involvement of pol theta was confirmed in experiments with extract from pol theta null animals. The presence of the SN BER in C. elegans is supported by these results, despite the absence of a pol beta-like enzyme or other X-family polymerase. C1 [Asagoshi, Kenjiro; Prasad, Rajendra; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Lehmann, Wade; Van Houten, Bennett] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Braithwaite, Elena K.; Freedman, Jonathan H.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Santana-Santos, Lucas; Van Houten, Bennett] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15213 USA. [Santana-Santos, Lucas; Van Houten, Bennett] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov OI Santana-Santos, Lucas/0000-0002-0872-5431 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES050158, Z01ES050159]; U.S. Government; NIH National Center for Research Resources; [Z01-ES061060]; [Z01ES102045]; [R01-ES019566] FX The Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (grants Z01ES050158 and Z01ES050159 to S. H. W., partial); Z01-ES061060 and Z01ES102045 to J.H.F., partial); (R01-ES019566 to B. V. H., partial). Funding for open access charge: U.S. Government funds.; We thank Bonnie Mesmer for editorial assistance, Julie A. Hall, Julie R. Rice, Kathryn L. Haas and Windy A. Boyd for their assistance with nematode genotyping and culturing and anonymous reviewers for suggestions. Nematodes strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. NR 51 TC 12 Z9 13 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 JAN PY 2012 VL 40 IS 2 BP 670 EP 681 DI 10.1093/nar/gkr727 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 876GP UT WOS:000299095900024 PM 21917855 ER PT J AU Callahan, KE Hickman, AB Jones, CE Ghirlando, R Furano, AV AF Callahan, Kathryn E. Hickman, Alison B. Jones, Charles E. Ghirlando, Rodolfo Furano, Anthony V. TI Polymerization and nucleic acid-binding properties of human L1 ORF1 protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RIBONUCLEOPROTEIN PARTICLE FORMATION; PRIMED REVERSE TRANSCRIPTION; LINE-1 RETROTRANSPOSITION; CHAPERONE ACTIVITY; MOUSE LINE-1; RNA-BINDING; HUMAN GENOMES; IN-VITRO; EVOLUTION; ELEMENT AB The L1 (LINE 1) retrotransposable element encodes two proteins, ORF1p and ORF2p. ORF2p is the L1 replicase, but the role of ORF1p is unknown. Mouse ORF1p, a coiled-coil-mediated trimer of similar to 42-kDa monomers, binds nucleic acids and has nucleic acid chaperone activity. We purified human L1 ORF1p expressed in insect cells and made two findings that significantly advance our knowledge of the protein. First, in the absence of nucleic acids, the protein polymerizes under the very conditions (0.05M NaCl) that are optimal for high (similar to 1 nM)-affinity nucleic acid binding. The non-coiled-coil C-terminal half mediates formation of the polymer, an active conformer that is instantly resolved to trimers, or multimers thereof, by nucleic acid. Second, the protein has a biphasic effect on mismatched double-stranded DNA, a proxy chaperone substrate. It protects the duplex from dissociation at 37 degrees C before eventually melting it when largely polymeric. Therefore, polymerization of ORF1p seemingly affects its interaction with nucleic acids. Additionally, polymerization of ORF1p at its translation site could explain the heretofore-inexplicable phenomenon of cis preference-the favored retrotransposition of the actively translated L1 transcript, which is essential for L1 survival. C1 [Callahan, Kathryn E.; Jones, Charles E.; Furano, Anthony V.] NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. [Callahan, Kathryn E.] Georgetown Univ, Dept Biochem & Mol & Cell Biol, Med Ctr, Washington, DC 20057 USA. [Hickman, Alison B.; Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Furano, AV (reprint author), NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. EM avf@helix.nih.gov FU NIDDK/NIH FX The Intramural Program of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH). Funding for open access charge: NIDDK/NIH. NR 50 TC 18 Z9 19 U1 0 U2 3 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 JAN PY 2012 VL 40 IS 2 BP 813 EP 827 DI 10.1093/nar/gkr728 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 876GP UT WOS:000299095900036 PM 21937507 ER PT J AU Barrett, T Clark, K Gevorgyan, R Gorelenkov, V Gribov, E Karsch-Mizrachi, I Kimelman, M Pruitt, KD Resenchuk, S Tatusova, T Yaschenko, E Ostell, J AF Barrett, Tanya Clark, Karen Gevorgyan, Robert Gorelenkov, Vyacheslav Gribov, Eugene Karsch-Mizrachi, Ilene Kimelman, Michael Pruitt, Kim D. Resenchuk, Sergei Tatusova, Tatiana Yaschenko, Eugene Ostell, James TI BioProject and BioSample databases at NCBI: facilitating capture and organization of metadata SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOMICS; SYSTEM AB As the volume and complexity of data sets archived at NCBI grow rapidly, so does the need to gather and organize the associated metadata. Although metadata has been collected for some archival databases, previously, there was no centralized approach at NCBI for collecting this information and using it across databases. The BioProject database was recently established to facilitate organization and classification of project data submitted to NCBI, EBI and DDBJ databases. It captures descriptive information about research projects that result in high volume submissions to archival databases, ties together related data across multiple archives and serves as a central portal by which to inform users of data availability. Concomitantly, the BioSample database is being developed to capture descriptive information about the biological samples investigated in projects. BioProject and BioSample records link to corresponding data stored in archival repositories. Submissions are supported by a web-based Submission Portal that guides users through a series of forms for input of rich metadata describing their projects and samples. Together, these databases offer improved ways for users to query, locate, integrate and interpret the masses of data held in NCBI's archival repositories. The BioProject and BioSample databases are available at http://www.ncbi.nlm.nih.gov/biosample, respectively. C1 [Barrett, Tanya; Clark, Karen; Gevorgyan, Robert; Gorelenkov, Vyacheslav; Gribov, Eugene; Karsch-Mizrachi, Ilene; Kimelman, Michael; Pruitt, Kim D.; Resenchuk, Sergei; Tatusova, Tatiana; Yaschenko, Eugene; Ostell, James] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Karsch-Mizrachi, I (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 45 Ctr Dr, Bethesda, MD 20892 USA. EM mizrachi@ncbi.nlm.nih.gov FU National Institutes of Health, National Library of Medicine FX Funding for Open Access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 17 TC 65 Z9 66 U1 0 U2 7 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 JAN PY 2012 VL 40 IS D1 BP D57 EP D63 DI 10.1093/nar/gkr1163 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300010 PM 22139929 ER PT J AU Benson, DA Karsch-Mizrachi, I Clark, K Lipman, DJ Ostell, J Sayers, EW AF Benson, Dennis A. Karsch-Mizrachi, Ilene Clark, Karen Lipman, David J. Ostell, James Sayers, Eric W. TI GenBank SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENERATION; DATABASE AB GenBank (R) is a comprehensive database that contains publicly available nucleotide sequences for more than 250 000 formally described species. These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole-genome shotgun (WGS) and environmental sampling projects. Most submissions are made using the web-based BankIt or standalone Sequin programs, and accession numbers are assigned by GenBank staff upon receipt. Daily data exchange with the European Nucleotide Archive (ENA) and the DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through the NCBI Entrez retrieval system, which integrates data from the major DNA and protein sequence databases along with taxonomy, genome, mapping, protein structure and domain information, and the biomedical journal literature via PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. To access GenBank and its related retrieval and analysis services, begin at the NCBI home page: www.ncbi.nlm.nih.gov. C1 [Benson, Dennis A.; Karsch-Mizrachi, Ilene; Clark, Karen; Lipman, David J.; Ostell, James; Sayers, Eric W.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Sayers, EW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM sayers@ncbi.nlm.nih.gov FU National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 11 TC 264 Z9 268 U1 1 U2 24 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 JAN PY 2012 VL 40 IS D1 BP D48 EP D53 DI 10.1093/nar/gkr1202 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300008 PM 22144687 ER PT J AU Federhen, S AF Federhen, Scott TI The NCBI Taxonomy database SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The NCBI Taxonomy database (http://www.ncbi.nlm.nih.gov/taxonomy)is the standard nomenclature and classification repository for the International Nucleotide Sequence Database Collaboration (INSDC), comprising the GenBank, ENA (EMBL) and DDBJ databases. It includes organism names and taxonomic lineages for each of the sequences represented in the INSDC's nucleotide and protein sequence databases. The taxonomy database is manually curated by a small group of scientists at the NCBI who use the current taxonomic literature to maintain a phylogenetic taxonomy for the source organisms represented in the sequence databases. The taxonomy database is a central organizing hub for many of the resources at the NCBI, and provides a means for clustering elements within other domains of NCBI web site, for internal linking between domains of the Entrez system and for linking out to taxon-specific external resources on the web. Our primary purpose is to index the domain of sequences as conveniently as possible for our user community. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Federhen, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM federhen@ncbi.nlm.nih.gov FU National Institutes of Health, National Library of Medicine; Intramural Research Program FX Intramural Research Program of the National Institutes of Health, National Library of Medicine. Funding for open access charge: Intramural Research Program. NR 16 TC 156 Z9 158 U1 2 U2 19 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 JAN PY 2012 VL 40 IS D1 BP D136 EP D143 DI 10.1093/nar/gkr1178 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300021 PM 22139910 ER PT J AU Galperin, MY Fernandez-Suarez, XM AF Galperin, Michael Y. Fernandez-Suarez, Xose M. TI The 2012 Nucleic Acids Research Database Issue and the online Molecular Biology Database Collection SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The 19th annual Database Issue of Nucleic Acids Research features descriptions of 92 new online databases covering various areas of molecular biology and 100 papers describing recent updates to the databases previously described in NAR and other journals. The highlights of this issue include, among others, a description of neXtProt, a knowledgebase on human proteins; a detailed explanation of the principles behind the NCBI Taxonomy Database; NCBI and EBI papers on the recently launched BioSample databases that store sample information for a variety of database resources; descriptions of the recent developments in the Gene Ontology and UniProt Gene Ontology Annotation projects; updates on Pfam, SMART and InterPro domain databases; update papers on KEGG and TAIR, two universally acclaimed databases that face an uncertain future; and a separate section with 10 wiki-based databases, introduced in an accompanying editorial. The NAR online Molecular Biology Database Collection, available at http://www.oxfordjournals.org/nar/database/a/, has been updated and now lists 1380 databases. Brief machine-readable descriptions of the databases featured in this issue, according to the BioDBcore standards, will be provided at the http://biosharing.org/biodbcore web site. The full content of the Database Issue is freely available online on the Nucleic Acids Research web site (http://nar.oxfordjournals.org/). C1 [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat NCBI, Natl Lib Med, Bethesda, MD 20894 USA. [Fernandez-Suarez, Xose M.] Wellcome Trust Genome Campus, EMBL European Bioinformat Inst, Cambridge CB10 1SD, England. RP Galperin, MY (reprint author), NIH, Natl Ctr Biotechnol Informat NCBI, Natl Lib Med, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov; xose@ebi.ac.uk RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU US National Institutes of Health at the National Library of Medicine; European Molecular Biology Laboratory; Oxford University Press FX Intramural Research Program of the US National Institutes of Health at the National Library of Medicine (to M.Y.G.); European Molecular Biology Laboratory (to X. M. F. S.). Funding for open access charge: waived by Oxford University Press. NR 44 TC 45 Z9 45 U1 0 U2 6 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 JAN PY 2012 VL 40 IS D1 BP D1 EP D8 DI 10.1093/nar/gkr1196 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300001 PM 22144685 ER PT J AU Karsch-Mizrachi, I Nakamura, Y Cochrane, G AF Karsch-Mizrachi, Ilene Nakamura, Yasukazu Cochrane, Guy CA Int Nucleotide Sequence Database C TI The International Nucleotide Sequence Database Collaboration SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The members of the International Nucleotide Sequence Database Collaboration (INSDC; http://www.insdc.org) set out to capture, preserve and present globally comprehensive public domain nucleotide sequence information. The work of the long-standing collaboration includes the provision of data formats, annotation conventions and routine global data exchange. Among the many developments to INSDC resources in 2011 are the newly launched BioProject database and improved handling of assembly information. In this article, we outline INSDC services and update the reader on developments in 2011. C1 [Karsch-Mizrachi, Ilene] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Nakamura, Yasukazu] Res Org Informat & Syst, Natl Inst Genet, Ctr Informat Biol, Mishima, Shizuoka 4118510, Japan. [Nakamura, Yasukazu] Res Org Informat & Syst, Natl Inst Genet, DNA Data Bank Japan, Mishima, Shizuoka 4118510, Japan. [Cochrane, Guy] Wellcome Trust Genome Campus, EMBL European Bioinformat Inst, Cambridge CB10 1SD, England. RP Karsch-Mizrachi, I (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 45 Ctr Dr, Bethesda, MD 20892 USA. EM mizrachi@ncbi.nlm.nih.gov RI Salzberg, Steven/F-6162-2011; OI Salzberg, Steven/0000-0002-8859-7432; Cochrane, Guy/0000-0001-7954-7057; Nakamura, Yasukazu/0000-0002-6782-5715; Danchin, Antoine/0000-0002-6350-5001 FU National Institutes of Health; National Library of Medicine; European Nucleotide Archive by the European Molecular Biology Laboratory; Wellcome Trust; European Commission; Biotechnology and Biological Sciences Research Council; Ministry of Education, Culture, Sports, Science and Technology of Japan; National Institutes of Health, National Library of Medicine FX NCBI by the Intramural Research Program of the National Institutes of Health; National Library of Medicine; European Nucleotide Archive by the European Molecular Biology Laboratory, the Wellcome Trust, the FP7 Programme of the European Commission and the Biotechnology and Biological Sciences Research Council; at DDBJ by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Funding for open access charge: the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 5 TC 44 Z9 45 U1 0 U2 7 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 JAN PY 2012 VL 40 IS D1 BP D33 EP D37 DI 10.1093/nar/gkr1006 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300005 PM 22080546 ER PT J AU Kodama, Y Shumway, M Leinonen, R AF Kodama, Yuichi Shumway, Martin Leinonen, Rasko CA Int Nucleotide Sequence Database C TI The sequence read archive: explosive growth of sequencing data SO NUCLEIC ACIDS RESEARCH LA English DT Article AB New generation sequencing platforms are producing data with significantly higher throughput and lower cost. A portion of this capacity is devoted to individual and community scientific projects. As these projects reach publication, raw sequencing datasets are submitted into the primary next-generation sequence data archive, the Sequence Read Archive (SRA). Archiving experimental data is the key to the progress of reproducible science. The SRA was established as a public repository for next-generation sequence data as a part of the International Nucleotide Sequence Database Collaboration (INSDC). INSDC is composed of the National Center for Biotechnology Information (NCBI), the European Bioinformatics Institute (EBI) and the DNA Data Bank of Japan (DDBJ). The SRA is accessible at www.ebi.ac.uk/ena from EBI and at trace.ddbj.nig.ac.jp from DDBJ. In this article, we present the content and structure of the SRA and report on updated metadata structures, submission file formats and supported sequencing platforms. We also briefly outline our various responses to the challenge of explosive data growth. C1 [Kodama, Yuichi] Res Org Informat & Syst, Ctr Informat Biol, Mishima, Shizuoka 4118540, Japan. [Kodama, Yuichi] Res Org Informat & Syst, DNA Data Bank Japan, Natl Inst Genet, Mishima, Shizuoka 4118540, Japan. [Shumway, Martin] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Leinonen, Rasko] Wellcome Trust Genome Campus, European Bioinformat Inst, Cambridge CB10 1SD, England. RP Kodama, Y (reprint author), Res Org Informat & Syst, Ctr Informat Biol, Mishima, Shizuoka 4118540, Japan. EM ykodama@genes.nig.ac.jp OI Cochrane, Guy/0000-0001-7954-7057; Leinonen, Rasko/0000-0002-2639-7187 FU DNA Data Bank of Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan; European Molecular Biology Laboratory; European Commission; Wellcome Trust; National Library of Medicine; NIH FX DNA Data Bank of Japan, Ministry of Education, Culture, Sports, Science and Technology of Japan; European Molecular Biology Laboratory, European Commission and the Wellcome Trust; National Library of Medicine; Intramural Research Program of the NIH. Funding for open access charge: Ministry of Education, Culture, Sports, Science and Technology of Japan (management expense grant). NR 8 TC 171 Z9 175 U1 4 U2 23 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 JAN PY 2012 VL 40 IS D1 BP D54 EP D56 DI 10.1093/nar/gkr854 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300009 PM 22009675 ER PT J AU Li, MLJ Wang, PW Liu, XR Lim, EL Wang, ZY Yeager, M Wong, MP Sham, PC Chanock, SJ Wang, JW AF Li, Mulin Jun Wang, Panwen Liu, Xiaorong Lim, Ee Lyn Wang, Zhangyong Yeager, Meredith Wong, Maria P. Sham, Pak Chung Chanock, Stephen J. Wang, Junwen TI GWASdb: a database for human genetic variants identified by genome-wide association studies SO NUCLEIC ACIDS RESEARCH LA English DT Article ID OPEN-ACCESS DATABASE; TRANSCRIPTION FACTOR; WEB DATABASE; SNP; ANNOTATION; PHENOTYPE; SELECTION; DISEASE; PROFILES; GENOTYPE AB Recent advances in genome-wide association studies (GWAS) have enabled us to identify thousands of genetic variants (GVs) that are associated with human diseases. As next-generation sequencing technologies become less expensive, more GVs will be discovered in the near future. Existing databases, such as NHGRI GWAS Catalog, collect GVs with only genome-wide level significance. However, many true disease susceptibility loci have relatively moderate P values and are not included in these databases. We have developed GWASdb that contains 20 times more data than the GWAS Catalog and includes less significant GVs (P < 1.0 x 10(-3)) manually curated from the literature. In addition, GWASdb provides comprehensive functional annotations for each GV, including genomic mapping information, regulatory effects (transcription factor binding sites, microRNA target sites and splicing sites), amino acid substitutions, evolution, gene expression and disease associations. Furthermore, GWASdb classifies these GVs according to diseases using Disease-Ontology Lite and Human Phenotype Ontology. It can conduct pathway enrichment and PPI network association analysis for these diseases. GWASdb provides an intuitive, multifunctional database for biologists and clinicians to explore GVs and their functional inferences. It is freely available at http://jjwanglab.org/gwasdb and will be updated frequently. C1 [Li, Mulin Jun; Wang, Panwen; Liu, Xiaorong; Lim, Ee Lyn; Wang, Zhangyong; Wang, Junwen] Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. [Lim, Ee Lyn] Univ Oxford, Trinity Coll, Oxford, England. [Wang, Zhangyong] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90024 USA. [Yeager, Meredith] SAIC Frederick Inc, Core Genotyping Facil, Frederick, MD USA. [Yeager, Meredith; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wong, Maria P.] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Sham, Pak Chung] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. RP Wang, JW (reprint author), Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. EM junwen@uw.edu RI Wang, Junwen/C-4432-2009; Wang, Junwen/D-3700-2011 OI Wang, Junwen/0000-0002-4432-4707 FU University of Hong Kong [201007176262]; Research Grants Council of Hong Kong [781511M, 778609M, N_HKU752/10]; Food and Health Bureau of Hong Kong [10091262]; National Cancer Institute (NCI), NIH, USA FX The Small Project Fund (201007176262) of the University of Hong Kong; Research Grants Council of Hong Kong (781511M, 778609M, N_HKU752/10); Food and Health Bureau of Hong Kong (10091262); The intramural research program of the National Cancer Institute (NCI), NIH, USA. Funding for open access charge: Research Grants Council (781511M) of Hong Kong. NR 43 TC 68 Z9 72 U1 1 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 JAN PY 2012 VL 40 IS D1 BP D1047 EP D1054 DI 10.1093/nar/gkr1182 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300157 PM 22139925 ER PT J AU Madej, T Addess, KJ Fong, JH Geer, LY Geer, RC Lanczycki, CJ Liu, CL Lu, SN Marchler-Bauer, A Panchenko, AR Chen, J Thiessen, PA Wang, YL Zhang, DC Bryant, SH AF Madej, Thomas Addess, Kenneth J. Fong, Jessica H. Geer, Lewis Y. Geer, Renata C. Lanczycki, Christopher J. Liu, Chunlei Lu, Shennan Marchler-Bauer, Aron Panchenko, Anna R. Chen, Jie Thiessen, Paul A. Wang, Yanli Zhang, Dachuan Bryant, Stephen H. TI MMDB: 3D structures and macromolecular interactions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN; DATABASE AB Close to 60% of protein sequences tracked in comprehensive databases can be mapped to a known three-dimensional (3D) structure by standard sequence similarity searches. Potentially, a great deal can be learned about proteins or protein families of interest from considering 3D structure, and to this day 3D structure data may remain an underutilized resource. Here we present enhancements in the Molecular Modeling Database (MMDB) and its data presentation, specifically pertaining to biologically relevant complexes and molecular interactions. MMDB is tightly integrated with NCBI's Entrez search and retrieval system, and mirrors the contents of the Protein Data Bank. It links protein 3D structure data with sequence data, sequence classification resources and PubChem, a repository of small-molecule chemical structures and their biological activities, facilitating access to 3D structure data not only for structural biologists, but also for molecular biologists and chemists. MMDB provides a complete set of detailed and pre-computed structural alignments obtained with the VAST algorithm, and provides visualization tools for 3D structure and structure/sequence alignment via the molecular graphics viewer Cn3D. MMDB can be accessed at http://www.ncbi.nlm.nih.gov/structure. C1 [Madej, Thomas; Addess, Kenneth J.; Fong, Jessica H.; Geer, Lewis Y.; Geer, Renata C.; Lanczycki, Christopher J.; Liu, Chunlei; Lu, Shennan; Marchler-Bauer, Aron; Panchenko, Anna R.; Chen, Jie; Thiessen, Paul A.; Wang, Yanli; Zhang, Dachuan; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Madej, T (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38 A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. EM madej@ncbi.nlm.nih.gov RI Geer, Lewis/H-2714-2014; OI Marchler-Bauer, Aron/0000-0003-1516-0712 FU National Library of Medicine at National Institutes of Health/DHHS FX Funding to pay the open access charge: Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. Comments, suggestions and questions are welcome and should be directed to: info@ncbi.nlm.nih.gov. NR 9 TC 53 Z9 55 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 JAN PY 2012 VL 40 IS D1 BP D461 EP D464 DI 10.1093/nar/gkr1162 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300067 PM 22135289 ER PT J AU Pruitt, KD Tatusova, T Brown, GR Maglott, DR AF Pruitt, Kim D. Tatusova, Tatiana Brown, Garth R. Maglott, Donna R. TI NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RESOURCES; DATABASE AB The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of genomic, transcript and protein sequence records. These records are selected and curated from public sequence archives and represent a significant reduction in redundancy compared to the volume of data archived by the International Nucleotide Sequence Database Collaboration. The database includes over 16 000 organisms, 2.4 x 10(6) genomic records, 13 x 10(6) proteins and 2 x 10(6) RNA records spanning prokaryotes, eukaryotes and viruses (RefSeq release 49, September 2011). The RefSeq database is maintained by a combined approach of automated analyses, collaboration and manual curation to generate an up-to-date representation of the sequence, its features, names and cross-links to related sources of information. We report here on recent growth, the status of curating the human RefSeq data set, more extensive feature annotation and current policy for eukaryotic genome annotation via the NCBI annotation pipeline. More information about the resource is available online (see http://www.ncbi.nlm.nih.gov/RefSeq/). C1 [Pruitt, Kim D.; Tatusova, Tatiana; Brown, Garth R.; Maglott, Donna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM pruitt@ncbi.nlm.nih.gov FU National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 14 TC 516 Z9 524 U1 1 U2 42 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 JAN PY 2012 VL 40 IS D1 BP D130 EP D135 DI 10.1093/nar/gkr1079 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300020 PM 22121212 ER PT J AU Sayers, EW Barrett, T Benson, DA Bolton, E Bryant, SH Canese, K Chetvernin, V Church, DM DiCuccio, M Federhen, S Feolo, M Fingerman, IM Geer, LY Helmberg, W Kapustin, Y Krasnov, S Landsman, D Lipman, DJ Lu, ZY Madden, TL Madej, T Maglott, DR Marchler-Bauer, A Miller, V Karsch-Mizrachi, I Ostell, J Panchenko, A Phan, L Pruitt, KD Schuler, GD Sequeira, E Sherry, ST Shumway, M Sirotkin, K Slotta, D Souvorov, A Starchenko, G Tatusova, TA Wagner, L Wang, YL Wilbur, WJ Yaschenko, E Ye, J AF Sayers, Eric W. Barrett, Tanya Benson, Dennis A. Bolton, Evan Bryant, Stephen H. Canese, Kathi Chetvernin, Vyacheslav Church, Deanna M. DiCuccio, Michael Federhen, Scott Feolo, Michael Fingerman, Ian M. Geer, Lewis Y. Helmberg, Wolfgang Kapustin, Yuri Krasnov, Sergey Landsman, David Lipman, David J. Lu, Zhiyong Madden, Thomas L. Madej, Tom Maglott, Donna R. Marchler-Bauer, Aron Miller, Vadim Karsch-Mizrachi, Ilene Ostell, James Panchenko, Anna Phan, Lon Pruitt, Kim D. Schuler, Gregory D. Sequeira, Edwin Sherry, Stephen T. Shumway, Martin Sirotkin, Karl Slotta, Douglas Souvorov, Alexandre Starchenko, Grigory Tatusova, Tatiana A. Wagner, Lukas Wang, Yanli Wilbur, W. John Yaschenko, Eugene Ye, Jian TI Database resources of the National Center for Biotechnology Information SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ONLINE MENDELIAN INHERITANCE; BIOLOGICAL PATHWAYS; PROTEIN SEQUENCES; GENOMES; SEARCH; ENTREZ; NCBI; SYSTEM; GENES; KEGG AB In addition to maintaining the GenBank (R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides analysis and retrieval resources for the data in GenBank and other biological data made available through the NCBI Website. NCBI resources include Entrez, the Entrez Programming Utilities, MyNCBI, PubMed, PubMed Central (PMC), Gene, the NCBI Taxonomy Browser, BLAST, BLAST Link (BLink), Primer-BLAST, COBALT, Splign, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, dbVar, Epigenomics, Genome and related tools, the Map Viewer, Model Maker, Evidence Viewer, Trace Archive, Sequence Read Archive, BioProject, BioSample, Retroviral Genotyping Tools, HIV-1/Human Protein Interaction Database, Gene Expression Omnibus (GEO), Probe, Online Mendelian Inheritance in Animals (OMIA), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD), the Conserved Domain Architecture Retrieval Tool (CDART), Biosystems, Protein Clusters and the PubChem suite of small molecule databases. Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov. C1 [Sayers, Eric W.; Barrett, Tanya; Benson, Dennis A.; Bolton, Evan; Bryant, Stephen H.; Canese, Kathi; Chetvernin, Vyacheslav; Church, Deanna M.; DiCuccio, Michael; Federhen, Scott; Feolo, Michael; Fingerman, Ian M.; Geer, Lewis Y.; Kapustin, Yuri; Krasnov, Sergey; Landsman, David; Lipman, David J.; Lu, Zhiyong; Madden, Thomas L.; Madej, Tom; Maglott, Donna R.; Marchler-Bauer, Aron; Miller, Vadim; Karsch-Mizrachi, Ilene; Ostell, James; Panchenko, Anna; Phan, Lon; Pruitt, Kim D.; Schuler, Gregory D.; Sequeira, Edwin; Sherry, Stephen T.; Shumway, Martin; Sirotkin, Karl; Slotta, Douglas; Souvorov, Alexandre; Starchenko, Grigory; Tatusova, Tatiana A.; Wagner, Lukas; Wang, Yanli; Wilbur, W. John; Yaschenko, Eugene; Ye, Jian] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Helmberg, Wolfgang] Med Univ Graz, Univ Clin Blood Grp Serol & Transfus Med, A-8036 Graz, Austria. RP Sayers, EW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM sayers@ncbi.nlm.nih.gov RI Geer, Lewis/H-2714-2014; OI Marchler-Bauer, Aron/0000-0003-1516-0712; Landsman, David/0000-0002-9819-6675 FU National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 60 TC 304 Z9 311 U1 2 U2 50 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 JAN PY 2012 VL 40 IS D1 BP D13 EP D25 DI 10.1093/nar/gkr1184 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300003 PM 22140104 ER PT J AU Shoemaker, BA Zhang, DC Tyagi, M Thangudu, RR Fong, JH Marchler-Bauer, A Bryant, SH Madej, T Panchenko, AR AF Shoemaker, Benjamin A. Zhang, Dachuan Tyagi, Manoj Thangudu, Ratna R. Fong, Jessica H. Marchler-Bauer, Aron Bryant, Stephen H. Madej, Thomas Panchenko, Anna R. TI IBIS (Inferred Biomolecular Interaction Server) reports, predicts and integrates multiple types of conserved interactions for proteins SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LIGAND-BINDING-SITES; WEB SERVER; ANNOTATION; SEQUENCES; PARTNERS; DATABASE AB We have recently developed the Inferred Biomolecular Interaction Server (IBIS) and database, which reports, predicts and integrates different types of interaction partners and locations of binding sites in proteins based on the analysis of homologous structural complexes. Here, we highlight several new IBIS features and options. The server's webpage is now redesigned to allow users easier access to data for different interaction types. An entry page is added to give a quick summary of available results and to now accept protein sequence accessions. To elucidate the formation of protein complexes, not just binary interactions, IBIS currently presents an expandable interaction network. Previously, IBIS provided annotations for four different types of binding partners: proteins, small molecules, nucleic acids and peptides; in the current version a new protein-ion interaction type has been added. Several options provide easy downloads of IBIS data for all Protein Data Bank (PDB) protein chains and the results for each query. In this study, we show that about one-third of all RefSeq sequences can be annotated with IBIS interaction partners and binding sites. The IBIS server is available at http://www.ncbi.nlm.nih.gov/Structure/ibis/ibis.cgi and updated biweekly. C1 [Shoemaker, Benjamin A.; Zhang, Dachuan; Tyagi, Manoj; Thangudu, Ratna R.; Fong, Jessica H.; Marchler-Bauer, Aron; Bryant, Stephen H.; Madej, Thomas; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. EM madej@ncbi.nlm.nih.gov; panch@ncbi.nlm.nih.gov RI Tyagi, Manoj/K-8438-2014; OI Marchler-Bauer, Aron/0000-0003-1516-0712 FU National Institutes of Health/Department of Health and Human Service (DHHS); National Library of Medicine; National Institutes of Health FX National Institutes of Health/Department of Health and Human Service (DHHS) (Intramural Research program of the National Library of Medicine). Funding for open access charge: National Institutes of Health Intramural Program. NR 25 TC 32 Z9 32 U1 0 U2 1 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 JAN PY 2012 VL 40 IS D1 BP D834 EP D840 DI 10.1093/nar/gkr997 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300125 PM 22102591 ER PT J AU Wang, YL Xiao, JW Suzek, TO Zhang, J Wang, JY Zhou, ZG Han, LY Karapetyan, K Dracheva, S Shoemaker, BA Bolton, E Gindulyte, A Bryant, SH AF Wang, Yanli Xiao, Jewen Suzek, Tugba O. Zhang, Jian Wang, Jiyao Zhou, Zhigang Han, Lianyi Karapetyan, Karen Dracheva, Svetlana Shoemaker, Benjamin A. Bolton, Evan Gindulyte, Asta Bryant, Stephen H. TI PubChem's BioAssay Database SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CHEMICAL BIOLOGY; CIRCADIAN CLOCK AB PubChem (http://pubchem.ncbi.nlm.nih.gov) is a public repository for biological activity data of small molecules and RNAi reagents. The mission of PubChem is to deliver free and easy access to all deposited data, and to provide intuitive data analysis tools. The PubChem BioAssay database currently contains 500 000 descriptions of assay protocols, covering 5000 protein targets, 30 000 gene targets and providing over 130 million bioactivity outcomes. PubChem's bioassay data are integrated into the NCBI Entrez information retrieval system, thus making PubChem data searchable and accessible by Entrez queries. Also, as a repository, PubChem constantly optimizes and develops its deposition system answering many demands of both high- and low-volume depositors. The PubChem information platform allows users to search, review and download bioassay description and data. The PubChem platform also enables researchers to collect, compare and analyze biological test results through web-based and programmatic tools. In this work, we provide an update for the PubChem BioAssay resource, including information content growth, data model extension and new developments of data submission, retrieval, analysis and download tools. C1 [Wang, Yanli; Xiao, Jewen; Suzek, Tugba O.; Zhang, Jian; Wang, Jiyao; Zhou, Zhigang; Han, Lianyi; Karapetyan, Karen; Dracheva, Svetlana; Shoemaker, Benjamin A.; Bolton, Evan; Gindulyte, Asta; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Suzek, Tugba/B-6943-2015; OI Suzek, Tugba/0000-0002-3243-1759 FU NIH; US government FX The NIH Intramural Research program. Funding for open access charge: US government. NR 13 TC 195 Z9 199 U1 2 U2 28 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 JAN PY 2012 VL 40 IS D1 BP D400 EP D412 DI 10.1093/nar/gkr1132 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 869MD UT WOS:000298601300059 PM 22140110 ER PT J AU Hostetler, JA Onorato, DP Bolker, BM Johnson, WE O'Brien, SJ Jansen, D Oli, MK AF Hostetler, Jeffrey A. Onorato, David P. Bolker, Benjamin M. Johnson, Warren E. O'Brien, Stephen J. Jansen, Deborah Oli, Madan K. TI Does genetic introgression improve female reproductive performance? A test on the endangered Florida panther SO OECOLOGIA LA English DT Article DE Abundance; Cumulative logit regression; Demography; Model-averaging; Season ID ET-AL. 2006; INBREEDING DEPRESSION; CARNIVORE MANAGEMENT; COUGAR DEMOGRAPHY; HUNTED POPULATION; DYNAMICS; METAPOPULATION; RESTORATION; ADVANTAGE; CONCOLOR AB Genetic introgression has been suggested as a management tool for mitigating detrimental effects of inbreeding depression, but the role of introgression in species conservation has been controversial, partly because population-level impacts of genetic introgressions are not well understood. Concerns about potential inbreeding depression in the endangered Florida panther (Puma concolor coryi) led to the release of eight female Texas pumas (P. c. stanleyana) into the Florida panther population in 1995. We used long-term reproductive data (1995-2008) collected from 61 female Florida panthers to estimate and model reproduction probability (probability of producing a litter) and litter size, and to investigate the influence of intentional genetic introgression on these parameters. Overall, 6-month probability of reproduction (+/- 1SE) was 0.232 +/- 0.021 and average litter size was 2.60 +/- 0.09. Although F(1) admixed females had a lower reproduction probability than females with other ancestries, this was most likely because kittens born to F(1) females survive better; consequently, these females are unavailable for breeding until kittens are independent. There was no evidence for the effect of ancestry on litter size or of heterozygosity on probability of reproduction or litter size. In contrast, earlier studies have shown that genetic introgression positively affected Florida panther survival. Our results, along with those of earlier studies, clearly suggest that genetic introgression can have differential effects on components of fitness and highlight the importance of examining multiple demographic parameters when evaluating the effects of management actions. C1 [Hostetler, Jeffrey A.; Oli, Madan K.] Univ Florida, Dept Wildlife Ecol & Conservat, Gainesville, FL 32611 USA. [Onorato, David P.] Florida Fish & Wildlife Conservat Commiss, Fish & Wildlife Res Inst, Naples, FL 34114 USA. [Bolker, Benjamin M.] McMaster Univ, Dept Math & Stat, Hamilton, ON L86 4K1, Canada. [Bolker, Benjamin M.] McMaster Univ, Dept Biol, Hamilton, ON L86 4K1, Canada. [Johnson, Warren E.; O'Brien, Stephen J.] Natl Canc Inst, Lab Genom Div, Frederick, MD 21702 USA. [Jansen, Deborah] Big Cypress Natl Preserve, Ochopee, FL 34141 USA. RP Hostetler, JA (reprint author), Natl Zool Pk, Migratory Bird Ctr, Smithsonian Conservat Biol Inst, Washington, DC 20013 USA. EM hostetlerj@si.edu RI Hostetler, Jeffrey/A-3345-2011; Johnson, Warren/D-4149-2016; OI Hostetler, Jeffrey/0000-0003-3669-1758; Johnson, Warren/0000-0002-5954-186X; Bolker, Benjamin/0000-0002-2127-0443 FU Florida Panther Research and Management Trust, National Park Service, University of Florida, United States Fish and Wildlife Service [401816G091] FX We thank D. Land, M. Cunningham, Roy McBride, M. Lotz, D. Shindle, M. Criffield, S. Schulze, D. Giardina, A. Johnson, L. Oberhofer, M. Alvarado, H. Fitting, T. O'Meara, and Rocky, Rowdy, and C. McBride and others for assistance with fieldwork. We also thank J. Nichols for statistical advice, M. Roelke for genetic analyses, and J. Nichols, M. Sunquist, and two anonymous reviewers for reviewing an earlier draft of this manuscript. This work was funded through the Florida Panther Research and Management Trust Fund, National Park Service, University of Florida, and grant Agreement No: 401816G091 from the United States Fish and Wildlife Service. The views and conclusions presented herein are those of the authors and do not necessarily reflect the views and conclusions of the federal government. NR 58 TC 6 Z9 6 U1 2 U2 76 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0029-8549 J9 OECOLOGIA JI Oecologia PD JAN PY 2012 VL 168 IS 1 BP 289 EP 300 DI 10.1007/s00442-011-2083-0 PG 12 WC Ecology SC Environmental Sciences & Ecology GA 875TN UT WOS:000299058100027 PM 21805300 ER PT J AU Bruno, RD Boulanger, CA Smith, GH AF Bruno, R. D. Boulanger, C. A. Smith, G. H. TI Notch-induced mammary tumorigenesis does not involve the lobule-limited epithelial progenitor SO ONCOGENE LA English DT Article DE lobular progenitor; PI-MEC; Int3; Notch4; mammary development ID GLAND DEVELOPMENT; TUMOR VIRUS; PROGESTERONE-RECEPTOR; STEM-CELLS; IN-VIVO; EXPRESSION; DIFFERENTIATION; RENEWAL; INT-3; GENE AB The mouse mammary epithelial cell hierarchy contains both multipotent stem cell as well as lineage-limited duct and lobular progenitor cell functions. The latter-also termed parity-identified mammary epithelial cells (PI-MECs)-are marked by beta-galactosidase (beta Gal) expression following pregnancy and involution in whey acidic protein promoter (WAP)-Cre/Rosa26-flox-stop-flox-lacZ (WC/R26) mice, and are the targets of tumorigenic transformation in mouse mammary tumor virus-erbB2 transgenic mice. In this study, we demonstrate that an epithelial population distinct from PI-MECs is transformed during WAP-Int3 tumorigenesis. As expected, WAP-Int3/WC/R26 triple-transgenic mice failed to undergo secretory alveolar development, failed to lactate and developed mammary tumors. Following pregnancy and involution, beta Gal+ mammary epithelial cells were found in the normal mammary tissue, but the resulting mammary tumors were all beta Gal-. WAP-Int3/WC/R26 mammary glands contained ample estrogen receptor alpha (ER alpha)+ MECs, but only rare (<1%) progesterone receptor (PR)+ and RANKL+ cells. In addition, dissociated MECs from WAP-Int3/WC/R26 glands failed to regenerate a mammary tree upon transplantation into a cleared fat-pad of a nu/nu recipient mouse. However, when mixed with normal MECs, PI-MECs from WAP-Int3/WC/R26 mice contributed progeny to the resulting functional outgrowth. The WAP-Int3/WC/R26-derived PI-MECs displayed all of the properties of fully functional lobular progenitors including giving rise to ER alpha+, PR+, smooth muscle actin+ and RANKL+ epithelial progeny. These results demonstrate that WAP-Int3 has no oncogenic effect upon PI-MECs and that the expansion of functional lobular progenitors is required for secretory alveolar development and lactation. Furthermore, lobular progenitor function is ultimately controlled by signals within its microenvironment. Oncogene (2012) 31, 60-67; doi: 10.1038/onc.2011.215; published online 13 June 2011 C1 [Smith, G. H.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 1112B, Bethesda, MD 20892 USA. EM smithg@mail.nih.gov OI Bruno, Robert/0000-0003-3329-9478 FU NCI's Center for Cancer Research FX The NCI's Center for Cancer Research Intramural Research Program funded this work. NR 23 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN PY 2012 VL 31 IS 1 BP 60 EP 67 DI 10.1038/onc.2011.215 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 877JT UT WOS:000299176200006 PM 21666720 ER PT J AU Lee, MH Lahusen, T Wang, RH Xiao, C Xu, X Hwang, YS He, WW Shi, Y Deng, CX AF Lee, M-H Lahusen, T. Wang, R-H Xiao, C. Xu, X. Hwang, Y-S He, W-W Shi, Y. Deng, C-X TI Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation SO ONCOGENE LA English DT Article DE BRCA1; breast cancer; promoter; nude mice; YY1 ID SPORADIC BREAST-CANCER; TUMOR-SUPPRESSOR; ADENOVIRUS E1A; TRANSCRIPTIONAL REPRESSION; GENE-EXPRESSION; FACTOR YY1; C-MYC; PROMOTER; BINDING; YIN-YANG-1 AB Expression of the breast cancer-associated gene 1 (BRCA1) in sporadic breast cancers is usually reduced, yet the underlying mechanisms remains elusive. To identify factors that are responsible for reduced BRCA1 expression, we screened 92 known transcription factors for their ability to regulate expression of BRCA1. Among several potential regulators, the Gli-Krueppel-related transcription factor Yin Yang 1 (YY1) showed the most dramatic transactivation of the BRCA1 promoter. YY1 binds to the promoter of BRCA1, and its overexpression resulted in increased expression of BRCA1 and a number of BRCA1 downstream genes. We further showed that overexpression of YY1 in cancer cells inhibited cell proliferation, foci formation and tumor growth in nude mice. To assess the clinical relevance between YY1 and BRCA1, we studied expression of YY1 and BRCA1 from human breast cancer samples and tissue arrays, and detected a significant positive correlation between the level of YY1 and BRCA1 expression in these cancers. Taken together, these findings suggest that YY1 is a key regulator of BRCA1 expression and may be causally linked to the molecular etiology of human breast cancer. Oncogene (2012) 31, 116-127; doi: 10.1038/onc.2011.217; published online 13 June 2011 C1 [Lee, M-H; Lahusen, T.; Wang, R-H; Xiao, C.; Xu, X.; Deng, C-X] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Hwang, Y-S] NCI, Lab Cell & Dev Signaling, NIH, Frederick, MD 21701 USA. [He, W-W] Origene Technol Inc, Rockville, MD USA. [Shi, Y.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA FX We thank members of Dr Deng laboratory for their critical discussion of this work and technical assistance. This research was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA. NR 54 TC 16 Z9 17 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN PY 2012 VL 31 IS 1 BP 116 EP 127 DI 10.1038/onc.2011.217 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 877JT UT WOS:000299176200011 PM 21666725 ER PT J AU Pla, AF Ong, HL Cheng, KT Brossa, A Bussolati, B Lockwich, T Paria, B Munaron, L Ambudkar, IS AF Pla, A. Fiorio Ong, H. L. Cheng, K. T. Brossa, A. Bussolati, B. Lockwich, T. Paria, B. Munaron, L. Ambudkar, I. S. TI TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling SO ONCOGENE LA English DT Article DE Ca2+ signals; TRP channels; endothelial cells; cell migration; actin remodeling; tumor angiogenesis ID PROTEIN-KINASE; ION CHANNELS; CA2+ ENTRY; PLASMA-MEMBRANE; IN-VIVO; ANGIOGENESIS; EXPRESSION; GROWTH; PROLIFERATION; TRANSLOCATION AB Changes in intracellular calcium [Ca2+](i) levels control critical cytosolic and nuclear events that are involved in the initiation and progression of tumor angiogenesis in endothelial cells (ECs). Therefore, the mechanism(s) involved in agonist-induced Ca-i(2+) signaling is a potentially important molecular target for controlling angiogenesis and tumor growth. Several studies have shown that blood vessels in tumors differ from normal vessels in their morphology, blood flow and permeability. We had previously reported a key role for arachidonic acid (AA)-mediated Ca2+ entry in the initial stages of tumor angiogenesis in vitro. In this study we assessed the mechanism involved in AA-induced EC migration. We report that TRPV4, an AA-activated channel, is differentially expressed in EC derived from human breast carcinomas (BTEC) as compared with 'normal' EC (HMVEC). BTEC display a significant increase in TRPV4 expression, which was correlated with greater Ca2+ entry, induced by AA or 4 alpha PDD (a selective TRPV4 agonist) in the tumor-derived ECs. Wound-healing assays revealed a key role of TRPV4 in regulating cell migration of BTEC but not HMVEC. Knockdown of TRPV4 expression completely abolished AA-induced BTEC migration, suggesting that TRPV4 mediates the pro-angiogenic effects promoted by AA. Furthermore, pre-incubation of BTEC with AA induced actin remodeling and a subsequent increase in the surface expression of TRPV4. This was consistent with the increased plasma membrane localization of TRPV4 and higher AA-stimulated Ca2+ entry in the migrating cells. Together, the data presented herein demonstrate that: (1) TRPV4 is differentially expressed in tumor-derived versus 'normal' EC; (2) TRPV4 has a critical role in the migration of tumor-derived but not 'normal' EC migration; and (3) AA induces actin remodeling in BTEC, resulting in a corresponding increase of TRPV4 expression in the plasma membrane. We suggest that the latter is critical for migration of EC and thus in promoting angiogenesis and tumor growth. Oncogene (2012) 31, 200-212; doi:10.1038/onc.2011.231; published online 20 June 2011 C1 [Pla, A. Fiorio; Brossa, A.; Munaron, L.] Univ Turin, Dept Anim & Human Biol, I-10123 Turin, Italy. [Pla, A. Fiorio; Munaron, L.] Ctr Complex Syst Mol Biol & Med SysBioM, Turin, Italy. [Pla, A. Fiorio; Munaron, L.] Nanostruct Interfaces & Surfaces Ctr Excellence, Turin, Italy. [Ong, H. L.; Cheng, K. T.; Lockwich, T.; Paria, B.; Ambudkar, I. S.] NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Brossa, A.; Bussolati, B.] Univ Turin, Ctr Mol Biotechnol, Dept Internal Med, Turin, Italy. RP Pla, AF (reprint author), Univ Turin, Dept Anim & Human Biol, V Accademia Albertina 13, I-10123 Turin, Italy. EM alessandra.fiorio@unito.it RI Fiorio Pla, Alessandra/B-6646-2012; OI Fiorio Pla, Alessandra/0000-0003-4576-1594; Bussolati, Benedetta/0000-0002-3663-5134 FU University of Torino; Regione Piemonte (Ricerca Scientifica Applicata Sanita'); National Institute of Dental and Craniofacial Research FX This work was supported by the University of Torino, Regione Piemonte (Ricerca Scientifica Applicata Sanita') and the National Institute of Dental and Craniofacial Research (Intramural Research). We thank Dr Kenneth Yamada (NIDCR, NIH, Bethesda, MD, USA) for the beta-actin-mCherry and Dr Michael X. Zhu (Department of Physiology and Cell Biology, Ohio State University, OH, USA) for the TRPV4-GFP construct. NR 53 TC 27 Z9 27 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 JAN PY 2012 VL 31 IS 2 BP 200 EP 212 DI 10.1038/onc.2011.231 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 879CN UT WOS:000299307400006 ER PT J AU Roescher, N Lodde, BM Vosters, JL Tak, PP Catalan, MA Illei, GG Chiorini, JA AF Roescher, N. Lodde, B. M. Vosters, J. L. Tak, P. P. Catalan, M. A. Illei, G. G. Chiorini, J. A. TI Temporal changes in salivary glands of non-obese diabetic mice as a model for Sjogren's syndrome SO ORAL DISEASES LA English DT Article DE Sjogren's syndrome; salivary gland; autoimmune sialadenitis; non-obese diabetic mouse; immunology ID INTERCELLULAR-ADHESION MOLECULE-1; NOD MOUSE MODEL; LYMPHOCYTIC INFILTRATION; LYMPHOID ORGANIZATION; RITUXIMAB TREATMENT; AUTOIMMUNE-DISEASE; CIRCULATING LEVELS; EPITHELIAL-CELLS; DENDRITIC CELLS; HIGH EXPRESSION AB OBJECTIVE: Non-obese diabetic (NOD) mice develop an autoimmune exocrinopathy that shows similarities with Sjogren's syndrome. They provide an experimental model to study the pathoetiogenesis of this disease. MATERIALS AND METHODS: Salivary gland (SG) function and salivary sodium content were measured in 8-, 12-, 16- and 20-week-old NOD and age-matched CB6 mice. In NOD mice, SG expression of phenotypic cell markers, B cell-stimulating and costimulatory molecules were evaluated. Cytokine levels were measured in serum and SG homogenates. RESULTS: Microscopically evident SG inflammation in NOD mice was preceded by expression of intercellular adhesion molecule 1 on epithelial cells in the presence of macrophages and relatively high levels of cytokines. Next, an influx consisting of mainly T, B, natural killer, plasma and dendritic cells was seen. Most cytokines, except for interleukin (IL) 12/IL23p40 and B cell-activating factor, decreased or remained stable over time, while glandular function deteriorated from 16 weeks of age onward compared with CB6 mice. CONCLUSION: Sjogren's syndrome-like disease in NOD mice occurs in multiple stages; immunological and physiological abnormalities can be detected before focal inflammation appears and salivary output declines. Extrapolating this knowledge to human subjects could help in understanding the pathogenesis and aid the identification of potential therapeutic targets. C1 [Roescher, N.; Lodde, B. M.; Vosters, J. L.; Tak, P. P.] Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, NL-1100 DE Amsterdam, Netherlands. [Roescher, N.; Vosters, J. L.; Illei, G. G.; Chiorini, J. A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Catalan, M. A.] Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, Bethesda, MD USA. RP Roescher, N (reprint author), Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, POB 22700, NL-1100 DE Amsterdam, Netherlands. EM n.roescher@amc.uva.nl OI Catalan, Marcelo/0000-0003-3544-2821 FU NIH; Dutch Arthritis Association; NIH Fellows Editorial Board for editorial assistance FX The authors declare no conflict of interest. This research was funded by an Intramural NIH grant to JAC and a grant from the Dutch Arthritis Association to JLV. We thank the NIH Fellows Editorial Board for editorial assistance, Corine van der Horst for technical assistance with the digital image analysis and Dr J. E. Melvin for assistance with the sodium measurements. NR 54 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD JAN PY 2012 VL 18 IS 1 BP 96 EP 106 DI 10.1111/j.1601-0825.2011.01852.x PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 869JD UT WOS:000298593300011 PM 21914088 ER PT J AU Shankaran, S Laptook, AR McDonald, SA Higgins, RD Tyson, JE Ehrenkranz, RA Das, A Sant'Anna, G Goldberg, RN Bara, R Walsh, MC AF Shankaran, Seetha Laptook, Abbot R. McDonald, Scott A. Higgins, Rosemary D. Tyson, Jon E. Ehrenkranz, Richard A. Das, Abhik Sant'Anna, Guilherme Goldberg, Ronald N. Bara, Rebecca Walsh, Michele C. CA Eunice Kennedy Shriver Natl Inst TI Temperature profile and outcomes of neonates undergoing whole body hypothermia for neonatal hypoxic-ischemic encephalopathy SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE encephalopathy; hypothermia; hypoxia-ischemia; newborn; temperature; whole-body cooling ID MODERATE HYPOTHERMIA; TRIAL AB Background: Decreases below the target temperature were noted among neonates undergoing cooling in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for neonatal hypoxic-ischemic encephalopathy. Objective: To examine the temperature profile and impact on outcome among >= 36 wk gestation neonates randomized at <= 6 hrs of age targeting an esophageal temperature of 33.5 degrees C for 72 hrs. Design, Setting, Patients: Infants with intermittent temperatures recorded of <32.0 degrees C during induction and maintenance of cooling were compared to all other cooled infants, and the relationship with outcome at 18 months was evaluated. Interventions: None. Measurements and Main Results: There were no differences in the stage of encephalopathy, acidosis, or 10 min Apgar scores between infants with temperatures of <32.0 degrees C during induction (n = 33) or maintenance (n = 10) and all other infants who were cooled (n = 58); however, birth weight was lower and the need for blood pressure support higher among infants with temperatures of <32.0 degrees C compared to all other cooled infants. No increase in acute adverse events was noted among infants with temperatures of <32.0 degrees C, and hours spent at <32 degrees C was not associated with the primary outcome of death or moderate/severe disability or the Bayley II Mental Developmental Index at 18 months. Conclusions: Term infants with a lower birth weight are at risk for decreasing temperatures of <32.0 degrees C while undergoing body cooling using a servo-controlled system. This information suggests extra caution during the application of hypothermia as these lower birth weight infants are at risk for overcooling. Our findings may assist in planning additional trials of lower target temperature for neonatal hypoxic-ischemic encephalopathy. (Pediatr Crit Care Med 2012; 13:53-59) C1 [Shankaran, Seetha; Bara, Rebecca] Wayne State Univ, Sch Med, Detroit, MI 48202 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [McDonald, Scott A.; Das, Abhik] RTI Int, Res Triangle Pk, NC USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Tyson, Jon E.] Univ Texas Houston, Houston, TX USA. [Ehrenkranz, Richard A.] Yale Univ, New Haven, CT USA. [Sant'Anna, Guilherme] McGill Univ, Montreal, PQ, Canada. [Goldberg, Ronald N.] Duke Univ, Durham, NC USA. [Walsh, Michele C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Shankaran, S (reprint author), Wayne State Univ, Sch Med, Detroit, MI 48202 USA. EM sshankar@med.wayne.edu FU Case Western University, Cleveland, OH [U10 HD21364]; University of Texas at Houston, TX [U10 HD21373]; Wayne State University, Detroit, MI [U10 HD21385]; University of Miami, FL [U10 HD21397]; Emory University, Atlanta, GA [U10 HD27851]; University of Cincinnati, OH [U10 HD27853]; Indiana University, Bloomington, IN [U10 HD27856]; Yale University, New Haven, CT [U10 HD27871]; Stanford University, Stanford, CA [U10 HD27880]; Brown University, Providence, RI [U10 HD27904]; University of Alabama, Birmingham, AL [U10 HD34216]; RTI International, Research Triangle Park, NC [U10 HD36790]; University of California-San Diego, CA [U10 HD40461]; Duke University, Durham, NC [U10 HD40492]; Wake Forest University, Winston-Salem, NC [U10 HD40498] FX Supported, in part, by grants U10 HD21364 (Case Western University, Cleveland, OH), U10 HD21373 (University of Texas at Houston, TX), U10 HD21385 (Wayne State University, Detroit, MI), U10 HD21397 (University of Miami, FL), U10 HD27851 (Emory University, Atlanta, GA), U10 HD27853 (University of Cincinnati, OH), U10 HD27856 (Indiana University, Bloomington, IN), U10 HD27871 (Yale University, New Haven, CT), U10 HD27880 (Stanford University, Stanford, CA), U10 HD27904 (Brown University, Providence, RI), U10 HD34216 (University of Alabama, Birmingham, AL), U10 HD36790 (RTI International, Research Triangle Park, NC), U10 HD40461 (University of California-San Diego, CA), U10 HD40492 (Duke University, Durham, NC), and U10 HD40498 (Wake Forest University, Winston-Salem, NC). NR 14 TC 17 Z9 18 U1 0 U2 3 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 JAN PY 2012 VL 13 IS 1 BP 53 EP 59 DI 10.1097/PCC.0b013e31821926bc PG 7 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 875YT UT WOS:000299073000021 PM 21499182 ER PT J AU Ballard, ED Bosk, A Snyder, D Pao, M Bridge, JA Wharff, EA Teach, SJ Horowitz, L AF Ballard, Elizabeth D. Bosk, Abigail Snyder, Deborah Pao, Maryland Bridge, Jeffrey A. Wharff, Elizabeth A. Teach, Stephen J. Horowitz, Lisa TI Patients' Opinions About Suicide Screening in a Pediatric Emergency Department SO PEDIATRIC EMERGENCY CARE LA English DT Article DE suicide risk; screening; qualitative; patient opinion ID PRIMARY-CARE; RISK; FEASIBILITY; ADOLESCENTS; CAREGIVERS; IDEATION AB Objective: Understanding how children react to suicide screening in an emergency department (ED) can inform implementation strategies. This qualitative study describes pediatric patients' opinions regarding suicide screening in that setting. Methods: As part of a multisite instrument validation study, patients 10 to 21 years presenting with both psychiatric and nonpsychiatric complaints to an urban, tertiary care pediatric ED were recruited for suicide screening. Interviews with subjects included the question, "do you think ER nurses should ask kids about suicide/thoughts about hurting them-selves...why/why not?'' Responses were transcribed verbatim and uploaded into NVivo8.0 qualitative software for coding and content analysis. Results: Of the 156 patients who participated in the study, 106 (68%) presented to the ED with nonpsychiatric complaints and 50 (32%) presented with psychiatric complaints. The patients' mean (SD) age was 14.6 (2.8) years (range, 10-21 years), and 56% of the sample was female. All patients answered the question of interest, and 149 (96%) of 156 patients supported the idea that nurses should ask youth about suicide in the ED. The 5 most frequently endorsed themes were as follows: (1) identification of youth at risk (31/156, 20%), (2) a desire to feel known and understood by clinicians (31/156, 20%), (3) connection of youth with help and resources (28/156, 18%), (4) prevention of suicidal behavior (25/156, 16%), and (5) lack of other individuals to speak with about these issues (19/156, 12%). Conclusions: Pediatric patients in the ED support suicide screening after being asked a number of suicide-related questions. Further work should evaluate the impact of suicide screening on referral practices and link screening efforts with evidence-based interventions. C1 [Ballard, Elizabeth D.; Bosk, Abigail; Snyder, Deborah; Pao, Maryland; Horowitz, Lisa] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Ballard, Elizabeth D.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43210 USA. [Bridge, Jeffrey A.] Ohio State Univ, Columbus, OH 43210 USA. [Wharff, Elizabeth A.] Childrens Hosp Boston, Dept Psychiat, Boston, MA USA. [Wharff, Elizabeth A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Div Emergency Med, Washington, DC 20010 USA. RP Horowitz, L (reprint author), NIH, Bldg 10-CRC,6-5340, Bethesda, MD 20892 USA. EM horowitzl@mail.nih.gov FU NIMH National Institutes of Health; National Institute of Mental Health FX The research for this article was supported by the Intramural Research Program of the NIMH National Institutes of Health and the National Institute of Mental Health. NR 24 TC 4 Z9 4 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD JAN PY 2012 VL 28 IS 1 BP 34 EP 38 DI 10.1097/PEC.0b013e31823f2315 PG 5 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 876JW UT WOS:000299104800009 PM 22193697 ER PT J AU Siberry, GK Warshaw, MG Williams, PL Spector, SA Decker, MD Jean-Philippe, P Yogev, R Heckman, BE Manzella, A Roa, J Nachman, S Lujan-Zilbermann, J AF Siberry, George K. Warshaw, Meredith G. Williams, Paige L. Spector, Stephen A. Decker, Michael D. Jean-Philippe, Patrick Yogev, Ram Heckman, Barbara E. Manzella, Adam Roa, Jhoanna Nachman, Sharon Lujan-Zilbermann, Jorge CA IMPAACT P1065 Protocol Team TI Safety and Immunogenicity of Quadrivalent Meningococcal Conjugate Vaccine in 2-to 10-year-old Human Immunodeficiency Virus-infected Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE pediatric HIV infection; meningococcal vaccine; conjugate vaccine ID ACTIVE ANTIRETROVIRAL THERAPY; POLYSACCHARIDE VACCINE; ADOLESCENTS; PREDICTORS; TRIAL AB Background: Human immunodeficiency virus (HIV)-infected children are at increased risk of meningococcal infection and poor response to quadrivalent meningococcal conjugate vaccine (MCV4), but MCV4 has not been studied in preadolescent HIV-infected children. Methods: The P1065 trial enrolled 2- to 10-year-old HIV-infected children with CD4 >= 25% to receive MCV4 at entry and at week 24. Rates of response (>= 4-fold increase in rabbit serum bactericidal antibody) against each meningococcal serogroup (A, C, Y, W-135), geometric mean titers, and rates of seroprotection (rabbit serum bactericidal antibody titer >= 1: 128) were determined from sera obtained at entry and weeks 4, 24, 28, and 72. Adverse events were assessed for 6 weeks after each MCV4 dose. Results: At entry, 47% of the 59 participants were male, 56% black, 31% Latino, median age was 6 years, 88% were receiving antiretroviral therapy, and 75% had viral load <400 copies/mL. There were no serious adverse events within 6 weeks after MCV4 doses; all vaccination reactions were mild. Response after a single MCV4 dose was high to serogroup A (92%) and W-135 (98%); responses improved after a second dose for serogroup C (43%-80%) (P = 0.0001) and Y (76%-84%) (P = 0.38). By week 72, seroprotection rates were 93%, 91%, 78%, and 46% for serogroups W-135, Y, A, and C, respectively. Conclusions: Two doses of MCV4 were safe and immunogenic in 2-to 10-year-old HIV-infected children. The second dose increased the proportion of children who made a response to serogroup C. Seroprotection waned substantially for serogroups A and C within 1 year of last MCV4 dose. C1 [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS PAMA Branch, NIH, Bethesda, MD USA. [Warshaw, Meredith G.; Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Spector, Stephen A.] Univ Calif San Diego, Dept Pediat, Div Infect Dis, San Diego, CA 92103 USA. [Spector, Stephen A.] Rady Childrens Hosp San Diego, La Jolla, CA USA. [Decker, Michael D.] Sanofi Pasteur Inc, Swiftwater, PA USA. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn Adv Mil Med, Div Aids, Bethesda, MD 20892 USA. [Yogev, Ram] Childrens Mem Hosp, Sect Pediat Adolescent & Maternal HIV Infect, Chicago, IL 60614 USA. [Heckman, Barbara E.; Manzella, Adam] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Roa, Jhoanna] Social & Sci Syst Inc, Silver Spring, MD USA. [Nachman, Sharon] SUNY Stony Brook, Dept Pediat, Div Infect Dis, Stony Brook, NY 11794 USA. [Lujan-Zilbermann, Jorge] Univ S Florida, Coll Med, Tampa, FL USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS PAMA Branch, NIH, 6100 Execut Blvd,Room 4B11H, Bethesda, MD USA. EM siberryg@mail.nih.gov OI Frenkel, Lisa M/0000-0001-9566-8959; Decker, Michael/0000-0003-1008-7472 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; IMPAACT Group [1 U01 AI068616]; National Institute of Allergy and Infectious Diseases (NIAID); NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network; NICHD [N01-DK-9-001/HHSN267200800001C]; National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). This project has also been supported with Federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. Sanofi Pasteur Inc. provided study vaccine and performed meningococcal serum bactericidal antibody activity assays. NR 19 TC 13 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JAN PY 2012 VL 31 IS 1 BP 47 EP 52 DI 10.1097/INF.0b013e318236c67b PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 875QV UT WOS:000299050100015 PM 21987006 ER PT J AU Alonso, WJ Laranjeira, BJ Pereira, SAR Florencio, CMGD Moreno, EC Miller, MA Giglio, R Schuck-Paim, C Moura, FEA AF Alonso, Wladimir J. Laranjeira, Bruno J. Pereira, Samuel A. R. Florencio, Caroline M. G. D. Moreno, Eduardo C. Miller, Mark A. Giglio, Ricardo Schuck-Paim, Cynthia Moura, Fernanda E. A. TI Comparative Dynamics, Morbidity and Mortality Burden of Pediatric Viral Respiratory Infections in an Equatorial City SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE influenza; RSV; pneumonia; tropics; ARI ID PARAINFLUENZA VIRUS-INFECTIONS; NORTHEASTERN BRAZIL; SEASONAL TRENDS; CHILDREN; INFLUENZA; TROPICS AB Background: Although acute respiratory infections (ARIs) are the global leading cause of pediatric morbidity and mortality, the relative impact of viral pathogens on pediatric ARIs is still poorly understood, especially in equatorial settings. Long-term studies of multiple viruses concurrently circulating in these regions are still lacking. Here, we report the results of a systematic prospective surveillance of multiple respiratory viruses conducted every weekday for nearly a decade in an equatorial city in Brazil. Methods: We analyzed the relative burden of influenza, parainfluenza, respiratory syncytial virus (RSV), adenovirus, and metapneumovirus, their seasonality, and their association with climatic and demographic factors, ARI diagnosis, and pediatric mortality. Results and Conclusions: RSV was the primary driver of severe childhood respiratory infections, including pneumonia. RSV was also the virus most strongly associated with respiratory-associated deaths, with RSV circulation and pediatric mortality being in phase. Annual circulation of influenza peaked much earlier than annual mortality due to respiratory causes. The results also show that viral circulation can be strongly seasonal even in equatorial regions, which lack seasons with low temperatures: RSV and influenza were concentrated in the rainy season, whereas parainfluenza predominantly circulated in the dry season. The consistent epidemiologic patterns observed can be used for an effective adjustment of the timing of therapeutic and prophylactic interventions in this and potentially in other equatorial regions. C1 [Moura, Fernanda E. A.] Univ Fed Ceara, Fac Med, Dept Pathol & Med, Virol Lab, BR-60430270 Fortaleza, Ceara, Brazil. [Alonso, Wladimir J.; Miller, Mark A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Giglio, Ricardo; Schuck-Paim, Cynthia] Origem Sci, Florianopolis, SC, Brazil. RP Moura, FEA (reprint author), Univ Fed Ceara, Fac Med, Dept Pathol & Med, Virol Lab, Rua Coronel Nunes de Melo 1315, BR-60430270 Fortaleza, Ceara, Brazil. EM fernandaedna@terra.com.br RI Moura, Fernanda/I-2739-2013 FU Fogarty International Center, National Institutes of Health; Fundacao Cearense de Apoio ao Desenvolvimento Cientifico e Tecnologico (FUNCAP); FUNCAP; Multinational Influenza Seasonal Mortality Study; Office of Global Health Affairs' International Influenza Unit (Department of Health and Human Services) FX M.A.M., supported by the Fogarty International Center, National Institutes of Health; F.E.A.M., supported by Fundacao Cearense de Apoio ao Desenvolvimento Cientifico e Tecnologico (FUNCAP); B.J.L. received a PhD grant from FUNCAP; S.A.R.P., C.M.G.D.F., and E.C.M. received grants from FUNCAP; W.J.A., supported by the Multinational Influenza Seasonal Mortality Study, a project led by the Fogarty International Center (NIH) and funded by the Office of Global Health Affairs' International Influenza Unit (Department of Health and Human Services). The authors have no other funding or conflicts of interest to disclose. NR 24 TC 24 Z9 26 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JAN PY 2012 VL 31 IS 1 BP E9 EP E14 DI 10.1097/INF.0b013e31823883be PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 875QV UT WOS:000299050100002 PM 22001966 ER PT J AU Joehanes, R Johnson, AD Barb, JJ Raghavachari, N Liu, PC Woodhouse, KA O'Donnell, CJ Munson, PJ Levy, D AF Joehanes, Roby Johnson, Andrew D. Barb, Jennifer J. Raghavachari, Nalini Liu, Poching Woodhouse, Kimberly A. O'Donnell, Christopher J. Munson, Peter J. Levy, Daniel TI Gene expression analysis of whole blood, peripheral blood mononuclear cells, and lymphoblastoid cell lines from the Framingham Heart Study SO PHYSIOLOGICAL GENOMICS LA English DT Article DE microarray; system biology; biomarker discovery; fingerprinting genes; data normalization; X-linked expression; cardiovascular disease ID EPSTEIN-BARR-VIRUS; MOLECULAR-GENETICS; IMMUNE-RESPONSES; LUNG-CANCER; PROFILES; DISEASE; ASSOCIATION; BIOMARKERS; RECEPTORS; PATHWAYS AB Joehanes R, Johnson AD, Barb JJ, Raghavachari N, Liu P, Woodhouse KA, O'Donnell CJ, Munson PJ, Levy D. Gene expression analysis of whole blood, peripheral blood mononuclear cells, and lymphoblastoid cell lines from the Framingham Heart Study. Physiol Genomics 44: 59-75, 2012. First published November 1, 2011; doi: 10.1152/physiolgenomics.00130.2011.-Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, there have been few systematic comparisons of various RNA sources in transcriptomic analysis or for biomarker discovery in the context of cardiovascular disease (CVD). As a pilot study of the Systems Approach to Biomarker Research (SABRe) in CVD Initiative, this investigation used Affymetrix Exon arrays to characterize gene expression of three blood-derived RNA sources: lymphoblastoid cell lines (LCL), whole blood using PAXgene tubes (PAX), and peripheral blood mononuclear cells (PBMC). Their performance was compared in relation to identifying transcript associations with sex and CVD risk factors, such as age, high-density lipoprotein, and smoking status, and the differential blood cell count. We also identified a set of exons that vary substantially between participants, but consistently in each RNA source. Such exons are thus stable phenotypes of the participant and may potentially become useful fingerprinting biomarkers. In agreement with previous studies, we found that each of the RNA sources is distinct. Unlike PAX and PBMC, LCL gene expression showed little association with the differential blood count. LCL, however, was able to detect two genes related to smoking status. PAX and PBMC identified Y-chromosome probe sets similarly and slightly better than LCL. C1 [Joehanes, Roby; Johnson, Andrew D.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Joehanes, Roby; Johnson, Andrew D.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Barb, Jennifer J.; Munson, Peter J.] NHLBI, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol,NIH, Bethesda, MD 20892 USA. [Raghavachari, Nalini; Liu, Poching; Woodhouse, Kimberly A.] NHLBI, DNA Sequencing & Genom Core, Genet & Dev Ctr, NIH, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Ctr Populat Studies, NIH, Bldg 10, Bethesda, MD 20892 USA. EM levyd@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU National Institutes of Health [NO1-HC-25195]; Division of Intramural Research, NHLBI, Bethesda, MD FX The National Heart, Lung, and Blood Institute's (NHLBI's) FHS is supported by National Institutes of Health Grant NO1-HC-25195. The SABRe CVD Initiative is funded by the Division of Intramural Research, NHLBI, Bethesda, MD. NR 80 TC 20 Z9 21 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JAN PY 2012 VL 44 IS 1 BP 59 EP 75 DI 10.1152/physiolgenomics.00130.2011 PG 17 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 879HK UT WOS:000299320100006 PM 22045913 ER PT J AU Westbroek, W Klar, A Cullinane, AR Ziegler, SG Hurvitz, H Ganem, A Wilson, K Dorward, H Huizing, M Tamimi, H Vainshtein, I Berkun, Y Lavie, M Gahl, WA Anikster, Y AF Westbroek, Wendy Klar, Aharon Cullinane, Andrew R. Ziegler, Shira G. Hurvitz, Haggit Ganem, Ashraf Wilson, Kirkland Dorward, Heidi Huizing, Marjan Tamimi, Haled Vainshtein, Igor Berkun, Yackov Lavie, Moran Gahl, William A. Anikster, Yair TI Cellular and clinical report of new Griscelli syndrome type III cases SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Griscelli syndrome type III; Melanophilin; melanocyte; melanosome; Myosin-5a; RAB27A; tripartite complex ID SMALL GTPASE RAB27B; MYOSIN-VA; MELANOSOME TRANSPORT; HUMAN MELANOCYTES; LINKS RAB27A; MELANOPHILIN; MUTATIONS; PROTEINS; SLAC2-A/MELANOPHILIN; DISEASE AB The RAB27A/Melanophilin/Myosin-5a tripartite protein complex is required for capturing mature melanosomes in the peripheral actin network of melanocytes for subsequent transfer to keratinocytes. Mutations in any one member of this tripartite complex cause three forms of Griscelli syndrome (GS), each with distinct clinical features but with a similar cellular phenotype. To date, only one case of GS type III (GSIII), caused by mutations in the Melanophilin (MLPH) gene, has been reported. Here, we report seven new cases of GSIII in three distinct Arab pedigrees. All affected individuals carried a homozygous missense mutation (c.102C>T; p.R35W), located in the conserved Slp homology domain of MLPH, and had hypomelanosis of the skin and hair. We report the first cellular studies on GSIII melanocytes, which demonstrated that MLPH(R35W) causes perinuclear aggregation of melanosomes in melanocytes, typical for GS. Additionally, co-immunoprecipitation assays showed that MLPH(R35W) lost its interaction with RAB27A, indicating pathogenicity of the R35W mutation. C1 [Westbroek, Wendy; Cullinane, Andrew R.; Ziegler, Shira G.; Wilson, Kirkland; Dorward, Heidi; Huizing, Marjan; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Klar, Aharon; Hurvitz, Haggit; Ganem, Ashraf; Tamimi, Haled; Vainshtein, Igor] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pediat, Bikur Cholim Gen Hosp, IL-91010 Jerusalem, Israel. [Berkun, Yackov; Lavie, Moran; Anikster, Yair] Edmond & Lily Safra Childrens Hosp, Metab Dis Unit, Sheba Med Ctr, Tel Hashomer, Israel. [Berkun, Yackov; Lavie, Moran; Anikster, Yair] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Westbroek, W (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM wwestbro@mail.nih.gov RI Berkun, Yackov/A-1694-2009 FU National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA FX We kindly acknowledge the patients and their families who participated in this study. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. NR 27 TC 10 Z9 10 U1 2 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JAN PY 2012 VL 25 IS 1 BP 47 EP 56 DI 10.1111/j.1755-148X.2011.00901.x PG 10 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 869ED UT WOS:000298577600009 PM 21883982 ER PT J AU Liu, WH Onda, M Kim, C Xiang, LM Weldon, JE Lee, B Pastan, I AF Liu, Wenhai Onda, Masanori Kim, Changhoon Xiang, Laiman Weldon, John E. Lee, Byungkook Pastan, Ira TI A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity SO PROTEIN ENGINEERING DESIGN & SELECTION LA English DT Article DE disulfide bond; immunotoxin; immunogenicity ID COMPUTER-AIDED-DESIGN; B-CELL EPITOPES; PHASE-I TRIAL; PSEUDOMONAS EXOTOXIN; RFB4(DSFV)-PE38 BL22; HEMATOLOGIC MALIGNANCIES; CONFORMATIONAL STABILITY; CANCER; TOXICITY; LYMPHOMA AB Recombinant immunotoxins (RITs) are anti-cancer agents that combine the Fv of an antibody against cancer cells with a protein toxin from bacteria or plants. Since RITs contain a non-human protein, immunogenicity can be an obstacle in their development. In this study, we have explored the hypothesis that increasing stability can reduce the immunogenicity of a RIT using HA22-LR, which is composed of an anti-CD22 Fv fused to domain III of Pseudomonas exotoxin A. We introduced a disulfide bond into domain III by identifying and mutating two structurally adjacent residues to cysteines at sites suggested by computer modeling. This RIT, HA22-LR-DB, displays a remarkable increase in thermal stability and an enhanced resistance to trypsin degradation. In addition, HA22-LR-DB retains cytotoxic and anti-tumor activity, while exhibiting significantly lower immunogenicity in mice. This study demonstrates that it is possible to design mutations in a protein molecule that will increase the stability of the protein and thereby reduce its immunogenicity. C1 [Liu, Wenhai; Onda, Masanori; Kim, Changhoon; Xiang, Laiman; Weldon, John E.; Lee, Byungkook; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI Lee, Byungkook/E-4564-2011; liu, wenhai/N-3783-2015; OI Lee, Byungkook/0000-0002-3339-4582; Weldon, John/0000-0002-6516-9064 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 32 TC 15 Z9 15 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-0126 J9 PROTEIN ENG DES SEL JI Protein Eng. Des. Sel. PD JAN PY 2012 VL 25 IS 1 BP 1 EP 6 DI 10.1093/protein/gzr053 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 879RD UT WOS:000299348700001 PM 22101015 ER PT J AU Shigunov, P Sotelo-Silveira, J Kuligovski, C de Aguiar, AM Rebelatto, CK Moutinho, JA Brofman, PS Krieger, MA Goldenberg, S Munroe, D Correa, A Dallagiovanna, B AF Shigunov, Patricia Sotelo-Silveira, Jose Kuligovski, Crisciele de Aguiar, Alessandra Melo Rebelatto, Carmen K. Moutinho, Jose A. Brofman, Paulo S. Krieger, Marco A. Goldenberg, Samuel Munroe, David Correa, Alejandro Dallagiovanna, Bruno TI PUMILIO-2 Is Involved in the Positive Regulation of Cellular Proliferation in Human Adipose-Derived Stem Cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID RNA-BINDING PROTEINS; CAENORHABDITIS-ELEGANS; DROSOPHILA-PUMILIO; MESSENGER-RNAS; SELF-RENEWAL; BONE-MARROW; GERM-CELLS; DIFFERENTIATION; FAMILY; PUF-8 AB Stem cells can either differentiate into more specialized cells or undergo self-renewal. Several lines of evidence from different organisms suggest that these processes depend on the post-transcriptional regulation of gene expression. The presence of the PUF [Pumilio/FBF (fem-3 binding factor)] domain defines a conserved family of RNA binding proteins involved in repressing gene expression. It has been suggested that a conserved function of PUF proteins is to repress differentiation and sustain the mitotic proliferation of stem cells. In humans, Pumilio-2 (PUM2) is expressed in embryonic stem cells and adult germ cells. Here we show that PUM2 is expressed in a subpopulation of adipose-derived stem cell (ASC) cultures, with a granular pattern of staining in the cytoplasm. Protein levels of PUM2 showed no changes during the differentiation of ASCs into adipocytes. Moreover, RNAi knockdown of pum2 did not alter the rate of adipogenic differentiation compared with wild-type control cells. A ribonomic approach was used to identify PUM2-associated mRNAs. Microarray analysis showed that PUM2-bound mRNAs are part of gene networks involved in cell proliferation and gene expression control. We studied pum2 expression in cell cultures with low or very high levels of proliferation and found that changes in pum2 production were dependent on the proliferation status of the cell. Transient knockdown of pum2 expression by RNAi impaired proliferation of ASCs in vitro. Our results suggest that PUM2 does not repress differentiation of ASCs but rather is involved in the positive control of ASCs division and proliferation. C1 [Shigunov, Patricia; Kuligovski, Crisciele; de Aguiar, Alessandra Melo; Krieger, Marco A.; Goldenberg, Samuel; Correa, Alejandro; Dallagiovanna, Bruno] Fiocruz MS, Lab Biol Basica Celulas Tronco, Inst Carlos Chagas, BR-81350010 Curitiba, Parana, Brazil. [Sotelo-Silveira, Jose; Munroe, David] NCI, Adv Technol Program, Lab Mol Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. [Sotelo-Silveira, Jose] Inst Invest Biol Clemente Estable, Dept Genet, Montevideo 11600, Uruguay. [Sotelo-Silveira, Jose] UdelaR, Sch Sci, Dept Cell & Mol Biol, Montevideo, Uruguay. [Rebelatto, Carmen K.; Brofman, Paulo S.] Pontificia Univ Catolica Parana, Nucleo Cardiomioplastia Celular, Curitiba, Parana, Brazil. [Moutinho, Jose A.] Inst Med & Cirurgia Parana, Curitiba, Parana, Brazil. RP Dallagiovanna, B (reprint author), Fiocruz MS, Lab Biol Basica Celulas Tronco, Inst Carlos Chagas, Rua Algacyr Munhoz Mader 3775, BR-81350010 Curitiba, Parana, Brazil. EM sotelojos@gmail.com; brunod@tecpar.br RI GOLDENBERG, SAMUEL/B-4116-2009; Aguiar, Alessandra /B-4899-2010; P, CM/B-1358-2013; Saude Publica, Inct/J-9544-2013 OI GOLDENBERG, SAMUEL/0000-0002-4892-163X; Aguiar, Alessandra /0000-0002-6167-8478; FU Ministerio da Saude; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq (CT-Saude/MS/SCTIE/DECIT/MCT/CNPq) [17/2008]; National Cancer Institute, National Institutes of Health [HSN261200800001E]; CNPq; CAPES FX We thank Marco Stimamiglio and Alexandra C. Senegaglia for scientific advice and helpful discussions. This work was supported by grants from Ministerio da Saude and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq (CT-Saude/MS/SCTIE/DECIT/MCT/CNPq No. 17/2008). This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HSN261200800001E. The content of this article 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. M.A.K., S.G., and B.D. received fellowships from CNPq and P.S. from CAPES. NR 36 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JAN PY 2012 VL 21 IS 2 BP 217 EP 227 DI 10.1089/scd.2011.0143 PG 11 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 877GF UT WOS:000299164600006 PM 21649561 ER PT J AU Ayres, DL Darling, A Zwickl, DJ Beerli, P Holder, MT Lewis, PO Huelsenbeck, JP Ronquist, F Swofford, DL Cummings, MP Rambaut, A Suchard, MA AF Ayres, Daniel L. Darling, Aaron Zwickl, Derrick J. Beerli, Peter Holder, Mark T. Lewis, Paul O. Huelsenbeck, John P. Ronquist, Fredrik Swofford, David L. Cummings, Michael P. Rambaut, Andrew Suchard, Marc A. TI BEAGLE: An Application Programming Interface and High-Performance Computing Library for Statistical Phylogenetics SO SYSTEMATIC BIOLOGY LA English DT Article DE Bayesian phylogenetics; GPU; maximum likelihood; parallel computing ID SEQUENCES AB Phylogenetic inference is fundamental to our understanding of most aspects of the origin and evolution of life, and in recent years, there has been a concentration of interest in statistical approaches such as Bayesian inference and maximum likelihood estimation. Yet, for large data sets and realistic or interesting models of evolution, these approaches remain computationally demanding. High-throughput sequencing can yield data for thousands of taxa, but scaling to such problems using serial computing often necessitates the use of nonstatistical or approximate approaches. The recent emergence of graphics processing units (GPUs) provides an opportunity to leverage their excellent floating-point computational performance to accelerate statistical phylogenetic inference. A specialized library for phylogenetic calculation would allow existing software packages to make more effective use of available computer hardware, including GPUs. Adoption of a common library would also make it easier for other emerging computing architectures, such as field programmable gate arrays, to be used in the future. We present BEAGLE, an application programming interface (API) and library for high-performance statistical phylogenetic inference. The API provides a uniform interface for performing phylogenetic likelihood calculations on a variety of compute hardware platforms. The library includes a set of efficient implementations and can currently exploit hardware including GPUs using NVIDIA CUDA, central processing units (CPUs) with Streaming SIMD Extensions and related processor supplementary instruction sets, and multicore CPUs via OpenMP. To demonstrate the advantages of a common API, we have incorporated the library into several popular phylogenetic software packages. The BEAGLE library is free open source software licensed under the Lesser GPL and available from http://beagle-lib.googlecode.com. An example client program is available as public domain software. C1 [Ayres, Daniel L.; Cummings, Michael P.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Darling, Aaron] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Zwickl, Derrick J.; Holder, Mark T.] Univ Kansas, Dept Ecol & Evolutionary Biol, Lawrence, KS 66045 USA. [Beerli, Peter] Florida State Univ, Dept Comp Sci, Tallahassee, FL 32306 USA. [Huelsenbeck, John P.] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Lewis, Paul O.] Univ Connecticut, Dept Ecol & Evolutionary Biol, Storrs, CT 06269 USA. [Ronquist, Fredrik] Swedish Museum Nat Hist, S-11418 Stockholm, Sweden. [Swofford, David L.] Duke Univ, Inst Genome Sci & Policy, Ctr Evolutionary Genom, Durham, NC 27708 USA. [Rambaut, Andrew] Univ Edinburgh, Inst Evolut Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. RP Ayres, DL (reprint author), Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. EM ayres@umiacs.umd.edu; a.rambaut@ed.ac.uk; msuchard@ucla.edu RI Huelsenbeck, John/C-6398-2013; Research, NRM-BIG/F-2603-2013; Beerli, Peter/A-3638-2009; Ronquist, Fredrik/Q-2013-2015; OI Beerli, Peter/0000-0003-0947-5451; Holder, Mark/0000-0001-5575-0536; Rambaut, Andrew/0000-0003-4337-3707; Darling, Aaron/0000-0003-2397-7925 FU National Science Foundation [DBI-0755048, DEB-0732920, DEB-1036448, DMS-0931642, EF-0331495, EF-0905606, EF-0949453]; National Institutes of Health [R01-HG006139, R01-GM037841, R01-GM078985, R01-GM086887, R01-NS063897]; Biotechnology and Biological Sciences Research Council [BB/ H011285/1]; Wellcome Trust [WT092807MA]; Google Summer of Code FX This work was supported by the National Science Foundation [grant numbers DBI-0755048, DEB-0732920, DEB-1036448, DMS-0931642, EF-0331495, EF-0905606, EF-0949453]; the National Institutes of Health [grant numbers R01-HG006139, R01-GM037841, R01-GM078985, R01-GM086887, R01-NS063897]; the Biotechnology and Biological Sciences Research Council [grant number BB/ H011285/1]; the Wellcome Trust [grant number WT092807MA]; and Google Summer of Code. NR 7 TC 103 Z9 104 U1 4 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1063-5157 EI 1076-836X J9 SYST BIOL JI Syst. Biol. PD JAN PY 2012 VL 61 IS 1 BP 170 EP 173 DI 10.1093/sysbio/syr100 PG 4 WC Evolutionary Biology SC Evolutionary Biology GA 877PZ UT WOS:000299195700013 PM 21963610 ER PT J AU Chen, XY AF Chen, Xiaoyuan (Shawn) TI One Year after a Successful Start of Theranostics SO THERANOSTICS LA English DT Editorial Material DE Theranostics; journal AB As Theranostics begins its second year of publication, I would like to thank our authors, reviewers, and audience for their outstanding support in 2011. I look forward to working with you in 2012 to continue our mission to distinguish Theranostics as a leader of publishing cutting edge research in this important and emerging field. C1 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 NR 0 TC 4 Z9 4 U1 1 U2 3 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2012 VL 2 IS 1 BP 1 EP 2 DI 10.7150/thno.2.1 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 876PZ UT WOS:000299121200001 PM 22272216 ER PT J AU Ma, DY Assumpcao, TCF Li, Y Andersen, JF Ribeiro, JMC Francischetti, IMB AF Ma, Dongying Assumpcao, Teresa C. F. Li, Yuan Andersen, John F. Ribeiro, Jose M. C. Francischetti, Ivo M. B. TI Triplatin, a platelet aggregation inhibitor from the salivary gland of the triatomine vector of Chagas disease, binds to TXA(2) but does not interact with glycoprotein PVI SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Snake venoms; protein function / activity; platelet physiology ID APOLIPOPROTEIN-D; THROMBUS FORMATION; RHODNIUS-PROLIXUS; COLLAGEN RECEPTOR; HISTAMINE-BINDING; ARACHIDONIC-ACID; PROTEINS; ACTIVATION; MECHANISM; CLONING AB Salivary glands from haematophagous animals express a notable diversity of negative modulators of platelet function. Triplatin is an inhibitor of collagen-induced platelet aggregation which has been described as an antagonist of glycoprotein VI (GPVI). Because triplatin displays sequence homology to members of the lipocalin family of proteins, we investigated whether triplatin mechanism of action could be explained by interaction with pro-haemostatic prostaglandins. Our results demonstrate that triplatin inhibits platelet aggregation induced by low doses of collagen, thromboxane A2 (TXA(2)) mimetic (U46619), and arachidonic acid (AA). On the other hand, it does not inhibit platelet aggregation by convulxin, PMA, or low-dose ADP. Isothermal titration calorimetry (ITC) revealed that triplatin binds AA, cTXA(2), TXB2, U46619 or prostaglandin (PG)H-2 mimetic (U51605). Consistent with its ligand specificity, triplatin induces relaxation of rat aorta contracted with U46619. Triplatin also interacts with PGF(2 alpha) and PGJ(2), but not with leukotrienes, AA or biogenic amines. Surface plasmon resonance experiments failed to demonstrate interaction of triplatin with GPVI; it also did to inhibit platelet adhesion to fibrillar or soluble collagen. Because triplatin displays sequence similarity to apolipoprotein D (ApoD) - a lipocalin associated with high-density lipoprotein, ApoD was tested as a putative TXA(2)-binding molecule. ITC failed to demonstrate binding of ApoD to all prostanoids described above, or to AA. Furthermore, ApoD was devoid of inhibitory properties towards platelets activation by AA, collagen, or U46619. In conclusion, triplatin mechanism of action has been elucidated without ambiguity as a novel TXA(2)- and PGF(2 alpha)- binding protein. It conceivably blocks platelet aggregation and vasoconstriction, thus contributing to successful blood feeding at the vector-host interface. C1 [Ma, Dongying; Assumpcao, Teresa C. F.; Li, Yuan; Andersen, John F.; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Francischetti, IMB (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Rm 2E28, Rockville, MD 20852 USA. EM ifrancischetti@niaid.nih.goy RI ma, dongying/D-8623-2012; Ribeiro, Jose/J-7011-2015 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank NIAID intramural editor Brenda Rae Marshall for assistance. We thank Dr. Jean-Luc Villeval (INSERM, France) for providing recombinant GPVI, Drs. Glenn Nardone (NIAID) for mass spectrometry results and Mark Garfield (NIAID) for identification of the N-terminus of triplatin. Because JA, JR and IF are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 50 TC 8 Z9 9 U1 2 U2 13 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JAN PY 2012 VL 107 IS 1 BP 111 EP 123 DI 10.1160/TH11-10-0685 PG 13 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 879UO UT WOS:000299357900017 PM 22159626 ER PT J AU Nair, S Muller, YL Ortega, E Kobes, S Bogardus, C Baier, LJ AF Nair, Saraswathy Muller, Yunhua Li Ortega, Emilio Kobes, Sayuko Bogardus, Clifton Baier, Leslie J. TI Association Analyses of Variants in the DIO2 Gene with Early-Onset Type 2 Diabetes Mellitus in Pima Indians SO THYROID LA English DT Article ID DEIODINASE THR92ALA POLYMORPHISM; THYROID-HORMONE; INSULIN-RESISTANCE; IODOTHYRONINE DEIODINASE; ENERGY-EXPENDITURE; HYPOTHYROIDISM; METABOLISM; RECEPTOR; OBESITY; HYPERINSULINEMIA AB Background: The type 2 deiodinase gene (DIO2) encodes a deiodinase that converts the thyroid prohormone, thyroxine, to the biologically active triiodothyronine. Thyroid hormones regulate energy balance and may also influence glucose metabolism. Therefore, we hypothesized that variations in DIO2 could contribute to obesity or type 2 diabetes mellitus (T2DM) in Pima Indians. Methods: Sequencing of the DIO2 gene in DNA from 83 Pima Indians identified 12 single-nucleotide polymorphisms (SNPs). Several of these SNPs were in perfect genotypic concordance among the 83 samples that were sequenced, and all 12 could be divided into five linkage disequilibrium groups. One representative SNP from each group (Thr92Ala, rs225011, rs225015, rs6574549, and a rare 5' flanking SNP) was selected for further genotyping for association analyses. In this study, the five selected variants in DIO2, as described above, were genotyped in three groups of Pima Indians: (i) a case (n = 150)/control (n = 150) group for early-onset T2DM (onset age < 25 years); (ii) a case (n = 362)/control (n = 127) group for obesity; (iii) a large (n = 1,311, cases n = 810/controls n = 501) family-based group, of which 256 nondiabetic subjects had undergone detailed metabolic phenotyping. Results: The Thr92Ala variant common in Pima Indians, rs225011, and rs225015 were modestly associated with early-onset T2DM (p = 0.01-0.04) in the case-control study, but were not associated with obesity in the obesity case-control study, nor associated with T2DM (at any age) or body-mass index (BMI; as a quantitative trait) in the family-based analysis. Thr92Ala, rs225011, rs225015, and rs6574549 were also nominally associated with hepatic glucose output (p = 0.02). rs6574549 was associated with fasting insulin (p = 0.02), insulin action (p = 0.04), and energy expenditure (p = 0.02). None of these nominal associations remained statistically significant after corrections for multiple testing. Conclusions: We propose that variation in DIO2 may have a subtle role in altering metabolic processes that lead to early-onset T2DM, but this gene does not have a large impact on T2DM at older ages, nor does DIO2 influence BMI in the Pima Indian population. C1 [Nair, Saraswathy] Univ Texas Brownsville, Dept Biol Sci, Brownsville, TX 78520 USA. [Nair, Saraswathy; Muller, Yunhua Li; Ortega, Emilio; Kobes, Sayuko; Bogardus, Clifton; Baier, Leslie J.] NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Ortega, Emilio] Hosp Clin Barcelona, ICMDM, Dept Endocrinol & Diabet, Barcelona, Spain. [Ortega, Emilio] Univ Barcelona, Barcelona, Spain. RP Nair, S (reprint author), Univ Texas Brownsville, Dept Biol Sci, LHSB 1-824,80 Ft Brown, Brownsville, TX 78520 USA. EM saraswathy.nair@utb.edu FU National Institute of Health, NIDDK FX The authors gratefully acknowledge the volunteers and leaders of the Gila River Indian Community, whose cooperation made these studies possible. The authors also acknowledge Dr. Joy Bunt and the nurses of the Clinical Research Center, and Dr. Arline Salbe and the Metabolic Kitchen staff, for the care of the research volunteers. The authors sincerely thank Dr. Robert Hanson for performing the power analyses, as well as help in conducting the multiple testing corrections in this study. This research was supported by the Intramural Research Program of the National Institute of Health, NIDDK. NR 42 TC 10 Z9 11 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD JAN PY 2012 VL 22 IS 1 BP 80 EP 87 DI 10.1089/thy.2010.0455 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 876NI UT WOS:000299113900012 PM 22142372 ER PT J AU Suhasini, AN Brosh, RM AF Suhasini, Avvaru N. Brosh, Robert M., Jr. TI Fanconi anemia and Bloom's syndrome crosstalk through FANCJ-BLM helicase interaction SO TRENDS IN GENETICS LA English DT Review ID SISTER-CHROMATID EXCHANGES; MAINTAIN GENOME STABILITY; REPLICATION PROTEIN-A; STRAND BREAK REPAIR; HOMOLOGOUS RECOMBINATION; LINK REPAIR; DNA-REPAIR; HUMAN-CELLS; SUMO MODIFICATION; RECQ HELICASES AB Fanconi anemia (FA) and Bloom's syndrome (BS) are rare hereditary chromosomal instability disorders. FA displays bone marrow failure, acute myeloid leukemia, and head and neck cancers, whereas BS is characterized by growth retardation, immunodeficiency, and a wide spectrum of cancers. The BLM gene mutated in BS encodes a DNA helicase that functions in a protein complex to suppress sister-chromatid exchange. Of the 15 FA genetic complementation groups implicated in interstrand crosslink repair, FANCJ encodes a DNA helicase involved in recombinational repair and replication stress response. Based on evidence that BLM and FANCJ interact we suggest that crosstalk between BLM and FA pathways is more complex than previously thought. We propose testable models for how FANCJ and BLM coordinate to help cells deal with stalled replication forks or double-strand breaks (DSB). Understanding how BLM and FANCJ cooperate will help to elucidate an important pathway for maintaining genomic stability. C1 [Suhasini, Avvaru N.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH; National Institute on Aging; Fanconi Anemia Research Fund FX This work was supported by the Intramural Research program of the NIH, National Institute on Aging, and the Fanconi Anemia Research Fund (R.M.B.). NR 70 TC 26 Z9 26 U1 2 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2012 VL 28 IS 1 BP 7 EP 13 DI 10.1016/j.tig.2011.09.003 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 879XV UT WOS:000299367100002 PM 22024395 ER PT J AU Ward, JM Elmore, SA Foley, JF AF Ward, J. M. Elmore, S. A. Foley, J. F. TI Pathology Methods for the Evaluation of Embryonic and Perinatal Developmental Defects and Lethality in Genetically Engineered Mice SO VETERINARY PATHOLOGY LA English DT Article DE mouse embryo; embryonic lethality; placenta; histology atlas; imaging; phenotyping ID MOUSE PLACENTA; VIRTUAL HISTOLOGY; STAINING METHODS; MURINE; MORPHOLOGY; EXPRESSION; ATLAS; RAS; DEFICIENCY; ACTIVATION AB The normal embryonic development of organs and other tissues in mice and all species is preprogrammed by genes. Inactivation of a gene involved in any stage of normal embryonic development can have severe consequences leading to embryonic or postnatal developmental defects and lethality. Pathology methods are reviewed for evaluating normal and abnormal placenta and embryo, especially after E12.5. These methods include pathology protocols for necropsy and histopathology in addition to references that will provide additional knowledge for embryo assessment including histology atlases and advanced embryo imaging techniques. C1 [Ward, J. M.] Global VetPathol, Montgomery Village, MD 20886 USA. [Elmore, S. A.; Foley, J. F.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Ward, JM (reprint author), Global VetPathol, Montgomery Village, MD 20886 USA. EM globalvetpathology@gmail.com FU National Institute of Environmental Health Sciences, National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 52 TC 4 Z9 4 U1 0 U2 2 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 JAN PY 2012 VL 49 IS 1 BP 71 EP 84 DI 10.1177/0300985811429811 PG 14 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 872ZW UT WOS:000298851100008 PM 22146849 ER PT J AU He, YL Korboukh, I Jin, J Huang, J AF He, Yunlong Korboukh, Ilia Jin, Jian Huang, Jing TI Targeting protein lysine methylation and demethylation in cancers SO ACTA BIOCHIMICA ET BIOPHYSICA SINICA LA English DT Review DE methylation; demethylation; methyltransferase; demethylase; cancer; epigenetics ID NF-KAPPA-B; G9A HISTONE METHYLTRANSFERASE; DOMAIN-CONTAINING PROTEINS; BREAST-CANCER; TRANSCRIPTIONAL REPRESSION; SELECTIVE INHIBITORS; CELL-PROLIFERATION; STRUCTURAL BASIS; PROSTATE-CANCER; SILENCED GENES AB During the last decade, we saw an explosion of studies investigating the role of lysine methylation/demethylation of histones and non-histone proteins, such as p53, NF-kappaB, and E2F1. These 'Ying-Yang' post-translational modifications are important to fine-tuning the activity of these proteins. Lysine methylation and demethylation are catalyzed by protein lysine methyl-transferases (PKMTs) and protein lysine demethylases (PKDMs). PKMTs, PKDMs, and their substrates have been shown to play important roles in cancers. Although the underlying mechanisms of tumorigenesis are still largely unknown, growing evidence is starting to link aberrant regulation of methylation to tumorigenesis. This review focuses on summarizing the recent progress in understanding of the function of protein lysine methylation, and in the discovery of small molecule inhibitors for PKMTs and PKDMs. We also discuss the potential and the caveats of targeting protein lysine methylation for the treatment of cancer. C1 [Korboukh, Ilia; Jin, Jian] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC 27599 USA. [He, Yunlong; Huang, Jing] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Jin, J (reprint author), Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC 27599 USA. EM jianjin@email.unc.edu; huangj3@mail.nih.gov RI Huang, Jing/A-2566-2009; He, Yunlong/D-1278-2017 OI Huang, Jing/0000-0002-7163-5156; FU Center for Cancer Research (CCR); National Cancer Institute; National Institutes of Health, USA; University Cancer Research Fund (UCRF); University of North Carolina at Chapel Hill FX This work was supported by the grants from the Intramural Research Program at the Center for Cancer Research (CCR), the National Cancer Institute and the National Institutes of Health, USA for J.H., the University Cancer Research Fund (UCRF) and the Carolina Partnership from the University of North Carolina at Chapel Hill for J.J. and I.K. NR 101 TC 27 Z9 29 U1 2 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1672-9145 J9 ACTA BIOCH BIOPH SIN JI Acta Biochim. Biophys. Sin. PD JAN PY 2012 VL 44 IS 1 SI SI BP 70 EP 79 DI 10.1093/abbs/gmr109 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 866NB UT WOS:000298386700008 PM 22194015 ER PT J AU Brzezinski, K Lazny, R Sienkiewicz, M Wojtulewski, S Dauter, Z AF Brzezinski, Krzysztof Lazny, Ryszard Sienkiewicz, Michal Wojtulewski, Slawomir Dauter, Zbigniew TI (2R)-8-Benzyl-2-[(S)-hydroxy(phenyl)methyl]-8-azabicyclo[3.2.1]octan-3-o ne SO ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE LA English DT Article ID ALDOL AB The crystal of the title compound, C21H23NO2, was chosen from a conglomerate formed by a racemic mixture. An intramolecular hydrogen bond is formed between hydroxy group and heterocyclic N atom of the azabicyclo[ 3.2.1] octan-3-one system. The crystal structure is stabilized by C-H center dot center dot center dot O interactions between aliphatic C-H groups and the carbonyl O atom. For the title chiral crystal, the highly redundant and accurate diffraction data set collected with low energy copper radiation gave a Flack parameter of 0.12 (18) for anomalous scattering effects originating from O atoms. C1 [Brzezinski, Krzysztof; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab,Biosci Div, Argonne, IL 60439 USA. [Lazny, Ryszard; Sienkiewicz, Michal; Wojtulewski, Slawomir] Univ Bialystok, Inst Chem, PL-15399 Bialystok, Poland. RP Brzezinski, K (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab,Biosci Div, Bldg 202, Argonne, IL 60439 USA. EM kbrzezinski@anl.gov FU University of Bialystok [BST-125]; Polish Ministry of Science and Higher Education [N N204 546939]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN2612008000001E] FX This work was supported in part by the University of Bialystok (BST-125), the Polish Ministry of Science and Higher Education (grant No. N N204 546939), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN2612008000001E. NR 10 TC 6 Z9 6 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-5368 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Struct Rep. Online PD JAN PY 2012 VL 68 DI 10.1107/S1600536811053190 PN 1 PG 11 WC Crystallography SC Crystallography GA 874NX UT WOS:000298966400060 PM 22259435 ER PT J AU Montine, TJ Phelps, CH Beach, TG Bigio, EH Cairns, NJ Dickson, DW Duyckaerts, C Frosch, MP Masliah, E Mirra, SS Nelson, PT Schneider, JA Thal, DR Trojanowski, JQ Vinters, HV Hyman, BT AF Montine, Thomas J. Phelps, Creighton H. Beach, Thomas G. Bigio, Eileen H. Cairns, Nigel J. Dickson, Dennis W. Duyckaerts, Charles Frosch, Matthew P. Masliah, Eliezer Mirra, Suzanne S. Nelson, Peter T. Schneider, Julie A. Thal, Dietmar Rudolf Trojanowski, John Q. Vinters, Harry V. Hyman, Bradley T. TI National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach SO ACTA NEUROPATHOLOGICA LA English DT Article ID BRAINNET EUROPE CONSORTIUM; LEWY BODY DISEASE; FRONTOTEMPORAL LOBAR DEGENERATION; VASCULAR COGNITIVE IMPAIRMENT; CEREBRAL AMYLOID ANGIOPATHY; HIPPOCAMPAL SCLEROSIS; DIAGNOSTIC GUIDELINES; SYNAPSE LOSS; NEUROFIBRILLARY PATHOLOGY; CONSENSUS RECOMMENDATIONS AB We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid beta deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations. C1 [Montine, Thomas J.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Phelps, Creighton H.] NIA, Bethesda, MD 20892 USA. [Beach, Thomas G.] Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ USA. [Bigio, Eileen H.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Bigio, Eileen H.] Northwestern Univ, NW Alzheimer Dis Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Cairns, Nigel J.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Cairns, Nigel J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Duyckaerts, Charles] Hop La Pitie Salpetriere, Serv Neuropathol Raymond Escourolle, Paris, France. [Frosch, Matthew P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, CS Kubik Lab Neuropathol, Boston, MA USA. [Masliah, Eliezer] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA. [Masliah, Eliezer] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA. [Mirra, Suzanne S.] Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USA. [Nelson, Peter T.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Schneider, Julie A.] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Dept Pathol, Chicago, IL 60612 USA. [Schneider, Julie A.] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Thal, Dietmar Rudolf] Univ Ulm, Neuropathol Lab, Inst Pathol, Ulm, Germany. [Trojanowski, John Q.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging,Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Vinters, Harry V.] Univ Calif Los Angeles, Dept Pathol & Lab Med Neuropathol, Los Angeles, CA USA. [Vinters, Harry V.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Hyman, Bradley T.] Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Montine, TJ (reprint author), Univ Washington, Sch Med, Dept Pathol, Box 359791, Seattle, WA 98104 USA. EM tmontine@uw.edu OI Dickson, Dennis W/0000-0001-7189-7917 FU National Institute on Aging [AG05134, AG05136, AG03991, AG05681, AG24904, AG28383, AG10161, AG17917, AG10124, AG13854, AG19610, NS62684, AG15819, AG12435, AG05131, AG016976, AG16570, AG15866, AG18840]; Alzheimer's Association; Arizona Department of Health Services [211002]; Deutsche Forschungsgemeinschaft (DFG) [TH-624-4-1]; Alzheimer Forschung Initiative (AFI) [10810]; Nancy and Buster Alvord Endowment; Charles and Joanne Knight Alzheimer Research Initiative FX Support was provided by the National Institute on Aging (AG05134, AG05136, AG03991, AG05681, AG24904, AG28383, AG10161, AG17917, AG10124, AG13854, AG19610, NS62684, AG16570, AG15819, AG12435, AG05131, AG016976, AG16570, AG15866 and AG18840) as well as the Alzheimer's Association, Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Consortium), Deutsche Forschungsgemeinschaft (DFG TH-624-4-1) and Alzheimer Forschung Initiative (AFI #10810), the Nancy and Buster Alvord Endowment, and the Charles and Joanne Knight Alzheimer Research Initiative. We thank Dr. Joshua Sonnen for providing some photomicrographs. The authors extend their deepest thanks to Dr. Heiko Braak, Dr. Kelly Del Tredici, Dr. Nina Silverberg, Dr. Walter Kukull, Dr. Kathleen Montine, Dr. Cerise Elliott, Dr. Bill Thies, Dr. Maria C. Carrillo, and Ms. Sarah Monsell for their valuable input. NR 64 TC 420 Z9 422 U1 6 U2 38 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JAN PY 2012 VL 123 IS 1 BP 1 EP 11 DI 10.1007/s00401-011-0910-3 PG 11 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 870BF UT WOS:000298643400001 PM 22101365 ER PT J AU Gamaleddin, I Wertheim, C Zhu, AZX Coen, KM Vemuri, K Makryannis, A Goldberg, SR Le Foll, B AF Gamaleddin, Islam Wertheim, Carrie Zhu, Andy Z. X. Coen, Kathleen M. Vemuri, Kiran Makryannis, Alex Goldberg, Steven R. Le Foll, Bernard TI Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking SO ADDICTION BIOLOGY LA English DT Article DE Cannabinoid; discrimination; nicotine; relapse; self-administration; WIN 55; 212-2 ID CONDITIONED PLACE PREFERENCES; PROGRESSIVE RATIO SCHEDULE; DISCRIMINATIVE-STIMULUS; ENDOCANNABINOID SYSTEM; ANANDAMIDE HYDROLYSIS; CB1 RECEPTORS; MODULATION; ADDICTION; COCAINE; REINFORCEMENT AB The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence. C1 [Gamaleddin, Islam; Zhu, Andy Z. X.; Coen, Kathleen M.; Le Foll, Bernard] Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Wertheim, Carrie; Goldberg, Steven R.] Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Pharmacol, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Toxicol, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Ctr Addict & Mental Hlth, Addict Program, Toronto, ON M5S 2S1, Canada. [Vemuri, Kiran; Makryannis, Alex] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. RP Le Foll, B (reprint author), Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Egyptian Ministry of Higher Education-Ain Shams University; NIDA, NIH, DHHS FX This research was supported by the Egyptian Ministry of Higher Education-Ain Shams University, the Intramural Research Program of NIDA, NIH, DHHS. NR 53 TC 37 Z9 37 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JAN PY 2012 VL 17 IS 1 BP 47 EP 61 DI 10.1111/j.1369-1600.2011.00314.x PG 15 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 865HW UT WOS:000298303000004 PM 21521420 ER PT J AU Kuzmin, A Liljequist, S Meis, J Chefer, V Shippenberg, T Bakalkin, G AF Kuzmin, Alexander Liljequist, Sture Meis, Jennifer Chefer, Vladimir Shippenberg, Toni Bakalkin, Georgy TI Repeated moderate-dose ethanol bouts impair cognitive function in Wistar rats SO ADDICTION BIOLOGY LA English DT Article DE Animal model; behavioral flexibility; binge drinking; cognitive impairment; ethanol; rat; spatial learning ID ALCOHOL-CONSUMPTION; MEMORY DEFICITS; BINGE DRINKING; BARNES MAZE; WITHDRAWAL; EXPOSURE; RECOVERY; RISK; NEUROTOXICITY; PERFORMANCE AB The effects of repeated, intermittent administration of a moderate dose of ethanol (3.4 g/kg/day x 6 days, intragastrically via gavages) on cognitive function were examined in male Wistar rats. No significant differences in weight gain between the ethanol- and water-treated rats were found. Analysis of physical dependence revealed no signs of spontaneous withdrawal, whereas withdrawal signs exacerbated by Ro15-4513, an inverse benzodiazepine agonist, were apparent 5 hours but not 24 hours after the cessation of ethanol treatment. Spatial learning and memory, as assessed in the Barnes maze, were impaired 36 days following the treatment but recovered by the 11th14th days. Reversal learning, however, was impaired throughout the 2-week observation period. Thus, bouts of moderate-dose ethanol administration transiently impair spatial learning and memory, and promote cognitive inflexibility. The employed ethanol exposure paradigm may provide a model of human cognitive deficits associated with alcohol binge drinking. C1 [Kuzmin, Alexander; Bakalkin, Georgy] Uppsala Univ, Div Biol Res Drug Dependence, Dept Pharmaceut Biosci, Uppsala, Sweden. [Kuzmin, Alexander; Liljequist, Sture] Karolinska Inst, Dept Clin Neurosci, Sect Mol & Behav Neurosci, S-10401 Stockholm, Sweden. [Meis, Jennifer; Chefer, Vladimir; Shippenberg, Toni] Natl Inst Drug Abuse, Integrat Neurosci Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bakalkin, G (reprint author), Uppsala Univ, Div Biol Res Drug Dependence, Dept Pharmaceut Biosci, Uppsala, Sweden. EM georgy.bakalkin@farmbio.uu.se OI Bakalkin, Georgy/0000-0002-8074-9833 FU Swedish Council for Working Life and Social Research (FAS); AFA Forsakring; Swedish Science Research Council; Alcohol Research Council of the Swedish Retailing Monopoly; Uppsala University; Karolinska Institutet FX This work was supported by grants from the Swedish Council for Working Life and Social Research (FAS), AFA Forsakring, Swedish Science Research Council, Alcohol Research Council of the Swedish Retailing Monopoly, and funds from Uppsala University and Karolinska Institutet. NR 39 TC 10 Z9 10 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JAN PY 2012 VL 17 IS 1 BP 132 EP 140 DI 10.1111/j.1369-1600.2010.00224.x PG 9 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 865HW UT WOS:000298303000011 PM 22026443 ER PT J AU Minkowski, CP Epstein, D Frost, JJ Gorelick, DA AF Minkowski, Carolynne P. Epstein, David Frost, J. James Gorelick, David A. TI Differential response to IV carfentanil in chronic cocaine users and healthy controls SO ADDICTION BIOLOGY LA English DT Article DE Agonist; carfentanil; cocaine; mu-opioid receptor; PET scan; receptor ID OPIOID RECEPTOR-BINDING; PREPROENKEPHALIN MESSENGER-RNA; ADENYLYL-CYCLASE ACTIVITY; NUCLEUS-ACCUMBENS; RAT-BRAIN; OPIATE; EXPRESSION; PET; SUFENTANIL; ALFENTANIL AB Chronic cocaine exposure in both rodents and humans increases regional brain mu-opioid receptor (mOR) binding potential, suggesting that cocaine users might have an altered response to mOR agonists. We evaluated the response to IV carfentanil (a selective mOR agonist) in 23 cocaine users [mean (standard deviation) age 33.8 (4.0) years, 83% men] who underwent positron emission tomography (PET) scanning with [C-11]-carfentanil [44.7 (19.5) ng/kg] while housed on a closed research ward and 15 healthy non-drug-using controls [43.9 (14.2) years, 80% men] scanned [49.5 (12.6) ng/kg] as outpatients. Cocaine users had used for 8.7 (4.3) years and on 73 (22)% of days in the two weeks prior to PET scanning. Common adverse effects associated with mOR agonists (nausea, dizziness, headache, vomiting, itchiness) were assessed by self-report (five-point Likert scales) during and for 90 minutes after the scans. Cocaine users were significantly less likely than controls to report any symptom (30.4% versus 60%) and had fewer total symptoms [0.43 (0.73) versus 1.1 (1.0)] during scans, even after statistically controlling for age and carfentanil dose. These differences were also present after the scans and at repeat scans performed after about one week or 12 weeks of monitored cocaine abstinence. In a larger group of cocaine users and separate controls, there was no significant group difference in carfentanil half-life, suggesting that the observed difference was pharmacodynamically, rather than pharmacokinetically, based. These findings suggest that cocaine users are less responsive than healthy controls to mOR agonist adverse effects despite having increased regional brain mOR binding potential. C1 [Minkowski, Carolynne P.; Epstein, David; Gorelick, David A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Gorelick, DA (reprint author), 251 Bayview Blvd,200, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU NIH [DA-09479, DA-11774, DA-12274]; IRP, National Institutes of Health, NIDA FX Supported by the IRP, National Institutes of Health, NIDA and NIH grants DA-09479, DA-11774 & DA-12274 (to Dr Frost). We thank Dr John Hilton for assay of plasma carfentanil concentrations. NR 31 TC 2 Z9 2 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JAN PY 2012 VL 17 IS 1 BP 149 EP 155 DI 10.1111/j.1369-1600.2010.00256.x PG 7 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 865HW UT WOS:000298303000013 PM 21054687 ER PT J AU Boettcher, E Csako, G Pucino, F Wesley, R Loomba, R AF Boettcher, E. Csako, G. Pucino, F. Wesley, R. Loomba, R. TI Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INSULIN-SENSITIZING AGENTS; PLACEBO-CONTROLLED TRIAL; CRYPTOGENIC CIRRHOSIS; DIABETES-MELLITUS; NATURAL-HISTORY; VITAMIN-E; DISEASE; ROSIGLITAZONE; TROGLITAZONE; RESISTANCE AB Background Thiazolidinediones (TZDs) have been used in the treatment of non-alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically. Aim To conduct a meta-analysis of randomised, placebo-controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH. Methods Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters. Results Four good quality RPCTs derived from three continents were included. The meta-analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.333.36), 2.58 (95% CI, 1.683.97) and 3.39 (95% CI, 2.195.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.0314.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.022.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment. Conclusions Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo-controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis. C1 [Boettcher, E.; Loomba, R.] Univ Calif San Diego, Div Gastroenterol, Dept Med, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Loomba, R.] Univ Calif San Diego, Div Epidemiol, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Csako, G.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Pucino, F.] NIDDK, Ctr Clin, NIH, Bethesda, MD USA. [Wesley, R.] NIH, Hosp Epidemiol Div, Ctr Clin, Bethesda, MD 20892 USA. RP Loomba, R (reprint author), Univ Calif San Diego, Div Gastroenterol, Dept Med, Dept Family & Prevent Med, 9500 Gilman Dr,MC 0063, La Jolla, CA 92093 USA. EM roloomba@ucsd.edu FU AGA-Foundation; Daiichi Sankyo Inc; National Institutes of Health [RO1AG28507, R37AG007181, RO1DK31801]; American Gastroenterological Association (AGA) Foundation - Sucampo - ASP Designated Research; T. Franklin Williams Scholarship Award; Atlantic Philanthropies, Inc; John A. Hartford Foundation; Association of Specialty Professors; American Gastroenterological Association; UCSD Digestive Diseases Research Development Center, U.S. PHS [DK080506] FX Declaration of personal interests: Rohit Loomba has served as a consultant for Corgenix Inc and an advisory board member for Gilead Inc and Daiichi Sankyo Inc, and has received research funding from the AGA-Foundation, Daiichi Sankyo Inc and National Institutes of Health. Declaration of funding interests: This work is supported in part by the American Gastroenterological Association (AGA) Foundation - Sucampo - ASP Designated Research Award in Geriatric Gastroenterology and by a T. Franklin Williams Scholarship Award. Funding provided by: Atlantic Philanthropies, Inc, the John A. Hartford Foundation, the Association of Specialty Professors, and the American Gastroenterological Association to Rohit Loomba, MD, MHSc. This research was funded in part with the support of the UCSD Digestive Diseases Research Development Center, U.S. PHS grant #DK080506. This work was supported in part by the National Institute of Health grants RO1AG28507, R37AG007181, and RO1DK31801 to Elizabeth Barrett-Connor, MD. NR 34 TC 81 Z9 85 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN PY 2012 VL 35 IS 1 BP 66 EP 75 DI 10.1111/j.1365-2036.2011.04912.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 860BX UT WOS:000297922600007 PM 22050199 ER PT J AU Lamas, GA Goertz, C Boineau, R Mark, DB Rozema, T Nahin, RL Drisko, JA Lee, KL AF Lamas, Gervasio A. Goertz, Christine Boineau, Robin Mark, Daniel B. Rozema, Theodore Nahin, Richard L. Drisko, Jeanne A. Lee, Kerry L. TI Design of the Trial to Assess Chelation Therapy (TACT) SO AMERICAN HEART JOURNAL LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; INTERMITTENT CLAUDICATION; ANTIOXIDANT VITAMINS; CLINICAL-TRIALS; DOUBLE-BLIND; PREVENTION; EDTA; QUESTIONNAIRE; METAANALYSIS AB TACT is an National Institutes of Health-sponsored, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial testing the benefits and risks of 40 infusions of a multicomponent disodium EDTA chelation solution compared with placebo and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow up 1,708 patients for an average of approximately 4 years. The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900-patient substudy will examine qualityof- life outcomes. The trial is designed to have N85% power to detect a 25% relative reduction in the primary end point for each treatment factor. Enrollment began in September 2003 and was completed in October 2010. (Am Heart J 2012; 163: 7-12.) C1 [Lamas, Gervasio A.] Mt Sinai Med Ctr, Miami Beach, FL 33140 USA. [Goertz, Christine] Palmer Ctr Chiropract Res, Davenport, IA USA. [Boineau, Robin] NHLBI, Bethesda, MD 20892 USA. [Mark, Daniel B.; Lee, Kerry L.] Duke Clin Res Inst, Durham, NC USA. [Rozema, Theodore] Biogenesis Med Ctr, Landrum, SC, Brazil. [Nahin, Richard L.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Drisko, Jeanne A.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Lamas, GA (reprint author), Mt Sinai Med Ctr, 4300 Alton Rd, Miami Beach, FL 33140 USA. EM gervasio.lamas@msmc.com OI Nahin, Richard/0000-0002-3682-4816; Mark, Daniel/0000-0001-6340-8087 FU Florida Heart Research Foundation FX The authors wish to acknowledge the valuable contributions of the following individuals: Ronald Hoffman, MD and Charles Hennekens, MD, DrPh, for protocol design; the CCC project directors (Ana Mon, MPH; Jacqueline Arciniega, MPH; Jaime Zimmerman, MPH; and Danielle Hollar, PhD); the CCC trial managers (Esteban Escolar, MD; Faisal Shamshad, MD; Pablo Guala, MD; Kayvan Amini, DO; Steven Hussein, MD; Alan Ackermann, DO); the project managers at the DCC (Sandra Tourt-Uhlig, RN, MSN; Joyce Good, RN, CCRC; Lindsay Lambe, BA, CNMT; Wanda Parker, RN, MSN; Nancy Clapp-Channing, BSN, MPH; Diane Minshall-Liu, CCRP); the NHLBI team members (Yves Rosenberg, MD; Mario Stylaniou, PhD; and Erin Iturriaga, RN, BS) and DSMB members (Howard Hodis, MD-Chair; Stephen Buckley, PharmD; Barry Davis, MD, PhD; Theodore Ganiats, MD; Robert Nash, MD; D. GeorgeWyse, MD, PhD; and Gail Geller, ScD, MHS); the project directors at Omnicomm Systems (Chris Droz, Brandon Diaz) and the central pharmacy team (Eric M. Alvarez, PharmD; Juan Mora RPh; Marcia Perez); the NCCAM Office of Communication and Outreach (Alyssa Cotler, MPH); the NHLBI Office of Communications (Susan Dambrauskas, NHLBI press team leader); and the Florida Heart Research Foundation for funding the pilot study. NR 32 TC 30 Z9 30 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JAN PY 2012 VL 163 IS 1 BP 7 EP 12 DI 10.1016/j.ahj.2011.10.002 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 863HI UT WOS:000298153000004 PM 22172430 ER PT J AU Flynn, KE Lin, L Moe, GW Howlett, JG Fine, LJ Spertus, JA McConnell, TR Pina, IL Weinfurt, KP AF Flynn, Kathryn E. Lin, Li Moe, Gordon W. Howlett, Jonathan G. Fine, Lawrence J. Spertus, John A. McConnell, Timothy R. Pina, Ileana L. Weinfurt, Kevin P. CA HF-ACTION Investigators TI Relationships between changes in patient-reported health status and functional capacity in outpatients with heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID QUALITY-OF-LIFE; CARDIAC RESYNCHRONIZATION; CONTROLLED-TRIAL; HF-ACTION; OUTCOMES; QUESTIONNAIRE; MORBIDITY; MORTALITY AB Background Heart failure trials use a variety of measures of functional capacity and quality of life. Lack of formal assessments of the relationships between changes in multiple aspects of patient-reported health status and measures of functional capacity over time limits the ability to compare results across studies. Methods Using data from HF-ACTION (N = 2331), we used the Pearson correlation coefficients and predicted change scores from linear mixed-effects modeling to demonstrate the associations between changes in patient-reported health status measured with the EQ-5D visual analog scale and the Kansas City Cardiomyopathy Questionnaire (KCCQ) and changes in peak VO(2) and 6-minute walk distance at 3 and 12 months. We examined a 5-point change in KCCQ within individuals to provide a framework for interpreting changes in these measures. Results After adjustment for baseline characteristics, correlations between changes in the visual analog scale and changes in peak VO2 and 6-minute walk distance ranged from 0.13 to 0.28, and correlations between changes in the KCCQ overall and subscale scores and changes in peak VO(2) and 6-minute walk distance ranged from 0.18 to 0.34. A 5-point change in KCCQ was associated with a 2.50-mL kg(-1) min(-1) change in peak VO(2) (95% CI 2.21-2.86) and a 112-m change in 6-minute walk distance (95% CI 96-134). Conclusions Changes in patient-reported health status are not highly correlated with changes in functional capacity. Our findings generally support the current practice of considering a 5-point change in the KCCQ within individuals to be clinically meaningful. (Am Heart J 2012;163:88-94.e3.) C1 [Flynn, Kathryn E.; Lin, Li; Weinfurt, Kevin P.] Duke Univ, Duke Clin Res Inst, Sch Med, Durham, NC 27715 USA. [Flynn, Kathryn E.; Weinfurt, Kevin P.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27715 USA. [Moe, Gordon W.] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Howlett, Jonathan G.] Univ Calgary, Calgary, AB, Canada. [Fine, Lawrence J.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Spertus, John A.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Spertus, John A.] Univ Missouri, Kansas City, KS USA. [McConnell, Timothy R.] Bloomsburg Univ, Dept Exercise Sci, Bloomsburg, PA USA. [Pina, Ileana L.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. RP Flynn, KE (reprint author), Duke Univ, Duke Clin Res Inst, Sch Med, POB 17969, Durham, NC 27715 USA. EM kathryn.flynn@duke.edu RI Flynn, Kathryn/M-5346-2013 OI Flynn, Kathryn/0000-0002-4427-3583 FU National Heart, Lung, and Blood Institute [5U01HL063747, 5U01HL066461, 5U01HL068973, 5U01HL066501, 5U01HL066482, 5U01HL064250, 5U01HL066494, 5U01HL064257, 5U01HL066497, 5U01HL068980, 5U01HL064265, 5U01HL066491, 5U01HL064264]; National Institute on Aging [R37AG018915, P60AG010484] FX HF-ACTION was funded by grants 5U01HL063747, 5U01HL066461, 5U01HL068973, 5U01HL066501, 5U01HL066482, 5U01HL064250, 5U01HL066494, 5U01HL064257, 5U01HL066497, 5U01HL068980, 5U01HL064265, 5U01HL066491, and 5U01HL064264 from the National Heart, Lung, and Blood Institute and grants R37AG018915 and P60AG010484 from the National Institute on Aging. NR 28 TC 13 Z9 13 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JAN PY 2012 VL 163 IS 1 BP 88 EP U120 DI 10.1016/j.ahj.2011.09.027 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 863HI UT WOS:000298153000015 PM 22172441 ER PT J AU Rienstra, M Sun, JX Lubitz, SA Frankel, DS Vasan, RS Levy, D Magnani, JW Sullivan, LM Meigs, JB Ellinor, PT Benjamin, EJ AF Rienstra, Michiel Sun, Jenny X. Lubitz, Steven A. Frankel, David S. Vasan, Ramachandran S. Levy, Daniel Magnani, Jared W. Sullivan, Lisa M. Meigs, James B. Ellinor, Patrick T. Benjamin, Emelia J. TI Plasma resistin, adiponectin, and risk of incident atrial fibrillation: The Framingham Offspring Study SO AMERICAN HEART JOURNAL LA English DT Article ID CONGESTIVE-HEART-FAILURE; C-REACTIVE PROTEIN; MYOCARDIAL-INFARCTION; OBESITY; ONSET; PIOGLITAZONE; HYPERTENSION; INFLAMMATION; INDIVIDUALS; POPULATION AB Background We sought to investigate whether higher concentrations of resistin and lower concentrations of adiponectin relate to incident atrial fibrillation (AF) and whether this association is mediated by AF risk factors and inflammation. Resistin and adiponectin are adipokines that have been associated with multiple known risk factors for AF including diabetes, obesity, inflammation, and heart failure. Methods We studied the relations between circulating concentrations of both adipokines and incident AF in participants of the Framingham Offspring Study. Results Participants (n = 2,487) had a mean age of 61 +/- 10 years, and 54% were women. During a mean follow-up of 7.6 +/- 2.0 years, 206 (8.3%) individuals (96 women) developed incident AF. Plasma resistin concentration was significantly associated with incident AF (multivariable-adjusted hazard ratio [HR] 1.17 per SD [0.41 ng/mL] of natural logarithmically transformed resistin, 95% CI 1.02-1.34, P =.028). The resistin-AF association was attenuated after further adjustment for C-reactive protein (HR per SD increase resistin 1.14, 95% CI 0.99-1.31, P =.073). Adiponectin concentrations were not significantly associated with incident AF (multivariable-adjusted HR of 0.95 per SD [0.62 mu g/mL] of logarithmically transformed adiponectin, 95% CI 0.81-1.10, P =.478). Conclusion In our community-based longitudinal study, higher mean concentrations of resistin were associated with incident AF, but the relation was attenuated by adjustment for C-reactive protein. We did not detect a statistically significant association between adiponectin and incident AF. Additional studies are needed to clarify the potential role of adipokines in AF and mechanisms linking adiposity to AF. (Am Heart J 2012; 163: 119-124. e1.) C1 [Rienstra, Michiel; Vasan, Ramachandran S.; Levy, Daniel; Magnani, Jared W.; Meigs, James B.; Ellinor, Patrick T.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Rienstra, Michiel; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rienstra, Michiel; Vasan, Ramachandran S.; Levy, Daniel; Magnani, Jared W.; Meigs, James B.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Sun, Jenny X.; Sullivan, Lisa M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA. [Frankel, David S.] Hosp Univ Penn, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Framingham, MA 01702 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Framingham, MA 01702 USA. [Vasan, Ramachandran S.; Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Framingham, MA 01702 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med,Dept Med, Boston, MA USA. RP Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Heart, Lung, and Blood Institute; NHLBI/NIH [N01-HC-25195]; Boston University School of Medicine; Netherlands Organization for Scientific Research [825.09.020]; National Institutes of Health [1R01HL092577, 1RC1HL101056, 1R01HL102214, R01AG028321, 6R01-NS17950, 5R21DA027021, 5RO1HL104156, 1K24HL105780, R01-DK-080739]; American Heart Association [09FTF2190028]; Evans Center for Interdisciplinary Biomedical Research ARC on "Atrial Fibrillation" at Boston University FX The Framingham Heart Study is supported by National Heart, Lung, and Blood Institute; Framingham Heart Study (NHLBI/NIH contract N01-HC-25195); and the Boston University School of Medicine. Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Rubicon grant 825.09.020). This work was supported by grants from the National Institutes of Health to Drs Benjamin and Ellinor (1R01HL092577); Dr Benjamin (1RC1HL101056, 1R01HL102214, R01AG028321; and support via 6R01-NS17950) and Dr Ellinor (5R21DA027021, 5RO1HL104156, 1K24HL105780); and Dr Vasan (R01-DK-080739). Dr Magnani is supported by American Heart Association Award 09FTF2190028. This work was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on "Atrial Fibrillation" at Boston University (http://www.bumc.bu.edu/evanscenteribr/). NR 37 TC 26 Z9 26 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JAN PY 2012 VL 163 IS 1 BP 119 EP U151 DI 10.1016/j.ahj.2011.09.029 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 863HI UT WOS:000298153000019 PM 22172445 ER PT J AU Daniel, CR Cross, AJ Graubard, BI Park, Y Ward, MH Rothman, N Hollenbeck, AR Chow, WH Sinha, R AF Daniel, Carrie R. Cross, Amanda J. Graubard, Barry I. Park, Yikyung Ward, Mary H. Rothman, Nathaniel Hollenbeck, Albert R. Chow, Wong-Ho Sinha, Rashmi TI Large prospective investigation of meat intake, related mutagens, and risk of renal cell carcinoma SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; KIDNEY CANCER; RED MEAT; HETEROCYCLIC AMINES; NATIONAL-INSTITUTES; N-NITROSATION; CONSUMPTION; COOKING AB Background: The evidence for meat intake and renal cell carcinoma (RCC) risk is inconsistent. Mutagens related to meat cooking and processing, and variation by RCC subtype may be important to consider. Objective: In a large US cohort, we prospectively investigated intake of meat and meat-related compounds in relation to risk of RCC, as well as clear cell and papillary RCC histologic subtypes. Design: Study participants (492,186) completed a detailed dietary assessment linked to a database of heme iron, heterocyclic amines (HCA), polycyclic aromatic hydrocarbons (PAHs), nitrate, and nitrite concentrations in cooked and processed meats. Over 9 (mean) y of follow-up, we identified 1814 cases of RCC (498 clear cell and 115 papillary adenocarcinomas). HRs and 95% CIs were estimated within quintiles by using multivariable Cox proportional hazards regression. Results: Red meat intake [62.7 g (quintile 5) compared with 9.8 g (quintile 1) per 1000 kcal (median)] was associated with a tendency toward an increased risk of RCC [HR: 1.19; 95% CI: 1.01, 1.40; P-trend = 0.06] and a 2-fold increased risk of papillary RCC [P-trend = 0.002]. Intakes of benzo(a) pyrene (BaP), a marker of PAHs, and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), an HCA, were associated with a significant 20-30% elevated risk of RCC and a 2-fold increased risk of papillary RCC. No associations were observed for the clear cell subtype. Conclusions: Red meat intake may increase the risk of RCC through mechanisms related to the cooking compounds BaP and PhIP. Our findings for RCC appeared to be driven by strong associations with the rarer papillary histologic variant. This study is registered at clinicaltrials.gov as NCT00340015. Am J Clin Nutr 2012;95:155-62. C1 [Daniel, Carrie R.; Cross, Amanda J.; Graubard, Barry I.; Park, Yikyung; Ward, Mary H.; Rothman, Nathaniel; Chow, Wong-Ho; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Daniel, CR (reprint author), 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM carrie.dan-iel@nih.hhs.gov RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, NIH; Florida Department of Health (FDOH) FX Supported by the Intramural Research Program of the National Cancer Institute, NIH.; 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. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected 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). Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Di vision of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, PA. 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. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. NR 43 TC 17 Z9 17 U1 0 U2 11 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 JAN PY 2012 VL 95 IS 1 BP 155 EP 162 DI 10.3945/ajcn.111.019364 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 866SF UT WOS:000298402100021 PM 22170360 ER PT J AU Beydoun, MA Ding, EL Beydoun, HA Tanaka, T Ferrucci, L Zonderman, AB AF Beydoun, May A. Ding, Eric L. Beydoun, Hind A. Tanaka, Toshiko Ferrucci, Luigi Zonderman, Alan B. TI Vitamin D receptor and megalin gene polymorphisms and their associations with longitudinal cognitive change in US adults SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NERVE GROWTH-FACTOR; D-BINDING PROTEIN; ALZHEIMERS-DISEASE; 1,25-DIHYDROXYVITAMIN D-3; D DEFICIENCY; AMYLOID-BETA; MEDIATED ENDOCYTOSIS; HIPPOCAMPAL-NEURONS; APOLIPOPROTEIN J; CELLULAR UPTAKE AB Background: Vitamin D receptor (VDR) and the megalin gene polymorphism's link with longitudinal cognitive change remains unclear. Objective: The associations of single nucleotide polymorphisms (SNPs) for VDR [rs11568820 (CdX-2:T/C), rs1544410 (BsmI:G/A), rs7975232 (ApaI:A/C), rs731236 (TaqI: G/A)], and Megalin (rs3755166: G/A; rs2075252: C/T; rs4668123:C/T) genes with longitudinal cognitive performance changes were examined. Design: Data from 702 non-Hispanic white participants in the Baltimore Longitudinal Study of Aging were used. Longitudinal annual rates of cognitive change (LARCCs) between age 50 y and the individual mean follow-up age were predicted with linear mixed models by using all cognitive score time points (prediction I) or time points before dementia onset (prediction II). Latent class, haplotype, and ordinary least squares (OLS) regression analyses were conducted. Results: Among key findings, in OLS models with SNP latent classes as predictors for LARCCs, Megalin(2) [rs3755166(-)/rs2075252(TT)/rs4668123(T-)] compared with Megalin(1) [rs3755166(-)/rs2075252 (CC)/rs4668123(-)] was associated with greater decline among men for verbal memory (prediction II). Significant sex differences were also found for SNP haplotype (SNPHAP). In women, VDR(1) [BsmI (G-)/ApaI(C-)/TaqI(A-); baT] was linked to a greater decline in category fluency (prediction I: beta = -0.031, P = 0.012). The Megalin1 SNPHAP (GCC) was related to greater decline among women for verbal memory, immediate recall [California Verbal Learning Test (CVLT), List A; prediction II: beta = -0.043, P = 0.006) but to slower decline among men for delayed recall (CVLT-DR: beta > 0, P < 0.0125; both predictions). In women, the Megalin2 SNPHAP (ACC) was associated with slower decline in category fluency (prediction II: beta = +0.026, P = 0.005). Another finding was that Megalin SNP rs3755166: G/A was associated with greater decline in global cognition in both sexes combined and in verbal memory in men. Conclusion: Sex-specific VDR and Megalin gene variations can modify age-related cognitive decline among US adults. Am J Clin Nutr 2012;95:163-78. C1 [Beydoun, May A.] NIA, NIH Biomed Res Ctr, IRP, NIH, Baltimore, MD 21224 USA. [Ding, Eric L.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. RP Beydoun, MA (reprint author), NIA, NIH Biomed Res Ctr, IRP, NIH, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Ding, Eric/0000-0002-5881-8097; Zonderman, Alan B/0000-0002-6523-4778 FU NIH, National Institute on Aging FX Supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 78 TC 20 Z9 20 U1 1 U2 4 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 JAN PY 2012 VL 95 IS 1 BP 163 EP 178 DI 10.3945/ajcn.111.017137 PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 866SF UT WOS:000298402100022 PM 22170372 ER PT J AU Edwards, TL Edwards, DRV Villegas, R Cohen, SS Buchowski, MS Fowke, JH Schlundt, D Long, JR Cai, QY Zheng, W Shu, XO Hargreaves, MK Jeffrey, S Williams, SM Signorello, LB Blot, WJ Matthews, CE AF Edwards, Todd L. Edwards, Digna R. Velez Villegas, Raquel Cohen, Sarah S. Buchowski, Maciej S. Fowke, Jay H. Schlundt, David Long, Ji Rong Cai, Qiuyin Zheng, Wei Shu, Xiao-Ou Hargreaves, Margaret K. Jeffrey, Smith Williams, Scott M. Signorello, Lisa B. Blot, William J. Matthews, Charles E. TI HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and Obesity in a Cohort of Caucasians and African Americans: An Evaluation of Gene-Environment Interactions and Candidate Genes SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE African continental ancestry group; body mass index; European continental ancestry group; genetics; molecular epidemiology; obesity ID ACTIVATED-RECEPTOR-GAMMA; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; FOOD FREQUENCY QUESTIONNAIRE; SOUTHERN COMMUNITY COHORT; TYPE-2 DIABETES-MELLITUS; 5-HT1B RECEPTOR; GLY482SER POLYMORPHISM; INSULIN-RESISTANCE; MAJOR DEPRESSION AB The World Health Organization estimates that the number of obese and overweight adults has increased to 1.6 billion, with concomitant increases in comorbidity. While genetic factors for obesity have been extensively studied in Caucasians, fewer studies have investigated genetic determinants of body mass index (BMI; weight (kg)/height(m)(2)) in African Americans. A total of 38 genes and 1,086 single nucleotide polymorphisms (SNPs) in African Americans (n = 1,173) and 897 SNPs in Caucasians (n = 1,165) were examined in the Southern Community Cohort Study (2002-2009) for associations with BMI and gene x environment interactions. A statistically significant association with BMI survived correction for multiple testing at rs4140535 (beta = -0.04, 95% confidence interval: -0.06, -0.02; P = 5.76 x 10(-5)) in African Americans but not in Caucasians. Gene-environment interactions were observed with cigarette smoking and a SNP in ADIPOR1 in African Americans, as well as between a different SNP in ADIPOR1 and physical activity in Caucasians. A SNP in PPARGC1A interacted with alcohol consumption in African Americans, and a different SNP in PPARGC1A was nominally associated in Caucasians. A SNP in CYP19A1 interacted with dietary energy intake in African Americans, and another SNP in CYP191A had an independent association with BMI in Caucasians. C1 [Edwards, Todd L.; Villegas, Raquel; Buchowski, Maciej S.; Fowke, Jay H.; Long, Ji Rong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou; Jeffrey, Smith; Signorello, Lisa B.; Blot, William J.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37203 USA. [Edwards, Todd L.; Villegas, Raquel; Fowke, Jay H.; Long, Ji Rong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Nashville, TN 37203 USA. [Edwards, Digna R. Velez] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37203 USA. [Cohen, Sarah S.; Signorello, Lisa B.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Buchowski, Maciej S.; Fowke, Jay H.; Schlundt, David; Long, Ji Rong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou; Hargreaves, Margaret K.; Jeffrey, Smith; Signorello, Lisa B.; Blot, William J.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Hargreaves, Margaret K.] Meharry Med Coll, Dept Internal Med, Nashville, TN 37208 USA. [Schlundt, David; Jeffrey, Smith] Vet Affairs Tennessee Valley Healthcare Syst, Med Res Serv, Nashville, TN USA. [Williams, Scott M.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Dept Mol Physiol & Biophys, Nashville, TN 37203 USA. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Edwards, TL (reprint author), Vanderbilt Univ, Med Ctr, Dept Med, 2525 W End Ave,Suite 600, Nashville, TN 37203 USA. EM todd.l.edwards@vanderbilt.edu RI Williams, Scott/B-9491-2012; Edwards, Todd/B-9750-2012; Velez Edwards, Digna/C-1090-2012; Buchowski, Maciej/A-2683-2008; Smith, Jeff/C-3484-2012; matthews, Charles/E-8073-2015 OI Buchowski, Maciej/0000-0002-0566-1743; matthews, Charles/0000-0001-8037-3103 FU Susan G. Komen for the Cure Foundation [OP05-0927-DR1]; National Cancer Institute [R01 CA092447]; Vanderbilt-Ingram Cancer Center [P30 CA68485]; Vanderbilt Clinical and Translational Research Scholar award [5KL2RR024975-04]; Building Interdisciplinary Research Careers in Women's Health career development program [K12HD4383] FX This project was funded in part by grant OP05-0927-DR1 from the Susan G. Komen for the Cure Foundation. The Southern Community Cohort Study is funded by grant R01 CA092447 from the National Cancer Institute. Sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (grant P30 CA68485). Dr. Todd L. Edwards also received support through Vanderbilt Clinical and Translational Research Scholar award 5KL2RR024975-04. Additional funds were provided by the Building Interdisciplinary Research Careers in Women's Health career development program (grant K12HD4383) for Dr. Digna Velez Edwards' salary. NR 67 TC 22 Z9 22 U1 1 U2 14 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 JAN 1 PY 2012 VL 175 IS 1 BP 11 EP 21 DI 10.1093/aje/kwr272 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 866MF UT WOS:000298384300002 PM 22106445 ER PT J AU Dodd, KW Midthune, D Kipnis, V AF Dodd, Kevin W. Midthune, Douglas Kipnis, Victor TI RE: "APPLICATION OF A REPEAT-MEASURE BIOMARKER MEASUREMENT ERROR MODEL TO 2 VALIDATION STUDIES: EXAMINATION OF THE EFFECT OF WITHIN-PERSON VARIATION IN BIOMARKER MEASUREMENTS" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID DOUBLY LABELED WATER; ENERGY-EXPENDITURE C1 [Dodd, Kevin W.; Midthune, Douglas; Kipnis, Victor] NCI, Biometry Res Grp, Canc Prevent Div, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Dodd, KW (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM doddk@mail.nih.gov NR 10 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2012 VL 175 IS 1 BP 84 EP 85 DI 10.1093/aje/kwr390 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 866MF UT WOS:000298384300010 PM 22088499 ER PT J AU Kopp, JB Winkler, CA AF Kopp, Jeffrey B. Winkler, Cheryl A. TI Genetic Risk Prediction for CKD: A Journey of a Thousand Miles SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; CARDIOVASCULAR RISK; SCORE; ASSOCIATION; CURVE; MODEL C1 [Kopp, Jeffrey B.; Winkler, Cheryl A.] NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS [Z01 DK043308-12] NR 28 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JAN PY 2012 VL 59 IS 1 BP 4 EP 8 DI 10.1053/j.ajkd.2011.11.011 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 863HO UT WOS:000298153600004 PM 22177444 ER PT J AU O'Seaghdha, CM Yang, Q Wu, HS Hwang, SJ Fox, CS AF O'Seaghdha, Conall M. Yang, Qiong Wu, Hongsheng Hwang, Shih-Jen Fox, Caroline S. TI Performance of a Genetic Risk Score for CKD Stage 3 in the General Population SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; genetics; risk prediction ID CHRONIC KIDNEY-DISEASE; CORONARY-HEART-DISEASE; GLOMERULAR-FILTRATION-RATE; DIABETIC-NEPHROPATHY; RENAL-INSUFFICIENCY; UNITED-STATES; PREVALENCE; ADULTS; PREDICTION; FRAMINGHAM AB Background: Recent genome-wide association studies have identified multiple genetic loci that increase the risk of chronic kidney disease (CKD) in the general population. We hypothesized that knowledge of these loci might permit improved CKD risk prediction beyond that provided by traditional phenotypic risk factors. Study Design: Observational cohort study. Setting & Participants: Participants who attended the 15th (1977-1979) and 24th (1995-1998) examination cycles of the original cohort or the 6th (1995-1998) and 8th cycles (2005-2008) of the offspring cohort of the Framingham Heart Study (n = 2,489). Predictors: Single-nucleotide polymorphisms at 16 stage 3 CKD loci were genotyped and used to construct a genetic risk score. Standard clinical predictors of incident stage 3 CKD also were used. Outcomes & Measurements: Incident stage 3 CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2) at follow-up. Participants with baseline stage 3 CKD were excluded. Logistic regression was used to generate C statistics, which measured the power of the genetic risk score to discriminate risk of incident CKD stage 3 with and without traditional risk factors. Results: There were 270 new stage 3 CKD cases during an average of 10.8 years of follow-up. Mean genetic risk score was 17.5 +/- 2.8 (SD) for those who developed stage 3 CKD and 17.3 +/- 2.6 for those who did not (P for genotype score difference = 0.2). The OR for stage 3 CKD was 1.06 (95% CI, 1.01-1.11; P = 0.03) per additional risk allele, adjusting for age and sex. In the age-and sex-adjusted model, the C statistic was 0.748 without the genotype score and 0.751 with the score (P difference = 0.3). The risk score was not statistically significant in a multivariable model adjusted for standard stage 3 CKD risk factors (P = 0.07). Limitations: All participants were of European ancestry; the genotype score may not be valid in different ancestral groups. Conclusions: A genetic score generated from 16 known CKD risk alleles did not predict new cases of stage 3 CKD in the community beyond knowledge of common clinical risk factors alone. Am J Kidney Dis. 59(1): 19-24. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Brigham & Womens Hosp, Boston, MA 02114 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Yang, Qiong; Wu, Hongsheng] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Wu, Hongsheng] Wentworth Inst Technol, Dept Comp Sci, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov RI Yang, Qiong/G-5438-2014 FU NHLBI's FHS [N01-HC-25195] FX This research was conducted in part using data and resources from the FHS of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and Boston University School of Medicine. This work was partially supported by the NHLBI's FHS (Contract No. N01-HC-25195). The sponsors had no role in the conduct or interpretation of the study. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. NR 41 TC 12 Z9 12 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JAN PY 2012 VL 59 IS 1 BP 19 EP 24 DI 10.1053/j.ajkd.2011.08.030 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 863HO UT WOS:000298153600008 PM 21995970 ER PT J AU Yin, F Wilson, T Della Fave, A Larsen, M Yoon, J Nugusie, B Freeland, H Chow, RD AF Yin, Fang Wilson, Thomas Della Fave, Albert Larsen, Moira Yoon, Jenni Nugusie, Binyam Freeland, Howard Chow, Robert Dobbin TI Inappropriate Use of D-Dimer Assay and Pulmonary CT Angiography in the Evaluation of Suspected Acute Pulmonary Embolism SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE D-dimer; CT angiography; pulmonary embolism; emergency department ID SIMPLE CLINICAL-MODEL; COMPUTED-TOMOGRAPHY; PROBABILITY; MANAGEMENT; THROMBOSIS; EXCLUSION; DIAGNOSIS; OUTCOMES AB The authors question whether the d-dimer assay and pulmonary computed tomography angiography (CTA) are being used appropriately to evaluate suspected acute pulmonary embolism (PE) at their hospital. To answer this question, a retrospective review was performed on all emergency department (ED) patients who underwent d-dimer assay and/or CTA from August 15, 2008, to August 14, 2009. The authors' algorithm for diagnosing PE requires that patients with low or intermediate probability of acute PE undergo a d-dimer assay, followed by CTA if the d-dimer is positive. Patients with high probability of PE should have CTA performed without a d-dimer assay. This result suggests that d-dimer assay and CTA are used inappropriately to evaluate patients with suspected acute PE in our ED. The low threshold for initiating an evaluation for PE decreases the prevalence of PE in this population. C1 [Yin, Fang; Wilson, Thomas; Della Fave, Albert; Larsen, Moira; Yoon, Jenni; Nugusie, Binyam; Freeland, Howard; Chow, Robert Dobbin] Good Samaritan Hosp Maryland, Baltimore, MD USA. RP Yin, F (reprint author), NHLBI, Hematol Branch, Bldg 10,CRC Room 4E-5140,10 Ctr Dr,MSC 1475, Bethesda, MD 21892 USA. EM fang.yin@nih.gov NR 19 TC 9 Z9 10 U1 0 U2 4 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 JAN-FEB PY 2012 VL 27 IS 1 BP 74 EP 79 DI 10.1177/1062860611407907 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 870FX UT WOS:000298655700010 PM 21666066 ER PT J AU Ananth, CV Wilcox, AJ Gyamfi-Bannerman, C AF Ananth, Cande V. Wilcox, Allen J. Gyamfi-Bannerman, Cynthia TI Obstetrical interventions among nulliparous women in the United States, 2005-07 SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Ananth, Cande V.; Gyamfi-Bannerman, Cynthia] Columbia Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY USA. [Wilcox, Allen J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 646 BP S289 EP S289 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900644 ER PT J AU Bailit, JL AF Bailit, Jennifer L. TI Use of maternal and neonatal outcomes to measure quality of care: is hospital performance consistent across outcomes? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Bailit, Jennifer L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 30 BP S20 EP S21 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900031 ER PT J AU Berggren, E AF Berggren, Erica TI The NICHD-MFMU GDM study: differences in perinatal outcomes between Hispanic women and Non-Hispanic White women with and without gestational diabetes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Berggren, Erica] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 556 BP S252 EP S253 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900554 ER PT J AU Bousleiman, S AF Bousleiman, Sabine TI Translating research into practice in obstetrics SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Bousleiman, Sabine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 635 BP S284 EP S285 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900633 ER PT J AU Bousleiman, S AF Bousleiman, Sabine TI Maternal risk factors and small for gestational age neonates SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Bousleiman, Sabine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 634 BP S284 EP S284 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900632 ER PT J AU Chiossi, G AF Chiossi, Giuseppe TI Timing of delivery and adverse outcomes in term singleton repeat cesarean deliveries (CD) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Chiossi, Giuseppe] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 38 BP S26 EP S26 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900039 ER PT J AU Cho, HJ Kim, YM Jeon, GH Kim, JY Kim, CJ Romero, R AF Cho, Hyun Jin Kim, Yeon Mee Jeon, Gyun-Ho Kim, Ji Yeon Kim, Chong Jai Romero, Roberto TI CD36 expression in trophoblasts: implications for preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Cho, Hyun Jin; Kim, Yeon Mee; Jeon, Gyun-Ho; Kim, Ji Yeon] Inje Univ, Haeundae Paik Hosp, Pusan, South Korea. [Kim, Chong Jai; Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 807 BP S355 EP S355 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889901073 ER PT J AU Fuchs, KM D'Alton, M AF Fuchs, Karin M. D'Alton, Mary TI Can sonographer education and image review standardize image acquisition and caliper placement in 2D ultrasounds? Experience from the NICHD Fetal Growth Study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Fuchs, Karin M.; D'Alton, Mary] NICHHD, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 23 BP S15 EP S16 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900024 ER PT J AU Gilbert, SA AF Gilbert, Sharon A. TI The MFMU Cesarean Registry: cost-effectiveness of a trial of labor compared with an elective repeat cesarean delivery after a previous cesarean in a minimally biased cohort SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Gilbert, Sharon A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 681 BP S303 EP S303 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900678 ER PT J AU Gilbert, SA AF Gilbert, Sharon A. TI The MFMU cesarean registry: propensity score analysis for bias reduction in comparing elective repeat cesarean delivery with trial of labor after a previous cesarean SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Gilbert, Sharon A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 29 BP S20 EP S20 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900030 ER PT J AU Grobman, W AF Grobman, William TI Randomized controlled trial of progesterone treatment for preterm birth prevention in nulliparous women with cervical length less than 30 mm SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Grobman, William] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Maternal Fetal Units Network, Bethesda, MD USA. NR 0 TC 10 Z9 10 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 838 BP S367 EP S367 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889901104 ER PT J AU Grobman, W AF Grobman, William TI Does risk adjustment for patient characteristics affect assessment of hospital quality performance? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Grobman, William] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Maternal Fetal Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 641 BP S287 EP S287 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900639 ER PT J AU Grobman, W AF Grobman, William TI The development of risk-adjusted outcomes to be used as quality indicators for obstetric care SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Grobman, William] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Maternal Fetal Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 640 BP S286 EP S287 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900638 ER PT J AU Grobman, W AF Grobman, William TI Is an individualized growth standard better than a population-based standard at predicting cerebral palsy or death among SGA infants? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Grobman, William] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Maternal Fetal Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 536 BP S242 EP S242 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900534 ER PT J AU Grobman, W AF Grobman, William TI Can differences in obstetric outcomes be explained by differences in the care provided? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Grobman, William] Natl Inst Hlth & Human Dev, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 6 BP S4 EP S4 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900007 ER PT J AU Horowitz, K Incerti, M Roberson, R Abebe, D Toso, L Caballero, M Spong, CY AF Horowitz, Kari Incerti, Maddalena Roberson, Robin Abebe, Daniel Toso, Laura Caballero, Madeline Spong, Catherine Y. TI Prenatal treatment prevents learning deficit in down syndrome model SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Horowitz, Kari] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Incerti, Maddalena] Univ Milano Bicocca, Monza, Italy. [Roberson, Robin; Abebe, Daniel; Toso, Laura; Caballero, Madeline; Spong, Catherine Y.] UPDN DIR, NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 53 BP S35 EP S35 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900054 ER PT J AU Horton, A AF Horton, Amanda TI The effect of magnesium sulfate administration for neuroprotection on latency in women with preterm premature rupture of membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Horton, Amanda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 456 BP S209 EP S209 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900455 ER PT J AU Jeon, GH Cho, HJ Kim, JY Kim, CJ Romero, R Kim, YM AF Jeon, Gyun-Ho Cho, Hyun Jin Kim, Ji Yeon Kim, Chong Jai Romero, Roberto Kim, Yeon Mee TI The expression of CD36 in preterm and term pregnancies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Jeon, Gyun-Ho; Cho, Hyun Jin; Kim, Ji Yeon; Kim, Yeon Mee] Inje Univ, Haeundae Paik Hosp, Pusan, South Korea. [Kim, Chong Jai; Romero, Roberto] NICHHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 117 BP S64 EP S65 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900118 ER PT J AU Johnson, M AF Johnson, Mark TI Risk factors for preterm delivery and uterine dehiscence following prenatal surgery for myelomeningocele SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Johnson, Mark] NICHD, MOMSTrial Grp, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 427 BP S197 EP S198 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900426 ER PT J AU Laughon, SK Hazrati, S Bowers, K Zhang, CL Grewal, U AF Laughon, S. Katherine Hazrati, Sahel Bowers, Katherine Zhang, Cuilin Grewal, Una TI Increased neonatal respiratory Morbidity associated with gestational and pregestational diabetes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Laughon, S. Katherine; Bowers, Katherine; Zhang, Cuilin; Grewal, Una] NICHD, NIH, Epidemiol Branch, Bethesda, MD USA. [Hazrati, Sahel] George Mason Univ, Fairfax, VA 22030 USA. RI Bowers, Katherine/N-5226-2015 NR 0 TC 7 Z9 7 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 75 BP S47 EP S47 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900076 ER PT J AU Lee, SM Romero, R Lee, YJ Park, IS Park, CW Yoon, BH AF Lee, Seung Mi Romero, Roberto Lee, You Jeong Park, In Sook Park, Chan-Wook Yoon, Bo Hyun TI Systemic inflammatory stimulation by microparticles derived from hypoxic trophoblast in preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Lee, Seung Mi] Seoul Metropolitan Govt Seoul Natl Univ Boramae M, Seoul, South Korea. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. [Lee, You Jeong] Seoul Natl Univ Coll Med, Dept Pathol, Seoul, South Korea. [Park, In Sook; Park, Chan-Wook] Seoul Natl Univ Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RI Park, Chan-Wook/J-5498-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 798 BP S351 EP S351 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889901064 ER PT J AU Lee, SM Romero, R Park, JW Kim, BJ Park, CW Park, JS Jun, JK Yoon, BH AF Lee, Seung Mi Romero, Roberto Park, Jeong Woo Kim, Byung Jae Park, Chan-Wook Park, Joong Shin Jun, Jong Kwan Yoon, Bo Hyun TI Histologic chorioamnionitis is a risk factor for adverse neonatal outcome in late preterm birth following preterm PROM SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Kim, Byung Jae] Seoul Metropolitan Govt Seoul Natl Univ Boramae M, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. [Park, Chan-Wook; Park, Joong Shin; Jun, Jong Kwan] Seoul Natl Univ Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Park, Jeong Woo] Seoul Natl Univ Coll Med, Deptartment Obstet & Gynecol, Seoul, South Korea. RI Park, Chan-Wook/J-5498-2012; Jun, Jong Kwan/D-5776-2012 OI Jun, Jong Kwan/0000-0002-0242-1736 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 524 BP S237 EP S237 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900522 ER PT J AU Lesko, J Peaceman, A AF Lesko, Jennifer Peaceman, Alan TI Pregnancy outcomes after bariatric surgery compared with body mass index matched controls SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Lesko, Jennifer] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Peaceman, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth &Huma, Maternal Fetal Med Units, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 322 BP S152 EP S153 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900321 ER PT J AU Olson, G AF Olson, Gayle TI Fetal growth restriction is associated with decreased developmental screening scores in childhood SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Olson, Gayle] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 409 BP S190 EP S191 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900408 ER PT J AU Olson, G AF Olson, Gayle TI The relationship of birth weight to body mass index and blood pressure at ages 3-5 years SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Olson, Gayle] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 408 BP S190 EP S190 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900407 ER PT J AU Park, CW Yoon, BH Jun, JK Park, JS Kim, BJ Romero, R AF Park, Chan-Wook Yoon, Bo Hyun Jun, Jong Kwan Park, Joong Shin Kim, Byung Jae Romero, Roberto TI Approximately one-fifth of patients with preterm labor and intact membranes and low amniotic fluid white blood cell counts have evidence of intra-amniotic inflammation and are at risk for impending preterm delivery when MMP-8 is used SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Park, Chan-Wook; Jun, Jong Kwan; Park, Joong Shin; Kim, Byung Jae] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. RI Park, Chan-Wook/J-5498-2012; Jun, Jong Kwan/D-5776-2012 OI Jun, Jong Kwan/0000-0002-0242-1736 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 469 BP S214 EP S214 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900468 ER PT J AU Park, CW Yoon, BH Jun, JK Park, JS Kim, SM Romero, R AF Park, Chan-Wook Yoon, Bo Hyun Jun, Jong Kwan Park, Joong Shin Kim, Sun Min Romero, Roberto TI The intraamniotic and fetal inflammatory response is more intense in preterm labor with intact membranes than in preterm PROM SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Park, Chan-Wook; Jun, Jong Kwan; Park, Joong Shin] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. RI Park, Chan-Wook/J-5498-2012; Jun, Jong Kwan/D-5776-2012 OI Jun, Jong Kwan/0000-0002-0242-1736 NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 468 BP S214 EP S214 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900467 ER PT J AU Peaceman, A AF Peaceman, Alan TI Prediction of cerebral palsy (CP) or death among preterm infants who survive the neonatal period SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Peaceman, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 451 BP S207 EP S207 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900450 ER PT J AU Pereira, L Wilmarth, P AF Pereira, Leonardo Wilmarth, Phil TI Prediction of preterm birth in twin gestations through analysis of maternal plasma at 24-30 weeks gestation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Pereira, Leonardo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. [Wilmarth, Phil] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 502 BP S227 EP S227 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900500 ER PT J AU Pinar, H Dudley, D AF Pinar, Hal Dudley, Donald CA SCRN Investigators TI Gestational age effects on pathologic findings of stillbirth placentas: evidence from a population-based study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Pinar, Hal] Brown Univ, Alpert Sch Med, Providence, RI 02912 USA. [Dudley, Donald] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet Gynecol, San Antonio, TX 78229 USA. [SCRN Investigators] Eunice Kennedy Shriver NICHD, Pregnancy & Perinatol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 107 BP S61 EP S62 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900108 ER PT J AU Pinar, H Dudley, D AF Pinar, Hal Dudley, Donald CA Stillbirth Collaborative Res Netwo TI Histologic features of the placenta in stillbirth: results of a case control study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Pinar, Hal] Brown Univ, Alpert Sch Med, Providence, RI 02912 USA. [Dudley, Donald] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet Gynecol, San Antonio, TX 78229 USA. [Stillbirth Collaborative Res Netwo] Eunice Kennedy Shriver NICHD, Pregnancy & Perinatol Branch, Bethesda, MD USA. RI Bukowski, Radek/B-6976-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 106 BP S61 EP S61 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900107 ER PT J AU Roberson, R Kuddo, T Caballero, M Horowitz, K Spong, CY AF Roberson, Robin Kuddo, Thea Caballero, Madeline Horowitz, Kari Spong, Catherine Y. TI Hippocampal and cerebellar BDNF levels in the Ts65Dn mouse model of Down syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Roberson, Robin; Kuddo, Thea; Caballero, Madeline; Spong, Catherine Y.] NICHD, UPDN, DIR, NIH, Bethesda, MD USA. [Horowitz, Kari] Univ Connecticut, Ctr Hlth, Farmington, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 720 BP S320 EP S320 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900715 ER PT J AU Roberson, R Kuddo, T Horowitz, K Caballero, M Spong, CY AF Roberson, Robin Kuddo, Thea Horowitz, Kari Caballero, Madeline Spong, Catherine Y. TI Cytokine and chemokine alterations in down syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Roberson, Robin; Kuddo, Thea; Caballero, Madeline; Spong, Catherine Y.] UPDN, NICHD, NIH, DIR, Bethesda, MD USA. [Horowitz, Kari] Univ Connecticut, Ctr Hlth, Farmington, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 59 BP S37 EP S37 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900060 ER PT J AU Schuit, E Stock, S Rouse, D Lim, AC Rode, L Norman, J Nassar, A Serra, V Combs, CA Rozenberg, P Cetingoz, E Briery, C Thom, E Caritis, S Klein, K Tabor, A Awwad, J Usta, I Perales, A Meseguer, J Maurel, K Garite, T Cam, C Karateke, A Morrison, J Magann, E Groenwold, RHH Moons, K Kwee, A Mol, BW AF Schuit, E. Stock, Sarah Rouse, Dwight Lim, A. C. Rode, Line Norman, Jane Nassar, Anwar Serra, Vicente Combs, C. Andrew Rozenberg, Patrick Cetingoz, Elcin Briery, Christian Thom, Elizabeth Caritis, Steve Klein, Katharina Tabor, Ann Awwad, Johnny Usta, Ihab Perales, Alfredo Meseguer, Juan Maurel, Kimberly Garite, Thomas Cam, Cetin Karateke, Ates Morrison, John Magann, Everett Groenwold, Rolf H. H. Moons, Karel Kwee, Anneke Mol, Ben Willem TI Progestogen in twin pregnancies: an individual participant data meta-analysis of randomized trials SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Schuit, E.; Groenwold, Rolf H. H.; Moons, Karel] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Rouse, Dwight] NICHD MFMU Network Twins Trial, Providence, RI USA. [Norman, Jane] Univ Edinburgh, MRC Ctr Reprod Hlth, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. [Nassar, Anwar; Awwad, Johnny; Usta, Ihab] Lebanese Progestogen Trial, Lebanon, NH USA. [Briery, Christian; Morrison, John; Magann, Everett] Mississippi Progestogen Trial, Mississippi State, MS USA. [Thom, Elizabeth] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Caritis, Steve] Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. RI Mol, Ben /I-4526-2012 NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 472 BP S215 EP S216 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900471 ER PT J AU Sibai, B Koch, M Freire, S Silva, JLPE Rudge, MVC Martins-Costa, S Goco, N Santos, CD Cecatti, JG Costa, R Ramos, JG Moss, N Spinnato, J AF Sibai, Baha Koch, Matthew Freire, Salvio Pinto e Silva, Joao Luiz Cunha Rudge, Marilza Vieira Martins-Costa, Sergio Goco, Norman Santos, Cleide de Barros Cecatti, Jose Guilherme Costa, Roberto Ramos, Jose Geraldo Moss, Nancy Spinnato, Joseph, II TI Are adverse perinatal outcomes (APOs) in chronic hypertension (CHTN) mostly related to superimposed preeclampsia (PE)? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Sibai, Baha] Univ Cincinnati, Cincinnati, OH USA. [Koch, Matthew] RTI Int Stat & Epidemiol Div, Durham, NC USA. [Freire, Salvio] Univ Fed Pernamucco, Recife, PE, Brazil. [Cecatti, Jose Guilherme] Univ Estadual Campinas, Campinas, Brazil. [Pinto e Silva, Joao Luiz; Cunha Rudge, Marilza Vieira; Costa, Roberto] Univ Estadual Paulista, Botucatu, SP, Brazil. [Martins-Costa, Sergio] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Goco, Norman] RTI Int Res Triangle Pk, Stat & Epidemiol Div, Durham, NC USA. [Santos, Cleide de Barros] Univ Fed Pernambuco, Recife, PE, Brazil. [Moss, Nancy] NICHD, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Spinnato, Joseph, II] Univ S Florida, Tampa, FL USA. RI Rudge, Marilza /C-8338-2012 OI Rudge, Marilza /0000-0002-9227-832X NR 0 TC 1 Z9 1 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 95 BP S57 EP S57 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900096 ER PT J AU Silver, B AF Silver, Bob TI First trimester free total and fetal DNA in the maternal circulation are not associated with preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Silver, Bob] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 744 BP S330 EP S330 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889901010 ER PT J AU Sutton, A AF Sutton, Amelia TI The impact of delivery timing on cesarean delivery risk in women with mild destational diabetes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Sutton, Amelia] Eunice Kennedy Shriver Natl Inst Child Hlth, Bethesda, MD USA. [Sutton, Amelia] Human Dev Maternal Fetal Med Units Network, Bethesda, MD USA. OI Sutton, Amelia/0000-0003-0493-0670 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 279 BP S135 EP S135 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900279 ER PT J AU Tita, A AF Tita, Alan TI Maternal and perinatal morbidity risks differ by type of pregnancy-associated hypertension in nulliparas SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Tita, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 734 BP S325 EP S325 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900729 ER PT J AU Tita, A AF Tita, Alan TI Pregnancy associated hypertension: cumulative risk varies by subtype, race and body mass index SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Tita, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 735 BP S326 EP S326 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889901001 ER PT J AU Tita, A AF Tita, Alan TI Burden of adverse maternal and perinatal outcomes by preterm birth type in nulliparas SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Tita, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 452 BP S207 EP S208 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900451 ER PT J AU Wapner, R AF Wapner, Ronald TI A multicenter, prospective, masked comparison of chromosomal microarray with standard karyotyping for routine and high risk prenatal diagnosis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 32nd Annual Scientific Meeting/Pregnancy Meeting of Society-for-Maternal-Fetal-Medicine CY FEB 06-11, 2012 CL Dallas, TX SP Soc Maternal Fetal Med C1 [Wapner, Ronald] NICHD, Prenatal Microarray Study Grp, Bethesda, MD USA. NR 0 TC 16 Z9 17 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2012 VL 206 IS 1 SU S MA 1 BP S2 EP S2 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 873NL UT WOS:000298889900002 ER PT J AU Dorsey, SG Lovering, RM Renn, CL Leitch, CC Liu, XY Tallon, LJ Sadzewicz, LD Pratap, A Ott, S Sengamalay, N Jones, KM Barrick, C Fulgenzi, G Becker, J Voelker, K Talmadge, R Harvey, BK Wyatt, RM Vernon-Pitts, E Zhang, C Shokat, K Fraser-Liggett, C Balice-Gordon, RJ Tessarollo, L Ward, CW AF Dorsey, Susan G. Lovering, Richard M. Renn, Cynthia L. Leitch, Carmen C. Liu, Xinyue Tallon, Luke J. Sadzewicz, Lisa DeShong Pratap, Abhishek Ott, Sandra Sengamalay, Naomi Jones, Kristie M. Barrick, Colleen Fulgenzi, Gianluca Becker, Jodi Voelker, Kevin Talmadge, Robert Harvey, Brandon K. Wyatt, Ryan M. Vernon-Pitts, Elizabeth Zhang, Chao Shokat, Kevan Fraser-Liggett, Claire Balice-Gordon, Rita J. Tessarollo, Lino Ward, Christopher W. TI Genetic deletion of trkB.T1 increases neuromuscular function SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE neurotrophin; neuromuscular junction; calcium; knockout mouse ID MOUSE SKELETAL-MUSCLE; CONTRACTION-INDUCED INJURY; FIBER-TYPE PLASTICITY; NEUROTROPHIC FACTOR; SIGNALING PATHWAYS; IN-VIVO; ECCENTRIC CONTRACTIONS; MUSCULAR-DYSTROPHY; TRK RECEPTORS; CA2+ SPARKS AB Dorsey SG, Lovering RM, Renn CL, Leitch CC, Liu X, Tallon LJ, Sadzewicz LD, Pratap A, Ott S, Sengamalay N, Jones KM, Barrick C, Fulgenzi G, Becker J, Voelker K, Talmadge R, Harvey BK, Wyatt RM, Vernon-Pitts E, Zhang C, Shokat K, Fraser-Liggett C, Balice-Gordon RJ, Tessarollo L, Ward CW. Genetic deletion of trkB.T1 increases neuromuscular function. Am J Physiol Cell Physiol 302: C141-C153, 2012. First published August 24, 2011; doi:10.1152/ajpcell.00469.2010.-Neurotrophin-dependent activation of the tyrosine kinase receptor trkB. FL modulates neuromuscular synapse maintenance and function; however, it is unclear what role the alternative splice variant, truncated trkB (trkB.T1), may have in the peripheral neuromuscular axis. We examined this question in trkB.T1 null mice and demonstrate that in vivo neuromuscular performance and nerve-evoked muscle tension are significantly increased. In vitro assays indicated that the gain-in-function in trkB.T1(-/-) animals resulted specifically from an increased muscle contractility, and increased electrically evoked calcium release. In the trkB.T1 null muscle, we identified an increase in Akt activation in resting muscle as well as a significant increase in trkB. FL and Akt activation in response to contractile activity. On the basis of these findings, we conclude that the trkB signaling pathway might represent a novel target for intervention across diseases characterized by deficits in neuromuscular function. C1 [Dorsey, Susan G.; Renn, Cynthia L.; Leitch, Carmen C.; Ward, Christopher W.] Univ Maryland Baltimore, Sch Nursing, Baltimore, MD USA. [Lovering, Richard M.] Univ Maryland Baltimore, Sch Med, Baltimore, MD USA. [Voelker, Kevin] Virginia Tech, Dept Human Nutr Foods & Exercise, Blacksburg, VA USA. [Talmadge, Robert] Calif State Polytech Univ Pomona, Dept Biol Sci, Pomona, CA 91768 USA. [Harvey, Brandon K.] NIDA, NIH, Bethesda, MD 20892 USA. [Wyatt, Ryan M.; Vernon-Pitts, Elizabeth; Balice-Gordon, Rita J.] Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. [Barrick, Colleen; Fulgenzi, Gianluca; Becker, Jodi; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Zhang, Chao; Shokat, Kevan] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Liu, Xinyue; Tallon, Luke J.; Sadzewicz, Lisa DeShong; Pratap, Abhishek; Ott, Sandra; Sengamalay, Naomi; Jones, Kristie M.; Fraser-Liggett, Claire] Univ Maryland Baltimore, Sch Med, Inst Genome Sci, Baltimore, MD USA. RP Ward, CW (reprint author), Univ Maryland, Sch Nursing, 655 W Lombard St,Rm 752, Baltimore, MD 21201 USA. EM sdorsey@son.umaryland.edu; ward@son.umaryland.edu OI Fraser, Claire/0000-0003-1462-2428; Fulgenzi, Gianluca/0000-0003-2646-7728 FU National Institutes of Health [AR002177, AR053318, RC2 NR011968, NR009672, NR011968, NS047777, K01AR053235, 1R01AR059179, NS046490]; National Cancer Institute Center for Cancer Research; National Institute of Drug Abuse FX This work was supported by grants from the National Institutes of Health to C. W. Ward (AR002177, AR053318, and RC2 NR011968), to S. G. Dorsey (NR009672 and NR011968), to R. M. Wyatt (NS047777), to R. Lovering (K01AR053235 and 1R01AR059179), and to R. Balice-Gordon (NS046490), and by intramural support from the National Cancer Institute Center for Cancer Research to C. Barrick and L. J. Tallon and intramural support from the National Institute of Drug Abuse to B. K. Harvey. NR 76 TC 8 Z9 8 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2012 VL 302 IS 1 BP C141 EP C153 DI 10.1152/ajpcell.00469.2010 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 866IN UT WOS:000298374100017 PM 21865582 ER PT J AU Pisitkun, T Hoffert, JD Saeed, F Knepper, MA AF Pisitkun, Trairak Hoffert, Jason D. Saeed, Fahad Knepper, Mark A. TI NHLBI-AbDesigner: an online tool for design of peptide-directed antibodies SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE immunogenicity; posttranslational modification; specificity; epitope; conservation ID THICK ASCENDING LIMB; LONG-TERM REGULATION; RAT-KIDNEY; COLLECTING DUCT; WATER CHANNEL; PLASMA-MEMBRANE; AQUAPORIN-2 PHOSPHORYLATION; VASOPRESSIN; LOCALIZATION; EXPRESSION AB Pisitkun T, Hoffert JD, Saeed F, Knepper MA. NHLBI-AbDesigner: an online tool for design of peptide-directed antibodies. Am J Physiol Cell Physiol 302: C154-C164, 2012. First published September 28, 2011; doi:10.1152/ajpcell.00325.2011.-Investigation of physiological mechanisms at a cellular level often requires production of high-quality antibodies, frequently using synthetic peptides as immunogens. Here we describe a new, web-based software tool called NHLBI-AbDesigner that allows the user to visualize the information needed to choose optimal peptide sequences for peptide-directed antibody production (http://helixweb.nih.gov/AbDesigner/). The choice of an immunizing peptide is generally based on a need to optimize immunogenicity, antibody specificity, multispecies conservation, and robustness in the face of posttranslational modifications (PTMs). AbDesigner displays information relevant to these criteria as follows: 1) "Immunogenicity Score," based on hydropathy and secondary structure prediction; 2) "Uniqueness Score," a predictor of specificity of an antibody against all proteins expressed in the same species; 3) "Conservation Score," a predictor of ability of the antibody to recognize orthologs in other animal species; and 4) "Protein Features" that show structural domains, variable regions, and annotated PTMs that may affect antibody performance. AbDesigner displays the information online in an interactive graphical user interface, which allows the user to recognize the trade-offs that exist for alternative synthetic peptide choices and to choose the one that is best for a proposed application. Several examples of the use of AbDesigner for the display of such trade-offs are presented, including production of a new antibody to Slc9a3. We also used the program in large-scale mode to create a database listing the 15-amino acid peptides with the highest Immunogenicity Scores for all known proteins in five animal species, one plant species (Arabidopsis thaliana), and Saccharomyces cerevisiae. C1 [Pisitkun, Trairak; Hoffert, Jason D.; Saeed, Fahad; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, 10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov RI Saeed, Fahad/D-1545-2013; OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural Budget of the National Heart, Lung, and Blood Institute [Z01-HL-001285] FX This work was supported by the Intramural Budget of the National Heart, Lung, and Blood Institute (Project Z01-HL-001285). NR 37 TC 9 Z9 9 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2012 VL 302 IS 1 BP C154 EP C164 DI 10.1152/ajpcell.00325.2011 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 866IN UT WOS:000298374100018 PM 21956165 ER PT J AU Pla, AF Avanzato, D Munaron, L Ambudkar, IS AF Pla, Alessandra Fiorio Avanzato, Daniele Munaron, Luca Ambudkar, Indu S. TI Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE tumor vascularization; endothelial cells; calcium ions; transient receptor potential channels ID ENDOTHELIAL PROGENITOR CELLS; RECEPTOR POTENTIAL CHANNELS; OPERATED CA2+ ENTRY; ARACHIDONIC-ACID; PLASMA-MEMBRANE; CATION CHANNELS; CALCIUM-ENTRY; IN-VIVO; ANGIOGENESIS; PERMEABILITY AB Fiorio Pla A, Avanzato D, Munaron L, Ambudkar IS. Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets. Am J Physiol Cell Physiol 302: C9-C15, 2012. First published August 10, 2011; doi:10.1152/ajpcell.00280.2011.-Tumor vascularization is a critical process that determines tumor growth and metastasis. In the last decade new experimental evidence obtained from in vitro and in vivo studies have challenged the classical angiogenesis model forcing us to consider new scenarios for tumor neovascularization. In particular, the genetic stability of tumor-derived endothelial cells (TECs) has been recently questioned in several studies, which show that TECs, as well as pericytes, differ significantly from their normal counterparts at genetic and functional levels. In addition to such an epigenetic action of tumor microenvironment on endothelial cells (ECs) commitment, the distinct characteristics of TECs could be due to differences in their origin compared with preexisting differentiated ECs. Intracellular Ca(2+) signals are involved at different critical phases in the regulation of the complex process of angiogenesis and tumor progression. These signals are generated by a wide variety of intrinsic and extrinsic factors. Several key components of Ca(2+) signaling including Ca(2+) channels in the plasma membrane, endoplasmic reticulum, calcium pumps, and mitochondria contribute to the generation, amplitude, and frequency of these Ca(2+) change. In particular, several members of the transient receptor potential (TRP) family of calcium-permeable channels have profound effects on the function of ECs. Because of its multifaceted role in the control of cell function, proliferation, and motility, TRP channels have been suggested as a potential molecular target for control of tumor neovascularization. Since plasma membrane Ca(2+) channels are easily and directly accessible via the bloodstream, they are potential targets for a number of pharmacological and antibody-targeted therapeutic strategies, with specificity being the main limitation. In this review we discuss recent advances in understanding the role of Ca(2+) channels, with specific reference to TRP channels, in tumor vascularization process. C1 [Pla, Alessandra Fiorio; Avanzato, Daniele; Munaron, Luca] Univ Turin, Dept Anim & Human Biol, I-10123 Turin, Italy. [Pla, Alessandra Fiorio; Munaron, Luca] Univ Turin, Ctr Complex Syst Mol Biol & Med SysBioM, I-10123 Turin, Italy. [Pla, Alessandra Fiorio; Munaron, Luca] Univ Turin, Nanostruct Interfaces & Surfaces Ctr Excelle, I-10123 Turin, Italy. [Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Pla, AF (reprint author), Univ Turin, Dept Anim & Human Biol, V Accademia Albertina 13, I-10123 Turin, Italy. EM alessandra.fiorio@unito.it RI Fiorio Pla, Alessandra/B-6646-2012 OI Fiorio Pla, Alessandra/0000-0003-4576-1594 NR 73 TC 33 Z9 33 U1 1 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2012 VL 302 IS 1 BP C9 EP C15 DI 10.1152/ajpcell.00280.2011 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 866IN UT WOS:000298374100002 ER PT J AU Zhao, BY Knepper, MA Chou, CL Pisitkun, T AF Zhao, Boyang Knepper, Mark A. Chou, Chung-Lin Pisitkun, Trairak TI Large-scale phosphotyrosine proteomic profiling of rat renal collecting duct epithelium reveals predominance of proteins involved in cell polarity determination SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE mass spectrometry; kidney; adherens junction; tight junction; cytoskeleton ID TANDEM MASS-SPECTRA; TYROSINE PHOSPHORYLATION; PHOSPHOPROTEOMIC ANALYSIS; TIGHT JUNCTIONS; QUANTITATIVE PHOSPHOPROTEOMICS; SIGNALING PATHWAYS; FOCAL ADHESION; IN-VIVO; NETWORKS; SPECTROMETRY AB Zhao B, Knepper MA, Chou CL, Pisitkun T. Large-scale phosphotyrosine proteomic profiling of rat renal collecting duct epithelium reveals predominance of proteins involved in cell polarity determination. Am J Physiol Cell Physiol 302: C27-C45, 2012. First published September 21, 2011; doi:10.1152/ajpcell.00300.2011.-Although extensive phosphoproteomic information is available for renal epithelial cells, previous emphasis has been on phosphorylation of serines and threonines with little focus on tyrosine phosphorylation. Here we have carried out large-scale identification of phosphotyrosine sites in pervanadate-treated native inner medullary collecting ducts of rat, with a view towards identification of physiological processes in epithelial cells that are potentially regulated by tyrosine phosphorylation. The method combined antibody-based affinity purification of tyrosine phosphorylated peptides coupled with immobilized metal ion chromatography to enrich tyrosine phosphopeptides, which were identified by LC-MS/MS. A total of 418 unique tyrosine phosphorylation sites in 273 proteins were identified. A large fraction of these sites have not been previously reported on standard phosphoproteomic databases. All results are accessible via an online database: http://helixweb.nih.gov/ESBL/Database/iPY/. Analysis of surrounding sequences revealed four overrepresented motifs: [D/E]xxY*, Y*xxP, DY*, and Y*E, where the asterisk symbol indicates the site of phosphorylation. These motifs plus contextual information, integrated using the NetworKIN tool, suggest that the protein tyrosine kinases involved include members of the insulin-and ephrin-receptor kinase families. Analysis of the gene ontology (GO) terms and KEGG pathways whose protein elements are overrepresented in our data set point to structures involved in epithelial cell-cell and cell-matrix interactions ("adherens junction," "tight junction," and "focal adhesion") and to components of the actin cytoskeleton as major sites of tyrosine phosphorylation in these cells. In general, these findings mesh well with evidence that tyrosine phosphorylation plays a key role in epithelial polarity determination. C1 [Zhao, Boyang; Knepper, Mark A.; Chou, Chung-Lin; Pisitkun, Trairak] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, 10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural Budget of the NHLBI [Z01-HL-001285]; National Institute of Biomedical Imaging and Bioengineering FX The authors thank Jennifer Huling from National Heart, Lung, and Blood Institute (NHLBI) for help in setting up the Rat Inner Medullary Collecting Duct Phosphotyrosine Database and Aleksandra Nita-Lazar from National Institute of Allergy and Infectious Diseases for information on the antiphosphotyrosine peptide immunoprecipitation protocol. This study was supported by the Intramural Budget of the NHLBI (NHLBI Project Z01-HL-001285). Mass spectrometry was done in the NHLBI Proteomics Core Facility (Marjan Gucek, Director). Boyang Zhao was a student intern from the University of Michigan in the National Institutes of Health Biomedical Engineering Summer Internship Program, funded by the National Institute of Biomedical Imaging and Bioengineering (present e-mail: bozhao@mit.edu). NR 70 TC 5 Z9 5 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2012 VL 302 IS 1 BP C27 EP C45 DI 10.1152/ajpcell.00300.2011 PG 19 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 866IN UT WOS:000298374100007 PM 21940666 ER PT J AU Ernst, PB Erickson, LD Loo, WM Scott, KG Wiznerowicz, EB Brown, CC Torres-Velez, FJ Alam, MS Black, SG McDuffie, M Feldman, SH Wallace, JL McKnight, GW Padol, IT Hunt, RH Tung, KS AF Ernst, P. B. Erickson, L. D. Loo, W. M. Scott, K. G. Wiznerowicz, E. B. Brown, C. C. Torres-Velez, F. J. Alam, M. S. Black, S. G. McDuffie, M. Feldman, S. H. Wallace, J. L. McKnight, G. W. Padol, I. T. Hunt, R. H. Tung, K. S. TI Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE parietal cell; autoantibodies; autoimmune gastritis; model of Crohn's disease ID INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; HELICOBACTER-PYLORI; CROHNS-DISEASE; MURINE MODEL; INTESTINAL INFLAMMATION; CYTOKINE PRODUCTION; CUTTING EDGE; B-CELLS; MOUSE AB Ernst PB, Erickson LD, Loo WM, Scott KG, Wiznerowicz EB, Brown CC, Torres-Velez FJ, Alam MS, Black SG, McDuffie M, Feldman SH, Wallace JL, McKnight GW, Padol IT, Hunt RH, Tung KS. Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice. Am J Physiol Gastrointest Liver Physiol 302: G105-G115, 2012. First published September 15, 2011; doi:10.1152/ajpgi.00194.2011.-SAMP1/YitFcs mice serve as a model of Crohn's disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD(4+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract. C1 [Ernst, P. B.; Erickson, L. D.; Loo, W. M.] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. [Ernst, P. B.; Wiznerowicz, E. B.; Black, S. G.] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. [McDuffie, M.] Univ Virginia, Dept Pediat, Charlottesville, VA 22908 USA. [Tung, K. S.] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. [Feldman, S. H.] Univ Virginia, Ctr Comparat Med, Charlottesville, VA 22908 USA. [Scott, K. G.] Univ Manitoba, Dept Biol, Winnipeg, MB, Canada. [Wallace, J. L.; McKnight, G. W.; Padol, I. T.; Hunt, R. H.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Wallace, J. L.; McKnight, G. W.; Padol, I. T.; Hunt, R. H.] McMaster Univ, Farncombe Inst, Hamilton, ON, Canada. [Brown, C. C.] Univ Georgia, Coll Vet Med, Dept Pathol, Athens, GA 30602 USA. [Torres-Velez, F. J.] NIAID, Infect Dis Pathogenesis Sect, Bethesda, MD 20892 USA. [Alam, M. S.] US FDA, Immunobiol Branch, Ctr Food Safety & Nutr, Laurel, MD USA. RP Ernst, PB (reprint author), Univ Calif San Diego, Dept Pathol, Div Comparat Pathol & Med, 9500 Gilman Dr,MC 0063, La Jolla, CA 92093 USA. EM pernst@ucsd.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-051677, DK-84063]; Canadian Association of Gastroenterology; National Institute of Allergy and Infectious Diseases [AI-41236, AI-51420, DK 57880] FX This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-051677 and DK-84063 (to P. B. Ernst), a Research Fellowship from the Canadian Association of Gastroenterology (to K. G. Scott), National Institute of Allergy and Infectious Diseases AI-41236 and AI-51420 (to K. S. Tung), and DK 57880 (M. McDuffie). NR 45 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JAN PY 2012 VL 302 IS 1 BP G105 EP G115 DI 10.1152/ajpgi.00194.2011 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 869ZZ UT WOS:000298640200011 PM 21921286 ER PT J AU Chantler, PD Melenovsky, V Schulman, SP Gerstenblith, G Becker, LC Ferrucci, L Fleg, JL Lakatta, EG Najjar, SS AF Chantler, Paul D. Melenovsky, Vojtech Schulman, Steven P. Gerstenblith, Gary Becker, Lewis C. Ferrucci, Luigi Fleg, Jerome L. Lakatta, Edward G. Najjar, Samer S. TI Use of the Frank-Starling mechanism during exercise is linked to exercise-induced changes in arterial load SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE arterial elastance; cardiovascular performance ID PRESERVED EJECTION FRACTION; BLOOD-PRESSURE RESPONSE; SYSTEMIC VASCULAR-RESISTANCE; HEART-FAILURE; CARDIAC-OUTPUT; CARDIOVASCULAR-RESPONSES; STROKE VOLUME; HEALTHY-MEN; WAVE-FORM; HUMANS AB Chantler PD, Melenovsky V, Schulman SP, Gerstenblith G, Becker LC, Ferrucci L, Fleg JL, Lakatta EG, Najjar SS. Use of the Frank-Starling mechanism during exercise is linked to exercise- induced changes in arterial load. Am J Physiol Heart Circ Physiol 302: H349-H358, 2012. First published October 14, 2011; doi: 10.1152/ajpheart.00147.2011.-Effective arterial elastance(E(A)) is a measure of the net arterial load imposed on the heart that integrates the effects of heart rate(HR), peripheral vascular resistance( PVR), and total arterial compliance(TAC) and is a modulator of cardiac performance. To what extent the change in E(A) during exercise impacts on cardiac performance and aerobic capacity is unknown. We examined E(A) and its relationship with cardiovascular performance in 352 healthy subjects. Subjects underwent rest and exercise gated scans to measure cardiac volumes and to derive E(A)[end-systolic pressure/stroke volume index(SV)], PVR[MAP/(SV*HR)], and TAC(SV/pulse pressure). E(A) varied with exercise intensity: the Delta E(A) between rest and peak exercise along with its determinants, differed among individuals and ranged from -44% to +149%, and was independent of age and sex. Individuals were separated into 3 groups based on their Delta E(A)I. Individuals with the largest increase in Delta E(A)(group 3;Delta E(A) >= 0.98 mmHg.m(2)/ml) had the smallest reduction in PVR, the greatest reduction in TAC and a similar increase in HR vs. group 1(Delta E(A) < 0.22 mmHg.m(2)/ml). Furthermore, group 3 had a reduction in end-diastolic volume, and a blunted increase in SV(80%), and cardiac output(27%), during exercise vs. group 1. Despite limitations in the Frank-Starling mechanism and cardiac function, peak aerobic capacity did not differ by group because arterial-venous oxygen difference was greater in group 3 vs. 1. Thus the change in arterial load during exercise has important effects on the Frank-Starling mechanism and cardiac performance but not on exercise capacity. These findings provide interesting insights into the dynamic cardiovascular alterations during exercise. C1 [Chantler, Paul D.; Melenovsky, Vojtech; Ferrucci, Luigi; Fleg, Jerome L.; Lakatta, Edward G.; Najjar, Samer S.] NIA, Intramural Res Program, Baltimore, MD 21225 USA. [Chantler, Paul D.] W Virginia Univ, Dept Exercise Physiol, Sch Med, Morgantown, WV 26506 USA. [Melenovsky, Vojtech] Inst Clin & Expt Med, Dept Cardiol, Prague, Czech Republic. [Schulman, Steven P.; Gerstenblith, Gary; Becker, Lewis C.] Johns Hopkins Univ Baltimore, Div Cardiol, Baltimore, MD USA. RP Lakatta, EG (reprint author), NIA, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21225 USA. EM lakattae@grc.nia.nih.gov OI Melenovsky, Vojtech/0000-0001-8921-7078 FU NIH, National Institute on Aging; State Department of Health, Czech Republic [NS 10497-3/2009]; [N01AG82109] FX This work was supported by contract N01AG82109 (Gary Gerstenblith), and, in part, by the Intramural Research Program of the NIH, National Institute on Aging. VM is currently supported from the State Department of Health, Czech Republic (grant NS 10497-3/2009). NR 52 TC 8 Z9 8 U1 2 U2 16 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JAN PY 2012 VL 302 IS 1 BP H349 EP H358 DI 10.1152/ajpheart.00147.2011 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 870BJ UT WOS:000298643800035 PM 22003052 ER PT J AU Yao, XL Dai, CL Fredriksson, K Lam, J Gao, MX Keeran, KJ Nugent, GZ Qu, X Yu, ZX Jeffries, N Lin, JP Kaler, M Shamburek, R Costello, R Csako, G Dahl, M Nordestgaard, BG Remaley, AT Levine, SJ AF Yao, Xianglan Dai, Cuilian Fredriksson, Karin Lam, Jonathan Gao, Meixia Keeran, Karen J. Nugent, Gayle Zywicke Qu, Xuan Yu, Zu-Xi Jeffries, Neal Lin, JingPing Kaler, Maryann Shamburek, Robert Costello, Rene Csako, Gyorgy Dahl, Morten Nordestgaard, Borge G. Remaley, Alan T. Levine, Stewart J. TI Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE asthma ID OBSTRUCTIVE PULMONARY-DISEASE; E-DEFICIENT MICE; APOE GENOTYPE; ASTHMA; ASSOCIATION; ATHEROSCLEROSIS; RISK; HYPERCHOLESTEROLEMIA; CELLS; GENE AB Yao X, Dai C, Fredriksson K, Lam J, Gao M, Keeran KJ, Nugent GZ, Qu X, Yu Z-X, Jeffries N, Lin J, Kaler M, Shamburek R, Costello R, Csako G, Dahl M, Nordestgaard BG, Remaley AT, Levine SJ. Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice. Am J Physiol Lung Cell Mol Physiol 302: L206-L215, 2012. First published November 4, 2011; doi:10.1152/ajplung.00110.2011.-Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (epsilon 2, epsilon 3, and epsilon 4) reflecting single amino acid substitutions at amino acids 112 and 158. The objective of this study was to assess whether the human apoE alleles modify airway responses to repeated nasal HDM challenges. Mice expressing the human apoE epsilon 2 (huApoE2), epsilon 3 (huApoE3), or epsilon 4 (huApoE4) alleles received nasal HDM challenges, and airway responses were compared with mice expressing the endogenous murine apoE gene (muApoE). huApoE3 mice displayed significant reductions in AHR, mucous cell metaplasia, and airway inflammation compared with muApoE mice. The attenuated severity of airway inflammation in huApoE3 mice was associated with reductions in lung mRNA levels of Th2 and Th17 cytokines, as well as chemokines (CCL7, CCL11, CCL24). huApoE4 mice had an intermediate phenotype, with attenuated AHR and IgE production, compared with muApoE mice, whereas airway inflammation and mucous cell metaplasia were not reduced. In contrast, HDM-induced airway responses were not modified in mice expressing the huApoE2 allele. We conclude that the polymorphic huApoE alleles differentially modulate HDM-induced airway disease, which can be stratified, in rank order of increasing disease severity, epsilon 3 < epsilon 4 < epsilon 2. These results raise the possibility that the polymorphic apoE alleles may modify disease severity in human asthma. C1 [Yao, Xianglan; Dai, Cuilian; Fredriksson, Karin; Lam, Jonathan; Gao, Meixia; Kaler, Maryann; Shamburek, Robert; Remaley, Alan T.; Levine, Stewart J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Nugent, Gayle Zywicke] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. [Qu, Xuan; Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Jeffries, Neal; Lin, JingPing] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Costello, Rene; Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Dahl, Morten; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. RP Levine, SJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov RI Dahl, Morten/F-4219-2014 OI Dahl, Morten/0000-0002-6686-312X FU Division of Intramural Research; NHLBI; NIH; Department of Laboratory Medicine, Clinical Center, NIH FX This work was funded by the Division of Intramural Research, NHLBI, NIH and the Department of Laboratory Medicine, Clinical Center, NIH. NR 42 TC 9 Z9 9 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JAN PY 2012 VL 302 IS 2 BP L206 EP L215 DI 10.1152/ajplung.00110.2011 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 875EP UT WOS:000299013500003 PM 22058162 ER PT J AU Stringaris, A Zavos, H Leibenluft, E Maughan, B Eley, TC AF Stringaris, Argyris Zavos, Helena Leibenluft, Ellen Maughan, Barbara Eley, Thalia C. TI Adolescent Irritability: Phenotypic Associations and Genetic Links With Depressed Mood SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID OPPOSITIONAL DEFIANT DISORDER; ANTISOCIAL-BEHAVIOR; ATTRIBUTIONAL STYLE; MAJOR DEPRESSION; CONDUCT DISORDER; CHILDREN; PREDICTORS; YOUTH; DIMENSIONS; CHILDHOOD AB Objective: Irritability has been proposed to underlie the developmental link between oppositional problems and depression. Little is known, however, about the genetic and environmental influences on irritability and its overlap with depression. Drawing on the notion of "generalist genes" (genes of general effect that underlie phenotypic overlap between disorders), the authors test the hypothesis that the association between irritability and depression is accounted for by genetic factors. Method: Data from the G1219 study, a U.K. twin/sibling sample (N=2,651), were used in a cross-sectional and longitudinal design. The irritable and headstrong/hurtful dimensions of oppositional behavior were derived using factor analysis. Regression was used to estimate the association between depression and delinquency. Multivariate genetic analyses were used to estimate the genetic overlaps between the two components of oppositionality (irritability and headstrong/hurtful behaviors) and depression and delinquency. Results: Irritability showed a significantly stronger phenotypic relationship with depression than with delinquency, whereas headstrong/hurtful behaviors were more strongly related to delinquency than to depression. In multivariate genetic analyses, the genetic correlation between irritability and depression (r(A)=0.70, 95% CI=0.59-0.82) was significantly higher than that between irritability and delinquency (r(A)=0.57, 95% CI=0.45-0.69); conversely, the genetic correlation between headstrong/hurtful behaviors and delinquency (r(A)=0.80, 95% CI=0.72-0.86) was significantly higher than that between headstrong/hurtful behaviors and depression (r(A)=0.46, 95% CI=0.36-0.57). In longitudinal models, the phenotypic association between irritability at wave 2 and depression at wave 3 was accounted for by the genetic association between irritability and depression at wave 2. Conclusions: These findings are consistent with the theory that genes with general effects underlie the relationship between irritability and depression. C1 [Stringaris, Argyris] Kings Coll London, Inst Psychiat, Dept Child & Adolescent Psychiat, London, England. Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London, England. NIMH, Sect Bipolar Spectrum Disorders, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Stringaris, A (reprint author), Kings Coll London, Inst Psychiat, Dept Child & Adolescent Psychiat, London, England. EM argyris.stringaris@kcl.ac.uk RI Zavos, Helena/B-2153-2013 FU Wellcome Trust FX Dr. Stringaris gratefully acknowledges the support of the Wellcome Trust. NR 34 TC 69 Z9 70 U1 1 U2 22 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2012 VL 169 IS 1 BP 47 EP 54 DI 10.1176/appi.ajp.2011.10101549 PG 8 WC Psychiatry SC Psychiatry GA 875UQ UT WOS:000299061100011 PM 22193524 ER PT J AU Hall, EC Pfeiffer, RM Engels, EA Segev, DL AF Hall, Erin C. Pfeiffer, Ruth M. Engels, Eric A. Segev, Dorry L. TI Association of Induction Therapy with Cancer after Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American-Society-of-Transplant-Surgeons (ASTS) 12th Annual State of the Art Winter Symposium/North-American-Transplant-Coordinators-Organization (NATCO) Symposium for Advanced Transplant Professionals CY JAN 12-15, 2012 CL Miami, FL SP Amer Soc Transplant Surg (ASTS), N Amer Transplant Coordinators Org (NATCO) C1 [Hall, Erin C.; Segev, Dorry L.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Hall, Erin C.; Pfeiffer, Ruth M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2012 VL 12 SU 2 SI SI BP 63 EP 63 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 867UW UT WOS:000298481300033 ER PT J AU Hall, EC Pfeiffer, RM Segev, DL Engels, EA AF Hall, Erin C. Pfeiffer, Ruth M. Segev, Dorry L. Engels, Eric A. TI Cumulative Incidence of Cancer after Solid Organ Transplant SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American-Society-of-Transplant-Surgeons (ASTS) 12th Annual State of the Art Winter Symposium/North-American-Transplant-Coordinators-Organization (NATCO) Symposium for Advanced Transplant Professionals CY JAN 12-15, 2012 CL Miami, FL SP Amer Soc Transplant Surg (ASTS), N Amer Transplant Coordinators Org (NATCO) C1 [Hall, Erin C.; Pfeiffer, Ruth M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Hall, Erin C.; Segev, Dorry L.] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2012 VL 12 SU 2 SI SI BP 92 EP 92 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 867UW UT WOS:000298481300122 ER PT J AU Sander, LC Bedner, M Tims, MC Yen, JH Duewer, DL Porter, B Christopher, SJ Day, RD Long, SE Molloy, JL Murphy, KE Lang, BE Lieberman, R Wood, LJ Payne, MJ Roman, MC Betz, JM NguyenPho, A Sharpless, KE Wise, SA AF Sander, L. C. Bedner, M. Tims, M. C. Yen, J. H. Duewer, D. L. Porter, B. Christopher, S. J. Day, R. D. Long, S. E. Molloy, J. L. Murphy, K. E. Lang, B. E. Lieberman, R. Wood, L. J. Payne, M. J. Roman, M. C. Betz, J. M. NguyenPho, A. Sharpless, K. E. Wise, S. A. TI Development and certification of green tea-containing standard reference materials SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Green tea; Camellia sinensis; Standard Reference Material; Catechins; Xanthines; Toxic elements; Theanine ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MICELLAR ELECTROKINETIC CHROMATOGRAPHY; COULOMETRIC ARRAY DETECTION; IONIZATION MASS-SPECTROMETRY; MS-ELECTROSPRAY DETECTION; COMMERCIAL CANNED GREEN; SOLID-PHASE EXTRACTION; GALLIC ACID; PURINE ALKALOIDS; INDIVIDUAL CATECHINS AB A suite of three green tea-containing Standard Reference Materials (SRMs) has been issued by the National Institute of Standards and Technology (NIST): SRM 3254 Camellia sinensis (Green Tea) Leaves, SRM 3255 Camellia sinensis (Green Tea) Extract, and SRM 3256 Green Tea-Containing Solid Oral Dosage Form. The materials are characterized for catechins, xanthine alkaloids, theanine, and toxic elements. As many as five methods were used in assigning certified and reference values to the constituents, with measurements carried out at NIST and at collaborating laboratories. The materials are intended for use in the development and validation of new analytical methods, and for use as control materials as a component in the support of claims of metrological traceability. C1 [Sander, L. C.; Bedner, M.; Tims, M. C.; Duewer, D. L.; Porter, B.; Long, S. E.; Molloy, J. L.; Murphy, K. E.; Lieberman, R.; Wood, L. J.; Sharpless, K. E.; Wise, S. A.] NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Yen, J. H.] NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. [Christopher, S. J.; Day, R. D.] NIST, Div Analyt Chem, Charleston, SC 29412 USA. [Lang, B. E.] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Payne, M. J.] Hershey Co, Hershey, PA 17033 USA. [Roman, M. C.] Tampa Bay Analyt Res Inc, Largo, FL 33777 USA. [Betz, J. M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [NguyenPho, A.] US FDA, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. RP Sander, LC (reprint author), NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. EM lane.sander@nist.gov FU National Institutes of Health, Office of Dietary Supplements FX Partial funding for this work was provided by the National Institutes of Health, Office of Dietary Supplements. M. Schantz and E. McGaw (NIST) are acknowledged for pesticide screening of the three SRMs. NR 59 TC 15 Z9 15 U1 0 U2 13 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2012 VL 402 IS 1 BP 473 EP 487 DI 10.1007/s00216-011-5472-7 PG 15 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 871PE UT WOS:000298749300051 PM 22127575 ER PT J AU Liu, G Choi, KY Bhirde, A Swierczewska, M Yin, J Lee, SW Park, JH Hong, JI Xie, J Niu, G Kiesewetter, DO Lee, S Chen, XY AF Liu, Gang Choi, Ki Young Bhirde, Ashwinkumar Swierczewska, Magdalena Yin, Juan Lee, Sang Wook Park, Jae Hyung Hong, Jong In Xie, Jin Niu, Gang Kiesewetter, Dale O. Lee, Seulki Chen, Xiaoyuan TI Sticky Nanoparticles: A Platform for siRNA Delivery by a Bis(zinc(II) dipicolylamine)-Functionalized, Self-Assembled Nanoconjugate SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE dipicolylamines; drug delivery; hyaluronic acid; nanoparticles; siRNA ID THERAPEUTICS; HYALURONAN; RECEPTOR; PROBE C1 [Liu, Gang; Choi, Ki Young; Bhirde, Ashwinkumar; Swierczewska, Magdalena; Niu, Gang; Kiesewetter, Dale O.; Lee, Seulki; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD USA. [Liu, Gang] N Sichuan Med Coll, Sichuan Key Lab Med Imaging, Chengtu, Peoples R China. [Yin, Juan] NCI, NIH, Bethesda, MD 20892 USA. [Lee, Sang Wook; Hong, Jong In] Seoul Natl Univ, Dept Chem, Seoul 151, South Korea. [Park, Jae Hyung] Sungkyunkwan Univ, Dept Polymer Sci & Engn, Seoul, South Korea. [Xie, Jin] Univ Georgia, Dept Chem, Athens, GA 30602 USA. [Xie, Jin] Univ Georgia, Bioimaging Res Ctr, Athens, GA 30602 USA. RP Lee, S (reprint author), Natl Inst Biomed Imaging & Bioengn NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD USA. EM seulki.lee@nih.gov; shawn.chen@nih.gov RI byun, jaehyun/G-5584-2014; CHOI, KI YOUNG/Q-7177-2016 FU NIBIB, NIH; NIH [K99/R00]; National Natural Science Foundation of China (NSFC) [81101101, 2011JQ0032, 81028009]; MEST (Korea) [2009-0080734] FX This work was supported by the Intramural Research Program of the NIBIB, NIH and partially supported by an NIH Pathway to Independence (K99/R00) Award, the National Natural Science Foundation of China (NSFC, grant nos. 81101101 and 2011JQ0032), the International Cooperative Program of the NSFC (grant no. 81028009), and NRF grant 2009-0080734 from the MEST (Korea). NR 25 TC 38 Z9 39 U1 1 U2 51 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PY 2012 VL 51 IS 2 BP 445 EP 449 DI 10.1002/anie.201105565 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 872ER UT WOS:000298792100018 PM 22110006 ER PT J AU Liu, Z Zhang, WP Xing, Q Ren, XF Liu, ML Tang, C AF Liu, Zhu Zhang, Wei-Ping Xing, Qiong Ren, Xuefeng Liu, Maili Tang, Chun TI Noncovalent Dimerization of Ubiquitin SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE dimerization; NMR spectroscopy; paramagnetic relaxation enhancement; protein-protein interactions; ubiquitin ID PARAMAGNETIC RELAXATION ENHANCEMENT; PROTEIN-PROTEIN ASSOCIATION; TRANSIENT ENCOUNTER COMPLEXES; STRUCTURAL BASIS; POLYUBIQUITIN CHAINS; BINDING DOMAINS; NMR; TETRAUBIQUITIN; RECOGNITION; MACROMOLECULES C1 [Liu, Zhu; Xing, Qiong; Liu, Maili; Tang, Chun] Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan 430071, Hubei, Peoples R China. [Zhang, Wei-Ping] Zhejiang Univ, Sch Med, Dept Pharmacol, Hangzhou 310003, Zhejiang, Peoples R China. [Ren, Xuefeng] NICHHD, NIH, Bethesda, MD 20892 USA. RP Tang, C (reprint author), Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan 430071, Hubei, Peoples R China. EM tanglab@wipm.ac.cn RI Liu, Maili/A-8543-2011 FU Ministry of Science and Technology of China [2009CB918600]; Chinese Academy of Sciences [KJCX2-EW-W05]; National Natural Sciences Foundation of China [21073230] FX Funding from the Ministry of Science and Technology of China (2009CB918600 to M. L.), the Chinese Academy of Sciences (KJCX2-EW-W05 to C. T.), and the National Natural Sciences Foundation of China (21073230 to C. T.) is acknowledged. We thank Christian Griesinger and G. Marius Clore for advice, and Yong Duan for careful reading of the manuscript. NR 37 TC 27 Z9 30 U1 1 U2 38 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PY 2012 VL 51 IS 2 BP 469 EP 472 DI 10.1002/anie.201106190 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 872ER UT WOS:000298792100023 PM 22109817 ER PT J AU Royak-Schaler, R Pelser, C Langenberg, P Hayes, J Gardner, L Nesbitt, K Citron, W Drogula, CL Dwyer, D AF Royak-Schaler, Renee Pelser, Colleen Langenberg, Patricia Hayes, Jennifer Gardner, Lisa Nesbitt, Kim Citron, Wendla Drogula, Cynthia L. Dwyer, Diane TI Characteristics Associated with the Initiation of Radiation Therapy after Breast-Conserving Surgery among African American and White Women Diagnosed with Early-Stage Breast Cancer in Maryland, 2000-2006 SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Breast Cancer; Breast-Conserving Surgery; Health Disparities; Radiation Therapy ID CARCINOMA IN-SITU; SURGICAL ADJUVANT BREAST; QUALITY-OF-LIFE; CONSERVATION THERAPY; RACIAL DISPARITIES; UNITED-STATES; PATIENT COMPLIANCE; PLUS TAMOXIFEN; SOCIAL-CLASS; HEALTH-CARE AB PURPOSE: Socioeconomic status appears to be an important independent barrier to breast cancer care, irrespective of insurance inequalities. Receiving radiation therapy (RT) reduces local recurrence and mortality in patients receiving breast-conserving surgery (BCS). We investigated racial and socioeconomic determinants of RT initiation after BCS in Maryland. METHODS: Maryland Cancer Registry breast cancer data for the diagnosis years 2000 through 2006 were analyzed for characteristics associated with receipt of RT after BCS. We used generalized regression models to estimate RT initiation among low-income patients, adjusting for racial, demographic, and clinical covariates. RESULTS: Low-income women were more likely to be African American; older; uninsured or to use Medicare, Medicaid, or Maryland breast cancer insurance; and have tumors that were estrogen receptor and progesterone-receptor negative. Among low-income women, those at risk of not initiating RT after BCS were more likely to be African American, be older than 80 years of age, and have tumors > 2 cm. CONCLUSIONS: Socioeconomic disparities were identified in the initiation of RT after BCS in Maryland from 2000 to 2006. In addition, racial disparities in RT after BCS were apparent for women diagnosed from 2000 to 2003. Additional research is needed to investigate uptake of prescribed treatments after BCS and develop strategies for reducing barriers to obtaining treatments among patients at risk for incomplete cancer care. Ann Epidemiol 2012;22:28-36. Published by Elsevier Inc. C1 [Pelser, Colleen] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Royak-Schaler, Renee; Pelser, Colleen; Langenberg, Patricia; Gardner, Lisa; Nesbitt, Kim] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hayes, Jennifer; Dwyer, Diane] Maryland Dept Hlth & Mental Hyg, Ctr Canc Surveillance & Control, Baltimore, MD USA. [Citron, Wendla] Univ Maryland, Sch Med, Div Radiat Oncol, Baltimore, MD 21201 USA. [Drogula, Cynthia L.] Univ Maryland, Div Surg Oncol, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Pelser, C (reprint author), NCI, Canc Prevent Fellowship Program, 6120 Execut Blvd,Room 150E,MSC 7150, Bethesda, MD 20892 USA. EM colleen.pelser@nih.gov OI Gardner, Lisa/0000-0003-3340-2818 FU American Cancer Society [RSGT-08-147-01-CPPB]; State of Maryland; Maryland Cigarette Restitution Fund; Centers for Disease Control and Prevention (CDC) FX This study was supported by grant # RSGT-08-147-01-CPPB from the American Cancer Society. Cancer incidence data were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://www.fha.state.md.us/cancer/registry/, 410-767-4055. The State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC) provide the funds that support the availability of the cancer registry data. NR 62 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JAN PY 2012 VL 22 IS 1 BP 28 EP 36 DI 10.1016/j.annepidem.2011.10.001 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 864EZ UT WOS:000298221100004 PM 22037379 ER PT J AU Sung, H Mendell, NR AF Sung, Heejong Mendell, Nancy R. TI Necessary and Sufficient Conditions for Equality of Sibling and Parent-Offspring Risk of a Disease Endophenotype in Case Families SO ANNALS OF HUMAN GENETICS LA English DT Article DE Linkage; sib pair; endophenotype; recurrence risk; additivity ID LINKAGE ANALYSIS; POWER; PAIRS AB A large number of linkage and association studies of complex diseases focus on analysis of a more common or more easily measured disease endophenotype. The motivation for this approach is that there is a pleiotropic locus common to both the disease and the endophenotype and that this locus is a major genetic determinant of the endophenotype. In this paper, we determine the conditions under which the risk of the endophenotype in siblings of affected probands with disease equals the risk of the endophenotype in the offspring (parents) of affected parents (offspring) with disease. In doing so we prove that this equality holds if and only if the penetrance of either the endophenotype or the disease (but not necessarily both) is additive. C1 [Sung, Heejong] Natl Human Genet Res Inst, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. [Mendell, Nancy R.] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. RP Sung, H (reprint author), Natl Human Genet Res Inst, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. EM sunghe@mail.nih.gov FU Division of Intramural Research; National Human Genome Research Institute; National Institutes of Health; National Institute of Mental Health [R01 44292, 071523] FX Funding for this project was supported in part by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and also part by Division of Extramural Research by National Institute of Mental Health R01 44292, National Institute of Mental Health R01 071523. The authors truly appreciate Dr. Steven Matthysse's suggestions and valuable comments. NR 8 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2012 VL 76 BP 86 EP 91 DI 10.1111/j.1469-1809.2011.00685.x PN 1 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 864QJ UT WOS:000298254600010 PM 22091704 ER PT J AU Kollmannsberger, C Hirte, H Siu, LL Mazurka, J Chi, K Elit, L Walsh, W Sederias, J Doyle, A Eisenhauer, EA Oza, AM AF Kollmannsberger, C. Hirte, H. Siu, L. L. Mazurka, J. Chi, K. Elit, L. Walsh, W. Sederias, J. Doyle, A. Eisenhauer, E. A. Oza, A. M. TI Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179) SO ANNALS OF ONCOLOGY LA English DT Article DE carboplatin; combination; paclitaxel; phase I; temsirolimus ID GYNECOLOGIC-ONCOLOGY-GROUP; RENAL-CELL CARCINOMA; MAMMALIAN TARGET; MTOR INHIBITOR; OVARIAN-CARCINOMA; INTERFERON-ALPHA; LUNG-CANCER; III TRIAL; CCI-779; CHEMOTHERAPY AB Background: The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus. Materials and methods: Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration. Results: Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n = 2) and grade 3 fatigue (n = 1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs. Conclusion: Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m(2), both given on day 1 with temsirolimus 25 mg on days 1 and 8. C1 [Siu, L. L.; Oza, A. M.] Univ Toronto, Univ Hlth Network, Drug Dev Program, Princess Margaret Hosp, Toronto, ON, Canada. [Kollmannsberger, C.; Chi, K.] Vancouver Canc Ctr, BC Canc Agcy, Div Med Oncol, Vancouver, BC, Canada. [Hirte, H.] Juravinski Canc Ctr, Div Med Oncol, Hamilton, ON, Canada. [Walsh, W.; Sederias, J.; Eisenhauer, E. A.] Queens Univ, Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. [Mazurka, J.; Elit, L.] Juravinski Canc Ctr, Div Gynecol Oncol, Hamilton, ON, Canada. [Doyle, A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Oza, AM (reprint author), Princess Margaret Hosp, Univ Hlth Network, Bras Family Drug Dev Program, 610 Univ Ave,Suite 5-700, Toronto, ON M5G 2M9, Canada. EM amit.oza@uhn.on.ca FU Canadian Cancer Society FX This study was funded by the Canadian Cancer Society through its core grant support to the NCIC-CTG. NR 27 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2012 VL 23 IS 1 BP 238 EP 244 DI 10.1093/annonc/mdr063 PG 7 WC Oncology SC Oncology GA 866MO UT WOS:000298385300035 PM 21447615 ER PT J AU Linkous, AG Yazlovitskaya, EM AF Linkous, Amanda G. Yazlovitskaya, Eugenia M. TI Novel Therapeutic Approaches for Targeting Tumor Angiogenesis SO ANTICANCER RESEARCH LA English DT Review DE VEGF; cPLA2; lysophospholipids; angiogenesis; cancer; review ID RENAL-CELL CARCINOMA; LYSOPHOSPHATIDIC ACID PRODUCTION; BEVACIZUMAB PLUS IRINOTECAN; HIGH-GRADE GLIOMAS; ANTIANGIOGENIC THERAPY; OVARIAN-CANCER; CYTOSOLIC PHOSPHOLIPASE-A2; LYSOPHOSPHOLIPASE-D; RECURRENT GLIOBLASTOMA; AUTOTAXIN INHIBITORS AB Current attempts to disrupt the complex process of tumor blood vessel formation are predominantly focused on targeting the vascular endothelial growth factor (VEGF)-VEGFR signaling pathway. Although clinically proven to inhibit VEGF and its receptors, these pharmacologic agents are selective, but not specific. Consequently, many of the approved inhibitors also impair other molecular targets leading to increased toxicity. Current efforts to unravel the complexity of tumor angiogenesis have identified several new candidates for antivascular therapy. In this review article, we identify well-established and novel angiogenic molecules and discuss benefits of the therapeutic approaches based on targeting of such factors. C1 [Yazlovitskaya, Eugenia M.] Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, Nashville, TN 37232 USA. [Yazlovitskaya, Eugenia M.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Linkous, Amanda G.] NIH, Neurooncol Branch, Bethesda, MD 20892 USA. RP Yazlovitskaya, EM (reprint author), Vanderbilt Univ, Med Ctr, Dept Med, Div Nephrol, C3210 Med Ctr N,1161 21st Ave S, Nashville, TN 37232 USA. EM eugenia.yazlovitskaya@vanderbilt.edu NR 76 TC 17 Z9 22 U1 0 U2 12 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JAN PY 2012 VL 32 IS 1 BP 1 EP 12 PG 12 WC Oncology SC Oncology GA 872BH UT WOS:000298780900001 PM 22213282 ER PT J AU Johnson, BC Metifiot, M Pommier, Y Hughes, SH AF Johnson, Barry C. Metifiot, Mathieu Pommier, Yves Hughes, Stephen H. TI Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; STRAND TRANSFER INHIBITORS; CARBOXYL-TERMINAL DOMAINS; CATALYTIC DOMAIN; DNA-BINDING; ZINC-BINDING; VIRAL-DNA; CRYSTAL-STRUCTURE; CROSS-RESISTANCE; RALTEGRAVIR AB The design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the viral DNA to inhibitor binding. Using the structure of PFV IN as the starting point, we generated a model of the corresponding HIV-1 complex and developed a molecular dynamics (MD)-based approach that correlates with the in vitro activities of novel compounds. Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for their in vitro activity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data. Three additional compounds were docked into the IN-DNA complex model and subjected to MD simulations. All three gave interaction potentials within 1 standard deviation of values estimated from the training set, and the most active compound was identified. Additional MD analysis of the raltegravir- and dolutegravir-bound complexes gave internal and interaction energy values that closely match the experimental binding energy of a compound related to raltegravir that has similar activity. These approaches can be used to gain a deeper understanding of the interactions of the inhibitors with the HIV-1 intasome and to identify promising scaffolds for novel integrase inhibitors, in particular, compounds that retain activity against a range of drug-resistant mutants, making it possible to streamline synthesis and testing. C1 [Johnson, Barry C.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Metifiot, Mathieu; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. EM hughesst@mail.nih.gov FU NIH, Center for Cancer Research, National Cancer Institute; NIH FX Our studies were supported by the NIH Intramural Program, Center for Cancer Research, National Cancer Institute, and by NIH grants from the AIDS Intramural Targeted Program (IATAP). NR 56 TC 28 Z9 28 U1 2 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2012 VL 56 IS 1 BP 411 EP 419 DI 10.1128/AAC.05292-11 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 866TB UT WOS:000298404900049 PM 22037850 ER PT J AU Kjellsson, MC Via, LE Goh, A Weiner, D Low, KM Kern, S Pillai, G Barry, CE Dartois, V AF Kjellsson, Maria C. Via, Laura E. Goh, Anne Weiner, Danielle Low, Kang Min Kern, Steven Pillai, Goonaseelan Barry, Clifton E., III Dartois, Veronique TI Pharmacokinetic Evaluation of the Penetration of Antituberculosis Agents in Rabbit Pulmonary Lesions SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID EPITHELIAL LINING FLUID; MYCOBACTERIUM-TUBERCULOSIS; CEREBROSPINAL-FLUID; INTRAPULMONARY CONCENTRATIONS; NONREPLICATING PERSISTENCE; CLINICAL PHARMACOKINETICS; FIBEROPTIC BRONCHOSCOPY; TISSUE CONCENTRATIONS; MOXIFLOXACIN; MODEL AB Standard antituberculosis (anti-TB) therapy requires the use of multiple drugs for a minimum of 6 months, with variable outcomes that are influenced by a number of microbiological, pathological, and clinical factors. This is despite the availability of antibiotics that have good activity against Mycobacterium tuberculosis in vitro and favorable pharmacokinetic profiles in plasma. However, little is known about the distribution of widely used antituberculous agents in the pulmonary lesions where the pathogen resides. The rabbit model of TB infection was used to explore the hypothesis that standard drugs have various abilities to penetrate lung tissue and lesions and that adequate drug levels are not consistently reached at the site of infection. Using noncompartmental and population pharmacokinetic approaches, we modeled the rate and extent of distribution of isoniazid, rifampin, pyrazinamide, and moxifloxacin in rabbit lung and lesions. Moxifloxacin reproducibly showed favorable partitioning into lung and granulomas, while the exposure of isoniazid, rifampin, and pyrazinamide in lesions was markedly lower than in plasma. The extent of penetration in lung and lesions followed different trends for each drug. All four agents distributed rapidly from plasma to tissue with equilibration half-lives of less than 1 min to an hour. The models adequately described the plasma concentrations and reasonably captured actual lesion concentrations. Though further refinement is needed to accurately predict the behavior of these drugs in human subjects, our results enable the integration of lesion-specific pharmacokinetic-pharmacodynamic (PK-PD) indices in clinical trial simulations and in in vitro PK-PD studies with M. tuberculosis. C1 [Goh, Anne; Low, Kang Min; Dartois, Veronique] Novartis Inst Trop Dis, Pharmacol Unit, Singapore, Singapore. [Kjellsson, Maria C.; Kern, Steven; Pillai, Goonaseelan] Novartis Pharma AG, Modeling & Simulat, Basel, Switzerland. [Kjellsson, Maria C.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden. [Via, Laura E.; Weiner, Danielle; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Dartois, V (reprint author), Novartis Inst Trop Dis, Pharmacol Unit, Singapore, Singapore. EM veronique.dartois@novartis.com RI Barry, III, Clifton/H-3839-2012; OI Kjellsson, Maria/0000-0003-3531-9452; Via, Laura/0000-0001-6074-9521 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; Bill & Melinda Gates (BMGF) Foundation Drug; BMGF and Wellcome Trust [42808, 37882] FX This project received funding from the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, from the Bill & Melinda Gates (BMGF) Foundation Drug Accelerator program, and the BMGF and Wellcome Trust Grand Challenges in Global Health initiative (grant numbers 42808 to Joanne Flynn, University of Pittsburgh, and 37882 to Douglas Young, Imperial College, London, United Kingdom). NR 61 TC 67 Z9 67 U1 2 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2012 VL 56 IS 1 BP 446 EP 457 DI 10.1128/AAC.05208-11 PG 12 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 866TB UT WOS:000298404900053 PM 21986820 ER PT J AU Bevilacqua, L Carli, V Sarchiapone, M George, DK Goldman, D Roy, A Enoch, MA AF Bevilacqua, Laura Carli, Vladimir Sarchiapone, Marco George, Danielle K. Goldman, David Roy, Alec Enoch, Mary-Anne TI Interaction Between FKBP5 and Childhood Trauma and Risk of Aggressive Behavior SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID BORDERLINE PERSONALITY-DISORDER; URINARY FREE CORTISOL; EARLY-LIFE STRESS; DSM-IV; SUICIDAL-BEHAVIOR; BIPOLAR DISORDER; HEALTHY CONTROLS; SEXUAL-ABUSE; VASOPRESSIN; POLYMORPHISMS AB Context: Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation. Objective: To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. Design: Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity. Setting: Penitentiary District of Abruzzo-Molise in central Italy. Participants: A population of 583 male Italian prisoners recruited between 2005 and 2008. Main Outcome Measures: A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed. Results: Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P=.012) and violent behavior in jail (P=.025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed. Conclusion: These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior. C1 [Bevilacqua, Laura; George, Danielle K.; Goldman, David; Enoch, Mary-Anne] NIAAA, LNG, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Carli, Vladimir; Sarchiapone, Marco] Univ Molise, Dept Hlth Sci, Campobasso, Italy. [Carli, Vladimir] Karolinska Inst, Stockholm, Sweden. [Roy, Alec] Vet Affairs Med Ctr, Psychiat Serv, E Orange, NJ USA. RP Bevilacqua, L (reprint author), NIAAA, LNG, Neurogenet Lab, NIH, 5625 Fishers Ln,Room 3S-32, Rockville, MD 20852 USA. EM laurabevilacqua27@gmail.com RI Carli, Vladimir/G-4728-2012; Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Sarchiapone, Marco/0000-0001-9583-3117 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; National Institute of Drug Abuse, National Institutes of Health [R01 DA 10336-02]; Pfizer; Lundbeck FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, and in part by grant R01 DA 10336-02 (Dr Roy) from the National Institute of Drug Abuse, National Institutes of Health. Dr Sarchiapone has received financial support from Pfizer and Lundbeck. NR 62 TC 45 Z9 46 U1 2 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X EI 1538-3636 J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JAN PY 2012 VL 69 IS 1 BP 62 EP 70 PG 9 WC Psychiatry SC Psychiatry GA 870NH UT WOS:000298675700008 PM 22213790 ER PT J AU Yeh, S Fahle, G Forooghian, F Faia, LJ Weichel, ED Stout, JT Flaxel, CJ Lauer, AK Sen, HN Nussenblatt, RB AF Yeh, Steven Fahle, Gary Forooghian, Farzin Faia, Lisa J. Weichel, Eric D. Stout, J. Timothy Flaxel, Christina J. Lauer, Andreas K. Sen, H. Nida Nussenblatt, Robert B. TI Polymerase Chain Reaction-Based Ganciclovir Resistance Testing of Ocular Fluids for Cytomegalovirus Retinitis SO ARCHIVES OF OPHTHALMOLOGY LA English DT Editorial Material C1 [Sen, H. Nida; Nussenblatt, Robert B.] NEI, NIH, Bethesda, MD 20892 USA. [Yeh, Steven] Emory Univ, Sch Med, Retina Serv, Emory Eye Ctr, Atlanta, GA USA. [Fahle, Gary] Dept Lab Med, Bethesda, MD USA. [Forooghian, Farzin] Univ British Columbia, Dept Ophthalmol & Visual Sci, Vancouver, BC V5Z 1M9, Canada. [Faia, Lisa J.] William Beaumont Hosp, Associated Retinal Consultants, Royal Oak, MI 48072 USA. [Weichel, Eric D.] Retina Grp Washington, Washington, DC USA. [Stout, J. Timothy; Flaxel, Christina J.; Lauer, Andreas K.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. RP Nussenblatt, RB (reprint author), NEI, NIH, Bldg 10,10N-112, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU NEI NIH HHS [P30 EY010572] NR 8 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JAN PY 2012 VL 130 IS 1 BP 113 EP 115 PG 3 WC Ophthalmology SC Ophthalmology GA 874LE UT WOS:000298957900015 PM 22232481 ER PT J AU Qu, AJ Shah, YM Manna, SK Gonzalez, FJ AF Qu, Aijuan Shah, Yatrik M. Manna, Soumen K. Gonzalez, Frank J. TI Disruption of Endothelial Peroxisome Proliferator-Activated Receptor gamma Accelerates Diet-Induced Atherogenesis in LDL Receptor-Null Mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; endothelial function; hypertension; lipids; lipoproteins ID LOW-DENSITY-LIPOPROTEIN; BONE-MARROW-TRANSPLANTATION; SMOOTH-MUSCLE-CELLS; PPAR-GAMMA; DEFICIENT MICE; CHOLESTEROL EFFLUX; SIGNALING PATHWAY; BLOOD-VESSELS; ATHEROSCLEROSIS; EXPRESSION AB Objective-Peroxisome proliferator-activated receptor gamma (PPAR gamma) is widely expressed in vessel walls, and it's activation by agonists showed beneficial effects in cardiovascular diseases. However, the role of endothelial cell (EC) PPAR gamma in atherogenesis is not fully understood. Methods and Results-To assess the contribution of endothelial-specific PPAR gamma in atherosclerosis, EC-specific PPAR gamma disruption and LDL receptor (LDLR) double-knockout (PPAR gamma(Delta EC)/LDLR(-/-)) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPAR gamma(Delta EC)/LDLR(-/-) mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPAR gamma disruption and LDLR double knockout (PPAR gamma(Delta M Phi)/LDLR(-/-)) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure in the PPAR gamma(Delta EC)/LDLR(-/-) mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPAR gamma(Delta EC)/LDLR(-/-) mice, as revealed by the increases of proinflammatory gene expression and macrophage infiltration in vivo and in vitro. Furthermore, in vivo endothelial permeability was also increased by endothelial PPAR gamma disruption. Bone-marrow transplantation studies, which reconstituted hematopoietic PPAR gamma, demonstrated that the accelerated atherogenesis was due to endothelial PPAR gamma deficiency. Conclusion-Endothelial PPAR gamma plays an important protective role in atherogenesis. (Arterioscler Thromb Vasc Biol. 2012;32:65-73.) C1 [Qu, Aijuan; Shah, Yatrik M.; Manna, Soumen K.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Div Gastroenterol, Dept Mol & Integrat Physiol & Internal Med, Ann Arbor, MI USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20814 USA. EM gonzalef@mail.nih.gov FU National Cancer Institute; National Institutes of Health [CA148828] FX This work was supported by the National Cancer Institute Intramural Research Program and National Institutes of Health Grant CA148828 (to Y.M.S.). NR 41 TC 17 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JAN PY 2012 VL 32 IS 1 BP 65 EP U178 DI 10.1161/ATVBAHA.111.239137 PG 14 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 865CP UT WOS:000298288700011 PM 22015658 ER PT J AU Conroy, MB Kwoh, CK Krishnan, E Nevitt, MC Boudreau, R Carbone, LD Chen, HP Harris, TB Newman, AB Goodpaster, BH AF Conroy, Molly B. Kwoh, C. Kent Krishnan, Eswar Nevitt, Michael C. Boudreau, Robert Carbone, Laura D. Chen, Hepei Harris, Tamara B. Newman, Anne B. Goodpaster, Bret H. CA Hlth ABC Study TI Muscle strength, mass, and quality in older men and women with knee osteoarthritis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID QUADRICEPS STRENGTH; COMPUTED-TOMOGRAPHY; SKELETAL-MUSCLE; HEALTH; ATTENUATION; EXERCISE AB Objective To examine the relationship between knee osteoarthritis (OA) and muscle parameters in a biracial cohort of older adults. Methods. Participants in the Health, Aging and Body Composition Study (n = 858) were included in this cross-sectional analysis. Computed tomography was used to measure muscle area, and quadriceps strength was measured isokinetically. Muscle quality (specific torque) was defined as strength per unit of muscle area for both the entire thigh and quadriceps. Knee OA was assessed based on radiographic features and knee pain. We compared muscle parameters between those with and without radiographic knee OA (+RKOA group and -RKOA group, respectively) and among 4 groups defined by +RKOA and -RKOA with and without pain. Results. The mean +/- SD age was 73.5 +/- 2.9 years and the mean +/- SD body mass index (BMI) was 27.9 +/- 4.8 kg/m(2). Fifty-eight percent of participants were women and 44% were African American. Compared to the +RKOA participants, -RKOA participants had a higher BMI (30.2 versus 26.8 kg/m(2)), larger thigh muscles (117.9 versus 108.9 cm(2)), and a greater amount of intermuscular fat (12.5 versus 9.9 cm(2); all P < 0.0001). In adjusted models, the +RKOA participants had significantly lower specific torque (P < 0.001), indicating poorer muscle quality, than +RKOA participants, but there was no difference between groups in quadriceps specific torque. The +RKOA without pain (P < 0.05) and the +RKOA with pain (P < 0.001) participants had lower specific torque compared to the -RKOA without pain group. There were no significant differences in quadriceps specific torque among groups. Conclusion. Muscle quality was significantly poorer in participants with RKOA regardless of pain status. Future studies should address how lifestyle interventions might affect muscle quality and progression of knee OA. C1 [Conroy, Molly B.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA 15213 USA. [Krishnan, Eswar] Stanford Univ, Palo Alto, CA 94304 USA. [Nevitt, Michael C.] Prevent Sci Grp, San Francisco, CA USA. [Carbone, Laura D.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Carbone, Laura D.] Dept Vet Affairs Med Ctr, Memphis, TN USA. [Chen, Hepei] Covance Labs, Chantilly, VA USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RP Conroy, MB (reprint author), Univ Pittsburgh, Ctr Res Hlth Care, 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM conroymb@upmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR012459]; NIH, National Institute on Aging; NIH [K23-HL-085405] FX Supported by the National Institute on Aging (contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106, and grant R01-AG028050) and the National Institute of Nursing Research (grant R01-NR012459) and partially supported by the Intramural Research program of the NIH, National Institute on Aging. Dr. Conroy's work was supported by a career development award from the NIH (K23-HL-085405). NR 21 TC 27 Z9 28 U1 2 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JAN PY 2012 VL 64 IS 1 BP 15 EP 21 DI 10.1002/acr.20588 PG 7 WC Rheumatology SC Rheumatology GA 868QB UT WOS:000298536700004 PM 22213722 ER PT J AU Cheng, S Wang, N Larson, MG Palmisano, JN Mitchell, GF Benjamin, EJ Vasan, RS Levy, D McCabe, EL Vita, JA Wang, TJ Shaw, SY Cohen, KS Hamburg, NM AF Cheng, Susan Wang, Na Larson, Martin G. Palmisano, Joseph N. Mitchell, Gary F. Benjamin, Emelia J. Vasan, Ramachandran S. Levy, Daniel McCabe, Elizabeth L. Vita, Joseph A. Wang, Thomas J. Shaw, Stanley Y. Cohen, Kenneth S. Hamburg, Naomi M. TI Circulating angiogenic cell populations, vascular function, and arterial stiffness SO ATHEROSCLEROSIS LA English DT Article DE Angiogenesis; Vascular function; Risk factors; Endothelium; Epidemiology ID ENDOTHELIAL PROGENITOR CELLS; CORONARY-HEART-DISEASE; COLONY-FORMING-UNITS; BONE-MARROW; CARDIOVASCULAR RISK; MONONUCLEAR-CELLS; AORTIC STIFFNESS; ADVANCING AGE; DYSFUNCTION; NUMBER AB Objective: Several bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness. Methods: We studied 1948 Framingham Heart Study participants (mean age, 66 +/- 9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing. Results: In unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (beta = -0.052 +/- 0.011, P < 0.001 and beta = -0.030 +/- 0.011, P = 0.008, respectively) and with higher carotid-brachial pulse wave velocity (beta = 0.144 +/- 0.043, P = 0.001 and beta = 0.112 +/- 0.043, P = 0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (beta = -0.229 +/- 0.094, P = 0.015). However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness. Conclusions: In our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors. (c) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Hamburg, Naomi M.] Boston Univ, Sch Med, Dept Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Cheng, Susan; Larson, Martin G.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Levy, Daniel; Wang, Thomas J.; Hamburg, Naomi M.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Cheng, Susan] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Wang, Na; Palmisano, Joseph N.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Wang, Na; Palmisano, Joseph N.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [McCabe, Elizabeth L.; Wang, Thomas J.; Shaw, Stanley Y.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Cohen, Kenneth S.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Cohen, Kenneth S.] Univ Chicago, Med Ctr, Hematol Oncol Sect, Chicago, IL 60637 USA. RP Hamburg, NM (reprint author), Boston Univ, Sch Med, Dept Med, Whitaker Cardiovasc Inst, 88 E Newton St C818, Boston, MA 02118 USA. EM naomi.hamburg@bmc.org OI Benjamin, Emelia/0000-0003-4076-2336; Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NIH/NHLBI [N01-HC25195]; NIH [1R01HL60040, 1R01HL70100, R01AG028321, HL083197, HL083781, HL102299]; Ellison Foundation; Itamar Medical FX The Framingham Heart Study is funded by NIH/NHLBI contract N01-HC25195. The project was supported NIH grants 1R01HL60040 (EJB), 1R01HL70100 (EJB), R01AG028321 (EJB), and HL083197 (TJW). Dr. Hamburg is supported by NIH grants HL083781 and HL102299. Dr. Cheng is supported by a grant from the Ellison Foundation. The work was supported by an unrestricted research grant to Dr. Benjamin from Itamar Medical. The grant was used to conduct statistical analyses following guidelines established by the National Heart, Lung, and Blood Institute: http://www.nhlbi.nih.gov/funding/policies/thirdparty.htm. NR 36 TC 3 Z9 3 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JAN PY 2012 VL 220 IS 1 BP 145 EP 150 DI 10.1016/j.atherosclerosis.2011.10.015 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 866IU UT WOS:000298374800024 PM 22093724 ER PT J AU Martinowich, K Schloesser, RJ Lu, Y Jimenez, DV Paredes, D Greene, JS Greig, NH Manji, HK Lu, B AF Martinowich, Keri Schloesser, Robert J. Lu, Yuan Jimenez, Dennisse V. Paredes, Daniel Greene, Joshua S. Greig, Nigel H. Manji, Husseini K. Lu, Bai TI Roles of p75(NTR), Long-Term Depression, and Cholinergic Transmission in Anxiety and Acute Stress Coping SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anxiety; basal forebrain; hippocampus; long-term depression; neurotrophin; p75(NTR) ID P75 NEUROTROPHIN RECEPTOR; BLACK-WHITE BOX; TYROSINE PHOSPHORYLATION; HIPPOCAMPAL NEUROGENESIS; SYNAPTIC PLASTICITY; FOS EXPRESSION; SPATIAL MEMORY; KNOCKOUT MICE; ANIMAL-MODEL; LTD AB Background: Stress is causally associated with anxiety. Although the underlying cellular mechanisms are not well understood, the basal forebrain cholinergic neurons have been implicated in stress response. p75(NTR) is a panneurotrophin receptor expressed almost exclusively in basal forebrain cholinergic neurons in adult brain. This study investigated whether and how p75(NTR), via regulation of the cholinergic system and hippocampal synaptic plasticity, influences stress-related behaviors. Methods: We used a combination of slice electrophysiology, behavioral analyses, pharmacology, in vivo microdialysis, and neuronal activity mapping to assess the role of p75(NTR) in mood and stress-related behaviors and its underlying cellular and molecular mechanisms. Results: We show that acute stress enables hippocampal long-term depression (LTD) in adult wild-type mice but not in mice lacking p75(NTR). The p75(NTR) mutant mice also exhibit two distinct behavioral impairments: baseline anxiety-like behavior and a deficit in coping with and recovering from stressful situations. Blockade of stress-enabled LTD with a GluA2-derived peptide impaired stress recovery without affecting baseline anxiety. Pharmacological manipulations of cholinergic transmission mimicked the p75(NTR) perturbation in both baseline anxiety and responses to acute stress. Finally, we show evidence of misregulated cholinergic signaling in animals with p75(NTR) deletion. Conclusions: Our results suggest that loss of p75(NTR) leads to changes in hippocampal cholinergic signaling, which may be involved in regulation of stress-enabled hippocampal LTD and in modulating behaviors related to stress and anxiety. C1 [Martinowich, Keri; Schloesser, Robert J.; Jimenez, Dennisse V.; Manji, Husseini K.] Natl Inst Neurol Disorders & Stroke, Mood & Anxiety Disorders Program, NIMH, Bethesda, MD USA. [Martinowich, Keri; Lu, Yuan; Greene, Joshua S.; Lu, Bai] Natl Inst Neurol Disorders & Stroke, Genes Cognit & Psychosis Program, NIMH, Bethesda, MD USA. [Paredes, Daniel] Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, Bethesda, MD USA. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Baltimore, MD 21224 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Lu, B (reprint author), Glaxo SmithKline, R&D China, Biol, Bldg 3,898 Halei Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China. EM bai.b.lu@gsk.com RI Paredes , Daniel/L-6610-2013; Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU National Institute of Mental Health; National Alliance for Research on Schizophrenia and Depression FX This work was supported by the National Institute of Mental Health Intramural Program. KM and RJS are supported by National Alliance for Research on Schizophrenia and Depression Young Investigator Awards. NR 46 TC 18 Z9 18 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2012 VL 71 IS 1 BP 75 EP 83 DI 10.1016/j.biopsych.2011.08.014 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 863BI UT WOS:000298137400014 PM 21978521 ER PT J AU Shi, GB Shaw, G Liang, YH Subburaman, P Li, Y Wu, Y Yan, HG Ji, XH AF Shi, Genbin Shaw, Gary Liang, Yu-He Subburaman, Priadarsini Li, Yue Wu, Yan Yan, Honggao Ji, Xinhua TI Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Antibacterial; Bisubstrate; Folate; HPPK; Pterin ID ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; ARGININE RESIDUE-82; CRYSTAL-STRUCTURE; TERNARY COMPLEX; NMR; CRYSTALLOGRAPHY; BIOSYNTHESIS; SOFTWARE; BINDING AB 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their K-d and IC50 values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure. Published by Elsevier Ltd. C1 [Shi, Genbin; Shaw, Gary; Liang, Yu-He; Subburaman, Priadarsini; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Li, Yue; Wu, Yan; Yan, Honggao] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@mail.nih.gov RI Ji, Xinhua/C-9664-2012; LIANG, YUHE/B-6704-2012 OI Ji, Xinhua/0000-0001-6942-1514; FU NIH [GM51901]; NIAID NIH/FDA [Y3-RC-8007-01]; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by NIH Grant GM51901 (H.Y.), NIAID Trans NIH/FDA Intramural Biodefense Program Y3-RC-8007-01 (X.J.), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Mass spectrometry experiments were conducted on an Agilent 1100 series LC/Mass Selective Detector maintained by the Biophysics Resource in the Structural Biophysics Laboratory, an Agilent 1200 LC/MSD-SL system in the Chemical Biology Laboratory, and a Thermoquest Surveyor Finnigan LCQ deca maintained by the Comparative Carcinogenesis Laboratory of National Cancer Institute at Frederick. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID and 22-BM beamlines at the Advanced Photon Source (APS), Argonne National Laboratory (ANL). NR 51 TC 7 Z9 7 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 JAN 1 PY 2012 VL 20 IS 1 BP 47 EP 57 DI 10.1016/j.bmc.2011.11.032 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 869XO UT WOS:000298633300005 PM 22169600 ER PT J AU Kim, YS Kil, MJ Kang, SU Ryu, H Kim, MS Cho, Y Bhondwe, RS Thorat, SA Sun, W Liu, KL Lee, JH Choi, S Pearce, LV Pavlyukovets, VA Morgan, MA Tran, R Lazar, J Blumberg, PM Lee, J AF Kim, Yong Soo Kil, Min-Jung Kang, Sang-Uk Ryu, HyungChul Kim, Myeong Seop Cho, Yongsung Bhondwe, Rahul S. Thorat, Shivaji A. Sun, Wei Liu, Keliang Lee, Jin Hee Choi, Sun Pearce, Larry V. Pavlyukovets, Vladimir A. Morgan, Matthew A. Tran, Richard Lazar, Jozsef Blumberg, Peter M. Lee, Jeewoo TI N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE TRPV1 antagonists; Analgesic; Molecular modeling; Capsaicin; Resiniferatoxin ID VANILLOID RECEPTOR; CAPSAICIN RECEPTORS; AGONISTS; CHANNEL; ANALOGS; POTENT AB Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kim, Yong Soo; Kil, Min-Jung; Kang, Sang-Uk; Ryu, HyungChul; Kim, Myeong Seop; Cho, Yongsung; Bhondwe, Rahul S.; Thorat, Shivaji A.; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. [Sun, Wei; Liu, Keliang] Shenyang Pharmaceut Univ, Shenyang 110016, Liaoning, Peoples R China. [Lee, Jin Hee; Choi, Sun] Ewha Womans Univ, Div Life & Pharmaceut Sci, Coll Pharm, Seoul 120750, South Korea. [Lee, Jin Hee; Choi, Sun] Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea. [Pearce, Larry V.; Pavlyukovets, Vladimir A.; Morgan, Matthew A.; Tran, Richard; Lazar, Jozsef; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Digital-biotech; National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; National Core Research Center (NCRC) of MEST [2011-0006244]; NRF through Center for Cell Signaling & Drug Discovery Research at Ewha Womans University; National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported by Research Funding from Digital-biotech, Grants R11-2007-107-02001-0 from the National Research Foundation of Korea (NRF), the National Core Research Center (NCRC) program (No. 2011-0006244) of MEST and NRF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and the intramural program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (project Z1A BC 005270). NR 20 TC 11 Z9 11 U1 0 U2 5 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 JAN 1 PY 2012 VL 20 IS 1 BP 215 EP 224 DI 10.1016/j.bmc.2011.11.008 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 869XO UT WOS:000298633300022 PM 22169633 ER PT J AU Sundaram, R McLain, AC Louis, GMB AF Sundaram, Rajeshwari McLain, Alexander C. Louis, Germaine M. Buck TI A survival analysis approach to modeling human fecundity SO BIOSTATISTICS LA English DT Article DE Censoring; Conception; Discrete survival; Fecundity; Random effects; Time-varying covariates ID MENSTRUAL-CYCLE; PREGNANCY; CONCEPTION; TIME; FECUNDABILITY; PROBABILITIES; FREQUENCY; VIABILITY AB Understanding conception probabilities is important not only for helping couples to achieve pregnancy but also in identifying acute or chronic reproductive toxicants that affect the highly timed and interrelated processes underlying hormonal profiles, ovulation, libido, and conception during menstrual cycles. Currently, 2 statistical approaches are available for estimating conception probabilities depending upon the research question and extent of data collection during the menstrual cycle: a survival approach when interested in modeling time-to-pregnancy (TTP) in relation to women or couples' purported exposure(s), or a hierarchical Bayesian approach when one is interested in modeling day-specific conception probabilities during the estimated fertile window. We propose a biologically valid discrete survival model that unifies the above 2 approaches while relaxing some assumptions that may not be consistent with human reproduction or behavior. This approach combines both the survival and the hierarchical models allowing investigators to obtain the distribution of TTP and day-specific probabilities during the fertile window in a single model. Our model allows for the consideration of covariate effects at both the cycle and the daily level while accounting for daily variation in conception. We conduct extensive simulations and utilize the New York State Angler Prospective Pregnancy Cohort Study to illustrate our approach. We also provide the code to implement the model in R software in the supplemental section of the supplementary material available at Biostatistics online. C1 [Sundaram, Rajeshwari; McLain, Alexander C.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Sundaram, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM sundaramr2@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 26 TC 10 Z9 10 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2012 VL 13 IS 1 BP 4 EP 17 DI 10.1093/biostatistics/kxr015 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 863TZ UT WOS:000298192300002 PM 21697247 ER PT J AU Zhang, B Chen, Z Albert, PS AF Zhang, Bo Chen, Zhen Albert, Paul S. TI Latent class models for joint analysis of disease prevalence and high-dimensional semicontinuous biomarker data SO BIOSTATISTICS LA English DT Article DE Categorical data; Chemical exposure biomarkers; Latent variables; Monte Carlo EM algorithm; Random effects ID EM ALGORITHM; MAXIMUM-LIKELIHOOD; LONGITUDINAL DATA; ENDOMETRIOSIS; REGRESSION; MIXTURES AB High-dimensional biomarker data are often collected in epidemiological studies when assessing the association between biomarkers and human disease is of interest. We develop a latent class modeling approach for joint analysis of high-dimensional semicontinuous biomarker data and a binary disease outcome. To model the relationship between complex biomarker expression patterns and disease risk, we use latent risk classes to link the 2 modeling components. We characterize complex biomarker-specific differences through biomarker-specific random effects, so that different biomarkers can have different baseline (low-risk) values as well as different between-class differences. The proposed approach also accommodates data features that are common in environmental toxicology and other biomarker exposure data, including a large number of biomarkers, numerous zero values, and complex mean-variance relationship in the biomarkers levels. A Monte Carlo EM (MCEM) algorithm is proposed for parameter estimation. Both the MCEM algorithm and model selection procedures are shown to work well in simulations and applications. In applying the proposed approach to an epidemiological study that examined the relationship between environmental polychlorinated biphenyl (PCB) exposure and the risk of endometriosis, we identified a highly significant overall effect of PCB concentrations on the risk of endometriosis. C1 [Zhang, Bo; Chen, Zhen; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. RP Zhang, B (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. EM bo.zhang@nih.gov FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences [1R01ES09044-01] FX Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences (Grant 1R01ES09044-01). NR 18 TC 2 Z9 2 U1 7 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD JAN PY 2012 VL 13 IS 1 BP 74 EP 88 DI 10.1093/biostatistics/kxr024 PG 15 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 863TZ UT WOS:000298192300007 PM 21908867 ER PT J AU Moore, HM AF Moore, H. M. TI The NCI Biospecimen Research Network SO BIOTECHNIC & HISTOCHEMISTRY LA English DT Article DE best practices; biobank; biospecimen; cancer; human; quality; research ID QUALITY; CANCER; TISSUE AB High quality cancer research using human biospecimens must be based on biospecimens that have been obtained according to rigorous ethical and procedural standards. Methods for biospecimen collection, stabilization, processing and storage for research, however, are highly variable and the biospecimens available for research often are of unknown quality. The National Cancer Institute Biospecimen Research Network program was initiated in 2006 to conduct, sponsor, report and collaborate on research to better understand the effects of different biospecimen collection methods on downstream molecular analysis. An online Biospecimen Research Database and an annual symposium, Advancing Cancer Research through Biospecimen Science, have been developed and many research projects are underway to develop a knowledge base from which to develop evidence-based biospecimen standard operating procedures and methods for assessing biospecimen quality. These efforts will enable better cancer research and development efforts. C1 [Moore, H. M.] NCI, Off Biorepositories & Biospecimen Res, Bethesda, MD 20892 USA. RP Moore, HM (reprint author), NCI, Off Biorepositories & Biospecimen Res, 11400 Rockville Pike,Suite 700, Bethesda, MD 20852 USA. EM moorehe@mail.nih.gov NR 14 TC 8 Z9 8 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1052-0295 J9 BIOTECH HISTOCHEM JI Biotech. Histochem. PD JAN PY 2012 VL 87 IS 1 BP 18 EP 23 DI 10.3109/10520295.2011.591833 PG 6 WC Biotechnology & Applied Microbiology; Cell Biology SC Biotechnology & Applied Microbiology; Cell Biology GA 874UA UT WOS:000298982400005 PM 21745162 ER PT J AU Malicdan, MCV Nishino, I AF Malicdan, May Christine V. Nishino, Ichizo TI Autophagy in Lysosomal Myopathies SO BRAIN PATHOLOGY LA English DT Article DE autophagy; Danon disease; LAMP-2; lysosome; myopathy; Pompe disease ID CHAPERONE-MEDIATED AUTOPHAGY; GLYCOGEN-STORAGE-DISEASE; ACID ALPHA-GLUCOSIDASE; POMPE-DISEASE; DANON-DISEASE; VACUOLAR MYOPATHY; OXIDATIVE STRESS; SKELETAL-MUSCLE; DISTAL MYOPATHY; LATE-ONSET AB Lysosomal myopathies are hereditary myopathies characterized morphologically by the presence of autophagic vacuoles. In mammals, autophagy plays an important role for the turnover of cellular components, particularly in response to starvation or glucagons. In normal muscle, autolysosomes or autophagosomes are typically inconspicuous. In distinct neuromuscular disorders, however, lysosomes become structurally abnormal and functionally impaired, leading to the accumulation of autophagic vacuoles in myofibers. In some instances, the accumulation of autophagic vacuoles can be a prominent feature, implicating autophagy as a contributor to disease pathomechanism and/or progression. At present, there are two disorders in the muscle that are associated with a primary defect in lysosomal proteins, namely Pompe disease and Danon disease. This review will give a brief discussion on these disorders, highlighting the role of autophagy in disease progression. C1 [Malicdan, May Christine V.; Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Neuromuscular Res, Kodaira, Tokyo 1870031, Japan. [Malicdan, May Christine V.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Nishino, I (reprint author), 4-1-1 Ogawahigashi Cho, Kodaira, Tokyo 1878502, Japan. EM nishino@ncnp.go.jp RI Malicdan, May Christine/F-2806-2013; OI Nishino, Ichizo/0000-0001-9452-112X NR 52 TC 33 Z9 34 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD JAN PY 2012 VL 22 IS 1 BP 82 EP 88 DI 10.1111/j.1750-3639.2011.00543.x PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 860CL UT WOS:000297924900010 PM 22150923 ER PT J AU Falk, RT Gentzschein, E Stanczyk, FZ Garcia-Closas, M Figueroa, JD Ioffe, OB Lissowska, J Brinton, LA Sherman, ME AF Falk, Roni T. Gentzschein, Elisabet Stanczyk, Frank Z. Garcia-Closas, Montserrat Figueroa, Jonine D. Ioffe, Olga B. Lissowska, Jolanta Brinton, Louise A. Sherman, Mark E. TI Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Sex steroid hormone; Breast adipose; Breast cancer; Intratissue; Hormone receptor ID CANCER RISK; AROMATASE EXPRESSION; RECEPTOR STATUS; MAMMARY-GLAND; ESTROGEN; DEHYDROEPIANDROSTERONE; INFLAMMATION; ANDROGENS; SULFATASE AB Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR -/-) participating in a breast cancer case-control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER-/PR- breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER-/PR- breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER-/PR- breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis. C1 [Falk, Roni T.; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Brinton, Louise A.; Sherman, Mark E.] NCI, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. [Gentzschein, Elisabet; Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Ioffe, Olga B.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Lissowska, Jolanta] Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. RP Falk, RT (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. EM falkr@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS [ZIA CP010126-18] NR 39 TC 17 Z9 17 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JAN PY 2012 VL 131 IS 1 BP 287 EP 294 DI 10.1007/s10549-011-1734-5 PG 8 WC Oncology SC Oncology GA 861GB UT WOS:000298006300029 PM 21870130 ER PT J AU Tewari, P Ryan, AW Hayden, PJ Catherwood, M Drain, S Staines, A Grant, T Nieters, A Becker, N de Sanjose, S Foretova, L Maynardie, M Cocco, P Boffetta, P Brennan, P Chanock, S Lawler, M Browne, PV AF Tewari, Prerna Ryan, Anthony W. Hayden, Patrick J. Catherwood, Mark Drain, Stephen Staines, Anthony Grant, Tim Nieters, Alexandra Becker, Nikolaus de Sanjose, Silvia Foretova, Lenka Maynardie, Mark Cocco, Pierluigi Boffetta, Paolo Brennan, Paul Chanock, Stephen Lawler, Mark Browne, Paul V. TI Genetic variation at the 8q24 locus confers risk to multiple myeloma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE multiple myeloma; germline variation; susceptibility; single nucleotide polymorphisms; aetiology ID GENOME-WIDE ASSOCIATION; CANCER C1 [Tewari, Prerna; Lawler, Mark; Browne, Paul V.] Trinity Coll Dublin, Durkan Leukaemia Labs, Dept Haematol, Dublin, Ireland. [Ryan, Anthony W.] Trinity Coll Dublin, Inst Mol Med, Dublin, Ireland. [Hayden, Patrick J.; Browne, Paul V.] St James Hosp, Dept Haematol, Dublin 8, Ireland. [Catherwood, Mark; Drain, Stephen] Belfast City Hosp, Dept Haematol, Belfast BT9 7AD, Antrim, North Ireland. [Staines, Anthony] Dublin City Univ, Sch Nursing, Dublin 9, Ireland. [Grant, Tim] Univ Coll Dublin, Sch Publ Hlth & Populat Sci, Dublin 2, Ireland. [Nieters, Alexandra; Becker, Nikolaus] German Canc Res Ctr, D-6900 Heidelberg, Germany. [de Sanjose, Silvia] Catalan Inst Oncol, Barcelona, Spain. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Maynardie, Mark] Registre Hemopathies Malignes Cote dOr, Dijon, France. [Cocco, Pierluigi] Univ Cagliari, Inst Occupat Med, Cagliari, Italy. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Chanock, Stephen] Natl Canc Inst Gaithersburg, Core Genotyping Facil, Adv Technol Corp, Gaithersburg, MA USA. RP Tewari, P (reprint author), Trinity Coll Dublin, Durkan Leukaemia Labs, Dept Haematol, Dublin, Ireland. EM tewarip@tcd.ie RI Ryan, Anthony/A-1336-2010; de Sanjose Llongueras, Silvia/H-6339-2014; OI Ryan, Anthony/0000-0001-5005-3344; Staines, Anthony/0000-0001-9161-1357; Browne, Paul/0000-0001-5310-1487 NR 9 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JAN PY 2012 VL 156 IS 1 BP 133 EP 137 DI 10.1111/j.1365-2141.2011.08798.x PG 6 WC Hematology SC Hematology GA 861YX UT WOS:000298058100015 PM 21770920 ER PT J AU Chen, SH Wu, HM Ossola, B Schendzielorz, N Wilson, BC Chu, CH Chen, SL Wang, Q Zhang, D Qian, L Li, X Hong, JS Lu, RB AF Chen, S. H. Wu, H. M. Ossola, B. Schendzielorz, N. Wilson, B. C. Chu, C. H. Chen, S. L. Wang, Q. Zhang, D. Qian, L. Li, X. Hong, J. S. Lu, R. B. TI Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE SAHA; neuroprotection; neurodegenerative disease; HDAC; neurotrophic factors; Parkinson's disease ID NEUROTROPHIC FACTOR GDNF; PARKINSONS-DISEASE; HUNTINGTONS-DISEASE; NERVOUS-SYSTEM; IN-VITRO; MICROGLIA; NEURODEGENERATION; BRAIN; CELLS; DEGENERATION AB BACKGROUND AND PURPOSE Prevention or disease-modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models. EXPERIMENTAL APPROACH Mesencephalic neuron glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme-linked immunosorbent assay and real-time RT PCR. KEY RESULTS In mesencephalic neuron glia cultures, SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. CONCLUSION AND IMPLICATIONS The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases. C1 [Hong, J. S.] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Chen, S. H.; Wu, H. M.; Chu, C. H.; Chen, S. L.; Lu, R. B.] Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Tainan 70428, Taiwan. [Chen, S. H.; Wu, H. M.; Chu, C. H.; Chen, S. L.; Lu, R. B.] Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70428, Taiwan. [Li, X.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Wu, H. M.] Changhua Christian Hosp, Dept Neurol, Changhua, Taiwan. [Wu, H. M.] China Med Univ, Grad Inst Acupuncture Sci, Taichung, Taiwan. [Lu, R. B.] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70428, Taiwan. RP Hong, JS (reprint author), NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov; rblu@mail.ncku.edu.tw FU National Cheng Kung University; Promoting Academic Excellence & Developing World Class Research Centers, Taiwan; NIH/NIEHS FX We thank Dr Ronald Cannon and Esteban Oyarzabal for critical reading of the manuscript, This project was supported by a grant from the National Cheng Kung University, Project of Promoting Academic Excellence & Developing World Class Research Centers, Taiwan. This research was also supported in part by the Intramural Research Program of the NIH/NIEHS. NR 47 TC 26 Z9 26 U1 3 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JAN PY 2012 VL 165 IS 2 BP 494 EP 505 DI 10.1111/j.1476-5381.2011.01575.x PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 867UV UT WOS:000298481200016 PM 21726209 ER PT J AU Leach, CR Klabunde, CN Alfano, CM Smith, JL Rowland, JH AF Leach, Corinne R. Klabunde, Carrie N. Alfano, Catherine M. Smith, Judith Lee Rowland, Julia H. TI Physician over-recommendation of mammography for terminally ill women SO CANCER LA English DT Article DE breast cancer; mammography; primary care; practice guidelines; screening ID PRIMARY-CARE-PHYSICIANS; CANCER SCREENING RECOMMENDATIONS; UNITED-STATES; OLDER WOMEN; SOCIETY GUIDELINES; LUNG-CANCER; BREAST; PATIENT; SURVIVAL; ISSUES AB BACKGROUND: There has been recent, sometimes intense, debate about when to begin screening and how often to screen women for breast cancer with mammography. However, there should be no controversy regarding screening women who are unlikely to benefit from the procedure, such as those with a serious, life-limiting illness who would not live long enough to benefit from the potential detection and treatment of breast cancer. Identifying characteristics of physicians who recommend mammography for terminally ill women can help guide efforts to minimize patient risks and make better use of health care resources. METHODS: The authors used data from a nationally representative survey of primary care physicians (PCPs) (N = 1196; response rate, 67.5%) conducted in 2006 and 2007 to examine PCPs' breast cancer screening recommendations for hypothetical patients ages 50 years, 65 years, and 80 years who were healthy, had a moderate comorbidity, or had a terminal comorbidity. RESULTS: Many PCPs (47.7%) reported that they would recommend mammography to a woman aged 50 years, 65 years, or 80 years with terminal lung cancer, indicating over-recommendation. Physician characteristics associated with over-recommending mammography included obstetrician/gynecologist (odds ratio [OR], 1.69) or internal medicine (OR, 0.45) specialty, being a woman (OR, 1.40), being a racial/ethnic minority (OR, 1.72), and working in a smaller practice (OR, 1.41). CONCLUSIONS: The current results indicated that physician over-recommendation of screening mammography among terminally ill women is common. Certain physician and practice characteristics, including specialty, were associated with over-recommending mammography. The authors concluded that an informed and shared mammography decisionmaking process for terminally ill women may eliminate unnecessary patient risks and health care expenditures. Cancer 2012; 118: 27-37. (C) 2011 American Cancer Society. C1 [Leach, Corinne R.] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30303 USA. [Leach, Corinne R.; Alfano, Catherine M.; Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Klabunde, Carrie N.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Smith, Judith Lee] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Leach, CR (reprint author), Amer Canc Soc, Behav Res Ctr, 250 Williams St, Atlanta, GA 30303 USA. EM corinne.leach@cancer.org FU National Cancer Institute [N02-PC-51,308]; 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 this study was provided by the National Cancer Institute (contract N02-PC-51,308), the Centers for Disease Control and Prevention (interagency agreement Y3-PC-6017-01), and the Agency for Healthcare Research and Quality (interagency agreements Y3-PC-5019-01 and Y3-PC-5019-02). NR 41 TC 10 Z9 10 U1 0 U2 3 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 JAN 1 PY 2012 VL 118 IS 1 BP 27 EP 37 DI 10.1002/cncr.26233 PG 11 WC Oncology SC Oncology GA 868TW UT WOS:000298549700006 PM 21681736 ER PT J AU Moore, LE Pfeiffer, RM Zhang, Z Lu, KH Fung, ET Bast, RC AF Moore, Lee E. Pfeiffer, Ruth M. Zhang, Zhen Lu, Karen H. Fung, Eric T. Bast, Robert C., Jr. TI Proteomic biomarkers in combination with CA 125 for detection of epithelial ovarian cancer using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial SO CANCER LA English DT Article DE ovarian cancer; biomarkers; Prostate; Lung; Colorectal; Ovarian Cancer Screening Trial; CA 125; early detection AB BACKGROUND: When epithelial ovarian cancer is detected at an early stage (I-II), the 5-year survival rate is between 70% and 90%; whereas, when it is detected in late stages (III-IV), the 5-year survival rate slips to <30%. In a previous report, the authors observed that proteomic biomarkers and cancer antigen 125 (CA 125) exhibited a sensitivity of 84% at a specificity of 98% for identifying sera from patients who had stage I disease at the time of surgery, significantly improving the sensitivity of CA 125 alone. The challenge, however, is to detect ovarian cancer before clinical diagnosis. The current study was part of a large effort to compare different multimarker biomarker panels for the early detection of ovarian cancer. Several biomarkers were evaluated alone and in combination with CA 125 in prediagnostically collected sera from women in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. METHODS: Proximal prediagnostic sera from 118 women with ovarian cancer (cases) and from 951 age-matched women (controls) (8 controls per case, including 4 randomly selected from the general population, 2 with CA 125 levels >= 35 U/mL, and 2 with a positive family history of breast/ovarian cancer) were analyzed using the CA 125 immunoassay and surface-enhanced laser desorption and ionization time-of-flight mass spectrometry to measure 7 proteins (apolipoprotein A1, truncated transthyretin, transferrin, hepcidin, b-2 microglobulin, connective tissue activating protein III), and interalpha-trypsin inhibitor heavy-chain 4). Data were analyzed by 2 statistical strategies that combined the 7 markers and CA 125 into 1 predictive score for disease classification. RESULTS: CA 125 levels were elevated (>= 35 U/mL) in 61.5% of 65 patients who had CA 125 data available from samples that were collected < 12 months before cancer diagnosis; however, levels of the additional 7 biomarkers were not different between cases and the 3 control groups individually or combined. Two panels that combined CA 125 and the 7 biomarkers failed to improve the sensitivity of CA 125 alone. CONCLUSIONS: In contrast to earlier findings from analyzes of postdiagnostically collected sera, the addition of 7 biomarkers to CA 125 did not improve sensitivity for preclinical diagnosis beyond CA 125 alone. Cancer 2012; 118: 91-100. (C) 2011 American Cancer Society. C1 [Moore, Lee E.; Pfeiffer, Ruth M.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Zhang, Zhen] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Fung, Eric T.] Vermillion Inc, Fremont, CA USA. [Bast, Robert C., Jr.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. RP Moore, LE (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. EM moorele@mail.nih.gov RI Bast, Robert/E-6585-2011 OI Bast, Robert/0000-0003-4621-8462 FU University of Texas MD Anderson SPORE in Ovarian Cancer from the National Cancer Institute [P50 CA83639]; Golfers Against Cancer; Tracey Jo Wilson Foundation; Mossy Foundation; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by funds from The University of Texas MD Anderson SPORE in Ovarian Cancer from the National Cancer Institute (grant P50 CA83639); by philanthropic support from Golfers Against Cancer, the Tracey Jo Wilson Foundation, and the Mossy Foundation; and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 20 TC 36 Z9 38 U1 0 U2 11 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 JAN 1 PY 2012 VL 118 IS 1 BP 91 EP 100 DI 10.1002/cncr.26241 PG 10 WC Oncology SC Oncology GA 868TW UT WOS:000298549700013 PM 21717433 ER PT J AU Jin, GX Fu, CH Zhao, H Cui, KM Chang, J Wong, STC AF Jin, Guangxu Fu, Changhe Zhao, Hong Cui, Kemi Chang, Jenny Wong, Stephen T. C. TI A Novel Method of Transcriptional Response Analysis to Facilitate Drug Repositioning for Cancer Therapy SO CANCER RESEARCH LA English DT Article ID INTERACTION DATABASE; NETWORK MOTIFS; TARGETED THERAPIES; CONNECTIVITY MAP; KNOWLEDGEBASE; SIMILARITY; SIGNATURES; DISCOVERY; GENES; TOOL AB Little research has been done to address the huge opportunities that may exist to reposition existing approved or generic drugs for alternate uses in cancer therapy. In addition, there has been little work on strategies to reposition experimental cancer agents for testing in alternate settings that could shorten their clinical development time. Progress in each area has lagged, in part, because of the lack of systematic methods to define drug off-target effects (OTE) that might affect important cancer cell signaling pathways. In this study, we addressed this critical gap by developing an OTE-based method to repurpose drugs for cancer therapeutics, based on transcriptional responses made in cells before and after drug treatment. Specifically, we defined a new network component called cancer-signaling bridges (CSB) and integrated it with a Bayesian factor regression model (BFRM) to form a new hybrid method termed CSB-BFRM. Proof-of-concept studies were conducted in breast and prostate cancer cells and in promyelocytic leukemia cells. In each system, CSB-BFRM analysis could accurately predict clinical responses to more than 90% of drugs approved by the U. S. Food and Drug Administration and more than 75% of experimental clinical drugs that were tested. Mechanistic investigation of OTEs for several high-ranking drug-dose pairs suggested repositioning opportunities for cancer therapy, based on the ability to enforce retinoblastoma-dependent repression of important E2F-dependent cell-cycle genes. Together, our findings establish new methods to identify opportunities for drug repositioning or to elucidate the mechanisms of action of repositioned drugs. Cancer Res; 72( 1); 33-44. (C) 2011 AACR. C1 [Jin, Guangxu; Fu, Changhe; Zhao, Hong; Cui, Kemi; Chang, Jenny; Wong, Stephen T. C.] Cornell Univ, Dept Syst Med & Bioengn, Methodist Hosp, Res Inst,Weill Med Coll, Houston, TX 77030 USA. [Jin, Guangxu; Zhao, Hong; Cui, Kemi; Chang, Jenny; Wong, Stephen T. C.] Cornell Univ, NCI Ctr Modeling Canc Dev, Methodist Hosp, Res Inst,Weill Med Coll, Houston, TX 77030 USA. [Chang, Jenny; Wong, Stephen T. C.] Methodist Hosp, Methodist Canc Ctr, Houston, TX 77030 USA. RP Wong, STC (reprint author), Cornell Univ, Dept Syst Med & Bioengn, Methodist Hosp, Res Inst,Weill Med Coll, 6670 Bertner St,MC R6-414, Houston, TX 77030 USA. EM stwong@tmhs.org RI Jin, Guangxu/B-4627-2012 OI Jin, Guangxu/0000-0002-6616-6981 FU NIH [U54CA149196] FX This work was supported by NIH grant U54CA149196 and John S. Dunn Research Foundation to S. T. C. Wong. NR 32 TC 29 Z9 29 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 1 PY 2012 VL 72 IS 1 BP 33 EP 44 DI 10.1158/0008-5472.CAN-11-2333 PG 12 WC Oncology SC Oncology GA 871RO UT WOS:000298755600005 PM 22108825 ER PT J AU Fitzgerald, DP Subramanian, P Deshpande, M Graves, C Gordon, I Qian, YZ Snitkovsky, Y Liewehr, DJ Steinberg, SM Paltan-Ortiz, JD Herman, MM Camphausen, K Palmieri, D Becerra, SP Steeg, PS AF Fitzgerald, Daniel P. Subramanian, Preeti Deshpande, Monika Graves, Christian Gordon, Ira Qian, Yongzhen Snitkovsky, Yeva Liewehr, David J. Steinberg, Seth M. Paltan-Ortiz, Jose D. Herman, Mary M. Camphausen, Kevin Palmieri, Diane Becerra, S. Patricia Steeg, Patricia S. TI Opposing Effects of Pigment Epithelium-Derived Factor on Breast Cancer Cell versus Neuronal Survival: Implication for Brain Metastasis and Metastasis-Induced Brain Damage SO CANCER RESEARCH LA English DT Article ID FLUORO-JADE-B; TUMOR-GROWTH; IDENTIFICATION; ANGIOGENESIS; PEDF; INHIBITOR; PHOTORECEPTORS; COLONIZATION; DEGENERATION; EXPRESSION AB Brain metastases are a significant cause of morbidity and mortality for patients with cancer, yet preventative and therapeutic options remain an unmet need. The cytokine pigment epithelium-derived factor ( PEDF) is downregulated in resected human brain metastases of breast cancer compared with primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here, we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences. Cancer Res; 72( 1); 144-53. (C) 2012 AACR. C1 [Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Subramanian, Preeti; Deshpande, Monika; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. [Graves, Christian; Gordon, Ira; Camphausen, Kevin] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Snitkovsky, Yeva; Paltan-Ortiz, Jose D.; Herman, Mary M.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Qian, Yongzhen] NCI, Lab Anim Sci Program, Applicat Int Corp, Frederick, MD 21701 USA. RP Steeg, PS (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bldg 37,Room 1122, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov RI Palmieri, Diane/B-4258-2015 FU National Cancer Institute; National Eye Institute; U.S. Department of Defense Breast Cancer Research [W81 XWH-062-0033]; GlaxoSmithKline; Millenium Pharmaceuticals FX This work was supported by the intramural research programs of the National Cancer Institute and the National Eye Institute and by the U.S. Department of Defense Breast Cancer Research Program, grant number: W81 XWH-062-0033. Dr. Patricia Steeg's laboratory lab receives research support from GlaxoSmithKline and Millenium Pharmaceuticals. NR 49 TC 25 Z9 26 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 1 PY 2012 VL 72 IS 1 BP 144 EP 153 DI 10.1158/0008-5472.CAN-11-1904 PG 10 WC Oncology SC Oncology GA 871RO UT WOS:000298755600015 PM 22215693 ER PT J AU Wang, CX Liu, ZH Woo, CW Li, ZJ Wang, LF Wei, JS Marquez, VE Bates, SE Jin, QH Khan, J Ge, K Thiele, CJ AF Wang, Chunxi Liu, Zhihui Woo, Chan-Wook Li, Zhijie Wang, Lifeng Wei, Jun S. Marquez, Victor E. Bates, Susan E. Jin, Qihuang Khan, Javed Ge, Kai Thiele, Carol J. TI EZH2 Mediates Epigenetic Silencing of Neuroblastoma Suppressor Genes CASZ1, CLU, RUNX3, and NGFR SO CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; GROUP PROTEIN EZH2; TUMOR-SUPPRESSOR; METHYLTRANSFERASE EZH2; PROSTATE-CANCER; STEM-CELLS; CHROMOSOME 1P; EXPRESSION; DIFFERENTIATION; REPRESSION AB Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with an undifferentiated status and generally poor prognosis, but the basis for these characteristics remains unknown. In this study, we show that upregulation of the Polycomb protein histone methyltransferase EZH2, which limits differentiation in many tissues, is critical to maintain the undifferentiated state and poor prognostic status of NB by epigenetic repression of multiple tumor suppressor genes. We identified this role for EZH2 by examining the regulation of CASZ1, a recently identified NB tumor suppressor gene whose ectopic restoration inhibits NB cell growth and induces differentiation. Reducing EZH2 expression by RNA interference-mediated knockdown or pharmacologic inhibiton with 3-deazaneplanocin A increased CASZ1 expression, inhibited NB cell growth, and induced neurite extension. Similarly, EZH2(-/-) mouse embryonic fibroblasts (MEF) displayed 3-fold higher levels of CASZ1 mRNA compared with EZH2(+/+) MEFs. In cells with increased expression of CASZ1, treatment with histone deacetylase (HDAC) inhibitor decreased expression of EZH2 and the Polycomb Repressor complex component SUZ12. Under steady-state conditions, H3K27me3 and PRC2 components bound to the CASZ1 gene were enriched, but this enrichment was decreased after HDAC inhibitor treatment. We determined that the tumor suppressors CLU, NGFR, and RUNX3 were also directly repressed by EZH2 like CASZ1 in NB cells. Together, our findings establish that aberrant upregulation of EZH2 in NB cells silences several tumor suppressors, which contribute to the genesis and maintenance of the undifferentiated phenotype of NB tumors. Cancer Res; 72(1); 315-24. (C) 2011 AACR. C1 [Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Ctr Canc Res,CRC, Bethesda, MD 20892 USA. [Wang, Lifeng; Wei, Jun S.; Khan, Javed] NCI, Oncogenom Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bates, Susan E.] NCI, Mol Therapeut Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Jin, Qihuang; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. [Marquez, Victor E.] NCI, Chem Biol Lab, NIH, Frederick, MD 21701 USA. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Ctr Canc Res,CRC, 1-3940,10 Ctr Dr,MSC 1105, Bethesda, MD 20892 USA. EM thielec@mail.nih.gov RI Wang, Lifeng/I-4888-2012; Khan, Javed/P-9157-2014; OI Wang, Lifeng/0000-0003-4752-6547; Khan, Javed/0000-0002-5858-0488; Ge, Kai/0000-0002-7442-5138 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported and funded by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 58 Z9 60 U1 0 U2 9 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 JAN 1 PY 2012 VL 72 IS 1 BP 315 EP 324 DI 10.1158/0008-5472.CAN-11-0961 PG 10 WC Oncology SC Oncology GA 871RO UT WOS:000298755600031 PM 22068036 ER PT J AU Sarkar, K Rey, S Zhang, XJ Sebastian, R Marti, GP Fox-Talbot, K Cardona, AV Du, JK Tan, YS Liu, LX Lay, F Gonzalez, FJ Harmon, JW Semenza, GL AF Sarkar, Kakali Rey, Sergio Zhang, Xianjie Sebastian, Raul Marti, Guy P. Fox-Talbot, Karen Cardona, Amanda V. Du, Junkai Tan, Yee Sun Liu, Lixin Lay, Frank Gonzalez, Frank J. Harmon, John W. Semenza, Gregg L. TI Tie2-dependent knockout of HIF-1 impairs burn wound vascularization and homing of bone marrow-derived angiogenic cells SO CARDIOVASCULAR RESEARCH LA English DT Article DE Hypoxia; Wound healing; Conditional knockout; Angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1; PROGENITOR CELLS; LIMB ISCHEMIA; DIABETIC MICE; TRANSCRIPTIONAL REGULATION; TUMOR ANGIOGENESIS; GENE-THERAPY; IN-VIVO; EXPRESSION AB Aims Hypoxia-inducible factor 1 (HIF-1) is a heterodimer composed of HIF-1 alpha and HIF-1 beta subunits. HIF-1 is known to promote tissue vascularization by activating the transcription of genes encoding angiogenic factors, which bind to receptors on endothelial cells (ECs) and bone marrow-derived angiogenic cells (BMDACs). In this study, we analysed whether HIF-1 activity in the responding ECs and BMDACs is also required for cutaneous vascularization during burn wound healing. Methods and results We generated mice with floxed alleles at the Hif1a or Arnt locus encoding HIF-1 alpha and HIF-1 beta, respectively. Expression of Cre recombinase was driven by the Tie2 gene promoter, which is expressed in ECs and bone marrow cells. Tie2Cre(+) and Tie2Cre(-) mice were subjected to burn wounds of reproducible diameter and depth. Deficiency of HIF-1 alpha or HIF-1 beta in Tie2-lineage cells resulted in delayed wound closure, reduced vascularization, decreased cutaneous blood flow, impaired BMDAC mobilization, and decreased BMDAC homing to burn wounds. Conclusion HIF-1 activity in Tie2-lineage cells is required for the mobilization and homing of BMDACs to cutaneous burn wounds and for the vascularization of burn wound tissue. C1 [Zhang, Xianjie; Sebastian, Raul; Marti, Guy P.; Du, Junkai; Liu, Lixin; Lay, Frank; Harmon, John W.] Johns Hopkins Univ, Sch Med, Hendrix Burn Lab, Baltimore, MD 21205 USA. [Rey, Sergio; Cardona, Amanda V.; Tan, Yee Sun; Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Sarkar, Kakali; Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sarkar, Kakali; Rey, Sergio; Cardona, Amanda V.; Tan, Yee Sun; Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Vasc Program, Inst Cell Engn, Baltimore, MD 21205 USA. [Zhang, Xianjie] Capital Med Univ, Beijing Tiantan Hosp, Sect Surg Sci, Beijing, Peoples R China. [Fox-Talbot, Karen] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USA. [Semenza, Gregg L.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Zhang, Xianjie; Sebastian, Raul; Marti, Guy P.; Du, Junkai; Liu, Lixin; Lay, Frank; Harmon, John W.] Johns Hopkins Univ, Sch Med, Sect Surg Sci, Baltimore, MD 21205 USA. RP Harmon, JW (reprint author), Johns Hopkins Univ, Sch Med, Sect Surg Sci, Baltimore, MD 21205 USA. EM jharmon2@jhmi.edu; gsemenza@jhmi.edu RI Rey, Sergio/B-6370-2009; OI marti, guy/0000-0003-1147-4001; Rey, Sergio/0000-0001-8954-7712 FU National Institute of General Medical Sciences [P20-GM078494]; Johns Hopkins Institute for Cell Engineering; Johns Hopkins University FX This work was supported by grant P20-GM078494 from the National Institute of General Medical Sciences, the Johns Hopkins Institute for Cell Engineering, and the Hendrix Burn Fund of Johns Hopkins University. G.L.S. is the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine. NR 52 TC 16 Z9 16 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JAN PY 2012 VL 93 IS 1 BP 162 EP 169 DI 10.1093/cvr/cvr282 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 866LF UT WOS:000298381600021 PM 22028336 ER PT J AU Ball, WS Byars, AW Schapiro, M Bommer, W Carr, A German, A Dunn, S Rivkin, MJ Waber, D Mulkern, R Vajapeyam, S Chiverton, A Davis, P Koo, J Marmor, J Mrakotsky, C Robertson, R McAnulty, G Brandt, ME Fletcher, JM Kramer, LA Yang, G McCormack, C Hebert, KM Volero, H Botteron, K McKinstry, RC Warren, W Nishino, T Almli, CR Todd, R Constantino, J McCracken, JT Levitt, J Alger, J O'Neill, J Toga, A Asarnow, R Fadale, D Heinichen, L Ireland, C Wang, DJ Moss, E Zimmerman, RA Bintliff, B Bradford, R Newman, J Evans, AC Arnaoutelis, R Pike, GB Collins, DL Leonard, G Paus, T Zijdenbos, A Das, S Fonov, V Fu, L Harlap, J Leppert, I Milovan, D Vins, D Zeffiro, T Van Meter, J Lange, N Froimowitz, MP Botteron, K Almli, CR Rainey, C Henderson, S Nishino, T Warren, W Edwards, JL Dubois, D Smith, K Singer, T Wilber, AA Pierpaoli, C Basser, PJ Chang, LC Walker, L Rumsey, J Baskir, L Stanford, L Sirocco, K Gwinn-Hardy, K Spinella, G McCracken, JT Alger, JR Levitt, J AF Ball, William S. Byars, Anna Weber Schapiro, Mark Bommer, Wendy Carr, April German, April Dunn, Scott Rivkin, Michael J. Waber, Deborah Mulkern, Robert Vajapeyam, Sridhar Chiverton, Abigail Davis, Peter Koo, Julie Marmor, Jacki Mrakotsky, Christine Robertson, Richard McAnulty, Gloria Brandt, Michael E. Fletcher, Jack M. Kramer, Larry A. Yang, Grace McCormack, Cara Hebert, Kathleen M. Volero, Hilda Botteron, Kelly McKinstry, Robert C. Warren, William Nishino, Tomoyuki Almli, C. Robert Todd, Richard Constantino, John McCracken, James T. Levitt, Jennifer Alger, Jeffrey O'Neill, Joseph Toga, Arthur Asarnow, Robert Fadale, David Heinichen, Laura Ireland, Cedric Wang, Dah-Jyuu Moss, Edward Zimmerman, Robert A. Bintliff, Brooke Bradford, Ruth Newman, Janice Evans, Alan C. Arnaoutelis, Rozalia Pike, G. Bruce Collins, D. Louis Leonard, Gabriel Paus, Tomas Zijdenbos, Alex Das, Samir Fonov, Vladimir Fu, Luke Harlap, Jonathan Leppert, Ilana Milovan, Denise Vins, Dario Zeffiro, Thomas Van Meter, John Lange, Nicholas Froimowitz, Michael P. Botteron, Kelly Almli, C. Robert Rainey, Cheryl Henderson, Stan Nishino, Tomoyuki Warren, William Edwards, Jennifer L. Dubois, Diane Smith, Karla Singer, Tish Wilber, Aaron A. Pierpaoli, Carlo Basser, Peter J. Chang, Lin-Ching Walker, Lindsay Rumsey, Judith Baskir, Lauren Stanford, Laurence Sirocco, Karen Gwinn-Hardy, Katrina Spinella, Giovanna McCracken, James T. Alger, Jeffry R. Levitt, Jennifer CA Brain Dev Cooperative Grp TI Total and Regional Brain Volumes in a Population-Based Normative Sample from 4 to 18 Years: The NIH MRI Study of Normal Brain Development SO CEREBRAL CORTEX LA English DT Article DE adolescents; brain volumes; children; healthy; MRI ID BODY-MASS INDEX; CEREBRAL ASYMMETRY; UNITED-STATES; MATTER VOLUME; PSYCHIATRIC-DISORDERS; SOCIOECONOMIC-STATUS; TEMPORALE ASYMMETRY; HEALTHY-INDIVIDUALS; SEXUAL-DIMORPHISM; HUMAN OBESITY AB Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross-sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents. C1 [Lange, Nicholas] McLean Hosp, Neurostat Lab, Belmont, MA 02478 USA. [Ball, William S.; Byars, Anna Weber; Schapiro, Mark; Bommer, Wendy; Carr, April; German, April; Dunn, Scott; Brain Dev Cooperative Grp] Childrens Hosp Med Ctr Cincinnati, Cincinnati, OH USA. [Rivkin, Michael J.; Waber, Deborah; Mulkern, Robert; Vajapeyam, Sridhar; Chiverton, Abigail; Davis, Peter; Koo, Julie; Marmor, Jacki; Mrakotsky, Christine; Robertson, Richard; McAnulty, Gloria] Childrens Hosp Boston, Boston, MA USA. [Brandt, Michael E.; Fletcher, Jack M.; Kramer, Larry A.; Yang, Grace; McCormack, Cara; Hebert, Kathleen M.; Volero, Hilda] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77225 USA. [Botteron, Kelly; Almli, C. Robert; Rainey, Cheryl; Henderson, Stan; Nishino, Tomoyuki; Warren, William; Edwards, Jennifer L.; Dubois, Diane; Smith, Karla; Singer, Tish; Wilber, Aaron A.] Washington Univ, Clin Coordinating Ctr, St Louis, MO 63130 USA. [O'Neill, Joseph; McCracken, James T.; Alger, Jeffry R.; Levitt, Jennifer] Univ Calif Los Angeles, Spect Proc Ctr, Los Angeles, CA 90024 USA. [Wang, Dah-Jyuu; Moss, Edward; Zimmerman, Robert A.; Bintliff, Brooke; Bradford, Ruth; Newman, Janice] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Evans, Alan C.; Arnaoutelis, Rozalia; Pike, G. Bruce; Collins, D. Louis; Leonard, Gabriel; Paus, Tomas; Zijdenbos, Alex; Das, Samir; Fonov, Vladimir; Fu, Luke; Harlap, Jonathan; Leppert, Ilana; Milovan, Denise; Vins, Dario] McGill Univ, Data Coordinating Ctr, Montreal, PQ H3A 2T5, Canada. [Zeffiro, Thomas; Van Meter, John] Georgetown Univ, Washington, DC 20057 USA. [Lange, Nicholas] Harvard Univ, McLean Hosp, Cambridge, MA 02138 USA. [Pierpaoli, Carlo; Basser, Peter J.; Chang, Lin-Ching; Walker, Lindsay] NIH, Diffus Tensor Proc Ctr, Bethesda, MD 20892 USA. RP Ball, WS (reprint author), McLean Hosp, Neurostat Lab, 115 Mill St, Belmont, MA 02478 USA. EM nlange@hms.harvard.edu RI Basser, Peter/H-5477-2011; Pike, Bruce/K-5562-2014; OI Pike, Bruce/0000-0001-8924-683X; Freund, Lisa/0000-0003-2095-4023; Gwinn, Katrina/0000-0002-8277-651X FU National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke [N01-HD02-3343, N01-MH9-0002, N01-NS-9-2314, -2315, -2316, -2317, -2319, -2320, NS34783] FX This project was supported with Federal funds from the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (Contract #s N01-HD02-3343; N01-MH9-0002; N01-NS-9-2314, -2315, -2316, -2317, -2319, and -2320; and NS34783). NR 63 TC 101 Z9 102 U1 3 U2 26 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JAN PY 2012 VL 22 IS 1 BP 1 EP 12 DI 10.1093/cercor/bhr018 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 863TI UT WOS:000298190500001 ER PT J AU Palmore, TN Henderson, DK AF Palmore, Tara N. Henderson, David K. TI Big Brother is Washing. Video Surveillance for Hand Hygiene Adherence, Through the Lenses of Efficacy and Privacy SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID NOSOCOMIAL INFECTIONS; CARE; PROGRAM; DEVICE C1 [Palmore, Tara N.; Henderson, David K.] NIH, Off Deputy Director Clin Care, Ctr Clin, Bethesda, MD 20892 USA. [Palmore, Tara N.; Henderson, David K.] NIH, Hosp Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Off Deputy Director Clin Care, Ctr Clin, Bldg 10,Room 6-1480,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 12 TC 4 Z9 5 U1 0 U2 3 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 JAN 1 PY 2012 VL 54 IS 1 BP 8 EP 9 DI 10.1093/cid/cir781 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 866LX UT WOS:000298383500004 PM 22109949 ER PT J AU Bennett, J AF Bennett, John TI Companion Drugs for Amphotericin B in Cryptococcal Meningitis: Flucytosine, Fluconazole, or ... Nothing? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material C1 NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bennett, J (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Bldg 10,Rm 11C304, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov FU Intramural NIH HHS NR 7 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 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 1 PY 2012 VL 54 IS 1 BP 129 EP 130 DI 10.1093/cid/cir758 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 866LX UT WOS:000298383500025 PM 22052886 ER PT J AU Martin, S Calabrese, SK Wolters, PL Walker, KA Warren, K Hazra, R AF Martin, Staci Calabrese, Sarah K. Wolters, Pamela L. Walker, Katherine A. Warren, Katherine Hazra, Rohan TI Family Functioning and Coping Styles in Families of Children With Cancer and HIV Disease SO CLINICAL PEDIATRICS LA English DT Article DE family functioning; coping; social support; cancer; HIV disease ID PSYCHOLOGICAL ADJUSTMENT; ASSESSMENT DEVICE; CHILDHOOD-CANCER; SOCIAL SUPPORT; HIV/AIDS; STIGMA; STRESS; ADOLESCENTS; STRATEGIES; ILLNESS AB Disease-specific characteristics of pediatric illnesses may influence the functioning of families and the coping responses they enact. This study compared family functioning and coping styles within and between 2 different medical groups: families of children with cancer (n = 44) and HIV disease (n = 65). Most caregivers reported healthy family functioning, and no between-group differences in functioning emerged. However, with regard to coping, more reliance on social support was indicated among the cancer group. Also, the HIV group largely sought support from family, whereas both family and nonfamily support were sought among the cancer group. Better functioning was related to reframing, an active coping style, within the cancer group and passive coping within the HIV group. Thus, coping strategies and their implications for family functioning vary by condition. Researchers should avoid combining various illness groups indiscriminately. Likewise, clinicians should be sensitive to disease-specific factors when helping families learn to cope with illness-related stressors. C1 [Martin, Staci] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Calabrese, Sarah K.] George Washington Univ, Washington, DC USA. [Walker, Katherine A.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Martin, S (reprint author), NCI, Pediat Oncol Branch, 9030 Old Georgetown Rd, Bethesda, MD 20892 USA. EM martins@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Medical Illness Counseling Center [HHSN261200477004C]; SAIC-Frederick, Inc. [HHSN261200800001E]; National Institute of Mental Health [F31-MH085584] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, as well as Federal Contracts HHSN261200477004C with the Medical Illness Counseling Center and HHSN261200800001E with SAIC-Frederick, Inc. Sarah K. Calabrese was supported by Grant Number F31-MH085584 from the National Institute of Mental Health. NR 32 TC 4 Z9 5 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD JAN PY 2012 VL 51 IS 1 BP 58 EP 64 DI 10.1177/0009922811417300 PG 7 WC Pediatrics SC Pediatrics GA 870GC UT WOS:000298656200008 PM 21868594 ER PT J AU Carson, SS Vu, M Danis, M Camhi, SL Scheunemann, LP Cox, CE Hanson, LC Nelson, JE AF Carson, Shannon S. Vu, Maihan Danis, Marion Camhi, Sharon L. Scheunemann, Leslie P. Cox, Christopher E. Hanson, Laura C. Nelson, Judith E. TI Development and validation of a printed information brochure for families of chronically critically ill patients SO CRITICAL CARE MEDICINE LA English DT Article DE communication; critically ill; information sharing; mechanical ventilation; tracheostomies; validation studies ID INTENSIVE-CARE-UNIT; PROLONGED MECHANICAL VENTILATION; CHRONIC CRITICAL ILLNESS; DECISION-MAKING; HEALTH; COMMUNICATION; DEPRESSION; RELATIVES; ANXIETY; MEMBERS AB Objective: Families and other surrogate decisionmakers for chronically critically ill patients often lack information about patient prognosis or options for care. This study describes an approach to develop and validate a printed information brochure about chronic critical illness aimed at improving comprehension of the disease process and outcomes for patients' families and other surrogate decisionmakers. Design: Investigators reviewed existing literature to identify key domains of informational needs. Content of these domains was incorporated in a draft brochure that included graphics and a glossary of terms. Clinical sensibility, balance, and emotional sensitivity of the draft brochure were tested in a series of evaluations by cohorts of experienced clinicians (n = 49) and clinical content experts (n = 8) with revisions after each review. Subjects: Cognitive testing of the brochure was performed through interviews of ten representative family members of chronically critically ill patients with quantitative and qualitative analysis of responses. Measurements and Main Results: Clinical sensibility and balance were rated in the two most favorable categories on a five-point scale by more than two thirds of clinicians and content experts. After review, family members described the brochure as clear and readable and recommended that the brochure be delivered to family members by clinicians followed by a discussion of its contents. They indicated that the glossary was useful and recommended supplementation by additional lists of local resources. After reading the brochure, their prognostic estimates became more consistent with actual outcomes. Conclusions: We have developed and validated a printed information brochure that may improve family comprehension of chronic critical illness and its outcomes. The structured process that is described can serve as a template for the development of other information aids for use with seriously ill populations. (Crit Care Med 2012; 40:73-78) C1 [Carson, Shannon S.; Scheunemann, Leslie P.; Hanson, Laura C.] Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA. [Vu, Maihan] Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. [Danis, Marion] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Camhi, Sharon L.] Univ Pittsburgh, Pittsburgh, PA USA. [Camhi, Sharon L.] Pittsburgh VA Healthcare Syst, Pittsburgh, PA USA. [Cox, Christopher E.] Duke Univ, Dept Med, Durham, NC USA. [Nelson, Judith E.] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Carson, SS (reprint author), Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA. EM scarson@med.unc.edu FU Department of Bioethics, National Institutes of Health Clinical Center FX This work was funded by the Department of Bioethics, National Institutes of Health Clinical Center. The views expressed here are those of the authors and do not necessarily reflect the policies of the US Department of Health and Human Services or the National Institutes of Health. NR 23 TC 14 Z9 15 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 73 EP 78 DI 10.1097/CCM.0b013e31822d7901 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800011 PM 21926610 ER PT J AU Berra, L Coppadoro, A Bittner, EA Kolobow, T Laquerriere, P Pohlmann, JR Bramati, S Moss, J Pesenti, A AF Berra, Lorenzo Coppadoro, Andrea Bittner, Edward A. Kolobow, Theodor Laquerriere, Patrice Pohlmann, Joshua R. Bramati, Simone Moss, Joel Pesenti, Antonio TI A clinical assessment of the Mucus Shaver: A device to keep the endotracheal tube free from secretions SO CRITICAL CARE MEDICINE LA English DT Article DE bacterial biofilm; endotracheal tube; endotracheal tube occlusion; endotracheal tube suctioning; mechanical ventilation; Mucus Shaver; secretion removal; ventilator-associated pneumonia ID VENTILATOR-ASSOCIATED PNEUMONIA; PSEUDOMONAS-AERUGINOSA BIOFILMS; MECHANICAL VENTILATION; BACTERIAL-COLONIZATION; TRACHEAL TUBE; INTUBATION; PREVENTION; RESISTANCE; INFECTION; DIAMETER AB Objective: We evaluated a new device designed to clean the endotracheal tube in mechanically ventilated patients, the Mucus Shaver. Design: Prospective, randomized trial. Setting: University hospital intensive care unit. Patients: We enrolled 24 patients expected to remain ventilated for >72 hrs. Interventions: The Mucus Shaver is a concentric inflatable catheter for the removal of mucus and secretions from the interior surface of the endotracheal tube. The Mucus Shaver is advanced to the distal endotracheal tube tip, inflated, and subsequently withdrawn over a period of 3-5 secs. Patients were prospectively randomized within 2 hrs of intubation to receive standard endotracheal tube suctioning treatment or standard suctioning plus Mucus Shaver use until extubation. Measurements and Main Results: During the study period, demographic data, recent medical history, adverse events, and staff evaluation of the Mucus Shaver were recorded. At extubation, each endotracheal tube was removed, cultured, and analyzed by scanning electron microscopy. Twelve patients were assigned to the study group and 12 were assigned to the control group. No adverse events related to the use of the Mucus Shaver were observed. At extubation, only one endotracheal tube from the Mucus Shaver group was colonized, whereas in the control group ten endotracheal tubes were colonized (8% vs. 83%; p < .001). Scanning electron microscopy showed little secretions on the endotracheal tubes from the study group, whereas thick bacterial deposits were present on all the endotracheal tubes from the control group (p < .001 by Fisher exact test, using a maximum biofilm thickness of 30 mu m as cut-off). The nursing staff was satisfied by the overall safety, feasibility, and efficacy of the Mucus Shaver. Conclusions: The Mucus Shaver is a safe, feasible, and efficient device for endotracheal tube cleaning in the clinical setting. The Mucus Shaver is helpful in preventing endotracheal tube colonization by potentially harmful microorganisms. (Crit Care Med 2012; 40:119-124) C1 [Berra, Lorenzo; Coppadoro, Andrea; Bittner, Edward A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. [Coppadoro, Andrea; Pesenti, Antonio] Univ Milano Bicocca, Dept Expt Med, Milan, Italy. [Kolobow, Theodor] NHLBI, Sect Pulm & Cardiac Assist Devices, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. [Laquerriere, Patrice] Univ Reims, INSERM, Electron Microscopy Lab, Reims, France. [Pohlmann, Joshua R.] Univ Michigan, Dept Gen Surg, Ann Arbor, MI 48109 USA. [Bramati, Simone] San Gerardo Hosp, Microbiol & Virol Dept, Monza, Italy. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Pesenti, Antonio] San Gerardo Hosp, Dept Perioperat Med & Intens Care, Monza, Italy. RP Berra, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. EM lberra@partners.org RI Pesenti, Antonio/H-7483-2012; Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 FU National Heart, Lung, and Blood Institute, Division of International Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; Department of Perioperative Medicine and Intensive Care, San Gerardo Hospital, Monza, Italy; National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Maryland FX Supported, in part, by the National Heart, Lung, and Blood Institute, Division of International Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, and by the Department of Perioperative Medicine and Intensive Care, San Gerardo Hospital, Monza, Italy. Dr. Moss and Dr. Kolobow were supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 30 TC 37 Z9 38 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 119 EP 124 DI 10.1097/CCM.0b013e31822e9fe3 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800017 PM 21926595 ER PT J AU Hicks, CW Sweeney, DA Danner, RL Eichacker, PQ Suffredini, AF Feng, J Sun, JF Behrend, EN Solomon, SB Natanson, C AF Hicks, Caitlin W. Sweeney, Daniel A. Danner, Robert L. Eichacker, Peter Q. Suffredini, Anthony F. Feng, Jing Sun, Junfeng Behrend, Ellen N. Solomon, Steven B. Natanson, Charles TI Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock SO CRITICAL CARE MEDICINE LA English DT Article DE animal; corticosteroids; infection; models; sepsis ID HYPERRENINEMIC HYPOALDOSTERONISM; SEVERE SEPSIS; CRITICALLY-ILL; UNITED-STATES; ALDOSTERONE; CORTICOSTEROIDS; HYDROCORTISONE; METAANALYSIS; MECHANISMS; RECEPTOR AB Objective: Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. Design, Setting, Subjects, and Interventions: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia. Measurements and Main Results: Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p <= .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p <= .05), consistent with adrenal suppression. Conclusions: In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes. (Crit Care Med 2012; 40:199-207) C1 [Hicks, Caitlin W.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Hicks, Caitlin W.] Natl Inst Hlth Res Scholar, Howard Hughes Med Inst, Bethesda, MD USA. [Hicks, Caitlin W.; Danner, Robert L.; Eichacker, Peter Q.; Suffredini, Anthony F.; Feng, Jing; Sun, Junfeng; Solomon, Steven B.; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Sweeney, Daniel A.] Washington Hosp, Med Intensivist Program, Fremont, CA USA. [Behrend, Ellen N.] Auburn Univ, Coll Vet Med, Dept Clin Sci, Auburn, AL 36849 USA. RP Hicks, CW (reprint author), Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. EM hicksc@ccf.org RI Hicks, Caitlin/E-8849-2012; OI Hicks, Caitlin/0000-0001-7638-1936 FU National Institutes of Health; Howard Hughes Medical Institute FX This study was funded, in part, by the National Institutes of Health and the Howard Hughes Medical Institute. All work pertaining to this manuscript was performed at the National Institutes of Health (NIH). The study was supported by NIH intramural funds but the opinions expressed herein do not necessarily represent the opinions of the US Government. NR 41 TC 12 Z9 13 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 199 EP 207 DI 10.1097/CCM.0b013e31822efa14 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800029 PM 21926575 ER PT J AU Gormley, NJ Bronstein, AC Rasimas, JJ Pao, M Wratney, AT Sun, JF Austin, HA Suffredini, AF AF Gormley, Nicole J. Bronstein, Alvin C. Rasimas, Joseph J. Pao, Maryland Wratney, Angela T. Sun, Junfeng Austin, Howard A. Suffredini, Anthony F. TI The rising incidence of intentional ingestion of ethanol-containing hand sanitizers SO CRITICAL CARE MEDICINE LA English DT Article DE alcohol poisoning; ethanol hand sanitizer; hand sanitizer ingestion; NPDS ID HOSPITALIZED PATIENT; ALCOHOL; INTOXICATION; ISOPROPANOL; HYGIENE AB Objective: To describe a case of intentional ingestion of hand sanitizer in our hospital and to review published cases and those reported to the American Association of Poison Control Centers' National Poison Data System. Design: A case report, a literature review of published cases, and a query of the National Poison Data System. Setting: Medical intensive care unit. Patient: Seventeen-yr-old male 37-kg with an intentional ingestion of a hand sanitizer product into his gastrostomy tube. Interventions: Intubation, ventilation, and hemodialysis. Measurements and Main Results: Incidence and outcome of reported cases of unintentional and intentional ethanol containing-hand sanitizer ingestion in the United States from 2005 through 2009. A literature search found 14 detailed case reports of intentional alcohol-based hand sanitizer ingestions with one death. From 2005 to 2009, the National Poison Data System received reports of 68,712 exposures to 96 ethanol-based hand sanitizers. The number of new cases increased by an average of 1,894 (95% confidence interval [CI] 1266-2521) cases per year (p = .002). In 2005, the rate of exposures, per year, per million U. S. residents was 33.7 (95% CI 28.4-39.1); from 2005 to 2009, this rate increased on average by 5.87 per year (95% CI 3.70-8.04; p = .003). In 2005, the rate of intentional exposures, per year, per million U. S. residents, was 0.68 (95% CI 0.17-1.20); from 2005 to 2009, this rate increased on average by 0.32 per year (95% CI 0.11-0.53; p = .02). Conclusions: The number of new cases per year of intentional hand sanitizer ingestion significantly increased during this 5-yr period. Although the majority of cases of hand sanitizer ingestion have a favorable outcome, 288 moderate and 12 major medical outcomes were reported in this National Poison Data System cohort. Increased awareness of the risks associated with intentional ingestion is warranted, particularly among healthcare providers caring for persons with a history of substance abuse, risk-taking behavior, or suicidal ideation. (Crit Care Med 2012; 40: 290-294) C1 [Gormley, Nicole J.; Sun, Junfeng; Suffredini, Anthony F.] NCI, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Bronstein, Alvin C.] Univ Colorado, Sch Med, Rocky Mt Poison Ctr, Denver, CO USA. [Rasimas, Joseph J.; Pao, Maryland] NIMH, Bethesda, MD 20892 USA. [Wratney, Angela T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Austin, Howard A.] NIDDK, Bethesda, MD USA. RP Gormley, NJ (reprint author), NCI, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. EM asuffredini@cc.nih.gov FU Clinical Center, National Institutes of Health (NIH); National Institute of Mental Health; National Institute of Diabetes and Digestive and Kidney Diseases, at the NIH, Bethesda, MD; American Association of Poison Control Centers' National Poison Data System, Rocky Mountain Poison Center, Denver, CO FX This study was supported by the Intramural Research Programs of the Clinical Center, National Institutes of Health (NIH), the National Institute of Mental Health, and the National Institute of Diabetes and Digestive and Kidney Diseases, at the NIH, Bethesda, MD, and the American Association of Poison Control Centers' National Poison Data System, Rocky Mountain Poison Center, Denver, CO. These organizations provided material support for design and conduct of the study; collection, management, analysis of the data; and preparation of the manuscript. NR 23 TC 8 Z9 8 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 290 EP 294 DI 10.1097/CCM.0b013e31822f09c0 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800043 PM 21926580 ER PT J AU Han, SH Sevransky, J AF Han, Seung-Hye Sevransky, Jonathan TI Another "negative" acute lung injury trial SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE acute lung injury; acute respiratory distress syndrome; clinical trials; sepsis ID TIDAL VOLUME VENTILATION; STRATEGIES; ABSENCE C1 [Han, Seung-Hye] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Sevransky, Jonathan] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. RP Han, SH (reprint author), NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 315 EP 316 DI 10.1097/CCM.0b013e318232d307 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800056 PM 22179356 ER PT J AU Carlson, DE AF Carlson, Drew E. TI Are you having a good day: A passing nicety or a fundamental question in the intensive care unit? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE circadian; clock genes; critical illness; diurnal; sepsis; trauma ID CIRCADIAN-RHYTHM; GENE-EXPRESSION; CLOCK; SEPSIS; SLEEP; TIME C1 NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Carlson, DE (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 15 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 344 EP 345 DI 10.1097/CCM.0b013e318232d2e0 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800075 PM 22179375 ER PT J AU Danis, M AF Danis, Marion TI Thorny questions on the way to disclosing rationing SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE disclosure; intensive care; public opinion; rationing; resource allocation; triage ID INTENSIVE-CARE; BEDSIDE; TRIAGE; MORTALITY; ADMISSION C1 Natl Inst Hlth Clin Ctr, Dept Bioeth, Bethesda, MD 20892 USA. RP Danis, M (reprint author), Natl Inst Hlth Clin Ctr, Dept Bioeth, Bethesda, MD 20892 USA. NR 13 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JAN PY 2012 VL 40 IS 1 BP 347 EP 348 DI 10.1097/CCM.0b013e31823291ea PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 866KO UT WOS:000298379800077 PM 22179377 ER PT J AU Ramanathan, HN Ye, YH AF Ramanathan, Harish N. Ye, Yihong TI Cellular strategies for making monoubiquitin signals SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Ubiquitin; monoubiquitination; ubiquitin conjugating enzymes/E2; histone; coupled monoubiquitination; ubiquitin-like proteins; ubiquitin chain; endocytosis ID UBIQUITIN-CONJUGATING ENZYME; HISTONE H2B MONOUBIQUITINATION; ATP-DEPENDENT PROTEOLYSIS; CRYSTAL-STRUCTURE; CHAIN FORMATION; DNA-REPAIR; SACCHAROMYCES-CEREVISIAE; MOLECULAR-MECHANISMS; POLYUBIQUITIN CHAINS; FUNCTIONAL DIVERSITY AB Post-translational modification of proteins with ubiquitin regulates a variety of eukaryotic cellular processes. Ubiquitin can be conjugated to substrates either as a single moiety (monoubiquitination) or as isopeptide bond-linked chains (polyubiquitination), creating an array of ubiquitin signals. It has been established that monoubiquitination can serve important functions in many biological processes such as the regulation of gene transcription, protein trafficking, and DNA repair. Surprisingly, little is known about the mechanisms by which monoubiquitin signals are produced in the cell. Here, we discuss the potential cellular strategies for generating monoubiquitinated proteins using a few, relatively well characterized examples of monoubiquitinated proteins. These strategies include coupling ubiquitination to low affinity ubiquitin binding, using monoubiquitination-dedicated E2 conjugating enzymes, and restricting ubiquitin chain elongation. Some of these principles may be applicable to protein modifications involving ubiquitin like proteins (UBLs), which often occur in monomeric form. C1 [Ramanathan, Harish N.; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov RI RAMANATHAN, HARISH/B-1274-2013 OI RAMANATHAN, HARISH/0000-0001-6073-2981 FU NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX The authors declare no competing financial interests. The authors' research is supported by the NIH intramural AIDS Targeted Antiviral Program (IATAP) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 94 TC 22 Z9 22 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD JAN PY 2012 VL 47 IS 1 BP 17 EP 28 DI 10.3109/10409238.2011.620943 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863TA UT WOS:000298189700002 PM 21981143 ER PT J AU Wang, PY Zhuang, J Hwang, PM AF Wang, Ping-yuan Zhuang, Jie Hwang, Paul M. TI p53: exercise capacity and metabolism SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE aerobic exercise; cancer; metabolism; mitochondria; p53 ID TUMOR-SUPPRESSOR P53; ACTIVATED PROTEIN-KINASE; HUMAN SKELETAL-MUSCLE; AXIS IN-VIVO; MITOCHONDRIAL RESPIRATION; PHYSICAL-ACTIVITY; DNA-DAMAGE; P53-INDUCIBLE REGULATOR; ANTIOXIDANT FUNCTION; ENDURANCE EXERCISE AB Purpose of review There is an inverse relationship between cancer incidence and cardiorespiratory fitness in large population studies. Mechanistic insights into these observations may strengthen the rationale for encouraging exercise fitness in the clinics for cancer prevention and may promote the development of new preventive strategies. Recent findings Studying the multifaceted activities of p53, a critical tumor suppressor gene, has revealed various cellular pathways necessary for adapting to environmental stresses. Genetic connections are being made between p53 and an increasing number of metabolic activities such as oxidative phosphorylation, glycolysis and fatty acid oxidation. In-vivo mouse models show that p53 plays an important role in determining both basal aerobic exercise capacity and its improvement by training. Summary The genetic pathways by which p53 regulates metabolism and exercise may help explain significant epidemiologic observations connecting cardiorespiratory fitness and cancer. Further understanding of these molecular pathways through human translational studies may promote the development of new cancer preventive strategies. C1 [Wang, Ping-yuan; Zhuang, Jie; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10 CRC,Rm 5-5330, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU National Heart, Lung and Blood Institute (NHLBI) FX This work was supported by the intramural program of National Heart, Lung and Blood Institute (NHLBI). NR 82 TC 16 Z9 16 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JAN PY 2012 VL 24 IS 1 BP 76 EP 82 DI 10.1097/CCO.0b013e32834de1d8 PG 7 WC Oncology SC Oncology GA 863GO UT WOS:000298151000013 PM 22123233 ER PT J AU Merikangas, KR Lamers, F AF Merikangas, Kathleen R. Lamers, Femke TI The 'true' prevalence of bipolar II disorder SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE bipolar II disorder; epidemiology; hypomania ID COMORBIDITY SURVEY REPLICATION; MAJOR DEPRESSIVE DISORDER; SUBTHRESHOLD BIPOLARITY; MENTAL-DISORDERS; SPECTRUM; EPISODES; METAANALYSIS; HYPOMANIA; ADULTS; MANIA AB Purpose of review Many studies - including meta-analyses - do not distinguish between bipolar I and II disorder. The aim of this study is to review the recent literature on the prevalence, correlates, consequences, and treatment patterns of bipolar II disorder. Recent findings In the past 2 years, several important studies have been conducted in the bipolar II field. The World Mental Health Survey initiative provides us with prevalence rate across 11 countries, while several meta-analyses on suicide and neurocognition directly compared bipolar I with bipolar II, informing us on the severe consequences of bipolar II disorder. Results from studies showed that the lifetime prevalence rate of bipolar II disorder in adults across 11 countries was 0.4%. Rates of bipolar II disorder in prospective studies of adolescents are substantially greater, with lifetime rates approaching 3-4%. Summary Evidence from these studies regarding comparable clinical consequences, patterns of comorbidity, suicide attempts, family history, and treatment patterns to bipolar I disorder document the validity of the bipolar II subtype. C1 [Merikangas, Kathleen R.; Lamers, Femke] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM Kathleen.Merikangas@nih.gov RI Lamers, Femke/G-5161-2012 FU National Institute of Mental Health [1Z011Z01MH002870]; Netherlands Organization for Scientific Research (NWO) FX This study was funded by an intramural grant (1Z011Z01MH002870) from the National Institute of Mental Health. F.L. is supported by a Rubicon fellowship from the Netherlands Organization for Scientific Research (NWO). The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US Government. NR 31 TC 20 Z9 23 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD JAN PY 2012 VL 25 IS 1 BP 19 EP 23 DI 10.1097/YCO.0b013e32834de3de PG 5 WC Psychiatry SC Psychiatry GA 863CS UT WOS:000298141000004 PM 22156934 ER PT J AU Rebustini, IT Hayashi, T Reynolds, AD Dillard, ML Carpenter, EM Hoffman, MP AF Rebustini, Ivan T. Hayashi, Toru Reynolds, Andrew D. Dillard, Melvin L. Carpenter, Ellen M. Hoffman, Matthew P. TI miR-200c regulates FGFR-dependent epithelial proliferation via Vldlr during submandibular gland branching morphogenesis SO DEVELOPMENT LA English DT Article DE miR-200c; Vldlr; Salivary gland; Mouse ID DENSITY LIPOPROTEIN RECEPTOR; EMBRYONIC STEM-CELLS; TO-MESENCHYMAL TRANSITION; BREAST-CANCER CELLS; MICRORNA EXPRESSION; DOWN-REGULATION; E-CADHERIN; PROSTATE-CANCER; GENE-EXPRESSION; SALIVARY-GLAND AB The regulation of epithelial proliferation during organ morphogenesis is crucial for normal development, as dysregulation is associated with tumor formation. Non-coding microRNAs (miRNAs), such as miR-200c, are post-transcriptional regulators of genes involved in cancer. However, the role of miR-200c during normal development is unknown. We screened miRNAs expressed in the mouse developing submandibular gland (SMG) and found that miR-200c accumulates in the epithelial end buds. Using both loss- and gain-of-function, we demonstrated that miR-200c reduces epithelial proliferation during SMG morphogenesis. To identify the mechanism, we predicted miR-200c target genes and confirmed their expression during SMG development. We discovered that miR-200c targets the very low density lipoprotein receptor (Vldlr) and its ligand reelin, which unexpectedly regulate FGFR-dependent epithelial proliferation. Thus, we demonstrate that miR-200c influences FGFR-mediated epithelial proliferation during branching morphogenesis via a Vldlr-dependent mechanism. miR-200c and Vldlr may be novel targets for controlling epithelial morphogenesis during glandular repair or regeneration. C1 [Rebustini, Ivan T.; Hayashi, Toru; Reynolds, Andrew D.; Dillard, Melvin L.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Carpenter, Ellen M.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Hoffman, MP (reprint author), Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov FU National Institute of Dental and Craniofacial Research at the National Institutes of Health FX The study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research at the National Institutes of Health. Deposited in PMC for release after 12 months. NR 124 TC 25 Z9 28 U1 1 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JAN 1 PY 2012 VL 139 IS 1 BP 191 EP 202 DI 10.1242/dev.070151 PG 12 WC Developmental Biology SC Developmental Biology GA 864OJ UT WOS:000298249200018 PM 22115756 ER PT J AU Brody, T Yavatkar, AS Kuzin, A Kundu, M Tyson, LJ Ross, J Lin, TY Lee, CH Awasaki, T Lee, T Odenwald, WF AF Brody, Thomas Yavatkar, Amarendra S. Kuzin, Alexander Kundu, Mukta Tyson, Leonard J. Ross, Jermaine Lin, Tzu-Yang Lee, Chi-Hon Awasaki, Takeshi Lee, Tzumin Odenwald, Ward F. TI Use of a Drosophila genome-wide conserved sequence database to identify functionally related cis-regulatory enhancers SO DEVELOPMENTAL DYNAMICS LA English DT Article DE cis-regulatory enhancers; conserved sequence clusters (CSCs); Drosophila melanogaster ID SPLIT COMPLEX GENES; TRANSCRIPTION FACTOR; DNA-BINDING; DEVELOPMENTAL ENHANCERS; NERVOUS-SYSTEM; POU-DOMAIN; ELEMENT; CNS; IDENTIFICATION; SUPPRESSOR AB Background: Phylogenetic footprinting has revealed that cis-regulatory enhancers consist of conserved DNA sequence clusters (CSCs). Currently, there is no systematic approach for enhancer discovery and analysis that takes full-advantage of the sequence information within enhancer CSCs. Results: We have generated a Drosophila genome-wide database of conserved DNA consisting of >100,000 CSCs derived from EvoPrints spanning over 90% of the genome. cis-Decoder database search and alignment algorithms enable the discovery of functionally related enhancers. The program first identifies conserved repeat elements within an input enhancer and then searches the database for CSCs that score highly against the input CSC. Scoring is based on shared repeats as well as uniquely shared matches, and includes measures of the balance of shared elements, a diagnostic that has proven to be useful in predicting cis-regulatory function. To demonstrate the utility of these tools, a temporally-restricted CNS neuroblast enhancer was used to identify other functionally related enhancers and analyze their structural organization. Conclusions: cis-Decoder reveals that co-regulating enhancers consist of combinations of overlapping shared sequence elements, providing insights into the mode of integration of multiple regulating transcription factors. The database and accompanying algorithms should prove useful in the discovery and analysis of enhancers involved in any developmental process. Developmental Dynamics 241:169189, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Brody, Thomas; Kuzin, Alexander; Kundu, Mukta; Ross, Jermaine; Odenwald, Ward F.] NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD 20892 USA. [Yavatkar, Amarendra S.; Tyson, Leonard J.] NIH, Div Intramural Res, Informat Technol Program, Bethesda, MD 20892 USA. [Lin, Tzu-Yang; Lee, Chi-Hon] NICHD, Sect Neuronal Connect, NIH, Bethesda, MD USA. [Awasaki, Takeshi; Lee, Tzumin] HHMI, Ashburn, VA USA. RP Brody, T (reprint author), NINDS, Neural Cell Fate Determinants Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM brodyt@ninds.nih.gov; ward@codon.nih.gov RI Lee, Chi-Hon/G-9190-2012; Lin, Tzu-Yang/D-8300-2013 FU NIH, NINDS FX Grant sponsor: Intramural Research Program of the NIH, NINDS. NR 64 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JAN PY 2012 VL 241 IS 1 SI SI BP 169 EP 189 DI 10.1002/dvdy.22728 PG 21 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 862MW UT WOS:000298097100015 PM 22174086 ER PT J AU Vijayakumar, A Wu, YJ Sun, H Li, XS Jeddy, Z Liu, CY Schwartz, GJ Yakar, S LeRoith, D AF Vijayakumar, Archana Wu, YingJie Sun, Hui Li, Xiaosong Jeddy, Zuha Liu, Chengyu Schwartz, Gary J. Yakar, Shoshana LeRoith, Derek TI Targeted Loss of GHR Signaling in Mouse Skeletal Muscle Protects Against High-Fat Diet Induced Metabolic Deterioration SO DIABETES LA English DT Article ID GROWTH-HORMONE; ADIPOSE-TISSUE; IN-VIVO; BODY-COMPOSITION; INSULIN; MICE; GLUCOSE; EXPRESSION; TRANSCRIPTION; ACTIVATION AB Growth hormone (GH) exerts diverse tissue-specific metabolic effects that are not revealed by global alteration of GH action. To study the direct metabolic effects of GH in the muscle, we specifically inactivated the growth hormone receptor (ghr) gene in postnatal mouse skeletal muscle using the Cre/loxP system (mGHRKO model). The metabolic state of the mGHRKO mice was characterized under lean and obese states. High-fat diet feeding in the niGHRKO mice was associated with reduced adiposity, improved insulin sensitivity, lower systemic inflammation, decreased muscle and hepatic triglyceride content, and greater energy expenditure compared with control mice. The obese mGHRKO mice also had an increased respiratory exchange ratio, suggesting increased carbohydrate utilization. GH-regulated suppressor of cytokine signaling-2 (socs2) expression was decreased in obese mGHRKO mice. Interestingly, muscles of both lean and obese mGHRKO mice demonstrated a higher interleukin-15 and lower myostatin expression relative to controls, indicating a possible mechanism whereby GHR signaling in muscle could affect liver and adipose tissue function. Thus, our study implicates skeletal muscle GHR signaling in mediating insulin resistance in obesity and, more importantly, reveals a novel role of muscle GHR signaling in facilitating cross-talk between muscle and other metabolic tissues. Diabetes 61:94-103, 2012 C1 [Vijayakumar, Archana; Wu, YingJie; Sun, Hui; Jeddy, Zuha; Yakar, Shoshana; LeRoith, Derek] Mt Sinai Sch Med, Dept Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Li, Xiaosong; Schwartz, Gary J.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Li, Xiaosong; Schwartz, Gary J.] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, NIH, Bethesda, MD USA. RP LeRoith, D (reprint author), Mt Sinai Sch Med, Dept Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. EM sy1007@nyu.edu; derek.leroith@mssm.edu FU National Institutes of Health NIH [DK-20541] FX X.L. and G.J.S. are supported by the NIH DK-20541 grant from the National Institutes of Health. NR 46 TC 34 Z9 35 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JAN PY 2012 VL 61 IS 1 BP 94 EP 103 DI 10.2337/db11-0814 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 871XZ UT WOS:000298772300013 PM 22187377 ER PT J AU Thearle, MS Muller, YL Hanson, RL Mullins, M AbdusSamad, M Tran, J Knowler, WC Bogardus, C Krakoff, J Baier, LJ AF Thearle, Marie S. Muller, Yunhua L. Hanson, Robert L. Mullins, Meghan AbdusSamad, Maryam Tran, John Knowler, William C. Bogardus, Clifton Krakoff, Jonathan Baier, Leslie J. TI Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians SO DIABETES LA English DT Article ID GENE-MUTATIONS; OBESE CHILDREN; MORBID-OBESITY; PREVALENCE; ASSOCIATION; POPULATION; VARIANTS; MELLITUS; SPECTRUM; COHORT AB Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5-20 years) and adulthood (ages 20-45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood. Diabetes 61:250-257, 2012 C1 [Thearle, Marie S.; Muller, Yunhua L.; Hanson, Robert L.; Mullins, Meghan; AbdusSamad, Maryam; Tran, John; Knowler, William C.; Bogardus, Clifton; Krakoff, Jonathan; Baier, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Thearle, MS (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM thearlem@mail.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 36 TC 14 Z9 14 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JAN PY 2012 VL 61 IS 1 BP 250 EP 257 DI 10.2337/db11-0708 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 871XZ UT WOS:000298772300029 PM 22106157 ER PT J AU Turkbey, B Bernardo, M Merino, MJ Wood, BJ Pinto, PA Choyke, PL AF Tuerkbey, Baris Bernardo, Marcelino Merino, Maria J. Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. TI MRI of localized prostate cancer: coming of age in the PSA era SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Review DE prostate cancer; magnetic resonance imaging; prostate specific antigen ID APPARENT DIFFUSION-COEFFICIENT; RADICAL RETROPUBIC PROSTATECTOMY; BEAM RADIATION-THERAPY; CONTRAST-ENHANCED MRI; ACTIVE SURVEILLANCE; ENDORECTAL MR; TRANSITION ZONE; 3 T; RECURRENCE; BIOPSY AB Prostate cancer is the most common cancer among American men. It varies widely in aggressiveness, ranging from completely indolent to highly aggressive. Currently, predicting the natural history of a particular tumor and deciding on the appropriate treatment, which might include active surveillance, surgery, radiation or hormonal therapies, are based on the condition and age of the patient as well as the presumed stage of the disease. Imaging plays an important role in staging localized prostate cancer. Magnetic resonance imaging (MRI) best depicts the zonal anatomy, with a superior soft tissue resolution providing better results for tumor localization, monitoring, and local staging. Previously, the major function of prostate MRI has been in staging, and this role remains important. In this article, we introduce the reader to the expanding roles that MRI plays in the management of localized prostate cancer. C1 [Tuerkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM bturkbey@yahoo.com NR 66 TC 20 Z9 22 U1 0 U2 6 PU TURKISH SOC RADIOLOGY PI ANKARA PA HOSDERE CAD, GUZELKENT SOK, CANKAYA EVLERI, F-2, ANKARA, 06540, TURKEY SN 1305-3825 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD JAN-FEB PY 2012 VL 18 IS 1 BP 34 EP 45 DI 10.4261/1305-3825.DIR.4478-11.1 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 872RZ UT WOS:000298828300005 PM 21922459 ER PT J AU Turkbey, B Aras, O Karabulut, N Turgut, AT Akpinar, E Alibek, S Pang, YX Erturk, SM El Khouli, RH Bluemke, DA Choyke, PL AF Turkbey, Baris Aras, Omer Karabulut, Nevzat Turgut, Ahmet Tuncay Akpinar, Erhan Alibek, Sedat Pang, Yuxi Erturk, Sukru Mehmet El Khouli, Riham H. Bluemke, David A. Choyke, Peter L. TI Diffusion-weighted MRI for detecting and monitoring cancer: a review of current applications in body imaging SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Review DE cancer; diffusion weighted magnetic resonance imaging; body applications ID UTERINE CERVICAL-CANCER; POSITRON-EMISSION-TOMOGRAPHY; URINARY-BLADDER CARCINOMA; MALIGNANT HEPATIC-LESIONS; ADVANCED BREAST-CANCER; CONTRAST-ENHANCED MRI; CELL LUNG-CANCER; PROSTATE-CANCER; LYMPH-NODES; NEOADJUVANT CHEMOTHERAPY AB Diffusion-weighted magnetic resonance imaging (MRI), Which involves the acquisition of a magnetic resonance signal related to the Brownian motion of water protons in tissue, has become a useful technique for assessing tumors. In this article, we review the basic concepts, imaging strategies, and body applications of diffusion-weighted MRI in detecting and monitoring cancer. C1 [Turkbey, Baris; Aras, Omer; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Karabulut, Nevzat] Pamukkale Univ, Sch Med, Dept Radiol, Denizli, Turkey. [Turgut, Ahmet Tuncay] Ankara Training & Educ Hosp, Dept Radiol, Ankara, Turkey. [Akpinar, Erhan] Hacettepe Univ, Fac Med, Dept Radiol, TR-06100 Ankara, Turkey. [Alibek, Sedat] Univ Erlangen Nurnberg, Inst Radiol, Erlangen, Germany. [Pang, Yuxi] Philips Healthcare, Cleveland, OH USA. [Erturk, Sukru Mehmet] Istanbul Sisli Etfal Training & Res Hosp, Dept Radiol, Istanbul, Turkey. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM bturkbey@yahoo.com RI KARABULUT, Nevzat/A-8010-2014; OI KARABULUT, Nevzat/0000-0002-0822-0281; Bluemke, David/0000-0002-8323-8086 NR 141 TC 28 Z9 31 U1 1 U2 25 PU TURKISH SOC RADIOLOGY PI ANKARA PA HOSDERE CAD, GUZELKENT SOK, CANKAYA EVLERI, F-2, ANKARA, 06540, TURKEY SN 1305-3825 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD JAN-FEB PY 2012 VL 18 IS 1 BP 46 EP 59 DI 10.4261/1305-3825.DIR.4708-11.2 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 872RZ UT WOS:000298828300006 PM 21928189 ER PT J AU Lam, TTY Ip, HS Ghedin, E Wentworth, DE Halpin, RA Stockwell, TB Spiro, DJ Dusek, RJ Bortner, JB Hoskins, J Bales, BD Yparraguirre, DR Holmes, EC AF Lam, Tommy Tsan-Yuk Ip, Hon S. Ghedin, Elodie Wentworth, David E. Halpin, Rebecca A. Stockwell, Timothy B. Spiro, David J. Dusek, Robert J. Bortner, James B. Hoskins, Jenny Bales, Bradley D. Yparraguirre, Dan R. Holmes, Edward C. TI Migratory flyway and geographical distance are barriers to the gene flow of influenza virus among North American birds SO ECOLOGY LETTERS LA English DT Article DE Avian influenza; ecological barriers; evolution; flyways; gene flow; phylogeography; spatial distance ID PATHOGENIC AVIAN INFLUENZA; WILD BIRDS; A VIRUSES; H5N1; EVOLUTION; PHYLOGENIES; WATERFOWL; PATTERNS; PARAMYXOVIRUSES; TRANSMISSION AB Despite the importance of migratory birds in the ecology and evolution of avian influenza virus (AIV), there is a lack of information on the patterns of AIV spread at the intra-continental scale. We applied a variety of statistical phylogeographic techniques to a plethora of viral genome sequence data to determine the strength, pattern and determinants of gene flow in AIV sampled from wild birds in North America. These analyses revealed a clear isolation-by-distance of AIV among sampling localities. In addition, we show that phylogeographic models incorporating information on the avian flyway of sampling proved a better fit to the observed sequence data than those specifying homogeneous or random rates of gene flow among localities. In sum, these data strongly suggest that the intra-continental spread of AIV by migratory birds is subject to major ecological barriers, including spatial distance and avian flyway. C1 [Lam, Tommy Tsan-Yuk; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Ip, Hon S.; Dusek, Robert J.] US Geol Survey, Natl Wildlife Hlth Ctr, Madison, WI 53711 USA. [Ghedin, Elodie] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA. [Ghedin, Elodie; Halpin, Rebecca A.; Stockwell, Timothy B.; Spiro, David J.] J Craig Venter Inst, Rockville, MD 20850 USA. [Wentworth, David E.] NYSDOH, Wadsworth Ctr, Albany, NY 12201 USA. [Bortner, James B.; Hoskins, Jenny] US Fish & Wildlife Serv, Portland, OR 97232 USA. [Dusek, Robert J.; Bales, Bradley D.] Oregon Dept Fish & Wildlife, Salem, OR 97303 USA. [Yparraguirre, Dan R.] Calif Dept Fish & Game, Sacramento, CA 95814 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu RI Lam, Tommy Tsan-Yuk/D-4837-2012; OI Wentworth, David/0000-0002-5190-980X; Dusek, Robert/0000-0001-6177-7479; Holmes, Edward/0000-0001-9596-3552 FU National Institutes of Health [R01 GM080533]; US Department of the Interior; US Fish and Wildlife Service; US Geological Survey, Biological Resources Discipline; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C] FX This research was funded in part by grant R01 GM080533 from the National Institutes of Health, by the US Department of the Interior and US Fish and Wildlife Service's Avian Health Program, and by the US Geological Survey, Biological Resources Discipline. We thank the US Fish and Wildlife Service, as well as State and Tribal agencies. It was also in part funded with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract numbers HHSN272200900007C. The samples from the PF were collected under the 'Surveillance for Early detection of Highly Pathogenic Avian Influenza H5N1 in Wild Migratory Birds: a Strategy for the Pacific Flyway' Pacific Flyway Council, 2006. We thank the field personnel who sampled birds throughout the flyway, and gratefully acknowledge the contributions of many biologists who have sequenced the influenza genomes published in GenBank. We also thank members of the Diagnostic Virology Laboratory at the National Wildlife Health Center, especially Katy Griffin, Jessica Montez, Samantha Scott and Kim Kooiman. Additional bioinformatic and computational resources were provided by the Computer Centre at The University of Hong Kong (HKU) and TWGrid in Taiwan. We also thank W. K. Kwan and Frankie Cheung (HKU) for technical support. Any use of trade, product, or firm names is for descriptive purposes only and does not imply endorsement by the US government. NR 46 TC 43 Z9 44 U1 2 U2 23 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1461-023X J9 ECOL LETT JI Ecol. Lett. PD JAN PY 2012 VL 15 IS 1 BP 24 EP 33 DI 10.1111/j.1461-0248.2011.01703.x PG 10 WC Ecology SC Environmental Sciences & Ecology GA 856KC UT WOS:000297637800004 PM 22008513 ER PT J AU Chowell, G Viboud, C Simonsen, L Miller, MA Acuna-Soto, R Diaz, JMO Martinez-Martin, AF AF Chowell, Gerardo Viboud, Cecile Simonsen, Lone Miller, Mark A. Acuna-Soto, Rodolfo Ospina Diaz, Juan M. Fernando Martinez-Martin, Abel TI The 1918-19 Influenza Pandemic in Boyaca, Colombia SO EMERGING INFECTIOUS DISEASES LA English DT Article ID SPANISH INFLUENZA; REPRODUCTION NUMBER; MORTALITY IMPACT; H1N1 INFLUENZA; TRANSMISSIBILITY; WAVE; CIRCULATION; EPIDEMICS; PATTERNS; CITY AB To quantify age-specific excess-mortality rates and transmissibility patterns for the 1918-20 influenza pandemic in Boyaca, Colombia, we reviewed archival mortality records. We identified a severe pandemic wave during October 1918-January1919 associated with 40 excess deaths per 10,000 population. The age profile for excess deaths was W shaped; highest mortality rates were among infants (<5 y of age), followed by elderly persons (>= 60 y) and young adults (25-29 y). Mean reproduction number was estimated at 1.4-1.7, assuming 3- or 4-day generation intervals. Boyaca, unlike cities in Europe, the United States, or Mexico, experienced neither a herald pandemic wave of deaths early in 1918 nor a recrudescent wave in 1920. In agreement with reports from Mexico, our study found no death-sparing effect for elderly persons in Colombia. We found regional disparities in prior immunity and timing of introduction of the 1918 pandemic virus across populations. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85282 USA. [Chowell, Gerardo] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Washington, DC USA. [Acuna-Soto, Rodolfo] Univ Nacl Autonoma Mexico, Delegacion Coyoacan, Mexico. [Ospina Diaz, Juan M.; Fernando Martinez-Martin, Abel] Univ Pedag & Tecnol Colombia, Boyaca, Colombia. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Box 872402, Tempe, AZ 85282 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Martinez Martin, Abel Fernando/0000-0002-4621-6072; Simonsen, Lone/0000-0003-1535-8526 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center; Office of Global Affairs, International Influenza Unit, in the Office of the Secretary of the Department of Health and Human Services FX This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study, which is an ongoing international collaborative effort for understanding influenza epidemiological and evolutionary patterns, and which is led by the Fogarty International Center, National Institutes of Health (www.origem.info/misms/index.php). Funding for this project comes in part (to L.S.) from the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, and from the Office of Global Affairs, International Influenza Unit, in the Office of the Secretary of the Department of Health and Human Services. NR 40 TC 10 Z9 10 U1 2 U2 7 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JAN PY 2012 VL 18 IS 1 BP 48 EP 56 DI 10.3201/eid1801.101969 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 874QK UT WOS:000298973000007 PM 22257780 ER PT J AU Liu, Y Poon, V Sanchez-Watts, G Watts, AG Takemori, H Aguilera, G AF Liu, Ying Poon, Victoria Sanchez-Watts, Graciela Watts, Alan G. Takemori, Hiroshi Aguilera, Greti TI Salt-Inducible Kinase Is Involved in the Regulation of Corticotropin-Releasing Hormone Transcription in Hypothalamic Neurons in Rats SO ENDOCRINOLOGY LA English DT Article ID MEDIATED GENE-EXPRESSION; BINDING PROTEIN-ACTIVITY; PARAVENTRICULAR NUCLEUS; CEREBROSPINAL-FLUID; RESPONSIVE ELEMENT; CREB ACTIVITY; SIK; CORTICOSTERONE; STAUROSPORINE; ACTIVATION AB Activation of CRH transcription requires phosphorylation of cAMP response element-binding protein (CREB) and translocation of the CREB coactivator, transducer of regulated CREB activity (TORC) from cytoplasm to nucleus. In basal conditions, transcription is low because TORC remains in the cytoplasm, inactivated by phosphorylation through Ser/Thr protein kinases of the AMP-dependent protein kinases (AMPK) family, including salt-inducible kinase (SIK). To determine which kinase is responsible for TORC phosphorylation in CRH neurons, we measured SIK1 and SIK2 mRNA in the hypothalamic paraventricular nucleus of rats by in situ hybridization. In basal conditions, low mRNA levels of the two kinases were found in the dorsomedial paraventricular nucleus, consistent with location in CRH neurons. One hour of restraint stress increased SIK1 mRNA levels, whereas SIK2 mRNA showed only minor increases. In 4B hypothalamic neurons, or primary cultures, SIK1 mRNA (but not SIK2 mRNA) was inducible by the cAMP stimulator, forskolin. Overexpression of either SIK1 or SIK2 in 4B cells reduced nuclear TORC2 levels (Western blot) and inhibited forskolin-stimulated CRH transcription (luciferase assay). Conversely, the nonselective SIK inhibitor, staurosporine, increased nuclear TORC2 content and stimulated CRH transcription in 4Bcells and primary neuronal cultures (heteronuclear RNA). Unexpectedly, in 4B cells specific short hairpin RNA knockdown of endogenous SIK2 but not SIK1 induced nuclear translocation of TORC2 and CRH transcription, suggesting that SIK2 mediates TORC inactivation in basal conditions, whereas induction of SIK1 limits transcriptional activation. The study provides evidence that SIK represses CRH transcription by inactivating TORC, providing a potential mechanism for rapid on/off control of CRH transcription. (Endocrinology 153: 223-233, 2012) C1 [Aguilera, Greti] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH,Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Sanchez-Watts, Graciela; Watts, Alan G.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Takemori, Hiroshi] Natl Inst Biomed Innovat, Lab Cell Signaling & Metab Dis, Osaka 5670085, Japan. RP Aguilera, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH,Program Dev Endocrinol & Genet, Bldg 10,CRC,Room 1E-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM greti_aguilera@nih.gov FU National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke [NS029728] FX This work was supported by the Intramural Research Program of the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (to G. A.), and the National Institute of Neurological Disorders and Stroke Grant NS029728 (to A.G.W.). NR 36 TC 23 Z9 25 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JAN PY 2012 VL 153 IS 1 BP 223 EP 233 DI 10.1210/en.2011-1404 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 869XC UT WOS:000298631500021 PM 22109884 ER PT J AU VanderWeele, TJ Mumford, SL Schisterman, EF AF VanderWeele, Tyler J. Mumford, Sunni L. Schisterman, Enrique F. TI Conditioning on Intermediates in Perinatal Epidemiology SO EPIDEMIOLOGY LA English DT Article ID BIRTH-WEIGHT PARADOX; INFANT-MORTALITY; PRINCIPAL STRATIFICATION; SENSITIVITY-ANALYSIS; PLACENTAL ABRUPTION; MEDIATION ANALYSIS; CEREBRAL-PALSY; PRETERM BIRTH; UNITED-STATES; BIAS AB It is common practice in perinatal epidemiology to calculate gestational-age-specific or birth-weight-specific associations between an exposure and a perinatal outcome. Gestational age or birth weight, for example, might lie on a pathway from the exposure to the outcome. This practice of conditioning on a potential intermediate has come under critique for various reasons. First, if one is interested in assessing the overall effect of an exposure on an outcome, it is not necessary to stratify, and indeed, it is important not to stratify, on an intermediate. Second, if one does condition on an intermediate, to try to obtain what might conceived of as a "direct effect" of the exposure on the outcome, then various biases and paradoxical results can arise. It is now well documented theoretically and empirically that, when there is an unmeasured common cause of the intermediate and the outcome, associations adjusted for the intermediate are subject to bias. In this paper, we propose 3 approaches to facilitate valid inference when effects conditional on an intermediate are in view. These 3 approaches correspond to (i) conditioning on the predicted risk of the intermediate, (ii) conditioning on the intermediate itself in conjunction with sensitivity analysis, and (iii) conditioning on the subgroup of individuals for whom the intermediate would occur irrespective of the exposure received. The second and third approaches both require sensitivity analysis, and they result in a range of estimates. Each of the 3 approaches can be used to resolve the "birth-weight paradox" that exposures such as maternal smoking seem to have a protective effect among low-birth-weight infants. The various methodologic approaches described in this paper are applicable to a number of similar settings in perinatal epidemiology. C1 [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. RP VanderWeele, TJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM tvanderw@hsph.harvard.edu OI Schisterman, Enrique/0000-0003-3757-641X FU National Institutes of Health [HD060696]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Supported by National Institutes of Health grant HD060696 (to T.J.V.) and Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (to S. L. M. and E. F. S.). The authors reported no other financial interests related to this research. NR 42 TC 63 Z9 63 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2012 VL 23 IS 1 BP 1 EP 9 DI 10.1097/EDE.0b013e31823aca5d PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 863IU UT WOS:000298156800001 PM 22157298 ER PT J AU VanderWeele, TJ Mumford, SL Schisterman, EF AF VanderWeele, Tyler J. Mumford, Sunni L. Schisterman, Enrique F. TI Choosing Effect Measures "If I Only Had a ... " SO EPIDEMIOLOGY LA English DT Editorial Material ID BIRTH-WEIGHT PARADOX C1 [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. RP VanderWeele, TJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM tvanderw@hsph.harvard.edu NR 7 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2012 VL 23 IS 1 BP 13 EP 14 DI 10.1097/EDE.0b013e31823b6990 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 863IU UT WOS:000298156800003 ER PT J AU Alonso, WJ Acuna-Soto, R Giglio, R Nuckols, J Leyk, S Schuck-Paim, C Viboud, C Miller, MA McCormick, BJJ AF Alonso, W. J. Acuna-Soto, R. Giglio, R. Nuckols, J. Leyk, S. Schuck-Paim, C. Viboud, C. Miller, M. A. McCormick, B. J. J. TI Spatio-temporal patterns of diarrhoeal mortality in Mexico SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Climate; diarrhoea; Mexico; mortality; seasonality ID ROTAVIRUS ACTIVITY; UNITED-STATES; ENTERIC DISEASES; TEMPORAL TRENDS; RISK-FACTORS; CHILDREN; BACTERIAL; VIETNAM; IMPACT; BRAZIL AB Diarrhoeal mortality rates in Mexican children dramatically declined during the 1980s and 1990s, concomitant with a temporal shift in peak deaths from summer to autumn-winter. The spatial dynamics of these patterns have not previously been studied. We first describe the seasonal features of paediatric diarrhoeal mortality in Mexico as a whole, then across individual states. While no geographical gradients in the magnitude of diarrhoeal mortality rates have been detected in recent years, we identified a distinct spatial pattern in the timing of peak mortality rate. In the 1980s the summer peak mortality was earliest around Mexico's capital and later in states to the southeast and northwest. Our results suggest that the direction and timing of those annual waves are related to the mean monthly precipitation and mean daily temperature. This pattern has disintegrated in recent years as the summer peak has diminished. C1 [Alonso, W. J.; Nuckols, J.; Leyk, S.; Viboud, C.; Miller, M. A.; McCormick, B. J. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Acuna-Soto, R.] Univ Nacl Autonoma Mexico, Sch Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico. [Giglio, R.] Univ Fed Santa Catarina, Dept Econ, BR-88040900 Florianopolis, SC, Brazil. [Leyk, S.] Univ Colorado, Dept Geog, Boulder, CO 80309 USA. RP McCormick, BJJ (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM ben.mccormick@nih.gov FU Bill and Melinda Gates Foundation; Fogarty International Center of the National Institutes of Health as part of the Mal-ED network FX We thank Dr Jaime Sepulveda and Dr Rafael Solano for kindly providing the mortality data and Dr Laura J. Ninger and Christine Jessup or their useful comments on the manuscript. This study was funded by the Bill and Melinda Gates Foundation and the Fogarty International Center of the National Institutes of Health as part of the Mal-ED network. NR 33 TC 7 Z9 7 U1 0 U2 11 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD JAN PY 2012 VL 140 IS 1 BP 91 EP 99 DI 10.1017/S0950268811000562 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 868TC UT WOS:000298547400012 PM 21489339 ER PT J AU Kim, I Kim, YJ Metais, JY Dunbar, CE Larochelle, A AF Kim, Inho Kim, Yoo-Jin Metais, Jean-Yves Dunbar, Cynthia E. Larochelle, Andre TI Transient silencing of PTEN in human CD34(+) cells enhances their proliferative potential and ability to engraft immunodeficient mice SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; MARROW REPOPULATING CELLS; GENE-TRANSFER; SELF-RENEWAL; CYCLE ENTRY; TRANSDUCTION; VECTORS AB The ability to expand hematopoietic stem and progenitor cells (HSPCs) in vitro will enhance the success of a wide range of transplant-related therapies. PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been implicated as a regulator of murine HSPC self-renewal, but little is understood about the role of PTEN in human HSPC regulation. We tested the impact of transient small interfering RNA (siRNA) induced inhibition of PTEN expression in human CD34(+) cells on their cell cycle profile, their susceptibility to retroviral transduction, and their ability to self-renew and repopulate nonobese diabetic/severe combined immunodeficiency disease with interleukin-2 receptor gamma-chain deficiency mice. Reduced PTEN messenger RNA and protein levels were confirmed in PTEN siRNA-treated CD34(+) cells compared with control siRNA-treated CD34(+) cells. Transient silencing of PTEN in CD34(+) cells promoted their entry into cell cycle, and increased their expansion in vitro compared with control siRNA-treated CD34(+) cells. When these cells were transduced with retroviral vectors, transduction efficiencies in the bulk CD34(+) cells transfected with PTEN siRNA were significantly higher compared with CD34(+) cells transfected with a control siRNA. Transient PTEN suppression in CD34(+) cells also increased their proliferation and engraftment potential in nonobese diabetic/severe combined immunodeficiency disease with interleukin-2 receptor gamma-chain deficiency mice, and maintained their multilineage differentiation capacity in vivo. No mice developed myeloproliferative disorders or leukemias. Similar to findings with murine HSPC, PTEN may also promote quiescence of human HSPC. With optimization of technologies for transfer of siRNA in primary CD34(+) cells, this approach may facilitate investigations into the mechanisms underlying HSPC self-renewal, and could find clinical applications in gene therapy protocols. Published by Elsevier Inc. on behalf of the ISEH - Society for Hematology and Stem Cells. C1 [Dunbar, Cynthia E.] NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH, Room 4E-5132,10 Ctr Dr, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI Kim, In Ho/J-5428-2012 FU National Heart, Lunch, and Blood Institute of the National Institutes of Health FX We thank Dr. David Stroncek and the Department of Transfusion Medicine staff for the apheresis and CD34+ cell selection from healthy donors. The gammaretrovirus vectors used in this study, MND.MFG.YFP c10 were a gift from Dr. Hans-Peter Kiem. We are also grateful to Keyvan Keyvanfar from the Hematology Branch flow facility for his assistance with flow sorting and analysis. This work was supported by the intramural research programs of the National Heart, Lunch, and Blood Institute (C.E.D.) of the National Institutes of Health. NR 18 TC 11 Z9 11 U1 1 U2 8 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 JAN PY 2012 VL 40 IS 1 BP 84 EP 91 DI 10.1016/j.exphem.2011.10.001 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 865VG UT WOS:000298338400008 PM 22019626 ER PT J AU Goldstein, AL Hannappel, E Sosne, G Kleinman, HK AF Goldstein, Allan L. Hannappel, Ewald Sosne, Gabriel Kleinman, Hynda K. TI Thymosin beta(4): a multi-functional regenerative peptide. Basic properties and clinical applications SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE apoptosis; inflammation; migration; regeneration; scar formation; stem cells; thymosin beta(4); tissue repair ID CORNEAL EPITHELIAL-CELLS; DEOXYNUCLEOTIDYL TRANSFERASE-ACTIVITY; ASPARTYL-LYSYL-PROLINE; IN-VITRO; INFLAMMATORY MEDIATORS; MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; SYNTHETIC PEPTIDE; GENE-EXPRESSION; CARDIAC REPAIR AB Introduction: Thymosin beta(4), a low molecular weight, naturally-occurring peptide plays a vital role in the repair and regeneration of injured cells and tissues. After injury, thymosin beta(4), is released by platelets, macrophages and many other cell types to protect cells and tissues from further damage and reduce apoptosis, inflammation and microbial growth. Thymosin beta(4) binds to actin and promotes cell migration, including the mobilization, migration, and differentiation of stem/progenitor cells, which form new blood vessels and regenerate the tissue. Thymosin beta(4) also decreases the number of myofibroblasts in wounds, resulting in decreased scar formation and fibrosis Areas covered: This article will cover the many thymosin beta(4) activities that directly affect the repair and regeneration cascade with emphasis on its therapeutic uses and potential. Our approach has been to evaluate the basic biology of the molecule as well as its potential for clinical applications in the skin, eye, heart and brain. Expert opinion: The considerable advances in our understanding of the functional biology and mechanisms of action of thymosin beta(4) have provided the scientific foundation for ongoing and projected clinical trials in the treatment of dermal wounds, corneal injuries and in the regeneration and repair of heart and CNS tissue following ischemic insults and trauma. C1 [Goldstein, Allan L.] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Hannappel, Ewald] Univ Erlangen Nurnberg, D-91054 Erlangen, Germany. [Sosne, Gabriel] Wayne State Univ, Sch Med, Dept Ophthalmol & Anat Cell Biol, Detroit, MI USA. [Kleinman, Hynda K.] NIDCR, NIH, Bethesda, MD 20892 USA. RP Goldstein, AL (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, 2300 I St NW, Washington, DC 20037 USA. EM bcmalg@gwumc.edu FU RegeneRx Biopharmaceuticals, Inc. FX AL Goldstein is founder and Chairman of the Board and Chief Scientific Advisor of RegeneRx Biopharmaceuticals, Inc. and owns shares of stock in the company. HK Kleinman is a paid consultant for RegeneRx Biopharmaceuticals, Inc. and is a member of their Scientific Advisory Board and does not own any stock. G Sosne and E Hannappel are non-paid members of the Scientific Advisory Board of RegeneRx Biopharmaceuticals, Inc. and does not own any stock. NR 97 TC 48 Z9 52 U1 1 U2 22 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 JAN PY 2012 VL 12 IS 1 BP 37 EP 51 DI 10.1517/14712598.2012.634793 PG 15 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 863TK UT WOS:000298190700004 PM 22074294 ER PT J AU Lazarus, LH Okada, Y AF Lazarus, Lawrence H. Okada, Yoshio TI Engineering endomorphin drugs: state of the art SO EXPERT OPINION ON THERAPEUTIC PATENTS LA English DT Review DE agonists; antagonists; endomorphins; opioid receptors; peptide synthesis; rational drug design ID MU-OPIOID RECEPTOR; RANDOMIZED CONTROLLED-TRIALS; BLOOD-BRAIN-BARRIER; SPINAL-CORD; IN-VITRO; MORPHINE-TOLERANCE; ENDOGENOUS LIGANDS; SUBSTANCE-P; ANTINOCICEPTIVE ACTIVITY; PEPTIDES ENDOMORPHIN-1 AB Introduction: Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH2) and -2 (EM-2; H-Tyr-Pro-Phe-Phe-NH2) are primarily considered agonists for the mu-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed mu/delta-opioid properties, suitable for application to health-related topics. While the application of endomorphins as anti-nociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability; formation of MOR antagonists or mixed and dual mu/delta-acting ligands could find considerable therapeutic potential. Areas covered: This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. Expert opinion: Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high-caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction. C1 [Lazarus, Lawrence H.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Okada, Yoshio] Kobe Gakuin Univ, Fac Pharmaceut Sci, Dept Med Chem, Nishi Ku, Kobe, Hyogo 6512180, Japan. RP Lazarus, LH (reprint author), NIEHS, Lab Toxicol & Pharmacol, 111 S TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM lazarus@niehs.nih.gov FU NIH; NIEHS FX The authors appreciate the consistent and professional support of Stephanie Holmgren, MLA, Library Information Services Branch, NIEHS, our numerous former colleagues the world over, Dr. Hiroaki Taguichi, Suzuka University of Medical Science, Mie, Japan, for preparing the scheme on the synthesis of 1,5-enediaol EM-2 analogues, and in part to the Intramural Research Program of the NIH and NIEHS. NR 149 TC 5 Z9 6 U1 2 U2 14 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3776 J9 EXPERT OPIN THER PAT JI Expert Opin. Ther. Patents PD JAN PY 2012 VL 22 IS 1 BP 1 EP 14 DI 10.1517/13543776.2012.646261 PG 14 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 873DD UT WOS:000298860200001 PM 22214283 ER PT J AU Monaco, MCG Major, EO AF Monaco, Maria Chiara G. Major, Eugene O. TI The link between VLA-4 and JC virus reactivation SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Review DE adhesion molecules; CNS; JCV; multiple sclerosis; natalizumab; progressive multifocal leukoencephalopathy; reactivation; treatment; VLA-4 ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RECONSTITUTION INFLAMMATORY SYNDROME; PEDIATRIC MULTIPLE-SCLEROSIS; B-CELL DEPLETION; HEMATOPOIETIC PROGENITOR CELLS; NATALIZUMAB-TREATED PATIENTS; CENTRAL-NERVOUS-SYSTEM; HIV-NEGATIVE PATIENTS; BLOOD-BRAIN-BARRIER; ADVERSE DRUG EVENTS AB Natalizumab represents an effective biological therapy to treat relapsing-remitting forms of multiple sclerosis and Crohn's disease by blocking the migration of inflammatory cells to the brain and gut. Natalizumab, however, is associated with a risk of progressive multifocal leukoencephalopathy (PML) caused by the reactivation of JC virus. The emergence of PML in this setting has moved PML from being a rare disease mostly seen in HIV-infected individuals to become an important cause of complications in patients receiving immunomodulatory treatments. The incidence of PML associated with natalizumab treatment is approximately 1.5:750, but this increases to approximately 1: 100 in patients after 24-36 doses based on available estimates of individuals who have a prior history of immunosuppressive treatment and are antibody positive to JC virus. Natalizumab treatment has raised questions about the pathogenesis of PML but also has provided the opportunity to investigate sites of virus latency and mechanisms of trafficking to the brain. C1 [Monaco, Maria Chiara G.; Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov NR 104 TC 8 Z9 8 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD JAN PY 2012 VL 8 IS 1 BP 63 EP 72 DI 10.1586/ECI.11.85 PG 10 WC Immunology SC Immunology GA 874NO UT WOS:000298965500016 PM 22149341 ER PT J AU Gurumurthy, M Mukherjee, T Dowd, CS Singh, R Niyomrattanakit, P Tay, JA Nayyar, A Lee, YS Cherian, J Boshoff, HI Dick, T Barry, CE Manjunatha, UH AF Gurumurthy, Meera Mukherjee, Tathagata Dowd, Cynthia S. Singh, Ramandeep Niyomrattanakit, Pornwaratt Tay, Jo Ann Nayyar, Amit Lee, Yong Sok Cherian, Joseph Boshoff, Helena I. Dick, Thomas Barry, Clifton E., III Manjunatha, Ujjini H. TI Substrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles SO FEBS JOURNAL LA English DT Article DE F420; mycobacterium; nitroimidazole; PA-824; tuberculosis ID COENZYME F-420; ANTITUBERCULAR ACTIVITY; BOVIS BCG; PA-824; DRUG; METRONIDAZOLE; ANALOGS; IDENTIFICATION; BIOSYNTHESIS; NO AB The bicyclic 4-nitroimidazoles PA-824 and OPC-67683 represent a promising novel class of therapeutics for tuberculosis and are currently in phase II clinical development. Both compounds are pro-drugs that are reductively activated by a deazaflavin (F(420)) dependent nitroreductase (Ddn). Herein we describe the biochemical properties of Ddn including the optimal enzymatic turnover conditions and substrate specificity. The preference of the enzyme for the (S) isomer of PA-824 over the (R) isomer is directed by the presence of a long hydrophobic tail. Nitroimidazo-oxazoles bearing only short alkyl substituents at the C-7 position of the oxazole were reduced by Ddn without any stereochemical preference. However, with bulkier substitutions on the tail of the oxazole, Ddn displayed stereospecificity. Ddn mediated metabolism of PA-824 results in the release of reactive nitrogen species. We have employed a direct chemiluminescence based nitric oxide (NO) detection assay to measure the kinetics of NO production by Ddn. Binding affinity of PA-824 to Ddn was monitored through intrinsic fluorescence quenching of the protein facilitating a turnover-independent assessment of affinity. Our results indicate that (R)-PA-824, despite not being turned over by Ddn, binds to the enzyme with the same affinity as the active (S) isomer. This result, in combination with docking studies in the active site, suggests that the (R) isomer probably has a different binding mode than the (S) with the C-3 of the imidazole ring orienting in a non-productive position with respect to the incoming hydride from F(420). The results presented provide insight into the biochemical mechanism of reduction and elucidate structural features important for understanding substrate binding. C1 [Gurumurthy, Meera; Niyomrattanakit, Pornwaratt; Tay, Jo Ann; Cherian, Joseph; Dick, Thomas; Manjunatha, Ujjini H.] Novartis Inst Trop Dis, Singapore 138670, Singapore. [Mukherjee, Tathagata; Dowd, Cynthia S.; Singh, Ramandeep; Nayyar, Amit; Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Lee, Yong Sok] Ctr Informat Technol, NIH, Ctr Mol Modeling, Bethesda, MD USA. RP Manjunatha, UH (reprint author), Novartis Inst Trop Dis, 10 Biopolis Rd, Singapore 138670, Singapore. EM cbarry@niaid.nih.gov; manjunatha.ujjini@novartis.com RI Barry, III, Clifton/H-3839-2012; Cherian, Joseph/Q-2522-2016 FU Bill and Melinda Gates Foundation; Wellcome Trust [11]; NITD; NIAID; Center for Information Technology FX This work was funded, in part, by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Program 11 to NITD through Imperial College London; by NITD and also in part by the intramural research program of NIAID (to CEB) and through the Center for Information Technology (to YSL). We thank Lacy Daniels for F420-2. The quantum chemical study utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cit.nih.gov). NR 41 TC 25 Z9 26 U1 0 U2 23 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 JAN PY 2012 VL 279 IS 1 BP 113 EP 125 DI 10.1111/j.1742-4658.2011.08404.x PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 862AY UT WOS:000298063400012 PM 22023140 ER PT J AU Patacsil, D Osayi, S Tran, AT Saenz, F Yimer, L Shajahan, AN Gokhale, PC Verma, M Clarke, R Chauhan, SC Kumar, D AF Patacsil, Dorrelyn Osayi, Sylvester Anh Thu Tran Saenz, Francisco Yimer, Lydia Shajahan, Ayesha N. Gokhale, Prafulla C. Verma, Mukesh Clarke, Robert Chauhan, Subhash C. Kumar, Deepak TI Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells SO GENES AND NUTRITION LA English DT Article DE Vitamin E; Vitamin E succinate; Survivin; Pancreatic cancer; Apoptosis ID ALPHA-TOCOPHERYL SUCCINATE; MDA-MB-435 CELLS; TUMOR-GROWTH; EXPRESSION; INDUCTION; PROTEINS; MOLECULE; ANALOGS; BCL-2 AB Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Identifying novel chemotherapeutic and chemopreventive approaches is critical in the prevention and treatment of cancers such as pancreatic cancer. Vitamin E succinate (VES) is a redox-silent analog of the fat-soluble vitamin alpha-tocopherol. In the present study, we explored the antiproliferative action of VES and its effects on inhibitor of apoptosis proteins in pancreatic cancer cells. We show that VES inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. Further, we demonstrate that VES downregulates the expression of survivin and X-linked inhibitor of apoptosis proteins. The apoptosis induced by VES was augmented by siRNA-mediated inhibition of survivin in PANC-1 cells. In summary, our results suggest that VES targets survivin signaling and induces apoptosis in pancreatic cancer cells. C1 [Patacsil, Dorrelyn; Osayi, Sylvester; Anh Thu Tran; Saenz, Francisco; Yimer, Lydia; Kumar, Deepak] Univ Dist Columbia, Canc Res Lab, Dept Biol & Environm Sci, Washington, DC 20008 USA. [Shajahan, Ayesha N.; Gokhale, Prafulla C.; Clarke, Robert; Kumar, Deepak] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Verma, Mukesh] NCI, Methods & Technol Branch, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Chauhan, Subhash C.] Sanford Res Univ S Dakota, Canc Biol Res Ctr, Sioux Falls, SD 57105 USA. RP Kumar, D (reprint author), Univ Dist Columbia, Canc Res Lab, Dept Biol & Environm Sci, Bldg 44,Room 312,4200 Connecticut Ave NW, Washington, DC 20008 USA. EM dkumar@udc.edu RI Clarke, Robert/A-6485-2008; OI Clarke, Robert/0000-0002-9278-0854; Osayi, Sylvester/0000-0001-8863-6975 FU NCI UDC-LCCC [U56]; USDA/UDC Agricultural Experiment Station; MBRS SCORE/SC1; NSF-HBCU-UP FX The studies were conducted using the Tissue Culture and Flow Cytometry and Cell Sorting Shared Resources of the Lombardi Comprehensive Cancer Center. We thank Karen Creswell for providing excellent technical assistance. Pilot funding from NCI UDC-LCCC U56 (DK, RC), USDA/UDC Agricultural Experiment Station (DK), MBRS SCORE/SC1 (DK), NSF-HBCU-UP fellowship (SO, AT, LY). NR 22 TC 8 Z9 9 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1555-8932 J9 GENES NUTR JI Genes Nutr. PD JAN PY 2012 VL 7 IS 1 SI SI BP 83 EP 89 DI 10.1007/s12263-011-0242-x PG 7 WC Genetics & Heredity; Nutrition & Dietetics SC Genetics & Heredity; Nutrition & Dietetics GA 872KQ UT WOS:000298808700010 PM 21842182 ER PT J AU Fagundes, CP Bennett, JM Alfano, CM Glaser, R Povoski, SP Lipari, AM Agnese, DM Yee, LD Carson, WE Farrar, WB Malarkey, WB Chen, M Kiecolt-Glaser, JK AF Fagundes, Christopher P. Bennett, Jeanette M. Alfano, Catherine M. Glaser, Ronald Povoski, Stephen P. Lipari, Adele M. Agnese, Doreen M. Yee, Lisa D. Carson, William E., III Farrar, William B. Malarkey, William B. Chen, Min Kiecolt-Glaser, Janice K. TI Social Support and Socioeconomic Status Interact to Predict Epstein-Barr Virus Latency in Women Awaiting Diagnosis or Newly Diagnosed With Breast Cancer SO HEALTH PSYCHOLOGY LA English DT Article DE socioeconomic status; cellular immunity; cancer survivorship; psychoneuroimmunology; psycho-oncology ID INSOMNIA SEVERITY INDEX; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; HEALTH; VALIDATION; DEPRESSION; STRESS; FAMILY; CYTOMEGALOVIRUS; MORTALITY AB Objective: Both higher socioeconomic status (SES) and supportive personal relationships confer health benefits, including better immune function. This study assessed the joint impact of SES and social support on the expression of a latent herpesvirus, Epstein-Barr virus (EBV), in a group of highly stressed women. Methods: Two-hundred and twenty four women either awaiting further evaluation following an abnormal mammogram or newly diagnosed with breast cancer completed questionnaires and provided blood samples to assess EBV viral capsid antigen (VCA) IgG antibody titers. Results: More highly educated women with more support from friends had lower EBV VCA antibody titers, reflecting a stronger cellular immune response to the latent virus; however, among less educated women, friend support was not associated with EBV antibody titers. As revealed in an ancillary analysis, more highly educated women with more friend support had lower systolic blood pressure (SBP); however, friend support was not associated with SBP among less educated women. Neither depression nor perceived stress mediated these associations. Neither cancer status nor cancer stage among those diagnosed with cancer was significantly related to these outcomes. Conclusion: Lower SES women may not reap the same immunological benefits from friend support when experiencing a stressful life event as their higher SES counterparts. C1 [Fagundes, Christopher P.] Ohio State Univ, Coll Med, Inst Behav Med Res, Columbus, OH 43210 USA. [Bennett, Jeanette M.] Ohio State Univ, Coll Dent, Columbus, OH 43210 USA. [Alfano, Catherine M.] NCI, Bethesda, MD 20892 USA. RP Fagundes, CP (reprint author), Ohio State Univ, Coll Med, Inst Behav Med Res, 460 Med Ctr Dr, Columbus, OH 43210 USA. EM christopher.fagundes@osumc.edu RI Kiecolt-Glaser, Janice/A-3236-2009; Agnese, Doreen/I-1351-2012; Povoski, Stephen/E-3887-2011; Carson, William/E-2846-2011; Glaser, Ronald/E-3124-2011; OI Kiecolt-Glaser, Janice/0000-0003-4900-9578; Bennett, Jeanette M./0000-0002-8487-9774 FU NIH [CA131029, CA126857, DE014320, UL1RR025755, CA016058]; American Cancer Society [PF-11-007-01-CPPB] FX Work on this project was supported by NIH grants CA131029, CA126857, DE014320, UL1RR025755, and CA016058, and a Postdoctoral Fellowship Grant from the American Cancer Society awarded to the first author PF-11-007-01-CPPB. We appreciate the helpful assistance of Arenda Nolan, Mary Lower, and Cathie Atkinson. NR 58 TC 14 Z9 14 U1 2 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD JAN PY 2012 VL 31 IS 1 BP 11 EP 19 DI 10.1037/a0025599 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA 878MM UT WOS:000299261200003 PM 22004465 ER PT J AU Dillard, AJ Ferrer, RA Ubel, PA Fagerlin, A AF Dillard, Amanda J. Ferrer, Rebecca A. Ubel, Peter A. Fagerlin, Angela TI Risk Perception Measures' Associations With Behavior Intentions, Affect, and Cognition Following Colon Cancer Screening Messages SO HEALTH PSYCHOLOGY LA English DT Article DE feelings-of-risk; comparative risk perceptions; absolute risk perceptions; behavioral intentions; cancer screening ID BREAST-CANCER; COLORECTAL-CANCER; WOMENS PERCEPTIONS; ATTITUDE-CHANGE; COMMUNICATION; ABSOLUTE; SUSCEPTIBILITY; PARTICIPATION; INFORMATION; MAMMOGRAPHY AB Objective: Risk perception is important for motivating health behavior (e. g., Janz & Becker, 1984), but different measures of the construct may change how important that relationship appears. In two studies, we examined associations between four measures of risk perception, health behavior intentions and possible behavioral determinants. Methods: Participants in these studies, who were due for colorectal cancer screening, read an online message about the importance of screening to reduce the chance of cancer. We examined bivariate and multivariate associations between risk perception measures, including absolute, comparative, and feelings-of-risk, and behavioral intentions to screen, general worry, and knowledge and attitudes related to screening. Results: Results across the two studies were consistent, with all risk perception measures being correlated with intentions and attitudes. Multivariate analyses revealed that feelings-of-risk was most predictive of all variables, with the exception of general worry, for which comparative measures were the most predictive. Conclusions: Researchers interested in risk perception should assess feelings-of-risk along with more traditional measures. Those interested in influencing health behavior specifically should attempt to increase feelings of vulnerability rather than numerical risk. C1 [Dillard, Amanda J.] Grand Valley State Univ, Dept Psychol, Allendale, MI 49401 USA. [Ferrer, Rebecca A.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ubel, Peter A.] Duke Univ, Fuqua Sch Business, Durham, NC 27706 USA. [Ubel, Peter A.] Duke Univ, Sanford Sch Publ Policy, Durham, NC 27706 USA. [Fagerlin, Angela] Univ Michigan, Div Gen Internal Med, Ann Arbor, MI 48109 USA. [Fagerlin, Angela] VA Hlth Care Syst, Ann Arbor, MI USA. RP Dillard, AJ (reprint author), Grand Valley State Univ, Dept Psychol, Allendale, MI 49401 USA. EM dillaram@gvsu.edu FU Foundation for Informed Medical Decision Making FX These studies were funded by a George Bennett Postdoctoral grant from the Foundation for Informed Medical Decision Making. We thank Bill Klein for comments on a draft of the manuscript. NR 46 TC 38 Z9 38 U1 8 U2 35 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JAN PY 2012 VL 31 IS 1 BP 106 EP 113 DI 10.1037/a0024787 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA 878MM UT WOS:000299261200015 PM 21806302 ER PT J AU Edlich, B Ahlenstiel, G Azpiroz, AZ Stoltzfus, J Noureddin, M Serti, E Feld, JJ Liang, TJ Rotman, Y Rehermann, B AF Edlich, Birgit Ahlenstiel, Golo Azpiroz, Aintzane Zabaleta Stoltzfus, Jonathan Noureddin, Mazen Serti, Elisavet Feld, Jordan J. Liang, T. Jake Rotman, Yaron Rehermann, Barbara TI Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients SO HEPATOLOGY LA English DT Article ID VIROLOGICAL RESPONSE; VIRUS; RIBAVIRIN; PEGINTERFERON; EXPRESSION; INFECTION; GAMMA; STAT1; HCV AB Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased interferon gamma (IFN-?) production in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is caused by type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-a-based therapy of HCV. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-a-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (tumor necrosis factorapoptosis-inducing ligand [TRAIL] expression and degranulation) and decreased IFN-? production. NK cells from patients with a greater than 2 log10 first-phase HCV RNA decline to IFN-a-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log10 first-phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (P = 0.024), but retained greater IFN-a responsiveness in vitro (P = 0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-a during the second-phase virological response. Conclusion: These data show that IFN-a-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells toward increased cytotoxicity and decreased IFN-? production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-a-based therapy. (Hepatology 2012;55:39-48) C1 [Edlich, Birgit; Ahlenstiel, Golo; Azpiroz, Aintzane Zabaleta; Stoltzfus, Jonathan; Noureddin, Mazen; Serti, Elisavet; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM Rehermann@nih.gov RI Zabaleta, Aintzane/K-8936-2014; OI Rotman, Yaron/0000-0002-7549-8216; Ahlenstiel, Golo/0000-0003-0026-1457 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program. NR 23 TC 56 Z9 58 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JAN PY 2012 VL 55 IS 1 BP 39 EP 48 DI 10.1002/hep.24628 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 867WS UT WOS:000298486100007 PM 21898483 ER PT J AU Lau, JYF Guyer, AE Tone, EB Jenness, J Parrish, JM Pine, DS Nelson, EE AF Lau, Jennifer Y. F. Guyer, Amanda E. Tone, Erin B. Jenness, Jessica Parrish, Jessica M. Pine, Daniel S. Nelson, Eric E. TI Neural responses to peer rejection in anxious adolescents: Contributions from the amygdala-hippocampal complex SO INTERNATIONAL JOURNAL OF BEHAVIORAL DEVELOPMENT LA English DT Article; Proceedings Paper CT 2nd Herzliyah Symposium on Developmental Psychopathology CY JUN 07-10, 2010 CL Sch Psychol, Herzliya, ISRAEL HO Sch Psychol DE adolescence; amygdala; anxiety; peer rejection ID GENERALIZED ANXIETY DISORDER; SOCIAL ANXIETY; PREFRONTAL CORTEX; EMOTIONAL INFORMATION; ANTERIOR CINGULATE; ATTENTIONAL BIAS; CHILDREN; DEPRESSION; COMMON; WORLD AB Peer rejection powerfully predicts adolescent anxiety. While cognitive differences influence anxious responses to social feedback, little is known about neural contributions. Twelve anxious and twelve age-, gender- and IQ-matched, psychiatrically healthy adolescents received "not interested" and "interested" feedback from unknown peers during a chat room task administered in a neuroimaging scanner. No group differences emerged in subjective ratings to peer feedback, but all participants reported more negative emotion at being rejected (than accepted) by peers to whom they had assigned high-desirability ratings. Further highlighting the salience of such feedback, all adolescents, independently of anxiety levels, manifested elevated responses in the amygdala-hippocampal complex bilaterally, during the anticipation of feedback. However, anxious adolescents differed from healthy adolescents in their patterns of persistent amygdala-hippocampal activation following rejection. These data carry interesting implications for using neuroimaging data to inform psychotherapeutic approaches to social anxiety. C1 [Lau, Jennifer Y. F.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Guyer, Amanda E.] Univ Calif, Davis, CA USA. [Tone, Erin B.] Georgia State Univ, Atlanta, GA 30303 USA. [Jenness, Jessica] Univ Denver, Denver, CO 80208 USA. [Parrish, Jessica M.] Catholic Univ, Washington, DC USA. [Pine, Daniel S.; Nelson, Eric E.] NIH, Bethesda, MD USA. RP Lau, JYF (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. EM jennifer.lau@psy.ox.ac.uk OI Nelson, Eric/0000-0002-3376-2453 NR 44 TC 19 Z9 19 U1 5 U2 23 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0165-0254 J9 INT J BEHAV DEV JI Int. J. Behav. Dev. PD JAN PY 2012 VL 36 IS 1 BP 36 EP 44 DI 10.1177/0165025411406854 PG 9 WC Psychology, Developmental SC Psychology GA 863SP UT WOS:000298188500006 ER PT J AU Patel, K Dixit, VD Lee, JH Kim, JW Schaffer, EM Nguyen, D Taub, DD AF Patel, Kalpesh Dixit, Vishwa Deep Lee, Jun Ho Kim, Jie Wan Schaffer, Eric M. Nguyen, Dzung Taub, Dennis D. TI The GHS-R Blocker D-[Lys3] GHRP-6 Serves as CCR5 Chemokine Receptor Antagonist SO INTERNATIONAL JOURNAL OF MEDICAL SCIENCES LA English DT Article DE MIP-1 alpha; MIP-1 beta; RANTES; CCR5; HIV-1; Ghrelin; GHRP-6; GHS-R1a; Inflammation; Cancer ID HIV ENTRY INHIBITORS; SMALL-MOLECULE; GHRELIN; GROWTH; PROGRESS AB [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. This antagonist is one of the most common antagonists utilized in vivo to block GHS-R function and activity. Here, we found that DLS also has the ability to modestly block chemokine function and ligand binding to the chemokine receptor CCR5. The DLS effects on RANTES binding and Erk signaling as well as calcium mobilization appears to be much stronger than its effects on MIP-1 alpha and MIP-1 beta. CCR5 have been shown to act as major co-receptor for HIV-1 entry into the CD4 positive host cells. To this end, we also found that DLS blocks M-tropic HIV-1 propagation in activated human PBMCs. These data demonstrate that DLS may not be a highly selective GHS-R1a inhibitor and may also effects on other G-protein coupled receptor (GPCR) family members. Moreover, DLS may have some potential clinical applications in blocking HIV infectivity and CCR5-mediated migration and function in various inflammatory disease states. C1 [Patel, Kalpesh; Dixit, Vishwa Deep; Lee, Jun Ho; Kim, Jie Wan; Schaffer, Eric M.; Nguyen, Dzung; Taub, Dennis D.] NIA, Lab Mol Biol & Immunol, Intramural Program, NIH, Baltimore, MD 21224 USA. RP Taub, DD (reprint author), NIA, Clin Immunol Sect, Lab Mol Biol & Immunol, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Taubd@grc.nia.nih.gov RI Patel, Kalpesh/G-6685-2012 OI Patel, Kalpesh/0000-0002-2952-6773 FU National Institute on Aging, National Institutes of Health FX We would like to thank Mr. Gary Collins for his assistance in the completion of this work. This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 16 TC 11 Z9 11 U1 0 U2 2 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-1907 J9 INT J MED SCI JI Int. J. Med. Sci. PY 2012 VL 9 IS 1 BP 51 EP 58 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 861IR UT WOS:000298013100009 PM 22211090 ER PT J AU Simone, CB Kramer, K O'Meara, WP Bekelman, JE Belard, A McDonough, J O'Connell, J AF Simone, Charles B., II Kramer, Kevin O'Meara, William P. Bekelman, Justin E. Belard, Arnaud McDonough, James O'Connell, John TI PREDICTED RATES OF SECONDARY MALIGNANCIES FROM PROTON VERSUS PHOTON RADIATION THERAPY FOR STAGE I SEMINOMA SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Seminoma; Secondary malignancies; Proton therapy; Dosimetry; Para-aortic ID TESTICULAR-CANCER; RANDOMIZED-TRIAL; 2ND CANCERS; ADJUVANT TREATMENT; TESTIS CANCER; RADIOTHERAPY; RISK; SURVEILLANCE; MORTALITY; SURVIVORS AB Purpose: Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities. Methods and Material: Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors. Results: Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22-5.01), large bowel (0.81; 95% CI, 0.39-1.01), and bladder (0.03; 95% CI, 0.01-0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, -0.01-0.06). Conclusions: For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined and warrants further study for patients with seminoma, to decrease radiation-induced toxicity. (C) 2012 Elsevier Inc. C1 [Simone, Charles B., II] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Simone, Charles B., II; Bekelman, Justin E.; McDonough, James] Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Kramer, Kevin; Belard, Arnaud] Henry M Jackson Fdn Advancement Mil Med, Rockville, MD USA. [O'Meara, William P.] Natl Naval Med Ctr, Div Radiat Oncol, Bethesda, MD USA. [O'Connell, John] Walter Reed Army Med Ctr, Radiat Oncol Serv, Washington, DC 20307 USA. RP Simone, CB (reprint author), NCI, NIH, Radiat Oncol Branch, Bldg 10 CRC,Room B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM csimone@alumni.upenn.edu FU U.S. Army Medical Research and Materiel Command [DAMD17-W81XWH-04-2-0022] FX This work was supported by U.S. Army Medical Research and Materiel Command under Contract Agreement No. DAMD17-W81XWH-04-2-0022. Views expressed in the manuscript are those of the authors and do not reflect official policies of the U.S. Government or Department of Army, Navy, or Defense. NR 33 TC 17 Z9 17 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JAN PY 2012 VL 82 IS 1 BP 242 EP 249 DI 10.1016/j.ijrobp.2010.11.021 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 868LZ UT WOS:000298526100036 PM 21236595 ER PT J AU Viswanathan, AN Creutzberg, CL Craighead, P McCormack, M Toita, T Narayan, K Reed, N Long, H Kim, HJ Marth, C Lindegaard, JC Cerrotta, A Small, W Trimble, E AF Viswanathan, Akila N. Creutzberg, Carien L. Craighead, Peter McCormack, Mary Toita, Takafumi Narayan, Kailash Reed, Nicholas Long, Harry Kim, Hak-Jae Marth, Christian Lindegaard, Jacob C. Cerrotta, Annmarie Small, William, Jr. Trimble, Edward TI INTERNATIONAL BRACHYTHERAPY PRACTICE PATTERNS: A SURVEY OF THE GYNECOLOGIC CANCER INTERGROUP (GCIG) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Brachytherapy; Cervical cancer; Radiation dose ID HIGH-DOSE-RATE; CERVICAL-CANCER; INTRACAVITARY BRACHYTHERAPY; FRACTIONATION SCHEDULE; RADIOTHERAPY; RECOMMENDATIONS; CARCINOMA; TRIAL AB Purpose: To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), Australia/New Zealand (ANZ), Europe (E), and North America (NAm). Methods and Materials: A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey. Results: A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation [SD] 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4:96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05;p = 0.02 for Asia vs. other regions). The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002). Conclusion: Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials. (C) 2012 Elsevier Inc. C1 [Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Viswanathan, Akila N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Creutzberg, Carien L.] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. [Craighead, Peter] Tom Baker Canc Clin, Calgary, AB, Canada. [McCormack, Mary] Univ Coll London Hosp, Dept Oncol, London, England. [Toita, Takafumi] Univ Ryukyus, Grad Sch Med Sci, Dept Radiol, Okinawa, Japan. [Narayan, Kailash] Univ Melbourne, Peter MacCallum Canc Ctr, Div Radiat Oncol, Melbourne, Vic, Australia. [Narayan, Kailash] Univ Melbourne, Dept Obstet & Gynecol, Melbourne, Vic, Australia. [Reed, Nicholas] Western Infirm & Associated Hosp, Beatson Oncol Ctr, Glasgow G11 6NT, Lanark, Scotland. [Long, Harry] Mayo Clin, Coll Med, Dept Oncol, Div Med Oncol, Rochester, MN USA. [Kim, Hak-Jae] Seoul Natl Univ Hosp, Dept Oncol, Seoul 110744, South Korea. [Marth, Christian] Med Univ Innsbruck, Innsbruck, Austria. [Lindegaard, Jacob C.] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Cerrotta, Annmarie] Fdn IRCCS Ist Nazl Tumori, Dept Radiat Therapy, Milan, Italy. [Small, William, Jr.] Robert H Lurie Comprehens Canc NW Univ, Chicago, IL USA. [Trimble, Edward] NCI, Bethesda, MD 20892 USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu RI Cerrotta, Annamaria/D-8063-2017; OI Cerrotta, Annamaria/0000-0001-7926-3716; Viswanathan, Akila/0000-0002-2003-0392 FU NCI NIH HHS [K07 CA117979] NR 20 TC 59 Z9 60 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JAN PY 2012 VL 82 IS 1 BP 250 EP 255 DI 10.1016/j.ijrobp.2010.10.030 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 868LZ UT WOS:000298526100037 PM 21183288 ER PT J AU Shomaker, LB Tanofsky-Kraff, M Zocca, JM Field, SE Drinkard, B Yanovski, JA AF Shomaker, Lauren B. Tanofsky-Kraff, Marian Zocca, Jaclyn M. Field, Sara E. Drinkard, Bart Yanovski, Jack A. TI Depressive Symptoms and Cardiorespiratory Fitness in Obese Adolescents SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article ID PHYSICAL-ACTIVITY; CHILDREN; CHILDHOOD; METAANALYSIS; EXERCISE; YOUNG; PREVALENCE; OVERWEIGHT; AMERICAN; VALIDITY AB Purpose: Depressive symptoms in adolescents have been associated with reduced physical activity. However, existing studies have relied on questionnaire measures of physical activity, which may not necessarily reflect actual energy expenditures. We sought to evaluate the relationship between depressive symptoms and objectively measured cardiorespiratory fitness among severely obese adolescents. Methods: One hundred thirty-four obese (body mass index [kg/m(2)]: >= 95th percentile) adolescent girls and boys (ages: 12-17 years) reported their depressive symptoms on the Children's Depression Inventory. Adolescents also participated in a maximal cycle ergometry exercise test to measure cardiorespiratory fitness. Body composition was assessed with dual-energy X-ray absorptiometry scanning. Results: Among the 103 adolescents who reached maximal exertion, those with elevated depressive symptoms (16%) displayed poorer cardiorespiratory fitness than those without elevated depressive symptoms (maximal oxygen uptake: 1,873.2 +/- 63.6 vs. 2,012.9 +/- 28.6 mL/min, p < .05). Symptoms of anhedonia also were related to lower fitness levels (p < .05). These effects were observed after accounting for age, sex, race, and lean mass. Conclusions: Among obese adolescents, elevated depressive symptoms are associated with poorer objectively measured cardiorespiratory fitness. Future experimental tests should investigate whether cardiorespiratory fitness acts as a mediator of adolescent depressive symptoms' effect on obesity or obesity-related health comorbidities. Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine. C1 [Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Shomaker, Lauren B.; Tanofsky-Kraff, Marian; Field, Sara E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Drinkard, Bart] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, 10 Ctr Dr,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU NICHD [1F32HD056762, 1ZIAHD000641]; NIMHD; OBSSR FX The present study was supported by National Research Service Award 1F32HD056762 from the NICHD (to L.S.), and Intramural Research Program grant 1ZIAHD000641 from the NICHD with supplemental funding from NIMHD and OBSSR (to J.Y.). NR 40 TC 12 Z9 14 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JAN PY 2012 VL 50 IS 1 BP 87 EP 92 DI 10.1016/j.jadohealth.2011.05.015 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 866HH UT WOS:000298370700013 PM 22188839 ER PT J AU Rao, JS Kellom, M Reese, EA Rapoport, SI Kim, HW AF Rao, Jagadeesh Sridhara Kellom, Matthew Reese, Edmund Arthur Rapoport, Stanley Isaac Kim, Hyung-Wook TI Dysregulated glutamate and dopamine transporters in postmortem frontal cortex from bipolar and schizophrenic patients SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Glutamate transporter; Dopamine reuptake transporter; Schizophrenia; Serotonin transporter ID DORSOLATERAL PREFRONTAL CORTEX; ARACHIDONIC-ACID; NMDA RECEPTOR; SEROTONIN TRANSPORTER; NEURODEGENERATIVE DISEASES; TRANSCRIPTION FACTOR; UNANESTHETIZED RATS; AFFECTIVE-DISORDER; ELDERLY-PATIENTS; GENE-EXPRESSION AB Background: Dysregulated glutamate, serotonin and dopamine neurotransmission has been reported in bipolar disorder (BD) and schizophrenia (SZ), but the underlying mechanisms of dysregulation are not clear. We hypothesized that they involve alterations in excitatory amino acid transporters (EAATs), the serotonin reuptake transporter (SERT), and the dopamine reuptake transporter (DAT). Methods: To test this hypothesis, we determined protein and mRNA levels of EMT subtypes 1-4, of the SERT and of the DAT in postmortem frontal cortex from BD (n = 10) and SZ (n = 10) patients and from healthy control (n = 10) subjects. Results: Compared to control levels, protein and mRNA levels of EAAT1 were increased significantly in cortex from both BD and SZ patients. EAAT2 protein and mRNA levels were decreased significantly in BD but not in SZ cortices. EAAT3 and EAAT 4 protein and mRNA levels were significantly higher in SZ but not in BD compared with control. DAT protein and mRNA levels were decreased significantly in both BD and SZ cortices. There was no significant change in SERT expression in either BD or SZ. Conclusions: The altered EAATs and DAT expression could result in altered glutamatergic and hyperdopaminergic function in BD and SZ. Differently altered EAATs involved in glutamatergic transmission could be therapeutic targets for treating BD and SZ. Published by Elsevier B.V. C1 [Rao, Jagadeesh Sridhara; Kellom, Matthew; Reese, Edmund Arthur; Rapoport, Stanley Isaac; Kim, Hyung-Wook] NIA, BPMS, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, BPMS, NIH, 9000 Rockville Pike,Bldg 9,Rm 1S-126, Bethesda, MD 20892 USA. EM jrao@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health, Bethesda [MD 20892]; PHS [R24MH068855] FX This research was entirely supported by the Intramural Research Programs of the National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.; We thank the Harvard Brain Bank, Boston, MA for providing the postmortem brain samples under PHS grant number R24MH068855. NR 71 TC 58 Z9 59 U1 2 U2 4 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 JAN PY 2012 VL 136 IS 1-2 BP 63 EP 71 DI 10.1016/j.jad.2011.08.017 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 867JW UT WOS:000298451700008 PM 21925739 ER PT J AU Whitehead, GS Wilson, RH Nakano, K Burch, LH Nakano, H Cook, DN AF Whitehead, Gregory S. Wilson, Rhonda H. Nakano, Keiko Burch, Lauranell H. Nakano, Hideki Cook, Donald N. TI IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; airway hyperresponsiveness; airway hyperresponsiveness; IL-17; T(H)17; T(H)2; IL-35; inducible costimulator; ovalbumin ID TH17 CELLS; T(H)17 CELLS; ASTHMA; INFLAMMATION; IL-17; HYPERRESPONSIVENESS; INTERLEUKIN-17; RESPONSES; MICE; CD4 AB Background: Recent evidence suggests that IL-17 contributes to airway hyperresponsiveness (AHR); however, the mechanisms that suppress the production of this cytokine remain poorly defined. Objective: We sought to identify the regulatory cells and molecules that suppress IL-17-dependent allergic airways disease. Methods: Mice were sensitized by means of airway instillations of ovalbumin together with low levels of LPS. Leukocyte recruitment to the lung and AHR were assessed after daily challenges with aerosolized ovalbumin. Flow cytometry, quantitative PCR, and gene-targeted mice were used to identify naturally arising subsets of regulatory T (Treg) cells and their cytokines required for the suppression of established allergic airway disease. Results: Allergic sensitization through the airway primed both effector and regulatory responses. Effector responses were initially dominant and led to airway inflammation and IL-17-dependent AHR. However, after multiple daily allergen challenges, IL-17 production and AHR decreased, even though pulmonary levels of T(H)17 cells remained high. This loss of AHR was reversible and required the expansion of a Treg cell subset expressing both forkhead box protein 3 and inducible costimulator. These Treg cells also expressed the regulatory cytokines IL-10, TGF-beta, and IL-35. Whereas IL-10 and TGF-beta were dispensable for suppression of AHR, IL-35 was required. Conclusion: IL-35 production by inducible costimulator-positive Treg cells can suppress IL-17 production and thereby reverse established, IL-17-dependent AHR in mice. Targeting this pathway might therefore be of therapeutic value for treating allergic asthma in human subjects. (J Allergy Clin Immunol 2012;129:207-15.) C1 [Cook, Donald N.] NIEHS, Lab Resp Biol, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Cook, DN (reprint author), NIEHS, Lab Resp Biol, Div Intramural Res, NIH, 111 TW Alexander Dr,Bldg 101,E244, Res Triangle Pk, NC 27709 USA. EM cookd@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 36 TC 70 Z9 82 U1 2 U2 17 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2012 VL 129 IS 1 BP 207 EP U301 DI 10.1016/j.jaci.2011.08.009 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA 869XT UT WOS:000298634000027 PM 21906794 ER PT J AU Vinella, D Potrykus, K Murphy, H Cashel, M AF Vinella, Daniel Potrykus, Katarzyna Murphy, Helen Cashel, Michael TI Effects on Growth by Changes of the Balance between GreA, GreB, and DksA Suggest Mutual Competition and Functional Redundancy in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID RNA-POLYMERASE; TRANSCRIPTION INITIATION; MOLECULAR-MECHANISM; IN-VIVO; RESISTANCE REGULATOR; ALLOSTERIC CONTROL; SECONDARY CHANNEL; DNA-REPLICATION; PPGPP; PROMOTER AB It is well known that ppGpp and DksA interact with bacterial RNA polymerase (RNAP) to alter promoter activity. This study suggests that GreA plays a major role and GreB plays a minor role in the ppGpp-DksA regulatory network. We present evidence that DksA and GreA/GreB are redundant and/or share similar functions: (i) on minimal medium GreA overproduction suppresses the growth defects of a dksA mutant; (ii) GreA and DksA overexpression partially suppresses the auxotrophy of a ppGpp-deficient strain; (iii) microarrays show that many genes are regulated similarly by GreA and DksA. We also find instances where GreA and DksA seem to act in opposition: (i) complete suppression of auxotrophy occurs by overexpression of GreA or DksA only in the absence of the other protein; (ii) PgadA and PgadE promoter fusions, along with many other genes, are dramatically affected in vivo by GreA overproduction only when DksA is absent; (iii) GreA and DksA show opposite regulation of a subset of genes. Mutations in key acidic residues of GreA and DksA suggest that properties seen here probably are not explained by known biochemical activities of these proteins. Our results indicate that the general pattern of gene expression and, in turn, the ability of Escherichia coli to grow under a defined condition are the result of a complex interplay between GreA, GreB, and DksA that also involves mutual control of their gene expression, competition for RNA polymerase binding, and similar or opposite action on RNA polymerase activity. C1 [Vinella, Daniel; Potrykus, Katarzyna; Murphy, Helen; Cashel, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Vinella, Daniel] CNRS, Chim Bacterienne Lab, Inst Federatif Rech 88, Inst Microbiol Mediterraneee, Marseille, France. RP Cashel, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM mcashel@nih.gov RI vinella, daniel/G-5504-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 54 TC 19 Z9 19 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JAN PY 2012 VL 194 IS 2 BP 261 EP 273 DI 10.1128/JB.06238-11 PG 13 WC Microbiology SC Microbiology GA 870NY UT WOS:000298677400008 PM 22056927 ER PT J AU Gillespie, JJ Joardar, V Williams, KP Driscoll, T Hostetler, JB Nordberg, E Shukla, M Walenz, B Hill, CA Nene, VM Azad, AF Sobral, BW Caler, E AF Gillespie, Joseph J. Joardar, Vinita Williams, Kelly P. Driscoll, Timothy Hostetler, Jessica B. Nordberg, Eric Shukla, Maulik Walenz, Brian Hill, Catherine A. Nene, Vishvanath M. Azad, Abdu F. Sobral, Bruno W. Caler, Elisabet TI A Rickettsia Genome Overrun by Mobile Genetic Elements Provides Insight into the Acquisition of Genes Characteristic of an Obligate Intracellular Lifestyle SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ACTIN-BASED MOTILITY; IV SECRETION SYSTEM; HUMAN GRANULOCYTIC EHRLICHIOSIS; IXODES-RICINUS TICKS; MULTIPLE SEQUENCE ALIGNMENT; BETA-LACTAMASE INDUCTION; BURGDORFERI SENSU-LATO; HOST-CELL INTERACTION; BORRELIA-BURGDORFERI; ESCHERICHIA-COLI AB We present the draft genome for the Rickettsia endosymbiont of Ixodes scapularis (REIS), a symbiont of the deer tick vector of Lyme disease in North America. Among Rickettsia species (Alphaproteobacteria: Rickettsiales), REIS has the largest genome sequenced to date (>2 Mb) and contains 2,309 genes across the chromosome and four plasmids (pREIS1 to pREIS4). The most remarkable finding within the REIS genome is the extraordinary proliferation of mobile genetic elements (MGEs), which contributes to a limited synteny with other Rickettsia genomes. In particular, an integrative conjugative element named RAGE (for Rickettsiales amplified genetic element), previously identified in scrub typhus rickettsiae (Orientia tsutsugamushi) genomes, is present on both the REIS chromosome and plasmids. Unlike the pseudogene-laden RAGEs of O. tsutsugamushi, REIS encodes nine conserved RAGEs that include F-like type IV secretion systems similar to that of the tra genes encoded in the Rickettsia bellii and R. massiliae genomes. An unparalleled abundance of encoded transposases (>650) relative to genome size, together with the RAGEs and other MGEs, comprise similar to 35% of the total genome, making REIS one of the most plastic and repetitive bacterial genomes sequenced to date. We present evidence that conserved rickettsial genes associated with an intracellular lifestyle were acquired via MGEs, especially the RAGE, through a continuum of genomic invasions. Robust phylogeny estimation suggests REIS is ancestral to the virulent spotted fever group of rickettsiae. As REIS is not known to invade vertebrate cells and has no known pathogenic effects on I. scapularis, its genome sequence provides insight on the origin of mechanisms of rickettsial pathogenicity. C1 [Gillespie, Joseph J.; Williams, Kelly P.; Driscoll, Timothy; Nordberg, Eric; Shukla, Maulik; Sobral, Bruno W.] Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Gillespie, Joseph J.; Azad, Abdu F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Joardar, Vinita; Walenz, Brian; Caler, Elisabet] J Craig Venter Inst, Rockville, MD USA. [Williams, Kelly P.] Sandia Natl Labs, Livermore, CA USA. [Hostetler, Jessica B.] NIAID, Lab Malaria & Vector Res LMVR, NIH, Hinxton, Cambs, England. [Hostetler, Jessica B.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Hill, Catherine A.] Purdue Univ, Dept Entomol Vector Biol & Publ Hlth Extens, W Lafayette, IN 47907 USA. [Nene, Vishvanath M.] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Nene, Vishvanath M.] Int Livestock Res Inst, Nairobi, Kenya. RP Gillespie, JJ (reprint author), Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. EM jgille@vbi.vt.edu OI Driscoll, Timothy/0000-0002-5119-0372; Gillespie, Joseph/0000-0002-5447-7264 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Department of Health and Human Services [N01-AI-33071, HHSN266200400038C, HHSN272200900040C, R01AI017828, R01AI59118] FX This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and Department of Health and Human Services under the following contract numbers: N01-AI-33071, HHSN266200400038C, and HHSN272200900040C (awarded to B.W.S.) and R01AI017828 and R01AI59118 (awarded to A.F.A.). NR 129 TC 43 Z9 43 U1 1 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JAN PY 2012 VL 194 IS 2 BP 376 EP 394 DI 10.1128/JB.06244-11 PG 19 WC Microbiology SC Microbiology GA 870NY UT WOS:000298677400021 PM 22056929 ER PT J AU Noinaj, N Wattanasak, R Lee, DY Wally, JL Piszczek, G Chock, PB Stadtman, TC Buchanan, SK AF Noinaj, Nicholas Wattanasak, Rut Lee, Duck-Yeon Wally, Jeremy L. Piszczek, Grzegorz Chock, P. Boon Stadtman, Thressa C. Buchanan, Susan K. TI Structural Insights into the Catalytic Mechanism of Escherichia coli Selenophosphate Synthetase SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SELENIUM; IDENTIFICATION; PROTEIN; SELENOPROTEINS; SELENOCYSTEINE; ULTRACENTRIFUGATION; BIOSYNTHESIS; INTERMEDIATE; PERSELENIDE; METABOLISM AB Selenophosphate synthetase (SPS) catalyzes the synthesis of selenophosphate, the selenium donor for the biosynthesis of selenocysteine and 2-selenouridine residues in seleno-tRNA. Selenocysteine, known as the 21st amino acid, is then incorporated into proteins during translation to form selenoproteins which serve a variety of cellular processes. SPS activity is dependent on both Mg2+ and K+ and uses ATP, selenide, and water to catalyze the formation of AMP, orthophosphate, and selenophosphate. In this reaction, the gamma phosphate of ATP is transferred to the selenide to form selenophosphate, while ADP is hydrolyzed to form orthophosphate and AMP. Most of what is known about the function of SPS has derived from studies investigating Escherichia coli SPS (EcSPS) as a model system. Here we report the crystal structure of the C17S mutant of SPS from E. coli (EcSPS(C17S)) in apo form (without ATP bound). EcSPS(C17S) crystallizes as a homodimer, which was further characterized by analytical ultracentrifugation experiments. The glycine-rich N-terminal region (residues 1 through 47) was found in the open conformation and was mostly ordered in both structures, with a magnesium cofactor bound at the active site of each monomer involving conserved aspartate residues. Mutating these conserved residues (D51, D68, D91, and D227) along with N87, also found at the active site, to alanine completely abolished AMP production in our activity assays, highlighting their essential role for catalysis in EcSPS. Based on the structural and biochemical analysis of EcSPS reported here and using information obtained from similar studies done with SPS orthologs from Aquifex aeolicus and humans, we propose a catalytic mechanism for EcSPS-mediated selenophosphate synthesis. C1 [Noinaj, Nicholas; Wally, Jeremy L.; Buchanan, Susan K.] NIDDK, NIH, Bethesda, MD 20892 USA. [Wattanasak, Rut; Lee, Duck-Yeon; Piszczek, Grzegorz; Chock, P. Boon; Stadtman, Thressa C.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Noinaj, N (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM noinajn@niddk.nih.gov FU NIH National Institute of Diabetes and Digestive and Kidney Diseases; NIH National Heart, Lung, and Blood Institute; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX N.N., J.L.W., and S.K.B. were supported by the Intramural Research Program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases. R.W., D.-Y.L., G.P., P.B.C., and T.C.S. were supported by the Intramural Research Program of the NIH National Heart, Lung, and Blood Institute. Data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline at the Advanced Photon Source, Argonne National Laboratory. 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. W-31-109-Eng-38. NR 47 TC 4 Z9 4 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JAN PY 2012 VL 194 IS 2 BP 499 EP 508 DI 10.1128/JB.06012-11 PG 10 WC Microbiology SC Microbiology GA 870NY UT WOS:000298677400031 PM 22081394 ER PT J AU Cushman, WC Davis, BR Pressel, SL Cutler, JA Einhorn, PT Ford, CE Oparil, S Probstfield, JL Whelton, PK Wright, JT Alderman, MH Basile, JN Black, HR Grimm, RH Hamilton, BP Haywood, LJ Ong, ST Piller, LB Simpson, LM Stanford, C Weiss, RJ AF Cushman, William C. Davis, Barry R. Pressel, Sara L. Cutler, Jeffrey A. Einhorn, Paula T. Ford, Charles E. Oparil, Suzanne Probstfield, Jeffrey L. Whelton, Paul K. Wright, Jackson T., Jr. Alderman, Michael H. Basile, Jan N. Black, Henry R. Grimm, Richard H., Jr. Hamilton, Bruce P. Haywood, L. Julian Ong, Stephen T. Piller, Linda B. Simpson, Lara M. Stanford, Carol Weiss, Robert J. CA ALLHAT Collaborative Res Grp TI Mortality and Morbidity During and After the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID CONVERTING-ENZYME-INHIBITOR; BLOOD-PRESSURE; CARDIOVASCULAR EVENTS; FOLLOW-UP; ALLHAT; OUTCOMES; THERAPY; RISK; PARTICIPANTS; HYPERTENSION AB A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and =1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.931.06) or lisinopril (HR, 0.97; CI, 0.901.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.021.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.011.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension. J Clin Hypertens (Greenwich). 2012; 14: 20-31. (C) 2011 Wiley Periodicals, Inc. C1 [Pressel, Sara L.] Univ Texas Hlth Sci Ctr Houston, Univ Texas Houston, ALLHAT Clin Trials Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Cutler, Jeffrey A.; Einhorn, Paula T.] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Oparil, Suzanne] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Probstfield, Jeffrey L.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Wright, Jackson T., Jr.] Case Western Reserve Univ, Med Ctr, Cleveland, OH 44106 USA. [Alderman, Michael H.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Basile, Jan N.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Black, Henry R.] NYU, Langone Med Ctr, New York, NY USA. [Grimm, Richard H., Jr.] Berman Ctr Outcomes & Clin Res, Minneapolis, MN USA. [Hamilton, Bruce P.] Baltimore Vet Adm, Med Ctr, Baltimore, MD USA. [Haywood, L. Julian] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Ong, Stephen T.] Healthcare Greater Washington, Oxon Hill, MD USA. [Stanford, Carol] Univ Missouri, Kansas City Sch Med, Kansas City, MO 64110 USA. [Weiss, Robert J.] Androscoggin Cardiol Associates, Auburn, AL USA. RP Pressel, SL (reprint author), Univ Texas Hlth Sci Ctr Houston, Univ Texas Houston, ALLHAT Clin Trials Ctr, Sch Publ Hlth, RAS W908,,1200 Herman Pressler Dr, Houston, TX 77030 USA. EM sara.l.pressel@uth.tmc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [NO1-HC-35130]; Pfizer; AstraZeneca; Bristol-Myers Squibb; Pfizer Inc.; Merck; GlaxoSmithKline; Forest; Novartis; Takeda FX This study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute (NHLBI). ALLHAT investigators received contributions of study medications supplied by Pfizer (amlodipine besylate and doxazosin mesylate), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer Inc. The authors report no conflicts of interest with regard to this paper. Michael H. Alderman has consulted for AstraZeneca, Merck, and Sankyo; has received honoraria from Bristol-Myers Squibb and Merck; has had grants/contracts with Sankyo; and has held a financial interest in Merck. Jan N. Basile has consulted for Abbott Laboratories, Boehringer Ingelheim, Daiichi Sankyo, Forest Laboratories, Forest Pharmaceuticals, Merck, Novartis, Reddy Pharmaceuticals, Sankyo, and SmithKline Beecham/Glaxo Wellcome; and has received honoraria from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Forest Laboratories, Merck, Novartis, and Pfizer; Henry R. Black has consulted for Abbott Laboratories, AstraZeneca, Aventis, Bayer Corporation, Biovail, Boehringer Ingelheim, Bristol-Meyers Squibb, CVRx, Daiichi Sankyo, Forest Pharmaceuticals, Gilead, GlaxoSmithKline, Horizons Pharmaceuticals, Inter-cure, Merck, Novartis, Pfizer, Sankyo, Sanofi Aventis, Sanofi-Synthelabo, Servier, and Takeda; has received honoraria from Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CV Therapeutics, Forest Laboratories, Merck, Novartis, Pfizer, Sanofi-Synthelabo, and Servier; and has had grants/contracts with Pfizer. William C. Cushman has consulted for Abbott Laboratories, Bristol-Myers Squibb, Calpis, Daiichi Sankyo, Forest Pharmaceuticals, Gilead Colorado, Johnson and Johnson, King, Myogen, Novartis, Pfizer, Pharmacopeia, Reddy Pharmaceuticals, Roche, Sankyo, Sanofi Aventis, Sanofi-Synthelabo, Sciele, Takeda, and Theravance; has received honoraria from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Forest Pharmaceuticals, King, and Novartis and has had grants/contracts with Abbott Laboratories, Biovail, King, and Novartis. Barry R. Davis has consulted for BioMarin, Forest Pharmaceuticals, GlaxoSmithKline, Merck, Proctor and Gamble, and Takeda; and has held a financial interest in Amgen. Charles E. Ford has consulted for BioMarin. Richard H. Grimm, Jr has consulted for Calpis, Merck, Merck/SP, Novartis, Pfizer, and Takeda; has received honoraria from AstraZeneca, Merck, Novartis, and Takeda; and has had grants/contracts with Merck, Novartis, and Pfizer. Bruce P. Hamilton has had grants/contracts with GlaxoSmithKline. L. Julian Haywood has held a financial interest in Pfizer. Stephen T. Ong has received honoraria from Novartis; and has had grants/contracts with Abbott Laboratories, Arena, Daiichi Sankyo, Ferring, Forest Pharmaceutical, Gilead Colorado, GlaxoSmithKline, Mylan Bertek, Novartis, Pharmacopeia, Roche, Sankyo, and Sanofi Aventis. Suzanne Oparil has consulted for Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Encysive Pharm, Forest Pharmaceuticals, GlaxoSmithKline, Merck, NicOx, Novartis, Pfizer, Salt Institute, Sankyo, Sanofi Aventis, Schering Plough, and SmithKline Beecham/Glaxo Wellcome; has received honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, and Encysive Pharm; has had grants/contracts with Daiichi Sankyo, Eisai Medical Research, Encysive Pharm, Gilead, Novartis, Pfizer, Sankyo, and Takeda; and has held a financial interest in Encysive Pharm. Jeffrey L.; Prob-stfield has consulted for Boehringer Ingelheim, King, and King Pharmceuticals/Monarch; has received honoraria from Boehringer Ingelheim; and has had grants/contracts with Boehringer Ingelheim, King, King Pharmaceuticals/Monarch, KOS, and Sanofi Aventis. Carol Stanford has held a financial interest in Pfizer. Robert J. Weiss has had grants/contracts with Forest, Novartis, and Takeda. Jackson T. Wright, Jr has consulted for Abbott Laboratories, AstraZeneca, Bayer Corporation, Biovail, CV Therapeutics, CVRx, Daiichi Sankyo, Forest Pharmaceuticals, GlaxoSmithKline, Merck, NitroMed, Novartis, Pfizer, Reliant Pharm, Sankyo, Sanofi Aventis, Sanofi-Synthelabo, and SmithKline Beecham/Glaxo Wellcome; and has had grants/contracts with GlaxoSmithKline and Novartis. Jeffrey A. Cutler, Paula T. Einhorn, Linda B. Piller, Sara L. Pressel, Lara M. Simpson, and Paul K. Whelton have no financial conflicts of interest to report. The NHLBI sponsored the study and was involved in all aspects other than direct operations of the study centers. This included collection, analysis, and interpretation of the data plus the decision to submit the manuscript for publication. Pfizer Inc, AstraZeneca, and Bristol-Myers Squibb had no role in the design and conduct of the study, the collection, analysis, and interpretation of the data or the preparation or approval of the manuscript. Editorial assistance was provided by Ellen Breckenridge, an employee of the ALLHAT Collaborative Research Group. The position was paid for by grant funds provided by the NHLBI for the ALLHAT project. NR 27 TC 20 Z9 23 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD JAN PY 2012 VL 14 IS 1 BP 20 EP 31 DI 10.1111/j.1751-7176.2011.00568.x PG 12 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 871IV UT WOS:000298732400006 PM 22235820 ER PT J AU Hlady, RA Novakova, S Opavska, J Klinkebiel, D Peters, SL Bies, J Hannah, J Iqbal, J Anderson, KM Siebler, HM Smith, LM Greiner, TC Bastola, D Joshi, S Lockridge, O Simpson, MA Felsher, DW Wagner, KU Chan, WC Christman, JK Opavsky, R AF Hlady, Ryan A. Novakova, Slavomira Opavska, Jana Klinkebiel, David Peters, Staci L. Bies, Juraj Hannah, Jay Iqbal, Javeed Anderson, Kristi M. Siebler, Hollie M. Smith, Lynette M. Greiner, Timothy C. Bastola, Dhundy Joshi, Shantaram Lockridge, Oksana Simpson, Melanie A. Felsher, Dean W. Wagner, Kay-Uwe Chan, Wing C. Christman, Judith K. Opavsky, Rene TI Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DNA METHYLATION; GENE-EXPRESSION; HEMATOPOIETIC STEM; CELLS; CANCER; METHYLTRANSFERASE; PATTERNS; DIFFERENTIATION; EPIGENETICS; HYPOMETHYLATION AB DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b(-/-) lymphomas, but not in Dnmt3b(-/-) pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Mend]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpresseci during tumor progression in Dnmt3b(-/-) lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b(+/+) cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies. C1 [Opavsky, Rene] UNMC, Eppley Inst Res Canc & Allied Dis, Nebraska Med Ctr 985950, DRCII, Omaha, NE 68198 USA. [Klinkebiel, David; Christman, Judith K.] UNMC, Coll Med, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. [Peters, Staci L.; Joshi, Shantaram; Opavsky, Rene] UNMC, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. [Bies, Juraj] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hannah, Jay; Bastola, Dhundy] Univ Nebraska, Coll Informat Sci & Technol, Omaha, NE 68182 USA. [Iqbal, Javeed; Greiner, Timothy C.; Chan, Wing C.; Opavsky, Rene] UNMC, Ctr Lymphoma & Leukemia Res, Omaha, NE 68198 USA. [Iqbal, Javeed; Greiner, Timothy C.; Chan, Wing C.] UNMC, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Anderson, Kristi M.; Siebler, Hollie M.] UNMC, Biomed Res Training Program, Omaha, NE 68198 USA. [Smith, Lynette M.] UNMC, Coll Publ Hlth, Omaha, NE 68198 USA. [Simpson, Melanie A.] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. [Felsher, Dean W.] Stanford Univ, Dept Med, Div Oncol, Sch Med,Dept Pathol, Stanford, CA 94305 USA. [Felsher, Dean W.] Stanford Univ, Dept Mol Imaging, Sch Med, Stanford, CA 94305 USA. RP Opavsky, R (reprint author), UNMC, Eppley Inst Res Canc & Allied Dis, Nebraska Med Ctr 985950, DRCII, Room 4031, Omaha, NE 68198 USA. EM ropavsky@unmc.edu RI Wagner, Kay-Uwe/B-6044-2009 FU Eppley Cancer Center; Nebraska Center for Cellular Signaling NIH [P20 RR018759]; National Center for Research Resources; National Center for Research Resources (NCRR) [1S 10RR027754-01]; Nebraska Research Network in Functional Genomics NE-INBRE [P20 RR16469]; Molecular Biology of Neurosensory Systems CoBRE [2P20RR018788-06]; Nebraska Research Initiative FX We thank Michael Brattain (Eppley Cancer Institute, UNMC), Robert Lewis (Eppley Cancer Institute, UNMC), and Harold Saavedra (Emory University) for critical reading of this manuscript and useful comments. This work was supported by an Eppley Cancer Center pilot project grant (to R. Opavsky) and by Nebraska Center for Cellular Signaling NIH grant P20 RR018759 from the National Center for Research Resources. T.C. Greiner is a grantee of the Lymphoma Research Foundation Mantle Cell Grant program. The UNMC Next Generation Sequencing Core received support from National Center for Research Resources (NCRR) grants, entitled UNMC SIG Supporting Next-generation DNA Sequencing Technology 1S 10RR027754-01, The Nebraska Research Network in Functional Genomics NE-INBRE P20 RR16469, the Molecular Biology of Neurosensory Systems CoBRE 2P20RR018788-06, and the Nebraska Research Initiative. The article contents are the sole responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. The authors also acknowledge the University of Nebraska Epigenomics Core Facility for performing the MSCC processing and analysis; Chittibabu Guda and Adam Cornish (Center for Bioinformatics and Systems Biology, UNMC) for developing perl scripts for MSCC repeat sequence analysis; and Jiangtao Luo for contributing to the statistical analysis. NR 46 TC 30 Z9 32 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2012 VL 122 IS 1 BP 163 EP 177 DI 10.1172/JCI57292 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 871WW UT WOS:000298769400022 PM 22133874 ER PT J AU Panigrahy, D Edin, ML Lee, CR Huang, S Bielenberg, DR Butterfield, CE Barnes, CM Mammoto, A Mammoto, T Luria, A Benny, O Chaponis, DM Dudley, AC Greene, ER Vergilio, JA Pietramaggiori, G Scherer-Pietramaggiori, SS Short, SM Seth, M Lih, FB Tomer, KB Yang, J Schwendener, RA Hammock, BD Falck, JR Manthati, VL Ingber, DE Kaipainen, A D'Amore, PA Kieran, MW Zeldin, DC AF Panigrahy, Dipak Edin, Matthew L. Lee, Craig R. Huang, Sui Bielenberg, Diane R. Butterfield, Catherine E. Barnes, Carmen M. Mammoto, Akiko Mammoto, Tadanori Luria, Ayala Benny, Ofra Chaponis, Deviney M. Dudley, Andrew C. Greene, Emily R. Vergilio, Jo-Anne Pietramaggiori, Giorgio Scherer-Pietramaggiori, Sandra S. Short, Sarah M. Seth, Meetu Lih, Fred B. Tomer, Kenneth B. Yang, Jun Schwendener, Reto A. Hammock, Bruce D. Falck, John R. Manthati, Vijaya L. Ingber, Donald E. Kaipainen, Arja D'Amore, Patricia A. Kieran, Mark W. Zeldin, Darryl C. TI Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SOLUBLE EPOXIDE HYDROLASE; ISCHEMIA-REPERFUSION INJURY; IN-VIVO; ENDOTHELIAL EXPRESSION; THERAPEUTIC TARGET; CORONARY-ARTERIES; ANGIOGENIC SWITCH; BLOOD-PRESSURE; CANCER-CELLS; NUDE-MICE AB Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer. C1 [Panigrahy, Dipak; Bielenberg, Diane R.; Butterfield, Catherine E.; Barnes, Carmen M.; Mammoto, Akiko; Mammoto, Tadanori; Benny, Ofra; Chaponis, Deviney M.; Dudley, Andrew C.; Greene, Emily R.; Short, Sarah M.; Seth, Meetu; Ingber, Donald E.; Kieran, Mark W.] Childrens Hosp Boston, Vasc Biol Program, Boston, MA USA. [Panigrahy, Dipak; Chaponis, Deviney M.; Greene, Emily R.; Kieran, Mark W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Edin, Matthew L.; Lee, Craig R.; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Huang, Sui] Univ Calgary, Inst Biocomplex & Informat, Calgary, AB, Canada. [Huang, Sui] Inst Syst Biol, Seattle, WA USA. [Luria, Ayala; Yang, Jun; Hammock, Bruce D.] UCD, Dept Entomol, Davis, CA USA. [Luria, Ayala; Yang, Jun; Hammock, Bruce D.] UCD, Ctr Canc, Davis, CA USA. [Vergilio, Jo-Anne] Harvard Univ, Sch Med, Dept Pathol, Childrens Hosp Boston, Boston, MA 02115 USA. [Pietramaggiori, Giorgio; Scherer-Pietramaggiori, Sandra S.] Univ Lausanne, Div Plast Surg, Lausanne, Switzerland. [Schwendener, Reto A.] Univ Zurich, Inst Mol Canc Res, Zurich, Switzerland. [Falck, John R.; Manthati, Vijaya L.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Ingber, Donald E.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Kaipainen, Arja] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02115 USA. RP Panigrahy, D (reprint author), 300 Longwood Ave, Boston, MA 02115 USA. EM dipak.panigrahy@childrens.harvard.edu; sui.huang@systemsbiology.org; mark_kieran@dfci.harvard.edu; zeldin@niehs.nih.gov RI Yang, Jun/B-2262-2010; Tomer, Kenneth/E-8018-2013; OI Yang, Jun/0000-0002-4630-3838; Kieran, Mark/0000-0003-2184-7692; Falck, John/0000-0002-9219-7845; Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301 FU National Cancer Institute [R01CA148633-01A1]; Stop and Shop Pediatric Brain Tumor Fund; C.J. Buckley Pediatric Brain Tumor Fund; Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034, Z01 ES050167]; NIH [R01 GM088199, CA045548]; Robert A. Welch Foundation; NIEHS [NIH P42 ES004699, NIH R01 ES002710, NIH R01 ES013933] FX We thank and gratefully acknowledge Kristin Johnson for photography and preparation of the figures; J. Alyce Bradbury, Joan P. Graves, Laura M. DeGraff, Ricky Sanchez, Lyndsay Leach, and Tony Walshe for excellent technical assistance; and Sung Hee Hwang for sEH inhibitors and eicosanoid profiling assays. We thank Isaiah J. Fidler for PC3M-LN4 cells. This work was supported by National Cancer Institute grant R01CA148633-01A1 (to D. Panigrahy); the Stop and Shop Pediatric Brain Tumor Fund and the C.J. Buckley Pediatric Brain Tumor Fund (to M.W. Kieran); Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences grants Z01 ES025034 and Z01 ES050167 (to D.C. Zeldin and K.B. Tomer); NIH grant R01 GM088199 (to C.R. Lee); the Robert A. Welch Foundation (to J.R Falck); NIEHS Superfund Basic Research Program grants NIH P42 ES004699, NIH R01 ES002710, and NIH R01 ES013933 (to B.D. Hammock); and NIH grant CA045548 (to D.E. Ingber). B.D. Hammock is a George and Judy Marcus Senior Fellow of the American Asthma Foundation. NR 62 TC 88 Z9 90 U1 2 U2 21 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2012 VL 122 IS 1 BP 178 EP 191 DI 10.1172/JCI58128 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 871WW UT WOS:000298769400023 PM 22182838 ER PT J AU Tian, J Berton, TR Shirley, SH Lambertz, I Gimenez-Conti, IB DiGiovanni, J Korach, KS Conti, CJ Fuchs-Young, R AF Tian, Jie Berton, Thomas R. Shirley, Stephanie H. Lambertz, Isabel Gimenez-Conti, Irma B. DiGiovanni, John Korach, Kenneth S. Conti, Claudio J. Fuchs-Young, Robin TI Developmental stage determines estrogen receptor alpha expression and non-genomic mechanisms that control IGF-1 signaling and mammary proliferation in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROWTH-FACTOR-I; BREAST-CANCER CELLS; TRANSGENIC MICE; CYCLIN D1; AFRICAN-AMERICAN; PHOSPHATIDYLINOSITOL 3-KINASE; GENE-TRANSCRIPTION; BINDING PROTEIN-3; GLAND DEVELOPMENT; DOCKING PROTEINS AB Insulin like growth factor-1 (IGF-1) stimulates increased proliferation and survival of mammary epithelial cells and also promotes mammary tumorigenesis. To study the effects of IGF-1 on the mammary gland in vivo, we used BK5.IGF-1 transgenic (Tg) mice. In these mice, IGF-1 overexpression is controlled by the bovine keratin 5 promoter and recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 that is seen in women. Studies have shown that BK5.IGF-1 Tg mice are more susceptible to mammary tumorigenesis than wild-type littermates. Investigation of the mechanisms underlying increased mammary cancer risk, reported here, revealed that IGF-1 preferentially activated the PI3K/Akt pathway in glands from prepubertal Tg mice, resulting in increased cyclin D1 expression and hyperplasia. However, in glands from postpubertal Tg mice, a pathway switch occurred and activation of the Ras/Raf/MAPK pathway predominated, without increased cyclin D1 expression or proliferation. We further showed that in prepubertal Tg glands, signaling was mediated by formation of an ER alpha/IRS-1 complex, which activated IRS-1 and directed signaling via the PI3K/Akt pathway. Conversely, in postpubertal Tg glands, reduced ER alpha expression failed to stimulate formation of the ER alpha/IRS-1 complex, allowing signaling to proceed via the alternate Ras/Raf/MAPK pathway. These in vivo data demonstrate that changes in ER alpha expression at different stages of development direct IGF-1 signaling and the resulting tissue responses. As ER alpha levels are elevated during the prepubertal and postmenopausal stages, these may represent windows of susceptibility during which increased IGF-1 exposure maximally enhances breast cancer risk. C1 [Fuchs-Young, Robin] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Dept Mol Carcinogenesis, Smithville, TX 78957 USA. [Shirley, Stephanie H.; Gimenez-Conti, Irma B.; DiGiovanni, John; Conti, Claudio J.; Fuchs-Young, Robin] Univ Texas MD Anderson Canc Ctr, Univ Texas Grad Sch Biomed Sci Houston, Houston, TX 77030 USA. [Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC USA. RP Fuchs-Young, R (reprint author), Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Dept Mol Carcinogenesis, POB 389, Smithville, TX 78957 USA. EM rfyoung@mdanderson.org OI Korach, Kenneth/0000-0002-7765-418X FU NIH/National Institute of Environmental Health Sciences (NIEHS) Center [ES07784]; NIH/National Cancer Institute [CA16672, CA104114]; US Army Medical Research and Material Command [DAMD17-01-0303] FX The work was supported by NIH/National Institute of Environmental Health Sciences (NIEHS) Center grant ES07784, NIH/National Cancer Institute grants CA16672 (Cancer Center Support Grant) and CA104114 (to R. Fuchs-Young), and US Army Medical Research and Material Command grant DAMD17-01-0303 (to J. Tian). We thank Noirin Cullinan-Ammann for assistance with animal maintenance. We also thank Joyce E. Rundhaug for advice and thoughtful comments on the manuscript. NR 70 TC 12 Z9 12 U1 1 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2012 VL 122 IS 1 BP 192 EP 204 DI 10.1172/JCI42204 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 871WW UT WOS:000298769400024 PM 22182837 ER PT J AU Rees, MG Ng, D Ruppert, S Turner, C Beer, NL Swift, AJ Morken, MA Below, JE Blech, I Mullikin, JC McCarthy, MI Biesecker, LG Gloyn, AL Collins, FS AF Rees, Matthew G. Ng, David Ruppert, Sarah Turner, Clesson Beer, Nicola L. Swift, Amy J. Morken, Mario A. Below, Jennifer E. Blech, Ilana Mullikin, James C. McCarthy, Mark I. Biesecker, Leslie G. Gloyn, Anna L. Collins, Francis S. CA NISC Comparative Sequencing Progr TI Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GENOME-WIDE ASSOCIATION; DIABETES SUSCEPTIBILITY LOCI; C-REACTIVE PROTEIN; RAT-LIVER; PLASMA-LEVELS; TRIGLYCERIDE LEVELS; IDENTIFIES LOCI; FINNISH MEN; GLUCOSE; METABOLISM AB Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease. C1 [Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Rees, Matthew G.; Beer, Nicola L.; McCarthy, Mark I.; Gloyn, Anna L.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Below, Jennifer E.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Below, Jennifer E.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Blech, Ilana] Hadassah Hebrew Univ, Sch Med, Jerusalem, Israel. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.; Gloyn, Anna L.] Churchill Hosp, Oxford Radcliffe Hosp Trust, Oxford Ctr Diabet Endocrinol & Metab, Natl Inst Hlth Res,Oxford Biomed Res Ctr, Oxford OX3 7LJ, England. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov FU NIH Division of Intramural Research; NHGRI [Z01-HG000024]; Oxford by the Medical Research Council (MRC) [81696]; Wellcome Trust [095101/Z/10/Z]; US Public Health Service [DK020595, DK073451, DK085501] FX We thank Stephen Wincovitch at the National Human Genome Research Institute (NHGRI) Microscopy Core for assistance gathering fluorescence images; Pedro Cruz for variant detection in GCKR exons across the ClinSeq sample cohort; Lori Bonnycastle, Mike Erdos, Narisu Narisu, Peter Chines, Heather Stringham, Anne Jackson, and Caitlin Krause for assistance with variant genotyping; Chris Groves, Mira Korner, and Ben Glaser for assistance with p.Ala519Thr genotyping; Nancy J. Cox, Graeme I. Bell, Veronica P. Paz, and Craig L. Hanis for assistance with p.Val103Met genotyping; Neal Oden for statistical discussions; Tanya Teslovich for discussions regarding SIFT and PolyPhen predictions; and Nicole Stone and Michael Stitzel for advice. This study was supported by the NIH Division of Intramural Research and NHGRI project number Z01-HG000024 (to F.S. Collins), in Oxford by the Medical Research Council (MRC) (81696) and the Wellcome Trust (095101/Z/10/Z), and by US Public Health Service grants DK020595 (to Graeme I. Bell.) and DK073451 and DK085501 (to Craig L. Hanis). A.L. Gloyn is a Wellcome Trust Senior Fellow in Basic Biomedical Research. NR 63 TC 22 Z9 22 U1 0 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2012 VL 122 IS 1 BP 205 EP 217 DI 10.1172/JCI46425 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 871WW UT WOS:000298769400025 PM 22182842 ER PT J AU Kashiwakura, JI Ando, T Matsumoto, K Kimura, M Kitaura, J Matho, MH Zajonc, DM Ozeki, T Ra, C MacDonald, SM Siraganian, RP Broide, DH Kawakami, Y Kawakami, T AF Kashiwakura, Jun-ichi Ando, Tomoaki Matsumoto, Kenji Kimura, Miho Kitaura, Jiro Matho, Michael H. Zajonc, Dirk M. Ozeki, Tomomitsu Ra, Chisel MacDonald, Susan M. Siraganian, Reuben P. Broide, David H. Kawakami, Yuko Kawakami, Toshiaki TI Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CONTROLLED TUMOR PROTEIN; MAST-CELL-DEFICIENT; FC-EPSILON-RI; AIRWAY HYPERRESPONSIVENESS; ANTIAPOPTOTIC ACTIVITY; TRANSLATIONAL CONTROL; CHRONIC INFLAMMATION; MESSENGER-RNA; TISSUE-TYPE; LATE PHASE AB IgE-mediated activation of mast cells and basophils underlies allergic diseases such as asthma. Histamine-releasing factor (HRF; also known as translationally controlled tumor protein [TCTP] and fortilin) has been implicated in late-phase allergic reactions (LPRs) and chronic allergic inflammation, but its functions during asthma are not well understood. Here, we identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. HRF was able to dimerize and bind to Igs via interactions of its N-terminal and internal regions with the Fab region of Igs. Therefore, HRF together with HRF-reactive IgE was able to activate mast cells in vitro. In mouse models of asthma and allergy, Ig-interacting HRF peptides that were shown to block HRF/Ig interactions in vitro inhibited IgE/HRF-induced mast cell activation and in vivo cutaneous anaphylaxis and airway inflammation. Intranasally administered HRF recruited inflammatory immune cells to the lung in naive mice in a mast cell- and Fc receptor-dependent manner. These results indicate that HRF has a proinflammatory role in asthma and skin immediate hypersensitivity, leading us to suggest HRF as a potential therapeutic target. C1 [Kashiwakura, Jun-ichi; Ando, Tomoaki; Kimura, Miho; Kitaura, Jiro; Matho, Michael H.; Zajonc, Dirk M.; Kawakami, Yuko; Kawakami, Toshiaki] La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA. [Kashiwakura, Jun-ichi; Ra, Chisel] Nihon Univ, Grad Sch Med Sci, Div Mol Cell Immunol & Allergol, Adv Med Res Ctr, Tokyo, Japan. [Matsumoto, Kenji] Natl Res Inst Child Hlth & Dev, Dept Allergy & Immunol, Tokyo, Japan. [Ozeki, Tomomitsu] ULVAC Inc, Chigasaki, Kanagawa, Japan. [MacDonald, Susan M.] Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD USA. [Siraganian, Reuben P.] Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, OIIB, NIH, Bethesda, MD USA. [Broide, David H.] UCSD, Dept Med, La Jolla, CA USA. RP Kawakami, T (reprint author), La Jolla Inst Allergy & Immunol, Div Cell Biol, 9420 Athena Circle, La Jolla, CA 92037 USA. EM toshi@liai.org RI Kawakami, Toshiaki/O-1616-2015 FU NIH; National Institute of Biomedical Innovation [ID10-43] FX We thank Jae-Youn Cho and Peter Rosenthal for superb technical assistance and Shane Crotty and Howard M. Grey for critically reading this manuscript. This study was supported in part by grants from the NIH (to T. Kawakami) and the National Institute of Biomedical Innovation (ID10-43; to K. Matsumoto). This is Publication 1262 from the La Jolla Institute for Allergy and Immunology. NR 66 TC 24 Z9 29 U1 0 U2 11 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2012 VL 122 IS 1 BP 218 EP 228 DI 10.1172/JCI59072 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 871WW UT WOS:000298769400026 PM 22133880 ER PT J AU Temmerman, ST Ma, CA Zhao, YG Keenan, J Aksentijevich, I Fessler, M Brown, MR Knutsen, A Shapiro, R Jain, A AF Temmerman, Stephane T. Ma, Chi A. Zhao, Yongge Keenan, Jeffrey Aksentijevich, Ivona Fessler, Margaret Brown, Margaret R. Knutsen, Alan Shapiro, Ralph Jain, Ashish TI Defective nuclear IKK alpha function in patients with ectodermal dysplasia with immune deficiency SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NF-KAPPA-B; DEPENDENT GENE-EXPRESSION; INCONTINENTIA PIGMENTI; GENOTOXIC STRESS; ACTIVATION; NEMO; KINASE; UBIQUITINATION; BINDING; MUTATIONS AB Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-kappa B essential modulator (NEMO; also known as I kappa B kinase gamma subunit [IKK gamma]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-kappa B proteins, resulting in defective expression of NF-kappa B target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-kappa B. However, cells deficient in full-length NEMO were defective in expression of NF-kappa B-regulated cytokines, such as IL-12, suggesting a downstream defect in chromatin accessibility for NF-kappa B transcription factors. TLR4-stimulated APCs from the patients were defective in IKK alpha-dependent H3 histone phosphorylation at the IL-12 promoter and recruitment of NF-kappa B heterodimers RelA and cRel to the promoter. Expression of a super-active form of IKK alpha restored IL-12 production in a NEMO knockdown human monocytic cell line following LPS treatment. Our findings suggest that NEMO regulates the nuclear function of IKK alpha and offer new insights into the mechanisms underlying diminished NF-kappa B signaling in patients with EDI. C1 [Temmerman, Stephane T.; Ma, Chi A.; Zhao, Yongge; Keenan, Jeffrey; Fessler, Margaret; Jain, Ashish] NIAID, Lab Host Def, Bethesda, MD 20892 USA. [Aksentijevich, Ivona] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Genet & Genom Branch, Bethesda, MD USA. [Brown, Margaret R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Knutsen, Alan] St Louis Univ, St Louis, MO 63103 USA. [Shapiro, Ralph] Midwest Immunol Clin, Minneapolis, MN USA. RP Jain, A (reprint author), NIH, CRC, Rm 5490,10 Ctr Dr, Bethesda, MD 20892 USA. EM ajain@niaid.nih.gov NR 34 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2012 VL 122 IS 1 BP 315 EP 326 DI 10.1172/JCI42534 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 871WW UT WOS:000298769400034 PM 22156202 ER PT J AU Pietilainen-Nicklen, J Virtanen, O Kolehmainen, P Uotila, L Salonen, O Lappalainen, M Farkkila, M Koskiniemi, M AF Pietilainen-Nicklen, Jenna Virtanen, Oskari Kolehmainen, Pekka Uotila, Lasse Salonen, Oili Lappalainen, Maija Farkkila, Markus Koskiniemi, Marjaleena TI ADEM and virus infection SO JOURNAL OF CLINICAL VIROLOGY LA English DT Editorial Material ID ACUTE DISSEMINATED ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS C1 [Pietilainen-Nicklen, Jenna; Kolehmainen, Pekka; Koskiniemi, Marjaleena] Univ Helsinki, Haartman Inst, Dept Virol, FIN-00014 Helsinki, Finland. [Uotila, Lasse] HUSLAB Lab Serv, Dept Clin Chem, Helsinki, Finland. [Pietilainen-Nicklen, Jenna; Farkkila, Markus] Univ Helsinki, Dept Neurol, FIN-00014 Helsinki, Finland. [Virtanen, Oskari] NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Salonen, Oili] Helsinki Med Imaging Ctr, Helsinki, Finland. RP Pietilainen-Nicklen, J (reprint author), Univ Helsinki, Haartman Inst, Dept Virol, Haartmaninkatu 3,POB 21, FIN-00014 Helsinki, Finland. EM jenna.pietilainen@helsinki.fi OI Lappalainen, Maija/0000-0001-5400-1250 NR 11 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 J9 J CLIN VIROL JI J. Clin. Virol. PD JAN PY 2012 VL 53 IS 1 BP 2 EP 5 DI 10.1016/j.jcv.2011.10.015 PG 4 WC Virology SC Virology GA 863DF UT WOS:000298142300001 PM 22112626 ER PT J AU Smith, AL St Claire, M Yellayi, S Bollinger, L Jahrling, PB Paragas, J Blaney, JE Johnson, RF AF Smith, Alvin L. St Claire, Marisa Yellayi, Srikanth Bollinger, Laura Jahrling, Peter B. Paragas, Jason Blaney, Joseph E. Johnson, Reed F. TI Intrabronchial inoculation of cynomolgus macaques with cowpox virus SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MONKEYPOX VIRUS; NONHUMAN-PRIMATES; LETHAL MONKEYPOX; VACCINIA VIRUS; SMALLPOX VIRUS; INFECTION; MODEL; POXVIRUS; CHALLENGE; PATHOLOGY AB The public health threat of orthopoxviruses from bioterrorist attacks has prompted researchers to develop suitable animal models for increasing our understanding of viral pathogenesis and evaluation of medical countermeasures (MCMs) in compliance with the FDA Animal Efficacy Rule. We present an accessible intrabronchial cowpox virus (CPXV) model that can be evaluated under biosafety level-2 laboratory conditions. In this dose-ranging study, utilizing cynomolgus macaques, signs of typical orthopoxvirus disease were observed with the lymphoid organs, liver, skin (generally mild) and respiratory tract as target tissues. Clinical and histopathological evaluation suggests that intrabronchial CPXV recapitulated many of the features of monkeypox and variola virus, the causative agent of smallpox, infections in cynomolgus macaque models. These similarities suggest that CPXV infection in non-human primates should be pursued further as an alternative model of smallpox. Further development of the CPXV primate model, unimpeded by select agent and biocontainment restrictions, should facilitate the development of MCMs for smallpox. C1 [Smith, Alvin L.; Jahrling, Peter B.; Blaney, Joseph E.; Johnson, Reed F.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [St Claire, Marisa; Yellayi, Srikanth; Bollinger, Laura; Jahrling, Peter B.; Paragas, Jason] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. RP Johnson, RF (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. EM johnsonreed@mail.nih.gov FU NIAID Division of Intramural Research; University of Florida FX This work was supported in part by the NIAID Division of Intramural Research. We wish to thank Catherine Jett, Leslie Wachter, Sarah Rovezzi, Lily Cheng and the Division of Intramural Research Comparative Medicine Branch staff for contribution to these studies. We also thank Grant McFadden Ph.D., University of Florida for cowpox Brighton Red. NR 34 TC 6 Z9 6 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JAN PY 2012 VL 93 BP 159 EP 164 DI 10.1099/vir.0.036905-0 PN 1 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 874QG UT WOS:000298972600019 PM 21940414 ER PT J AU Pang, T Benicky, J Wang, J Orecna, M Sanchez-Lemus, E Saavedra, JM AF Pang, Tao Benicky, Julius Wang, Juan Orecna, Martina Sanchez-Lemus, Enrique Saavedra, Juan M. TI Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-gamma activation in human monocytes SO JOURNAL OF HYPERTENSION LA English DT Article DE angiotensin receptor blockers; cytokines; inflammation; peroxisome proliferator-activated receptor-gamma; transcription factors ID FACTOR-KAPPA-B; NECROSIS-FACTOR-ALPHA; ANGIOTENSIN-II; PPAR-GAMMA; GENE-EXPRESSION; MATRIX METALLOPROTEINASE-1; THERAPEUTIC IMPLICATIONS; VASCULAR INFLAMMATION; MONONUCLEAR-CELLS; OXIDATIVE STRESS AB Objective Angiotensin II type 1 receptor (AT(1)) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT(1). To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-gamma (PPAR gamma)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPAR gamma-stimulating activity. Methods Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT(1) mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPAR gamma activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPAR gamma gene silencing. Results In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-kappa B activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-alpha, inhibitor of kappa B-alpha, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPARg target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPARg antagonism and PPARg gene silencing. Antiinflammatory effects of ARBs correlated with their PPAR gamma agonist potency. Conclusion Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPAR gamma activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role. J Hypertens 30:87-96 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Pang, Tao; Benicky, Julius; Wang, Juan; Orecna, Martina; Sanchez-Lemus, Enrique; Saavedra, Juan M.] NIMH, Pharmacol Sect, Div Intramural Res Programs, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Pang, T (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, Dept Hlth & Human Serv,NIH, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM pangt@mail.nih.gov FU Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, USA FX This study was supported by the Division of Intramural Research Programs, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, USA. NR 53 TC 28 Z9 29 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JAN PY 2012 VL 30 IS 1 BP 87 EP 96 DI 10.1097/HJH.0b013e32834dde5f PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 863HP UT WOS:000298153700016 PM 22124178 ER PT J AU Wang, ZP Lai, YP Bernard, JJ MacLeod, DT Cogen, AL Moss, B Di Nardo, A AF Wang, Zhenping Lai, Yuping Bernard, Jamie J. MacLeod, Daniel T. Cogen, Anna L. Moss, Bernard Di Nardo, Anna TI Skin Mast Cells Protect Mice against Vaccinia Virus by Triggering Mast Cell Receptor S1PR2 and Releasing Antimicrobial Peptides SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HERPES-SIMPLEX-VIRUS; HISTAMINE-RELEASE; IMMUNE-RESPONSE; ANTIVIRAL ACTIVITY; ECZEMA HERPETICUM; APOPTOTIC MIMICRY; SYNTHETIC PEPTIDE; ATOPIC-DERMATITIS; S1P(2) RECEPTOR; INFECTION AB Mast cells (MCs) are well-known effectors of allergic reactions and are considered sentinels in the skin and mucosa. In addition, through their production of cathelicidin, MCs have the capacity to oppose invading pathogens. We therefore hypothesized that MCs could act as sentinels in the skin against viral infections using antimicrobial peptides. In this study, we demonstrate that MCs react to vaccinia virus (VV) and degranulate using a membrane-activated pathway that leads to antimicrobial peptide discharge and virus inactivation. This finding was supported using a mouse model of viral infection. MC-deficient (Kit(wsh-/-)) mice were more susceptible to skin VV infection than the wild type animals, whereas Kit(wsh-/-) mice reconstituted with MCs in the skin showed a normal response to VV. Using MCs derived from mice deficient in cathelicidin antimicrobial peptide, we showed that antimicrobial peptides are one important antiviral granule component in in vivo skin infections. In conclusion, we demonstrate that MC presence protects mice from VV skin infection, MC degranulation is required for protecting mice from VV, neutralizing Ab to the L1 fusion entry protein of VV inhibits degranulation apparently by preventing S1PR2 activation by viral membrane lipids, and antimicrobial peptide release from MC granules is necessary to inactivate VV infectivity. The Journal of Immunology, 2012, 188: 345-357. C1 [Wang, Zhenping; Lai, Yuping; Bernard, Jamie J.; MacLeod, Daniel T.; Cogen, Anna L.; Di Nardo, Anna] Univ Calif San Diego, Dept Med, Div Dermatol, La Jolla, CA 92093 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Di Nardo, A (reprint author), Univ Calif San Diego, Dept Med, Div Dermatol, 9500 Gilman Dr 0869, La Jolla, CA 92093 USA. EM adinardo@ucsd.edu RI Wang, Zhenping/B-4863-2016 FU National Institutes of Health-National Institute of Allergy and Infectious Diseases [1R21A1074766-01A2, 1R01AI093957]; Division of Intramural Research, National Institutes of Health-National Institute of Allergy and Infectious Diseases FX This work was supported by the National Institutes of Health-National Institute of Allergy and Infectious Diseases Grants 1R21A1074766-01A2 and 1R01AI093957 (to A.D.N.) by the Division of Intramural Research, National Institutes of Health-National Institute of Allergy and Infectious Diseases Grants (to B.M.). NR 117 TC 33 Z9 33 U1 2 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 1 PY 2012 VL 188 IS 1 BP 345 EP 357 DI 10.4049/jimmunol.1101703 PG 13 WC Immunology SC Immunology GA 869WE UT WOS:000298628400041 PM 22140255 ER PT J AU Koscso, B Csoka, B Selmeczy, Z Himer, L Pacher, P Virag, L Hasko, G AF Koscso, Balazs Csoka, Balazs Selmeczy, Zsolt Himer, Leonora Pacher, Pal Virag, Laszlo Hasko, Gyoergy TI Adenosine Augments IL-10 Production by Microglial Cells through an A(2B) Adenosine Receptor-Mediated Process SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; INNATE IMMUNITY; TNF-ALPHA; RAW-264.7 MACROPHAGES; CREB ACTIVATION; A(2A) RECEPTORS; BINDING PROTEIN; BRAIN; INTERLEUKIN-10; EXPRESSION AB Microglia are activated by pathogen-associated molecular patterns and produce proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-12, and the anti-inflammatory cytokine IL-10. Adenosine is an endogenous purine nucleoside and a ligand of four G protein-coupled adenosine receptors (ARs), which are the A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR. ARs have been shown to suppress TNF-alpha production by microglia, but their role in regulating IL-10 production has not been studied. In this study, we demonstrate that adenosine augments IL-10 production by activated murine microglia while suppressing the production of proinflammatory cytokines. Because the order of potency of selective AR agonists in inducing IL-10 production was NECA > IB-MECA > CCPA >= CGS21680, and the A(2B)AR antagonist MRS1754 prevented the effect of NECA, we conclude that the stimulatory effect of adenosine on IL-10 production is mediated by the A(2B)AR. Mechanistically, adenosine augmented IL-10 mRNA accumulation by a transcriptional process. Using mutant IL-10 promoter constructs we showed that a CREB-binding region in the promoter mediated the augmenting effect of adenosine on IL-10 transcription. Chromatin immunoprecipitation analysis demonstrated that adenosine induced CREB phosphorylation at the IL-10 promoter. Silencing CREB using lentivirally delivered short hairpin RNA blocked the enhancing effect of adenosine on IL-10 production, confirming a role for CREB in mediating the stimulatory effect of adenosine on IL-10 production. In addition, adenosine augmented IL-10 production by stimulating p38 MAPK. Collectively, our results establish that A(2B)ARs augment IL-10 production by activated murine microglia. The Journal of Immunology, 2012, 188:445-453. C1 [Koscso, Balazs; Csoka, Balazs; Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Koscso, Balazs; Selmeczy, Zsolt; Himer, Leonora] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1083 Budapest, Hungary. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD 20892 USA. [Virag, Laszlo; Hasko, Gyoergy] Univ Debrecen, Dept Med Chem, Med & Hlth Sci Ctr, H-4032 Debrecen, Hungary. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008; Virag, Laszlo/E-6124-2010; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU National Institutes of Health [R01GM66189]; U.S. Army Medical Research and Materiel Command [09065004]; Hungarian Scientific Research Fund [CK 78275, TAMOP-4.2.2-08/1-2008-0019]; National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism FX This work was supported by National Institutes of Health Grant R01GM66189, U.S. Army Medical Research and Materiel Command Grant 09065004, and Hungarian Scientific Research Fund Grants CK 78275 and TAMOP-4.2.2-08/1-2008-0019, and the Intramural Research Program of the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (to P. P.). NR 63 TC 29 Z9 29 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 1 PY 2012 VL 188 IS 1 BP 445 EP 453 DI 10.4049/jimmunol.1101224 PG 9 WC Immunology SC Immunology GA 869WE UT WOS:000298628400051 PM 22116830 ER PT J AU Tsuno, T Mejido, J Zhao, TM Phillips, T Myers, TG Bekisz, J Zoon, KC AF Tsuno, Takaya Mejido, Josef Zhao, Tongmao Phillips, Terry Myers, Timothy G. Bekisz, Joseph Zoon, Kathryn C. TI BID is a Critical Factor Controlling Cell Viability Regulated by IFN-alpha SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE IFN-alpha; cell viability; TRAIL; BID; apoptosis ID IMMUNOAFFINITY CAPILLARY-ELECTROPHORESIS; MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; CYTOCHROME-C; INDUCED APOPTOSIS; BCL-2 PROTEINS; DEATH; BAX; INTERFERON; CLEAVAGE; PATHWAY AB Clinical applications of human interferon (IFN)-alpha have met with varying degrees of success. Nevertheless, key molecules in cell viability regulated by IFN-alpha have not been clearly identified. Our previous study indicated that IFN (alpha, beta, and omega) receptor (IFNAR) 1/2- and IFN regulatory factor 9-RNA interference (RNAi) completely restored cell viability after IFN-alpha treatment in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-a. In this study, IFNAR1/2- and IFN regulatory factor 9-RNAi inhibited the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), but not of Fas ligand, after IFN-alpha treatment. In fact, TRAIL but not Fas ligand inhibited the viability of OVCAR3 cells. IFN-alpha notably upregulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. After TRAIL signaling, caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly restored cell viability in response to IFN-alpha and TRAIL in OVCAR3 cells. Furthermore, BID-RNAi prevented both IFN-alpha and TRAIL from collapsing the mitochondrial membrane potential (Delta Psi(m)). Finally, we provided important evidence that BID overexpression led to significant inhibition of cell viability after IFN-alpha or TRAIL treatments in human lung carcinoma A549 cells resistant to IFN-alpha. Thus, this study suggests that BID is crucial for cell viability regulated by IFN-alpha which can induce mitochondria-mediated apoptosis, indicating a notable potential to be a targeted therapy for IFN-alpha resistant tumors. C1 [Tsuno, Takaya; Mejido, Josef; Zhao, Tongmao; Bekisz, Joseph; Zoon, Kathryn C.] NIAID, Div Intramural Res, NIH, Cytokine Biol Sect, Bethesda, MD 20892 USA. [Phillips, Terry] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Myers, Timothy G.] NIAID, Data Anal & Bioinformat Unit, Genom Technol Sect, Res Technol Branch,NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Div Intramural Res, NIH, Cytokine Biol Sect, 33 North Dr, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU NIAID, NIH FX This study was funded by the Intramural Research Program of the NIAID, NIH. NR 37 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD JAN PY 2012 VL 35 IS 1 BP 23 EP 31 DI 10.1097/CJI.0b013e3182372dcf PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 865QZ UT WOS:000298326700003 PM 22130162 ER PT J AU Hogan, CM DeGruttola, V Sun, X Fiscus, SA Del Rio, C Hare, CB Markowitz, M Connick, E Macatangay, B Tashima, KT Kallungal, B Camp, R Morton, T Daar, ES Little, S AF Hogan, Christine M. DeGruttola, Victor Sun, Xin Fiscus, Susan A. Del Rio, Carlos Hare, C. Bradley Markowitz, Martin Connick, Elizabeth Macatangay, Bernard Tashima, Karen T. Kallungal, Beatrice Camp, Rob Morton, Tia Daar, Eric S. Little, Susan CA A5217 Study Team TI The Setpoint Study (ACTG A5217): Effect of Immediate Versus Deferred Antiretroviral Therapy on Virologic Set Point in Recently HIV-1-Infected Individuals SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACUTE HIV-INFECTION; VIRUS TYPE-1 INFECTION; CD4 CELL COUNTS; IMMUNE-RESPONSES; OBSERVATIONAL COHORT; CONTROLLED TRIAL; VIRAL LOAD; SEROCONVERSION; INTERRUPTION; AIDS AB Background. The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved. Methods. A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group). Results. At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized >= 72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings. Conclusions. Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment. C1 [Hogan, Christine M.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53203 USA. [Hogan, Christine M.] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Markowitz, Martin] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [DeGruttola, Victor; Sun, Xin] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Fiscus, Susan A.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill Sch Med, Chapel Hill, NC 27515 USA. [Del Rio, Carlos] Emory Univ, Dept Global Hlth, Atlanta, GA 30322 USA. [Del Rio, Carlos] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Hare, C. Bradley] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Daar, Eric S.] Harbor UCLA Med Ctr, Dept Med, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Little, Susan] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Connick, Elizabeth] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Macatangay, Bernard] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Tashima, Karen T.] Brown Univ, Miriam Hosp, Providence, RI USA. [Tashima, Karen T.] Brown Univ, Dept Med, Providence, RI 02912 USA. [Kallungal, Beatrice] Social & Sci Syst, Silver Spring, MD USA. [Morton, Tia] NIAID, Bethesda, MD 20892 USA. [Camp, Rob] ACTG Community Advisory Board, Barcelona, Spain. RP Hogan, CM (reprint author), Med Coll Wisconsin, Dept Med, 820 N Plankinton Ave, Milwaukee, WI 53203 USA. EM chogan@mcw.edu RI del Rio, Carlos/B-3763-2012 OI del Rio, Carlos/0000-0002-0153-3517 FU Clinical Trial Unit [CTU] [U01 AI69450, AI069474, AI69432, AI69472, AI 069434, AI27664, AI 069495, U01-AI-096497-05, AI069477, AI 069471, AI06943-01, AI 069424, 5-U01 AI069423, U01 AI069471, 5UO1 AI069502, AI27665, AI069472, AI25859, AI46370, U01-AI069447, U01AI069438, U01AI069511-02, 5UO1 AI069418]; Colorado Clinical and Translational Sciences Institute [CCTSI] [UL1 RR025780]; AIEDRP [P01 AI55356, M01 RR00051, AI43638, AI74621]; Aaron Diamond AIDS Research Center, The Rockefeller University Hospital (AIEDRP) [P01 AI041534, AI047033]; California HIV Research Program [RN07-SD-702]; Clinical Research Center [CRC] [UL1-RR-025014, RR00425, 5-MO1 RR00044]; Center for AIDS Research [CFAR] [P30-AI-045008-12, AI050410, P30 AI050409]; CTSA [UL 1RR025747]; Atlanta Clinical and Translational Science Award [UL1 RR025009]; National Institute of Allergy and Infectious Diseases [U01AI068636, AI68634]; National Institute of Mental Health; National Institute of Dental and Craniofacial Research FX We gratefully acknowledge the hard work of the study staff at all the ACTG and Acute Infection and Early Disease Research Program (AIEDRP) sites who screened and enrolled patients for this trial: M. Graham Ray and Beverly Putnam, University of Colorado Hospital Clinical Research Site (CRS) (Clinical Trial Unit [CTU] grant U01 AI69450, Colorado Clinical and Translational Sciences Institute [CCTSI] grant UL1 RR025780, AIEDRP grant P01 AI55356, M01 RR00051); Aaron Diamond AIDS Research Center, The Rockefeller University Hospital (AIEDRP grants P01 AI041534 and AI047033); Michael F. Para, MD, and Kathy J. Watson, RN, Ohio State University (CTU grant AI069474); Joanne Santangelo, NP, and Dee Dee Pacheco, University of California, San Diego (CTU grant AI69432, AIEDRP grant AI43638, P01 grant AI74621, California HIV Research Program grant RN07-SD-702); Pamela Poethke, RN, Miriam Hospital (CTU grant AI69472); Janine Maenza, MD, and Claire Stevens, PA-C, University of Washington AIDS Clinical Trials Unit (CTU grant AI 069434, Clinical Research Center [CRC] grant UL1-RR-025014), University of Washington Primary Infection Clinic (CTU grant AI27664); Ge-Youl Kim, RN, BSN, and Michael K. Klebert, PhD, RN, ANP-BC, Washington University (CTU grant AI 069495); Pablo Tebas, MD, and Joseph Quinn, RN, BSN, University of Pennsylvania (CTU grant U01-AI-096497-05 and Center for AIDS Research [CFAR] grant P30-AI-045008-12); Margaret A. Fischl, MD, and Hector Bolivar, MD, University of Miami AIDS Clinical Research Unit (CTU grant AI069477); Karen Coleman and Baiba Berzins, Northwestern University CRS (CTU grant AI 069471); Timothy Lane, MD, and Kim Epperson RN, BSN, Moses H. Cone Memorial Hospital (CTU grant AI06943-01); Mario Guerrero and Sadia Shaik, Harbor-UCLA Medical Center (CTU grant AI 069424, CRC grant RR00425); Javier R. Lama, MD, MPH, Investigaciones Medicas en Salud (INMENSA) CTU grant U01AI069438); Donna Pittard, BSN, and Susan Pedersen, BS, BSN, UNC AIDS Clinical Trials Unit (CTU grant 5-U01 AI069423, Center for AIDS Research [CFAR] grant AI050410, CTSA grant UL 1RR025747); Carol Greisberger, RN, BSN, and Mary Adams, RN, BSN, MPh, University of Rochester CRS (CTU grant U01AI069511-02 [as of 12 February 2008], CRC grant 5-MO1 RR00044); Allan S. Tenorio, MD, and Beverly E. Sha, MD, Rush University Medical Center (CTU grant U01 AI069471); C. Bradley Hare, MD, and Deborah Zeitschel, RN, MSN, UCSF AIDS CTU/CRS (CTU grant 5UO1 AI069502); Susan Aileen Olender, MD, Chrisa Hunnewell, ANP, and Madeline Torres, RN, BSN, Columbia University (CTU grant AI27665); Eric Rosenberg, MD, Amy Sbrolla, RN, and Teri Flynn, ANP, Massachusetts General Hospital, Boston (CTU grant AI069472), Brigham and Women's Hospital (CTU grant AI69472), Indiana University (CTU grant AI25859), Beth Israel Medical Center (CTU grant AI46370); Charles E. Davis, Jr, MD, and William Blattner, MD, University of Maryland IHV Baltimore Treatment CRS (CTU grant U01-AI069447); Juan V. Guanira, MD, MPH, Asociacion Civil Impacta Salud y EducaciondMiraflores (CTU grant U01AI069438); Christine Hurley, RN, and Roberto Corales, DO-AIDS Care (CTU grant U01AI069511-02 [as of 12 February 2008], CRC grant 5-MO1 RR00044); Molly Eaton, MD, and Ericka Patrick, RN, Ponce de Leon Center (CTU grant 5UO1 AI069418, CFAR grant P30 AI050409, Atlanta Clinical and Translational Science Award grant UL1 RR025009).; This work was supported by the National Institute of Allergy and Infectious Diseases (U01AI068636), the National Institute of Mental Health, and the National Institute of Dental and Craniofacial Research. The protocol was originally developed as Study AIN503 within the Acute Infection and Early Disease Research Program (U01AI043638). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The project was also supported by a grant (AI68634) from the National Institute of Allergy and Infectious Diseases to the Statistical and Data Analysis Center and from individual site grants listed in the Acknowledgments.; S. F. is a consultant for Gen-Probe, Abbott Molecular and Roche Molecular Systems. C. B. H. has received consulting fees and honoraria from Abbott Laboratories and consulting and speaker's fees and honoraria from Gilead Sciences. M. M. has received consulting and speaker's fees from Gilead Sciences. K. T. T. has received research grants from GlaxoSmithKline, Merck, and Tibotec and consulting fees from Merck. R. C. is a DSMB member and has received honoraria from Takeda. E. S. D. has received research grants from Abbott, Merck, Pfizer, Gilead, and ViiV and consulting fees from Gilead, ViiV, Merck, and Bristol-Myers Squibb. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. NR 45 TC 56 Z9 56 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2012 VL 205 IS 1 BP 87 EP 96 DI 10.1093/infdis/jir699 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 866MW UT WOS:000298386200014 PM 22180621 ER PT J AU Lisco, A Munawwar, A Introini, A Vanpouille, C Saba, E Feng, XM Grivel, JC Singh, S Margolis, L AF Lisco, Andrea Munawwar, Arshi Introini, Andrea Vanpouille, Christophe Saba, Elisa Feng, Xingmin Grivel, Jean-Charles Singh, Sarman Margolis, Leonid TI Semen of HIV-1-Infected Individuals: Local Shedding of Herpesviruses and Reprogrammed Cytokine Network SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-1 INFECTION; TRANSMISSION; VIRUSES; EXPANSION; PLASMA; RANTES; CELLS AB Background. Semen is the main carrier of sexually transmitted viruses, including human immunodeficiency virus type 1 (HIV-1). However, semen is not just a mere passive transporter of virions but also plays an active role in HIV-1 transmission through cytokines and other biological factors. Methods. To study the relationship between viruses and the chemokine-cytokine network in the male genital tract, we measured the concentrations of 21 cytokines/chemokines and the loads of HIV-1 and of 6 herpesviruses in seminal and blood plasma from HIV-1-infected and HIV-uninfected men. Results. We found that (1) semen is enriched in cytokines and chemokines that play key roles in HIV-1 infection or transmission; (2) HIV-1 infection changes the chemokine-cytokine network in semen, further enriching it in cytokines that modulate its replication; (3) HIV-1 infection is associated with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) compartmentalized seminal reactivation; (4) CMV and EBV concomitant seminal shedding is associated with higher HIV-1 loads in blood and seminal plasma; and (5) CMV seminal reactivation increases the seminal levels of the CCR5 ligands RANTES and eotaxin, and of the CXCR3 ligand monokine induced by gamma interferon (MIG). Conclusions. HIV-1 infection results in an aberrant production of cytokines and reactivation of EBV and CMV that further changes the seminal cytokine network. The altered seminal milieu in HIV-1 infection may be a determinant of HIV-1 sexual transmission. C1 [Lisco, Andrea; Introini, Andrea; Vanpouille, Christophe; Saba, Elisa; Grivel, Jean-Charles; Margolis, Leonid] NHLBI, Sect Intercellular Interact, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Feng, Xingmin] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Munawwar, Arshi; Singh, Sarman] All India Inst Med Sci, Div Clin Microbiol, New Delhi, India. [Saba, Elisa] Ist Sci San Raffaele, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy. RP Margolis, L (reprint author), NICHHD, Sect Intercellular Interact, NIH, Bldg 10,Room 9D58, Bethesda, MD 20892 USA. EM margolil@mail.nih.gov OI Singh, Prof. Sarman/0000-0002-0749-9647; Introini, Andrea/0000-0002-9929-8964 FU National Institute of Child Health and Human Development (NICHD); NIH; Indian Council of Medical Research, New Delhi FX This work was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD) and the NIH Intramural-to-India (I-to-I) Program. The work of S. S. was supported by the Extramural Research Grant from Indian Council of Medical Research, New Delhi. NR 24 TC 29 Z9 30 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2012 VL 205 IS 1 BP 97 EP 105 DI 10.1093/infdis/jir700 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 866MW UT WOS:000298386200015 PM 22107749 ER PT J AU Carrillo-Carrasco, N Chandler, RJ Venditti, CP AF Carrillo-Carrasco, Nuria Chandler, Randy J. Venditti, Charles P. TI Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Review ID COBALAMIN-C DISEASE; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE DEFICIENCY; HEMOLYTIC-UREMIC SYNDROME; NITROUS-OXIDE; INBORN-ERRORS; PRENATAL-DIAGNOSIS; HUMAN-FIBROBLASTS; B-12 TRAFFICKING; ACIDURIA; METABOLISM AB Combined methylmalonic acidemia and homocystinuria, cblC type, is an inborn error of intracellular cobalamin metabolism with a wide spectrum of clinical manifestations that is stated to be the most common inherited disorder of cobalamin metabolism. This metabolic disease is caused by mutations in the MMACHC gene and results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, cofactors for the methylmalonyl-CoA mutase and methionine synthase enzymes. Elevated methylmalonic acid and homocysteine with decreased methionine production are the biochemical hallmarks of this disorder. Awareness of the diverse clinical presentations associated with cblC disease is necessary to provide a timely diagnosis, to guide management of affected individuals and to establish a framework for the future treatment of individuals detected through expanded newborn screening. This article reviews the biochemistry, clinical presentations, genotype-phenotype correlations, diagnosis and management of cblC disease. C1 [Carrillo-Carrasco, Nuria; Chandler, Randy J.; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Chandler, Randy J.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 FU National Human Genome Research Institute, National Institutes of Health FX The Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, supported this research. We would like to thank Jennifer Sloan, Brian Brooks, Natalie Hauser and Irini Manoli for helpful discussions, and Maria Teresa Amador for the preparation of Fig. 1. NR 100 TC 42 Z9 53 U1 2 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD JAN PY 2012 VL 35 IS 1 BP 91 EP 102 DI 10.1007/s10545-011-9364-y PG 12 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 870EU UT WOS:000298652700012 PM 21748409 ER PT J AU Carrillo-Carrasco, N Venditti, CP AF Carrillo-Carrasco, Nuria Venditti, Charles P. TI Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Review ID HEMOLYTIC-UREMIC-SYNDROME; COBALAMIN-C DISEASE; ELEVATED HOMOCYSTEINE LEVELS; NITRIC-OXIDE SYNTHASE; MURINE MODEL; GLUTATHIONE-PEROXIDASE; CLINICAL HETEROGENEITY; RETINAL DEGENERATION; CONGENITAL DEFECT; PROTEIN HOMOCYSTEINYLATION AB Combined methylmalonic acidemia and homocystinuria, cblC type, is stated to be the most common inborn error of intracellular cobalamin metabolism. The disorder can display a wide spectrum of clinical manifestations, spanning the prenatal period through late adulthood. While increased homocysteine concentrations and impaired methyl group metabolism may contribute to disease-related complications, the characteristic macular and retinal degeneration seen in many affected patients appears to be unique to cblC disease. The early detection of cblC disease by newborn screening mandates a careful assessment of therapeutic approaches and provides a new opportunity to improve the outcome of affected patients. The following article reviews the current knowledge on the complications, pathophysiology, and outcome of cblC disease in an effort to better guide clinical practice and future therapeutic trials. C1 [Carrillo-Carrasco, Nuria; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 FU Intramural NIH HHS [Z01 HG200318-05] NR 115 TC 29 Z9 31 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD JAN PY 2012 VL 35 IS 1 BP 103 EP 114 DI 10.1007/s10545-011-9365-x PG 12 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 870EU UT WOS:000298652700013 PM 21748408 ER PT J AU Kuehn, D Carter, T Kay, D Brown, M Liu, A Romitti, P Druschel, C Brody, L Mills, J AF Kuehn, D. Carter, T. Kay, D. Brown, M. Liu, A. Romitti, P. Druschel, C. Brody, L. Mills, J. TI VITAMIN A PATHWAY GENES LINKED TO CONGENITAL DIAPHRAGMATIC HERNIA SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Western Regional Meeting CY JAN 25-28, 2012 CL Carmel, CA C1 [Kuehn, D.; Carter, T.; Liu, A.; Mills, J.] Eunice Kennedy Shriver NICHD, NIH, DHHS, Bethesda, MD USA. [Kuehn, D.] USUHS, Bethesda, MD USA. [Kay, D.] NY State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Romitti, P.] U Iowa, Iowa City, IA USA. [Brody, L.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD JAN PY 2012 VL 60 IS 1 BP 393 EP 393 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 869XV UT WOS:000298634402301 ER PT J AU Anzinger, JJ Chang, J Xu, Q Barthwal, MK Bohnacker, T Wymann, MP Kruth, HS AF Anzinger, Joshua J. Chang, Janet Xu, Qing Barthwal, Manoj K. Bohnacker, Thomas Wymann, Matthias P. Kruth, Howard S. TI Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3K gamma-dependent fluid-phase pinocytosis of native LDL SO JOURNAL OF LIPID RESEARCH LA English DT Article DE atherosclerosis; cholesterol; granulocyte-macrophage colony-stimulating factor; phosphoinositide 3-kinase; low density lipoprotein ID LOW-DENSITY-LIPOPROTEIN; COLONY-STIMULATING FACTOR; RECEPTOR-MEDIATED ENDOCYTOSIS; HUMAN ATHEROSCLEROTIC LESIONS; DENDRITIC CELLS; PHOSPHOINOSITIDE 3-KINASE; HYPERLIPIDEMIC MICE; CULTURED-CELLS; MACROPINOCYTOSIS; CHOLESTEROL AB Accumulation of cholesterol by macrophage uptake of LDL is a key event in the formation of atherosclerotic plaques. Previous research has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is present in atherosclerotic plaques and promotes aortic lipid accumulation. However, it has not been determined whether murine GM-CSF-differentiated macrophages take up LDL to become foam cells. GM-CSF-differentiated macrophages from LDL receptor-null mice were incubated with LDL, resulting in massive macrophage cholesterol accumulation. Incubation of LDL receptor-null or wild-type macrophages with increasing concentrations of (125)I-LDL showed nonsaturable macrophage LDL uptake that was linearly related to the amount of LDL added, indicating that LDL uptake was mediated by fluid-phase pinocytosis. Previous studies suggest that phosphoinositide 3-kinases (PI3K) mediate macrophage fluid-phase pinocytosis, although the isoform mediating this process has not been determined. Because PI3K gamma is known to promote aortic lipid accumulation, we investigated its role in mediating macrophage fluid-phase pinocytosis of LDL. Wild-type macrophages incubated with LDL and the PI3K gamma inhibitor AS605240 or PI3K gamma-null macrophages incubated with LDL showed an similar to 50% reduction in LDL uptake and cholesterol accumulation compared with wild-type macrophages incubated with LDL only. These results show that GM-CSF-differentiated murine macrophages become foam cells by fluid-phase pinocytosis of LDL and identify PI3K gamma as contributing to this process.-Anzinger, J. J., J. Chang, Q. Xu, M. K. Barthwal, T. Bohnacker, M. P. Wymann, and H.S. Kruth. Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3K gamma-dependent fluid-phase pinocytosis of native LDL. J. Lipid Res. 2012. 53: 34-42. C1 [Anzinger, Joshua J.; Chang, Janet; Xu, Qing; Barthwal, Manoj K.; Kruth, Howard S.] NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. [Bohnacker, Thomas; Wymann, Matthias P.] Univ Basel, Inst Biochem & Genet, Dept Biomed, Basel, Switzerland. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov RI Wymann, Matthias/C-3227-2008 FU National Heart, Lung, and Blood Institute, National Institutes of Health; Indo-US Science and Technology Forum; International Atherosclerosis Society FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. M.K.B. was supported by a fellowship from the Indo-US Science and Technology Forum and received additional support from the International Atherosclerosis Society. NR 42 TC 13 Z9 14 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JAN PY 2012 VL 53 IS 1 BP 34 EP 42 DI 10.1194/jlr.M018887 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TI UT WOS:000298405900004 PM 22058424 ER PT J AU Vaisman, BL Demosky, SJ Stonik, JA Ghias, M Knapper, CL Sampson, ML Dai, CL Levine, SJ Remaley, AT AF Vaisman, Boris L. Demosky, Stephen J. Stonik, John A. Ghias, Mona Knapper, Cathy L. Sampson, Maureen L. Dai, Cuilian Levine, Stewart J. Remaley, Alan T. TI Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces diet-induced atherosclerosis SO JOURNAL OF LIPID RESEARCH LA English DT Article DE endothelial cells; cholesterol efflux; reverse cholesterol transport; high density lipoprotein; ATP binding cassette transporter A1 ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; TRANSGENIC MICE; CARDIOVASCULAR-DISEASE; SCAVENGER RECEPTOR; CELL BIOLOGY; OXIDATIVE STRESS; KAWASAKI-DISEASE; GENE-EXPRESSION; DYSFUNCTION AB The role of endothelial ABCA1 expression in reverse cholesterol transport (RCT) was examined in transgenic mice, using the endothelial-specific Tie2 promoter. Human ABCA1 (hABCA1) was significantly expressed in endothelial cells (EC) of most tissues except the liver. Increased expression of ABCA1 was not observed in resident peritoneal macrophages. ApoA-I-mediated cholesterol efflux from aortic EC was 2.6-fold higher (P < 0.0001) for cells from transgenic versus control mice. On normal chow diet, Tie2 hABCA1 transgenic mice had a 25% (P < 0.0001) increase in HDL-cholesterol (HDL-C) and more than a 2-fold increase of eNOS mRNA in the aorta (P < 0.04). After 6 months on a high-fat, high-cholesterol (HFHC) diet, transgenic mice compared with controls had a 40% increase in plasma HDL-C (P < 0.003) and close to 40% decrease in aortic lesions (P < 0.02). Aortas from HFHC-fed transgenic mice also showed gene expression changes consistent with decreased inflammation and apoptosis. Beneficial effects of the ABCA1 transgene on HDL-C levels or on atherosclerosis were absent when the transgene was transferred onto ApoE or Abca1 knockout mice. In summary, expression of hABCA1 in EC appears to play a role in decreasing diet-induced atherosclerosis in mice and is associated with increased plasma HDL-C levels and beneficial gene expression changes in EC.-Vaisman, B.L., S.J. Demosky, J.A. Stonik, M. Ghias, C.L. Knapper, M.L. Sampson, C. Dai, S.J. Levine, and A. T. Remaley. Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces dietinduced atherosclerosis. J. Lipid Res. 2012. 53: 158-167. C1 [Vaisman, Boris L.; Demosky, Stephen J.; Stonik, John A.; Ghias, Mona; Knapper, Cathy L.; Dai, Cuilian; Levine, Stewart J.; Remaley, Alan T.] NHLBI, Cardiovasc Pulm Branch, Bethesda, MD 20892 USA. [Sampson, Maureen L.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Vaisman, BL (reprint author), NHLBI, Cardiovasc Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. EM borisv@mail.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health FX This work was supported by intramural funds from National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 64 TC 27 Z9 30 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JAN PY 2012 VL 53 IS 1 BP 158 EP 167 DI 10.1194/jlr.M018713 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TI UT WOS:000298405900016 PM 22039582 ER PT J AU Knerr, PJ Branco, MC Nagarkar, R Pochan, DJ Schneider, JP AF Knerr, Patrick J. Branco, Monica C. Nagarkar, Radhika Pochan, Darrin J. Schneider, Joel P. TI Heavy metal ion hydrogelation of a self-assembling peptide via cysteinyl chelation SO JOURNAL OF MATERIALS CHEMISTRY LA English DT Article ID DESIGNED PEPTIDE; AS(III) BINDING; REMOVAL; PROTEIN; COORDINATION; WATER; REMEDIATION AB Hydrogel materials are finding use in heavy metal ion detection and remediation. MBHP is a twenty-residue peptide capable of undergoing hydrogelation in response to heavy metal ion binding. The unstructured peptide binds monomethylarsonous acid, Pb(2+), Zn(2+), Cd(2+) or Hg(2+) and subsequently folds into an amphiphilic beta-hairpin that rapidly self-assembles into a beta-sheet rich fibrillar network as shown by CD spectroscopy and transmission electron microscopy. LCMS shows that MBHP binds metal ions with a 1 : 1 stoichiometry. Oscillatory rheology indicates that moderately rigid hydrogels are formed as a result of metal ion binding, peptide folding and ultimate self-assembly with storage moduli (G') ranging from similar to 1000-4000 Pa. C1 [Branco, Monica C.; Schneider, Joel P.] NCI, Biol Chem Lab, Frederick, MD 21701 USA. [Knerr, Patrick J.; Nagarkar, Radhika] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, Frederick, MD 21701 USA. EM schneiderjp@mail.nih.gov RI Schneider, Joel/N-2610-2014 FU National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 50 TC 29 Z9 29 U1 5 U2 70 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0959-9428 J9 J MATER CHEM JI J. Mater. Chem. PY 2012 VL 22 IS 4 BP 1352 EP 1357 DI 10.1039/c1jm14418a PG 6 WC Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 873JG UT WOS:000298878100016 ER PT J AU Miller, FG AF Miller, Franklin G. TI Research and complicity: the case of Julius Hallervorden SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID EUTHANASIA PROGRAM; SCIENCE AB The charge of complicity has been raised in debates over the ethics of fetal tissue transplantation and embryonic stem cell research. However, the applicability of the concept of complicity to these types of research is neither clear nor uncontroversial. This article discusses the historical case of Julius Hallervorden, a distinguished German neuropathologist who conducted research on brains of mentally handicapped patients killed in the context of the Nazi 'euthanasia' programme. It is argued that this case constitutes a paradigm of complicity in research that is useful in assessing complicity in contemporary research ethics. C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Clinical Center, NIH FX This research was supported by the Intramural Research Program of the Clinical Center, NIH. NR 17 TC 5 Z9 5 U1 2 U2 8 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD JAN PY 2012 VL 38 IS 1 BP 53 EP 56 DI 10.1136/jme.2011.044586 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 863AU UT WOS:000298136000014 PM 21693567 ER PT J AU Texel, SJ Camandola, S Ladenheim, B Rothman, SM Mughal, MR Unger, EL Cadet, JL Mattson, MP AF Texel, Sarah J. Camandola, Simonetta Ladenheim, Bruce Rothman, Sarah M. Mughal, Mohamed R. Unger, Erica L. Cadet, Jean Lud Mattson, Mark P. TI Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE anxiety; BDNF; iron; learning and memory; norepinephrine; serotonin ID INHERITED NEURODEGENERATIVE DISEASE; TRYPTOPHAN-HYDROXYLASE ACTIVITY; NEUROTROPHIC FACTOR; MESSENGER-RNA; RAT-BRAIN; MOOD DISORDERS; DEPRESSION; MICE; NOREPINEPHRINE; EXPRESSION AB Ceruloplasmin (Cp) is a ferroxidase involved in iron metabolism by converting Fe2+ to Fe3+, and by regulating cellular iron efflux. In the ceruloplasmin knockout (CpKO) mouse, the deregulation of iron metabolism results in moderate liver and spleen hemosiderosis, but the impact of Cp deficiency on brain neurochemistry and behavior in this animal model is unknown. We found that in contrast to peripheral tissues, iron levels in the hippocampus are significantly reduced in CpKO mice. Although it does not cause any discernable deficits in motor function or learning and memory, Cp deficiency results in heightened anxiety-like behavior in the open field and elevated plus maze tests. This anxiety phenotype is associated with elevated levels of plasma corticosterone. Previous studies provided evidence that anxiety disorders and long-standing stress are associated with reductions in levels of serotonin (5HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus. We found that levels of 5HT and norepinephrine (NE), and the expression of BDNF and its receptor trkB, are significantly reduced in the hippocampus of CpKO mice. Thus, Cp deficiency causes an anxiety phenotype by a mechanism that involves decreased levels of iron, 5HT, NE, and BDNF in the hippocampus. C1 [Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, BRC, Baltimore, MD 21224 USA. [Texel, Sarah J.; Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ladenheim, Bruce; Cadet, Jean Lud] Natl Inst Drug Abuse, Mol Neuropsychiat Branch, Intramural Res Program, Baltimore, MD USA. [Unger, Erica L.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, BRC, 251 Bayview, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. We thank Henriette van Praag for valuable advice on behavioral testing procedures and Chris Earley for comments on the manuscript. NR 60 TC 12 Z9 13 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JAN PY 2012 VL 120 IS 1 BP 125 EP 134 DI 10.1111/j.1471-4159.2011.07554.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 861ZV UT WOS:000298060500013 PM 22035068 ER PT J AU Depboylu, C Weihe, E Eiden, LE AF Depboylu, Candan Weihe, Eberhard Eiden, Lee E. TI Lentiviral Infection of Rhesus Macaques Causes Long-Term Injury to Cortical and Hippocampal Projections of Prostaglandin-Expressing Cholinergic Basal Forebrain Neurons SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE AIDS; Antiretroviral treatment; Cholinergic; Dementia; Encephalitis; Prostaglandins ID IMMUNODEFICIENCY-VIRUS ENCEPHALITIS; MESSENGER-RNA EXPRESSION; NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; CEREBRAL-CORTEX; NUCLEUS BASALIS; RAT-BRAIN; ACETYLTRANSFERASE ACTIVITY; INDUCIBLE CYCLOOXYGENASE; IMPAIRED PERFORMANCE AB The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiency syndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenase isotypes 1 and 2 (COX1 and COX2) in the brains of SIV-infected macaques with or without encephalitis and antiretroviral therapy and uninfected controls. Cyclooxygenase isotype 1, but not COX2, was coexpressed with markers of cholinergic phenotype, that is, choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human, brain. Cyclooxygenase isotype 1 was decreased in basal forebrain neurons in macaques with AIDS versus uninfected and asymptomatic SIV-infected macaques. The VAChT-positive fiber density was reduced in frontal, parietal, and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2',3'-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results further imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent irreversible brain damage. C1 [Depboylu, Candan; Weihe, Eberhard] Univ Marburg, Dept Mol Neurosci, Inst Anat & Cell Biol, Marburg, Germany. [Depboylu, Candan] Univ Marburg, Dept Neurol, Marburg, Germany. [Eiden, Lee E.] NIMH, SMN, LCMR, IRP,NIH, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, SMN, LCMR, IRP,NIH, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU Volkswagen-Stiftung [VW-I-71450, VW-I-75184]; National Institute of Mental Health [Z01 MH002386-24] FX This work was supported by the Volkswagen-Stiftung (project numbers VW-I-71450 and VW-I-75184) and the National Institute of Mental Health Intramural Research Program (project number Z01 MH002386-24). NR 55 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JAN PY 2012 VL 71 IS 1 BP 15 EP 27 DI 10.1097/NEN.0b013e31823cfac5 PG 13 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 869XY UT WOS:000298634800002 PM 22157616 ER PT J AU Venkatakrishnan, A Sandrini, M AF Venkatakrishnan, Anusha Sandrini, Marco TI Combining transcranial direct current stimulation and neuroimaging: novel insights in understanding neuroplasticity SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE neuroimaging; functional magnetic resonance imaging; electroencephalography; graph theory ID HUMAN BRAIN; MODULATION; ACTIVATION AB Venkatakrishnan A, Sandrini M. Combining transcranial direct current stimulation and neuroimaging: novel insights in understanding neuroplasticity. J Neurophysiol 107: 1-4, 2012. First published August 10, 2011; doi: 10.1152/jn.00557.2011.-In recent years, noninvasive brain stimulation techniques like transcranial direct current stimulation (tDCS) have gained immense popularity owing to their effects on modulating cortical activity and consequently motor and cognitive performance. However, the neurophysiology underlying such neuroplastic changes is less understood. This article critically evaluates the contemporary approach of combined tDCS and neuroimaging as a means to provide novel insights in understanding the neurophysiological and neuroplastic processes modulated by this brain stimulation technique. We end by briefly suggesting further lines of inquiry. C1 [Venkatakrishnan, Anusha; Sandrini, Marco] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Venkatakrishnan, Anusha; Sandrini, Marco] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Venkatakrishnan, Anusha] Univ Maryland, Grad Program Neurosci & Cognit Sci, College Pk, MD 20742 USA. RP Venkatakrishnan, A (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, NIH Bldg 10,Rm 7D52, Bethesda, MD 20892 USA. EM venkatakrishna@ninds.nih.gov RI Sandrini, Marco/J-2276-2014; OI Sandrini, Marco/0000-0002-1664-5722; Venkatakrishnan, Anusha/0000-0002-9449-3971 FU Department of Defense in the Center for Neuroscience and Regenerative Medicine FX This work was supported by funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine to A. Venkatakrishnan and M. Sandrini. NR 12 TC 25 Z9 26 U1 1 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JAN PY 2012 VL 107 IS 1 BP 1 EP 4 DI 10.1152/jn.00557.2011 PG 4 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 870AZ UT WOS:000298642800001 PM 21832036 ER PT J AU Nayak, TK Garmestani, K Milenic, DE Brechbiel, MW AF Nayak, Tapan K. Garmestani, Kayhan Milenic, Diane E. Brechbiel, Martin W. TI PET and MRI of Metastatic Peritoneal and Pulmonary Colorectal Cancer in Mice with Human Epidermal Growth Factor Receptor 1-Targeted Zr-89-Labeled Panitumumab SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE immunoPET; PET; MRI; HER1; metastatic colorectal cancer; panitumumab; Zr-89 ID EXPRESSION; CARCINOMA; CETUXIMAB; THERAPY; TUMORS; KRAS AB Human epidermal growth factor receptor 1 (HER1) plays an important role in the pathogenesis of colorectal cancer. Panitumumab is an anti-HER1 monoclonal antibody approved for use in colorectal cancer. However, few data exist regarding HER1 status in the corresponding distant metastases, and little corresponding information is available regarding the localization of panitumumab at primary and metastatic lesions. The utility of PET and MRI using Zr-89-panitumumab to assess the status of HER1 in distant metastases with different metastasis models is presented in this study. Methods: In vivo biodistribution and PET studies were performed in HER1-expressing LS-174T and HER1-negative A375 tumor xenografts. Additionally, studies were performed in different models of intraperitoneal and pulmonary metastases. MRI studies were performed for metastatic models to characterize the targeting potential of Zr-89-panitumumab at different lesion sites. Results: HER1-mediated targeting was achieved in all HER1-expressing models. The LS-174T tumor area under the curve (AUC) was 3.7-fold greater than the AUC for A375. The LS-174T tumor AUC of 204.13 +/- 9.67 was significantly greater (P < 0.001) than the LS-174T tumor AUC of 36.45 +/- 1.39 obtained from mice coinjected with 0.1 mg of panitumumab for blocking the target. Differences were observed in 2 intraperitoneal models; tumor uptake in mice with a 3-d tumor burden was more than 2-fold greater than the mice with a 7-d tumor burden. PET and MRI studies revealed HER1-mediated tumor targeting in all metastatic models. However, significant differences were observed between different LS-174T tumor models. Peak tumor uptake of approximately 40 percentage injected dose per gram (%ID/g) was observed at 3-4 d after injection for the subcutaneous tumor model, in contrast to approximately 75 %ID/g at 2 d after injection for the thoracic tumors and approximately 95 %ID/g at 1-2 d after injection for the intraperitoneal tumors. Conclusion: The potential utility of Zr-89-panitumumab in assessing HER1 status in distant metastases and understanding the variations in antibody uptake at different lesion sites is demonstrated in this study. Zr-89-panitumumab can play a vital role in patient stratification and immunotherapy and therefore warrants further investigation for clinical translation. C1 [Nayak, Tapan K.; Garmestani, Kayhan; Milenic, Diane E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Nayak, TK (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC 1002,Room B3B69, Bethesda, MD 20892 USA. EM tapann@gmail.com OI Nayak, Tapan/0000-0002-3706-6092 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; U.S. Department of Health and Human Services FX We thank Lawrence Szajek (Clinical Center, NIH) for his assistance in irradiating the yttrium target. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research, and the U.S. Department of Health and Human Services. No other potential conflict of interest relevant to this article was reported. NR 26 TC 41 Z9 42 U1 4 U2 11 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN 1 PY 2012 VL 53 IS 1 BP 113 EP 120 DI 10.2967/jnumed.111.094169 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 870HV UT WOS:000298660900027 PM 22213822 ER PT J AU Pitchakarn, P Ohnuma, S Pintha, K Pompimon, W Ambudkar, SV Limtrakul, P AF Pitchakarn, Pornsiri Ohnuma, Shinobu Pintha, Komsak Pompimon, Wilart Ambudkar, Suresh V. Limtrakul, Pornngarm TI Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE ABC transporter; Bitter melon; Chemosensitivity; Multidrug resistance; P-glycoprotein; Kuguacin J ID BITTER-MELON MOMORDICA; CUCURBITANE TRITERPENOIDS; ATPASE ACTIVITY; CELLS; MODULATION; EXTRACT; EXPRESSION; CURCUMIN; ABCB1; TRANSPORTERS AB Multidrug resistance (MDR) is a major factor in the failure of chemotherapy in cancer patients. Resistance to chemotherapy has been correlated to the overexpression of ABC drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. Our previous study showed that bitter melon (Momordica charantia) leaf extract (BMLE) was able to reverse the MDR phenotype by increasing the intracellular accumulation of chemotherapeutic drugs. In the present study, bioguided fractionation was used to identify the active component(s) of BMLE that is able to modulate the function of P-gp and the MDR phenotype in a human cervical carcinoma cell line (KB-V1). We found that kuguacin J, one of the active components in BMLE, increased sensitivity to vinblastine and paclitaxel in KB-V1 cells. A flow cytometry assay indicated that kuguacin J inhibits the transport function of P-gp and thereby significantly increases the accumulation of rhodamine 123 and calcein AM in the cells. These results were confirmed by [(3)H]-vinblastine transport assay. Kuguacin J significantly increases intracellular [(3)H]-vinblastine accumulation and decreased the [(3)H]-vinblastine efflux in the cells. Kuguacin J also inhibited the incorporation of [(125)I]-iodoarylazidoprazosin into P-gp in a concentration-dependent manner, indicating that kuguacin J directly interacts with the drug-substrate-binding site on P-gp. These results indicate that kuguacin J modulates the function of P-gp by directly interacting at the drug-substrate-binding site, and it appears to be an effective inhibitor of P-gp activity in vitro and thus could be developed as an effective chemosensitizer to treat multidrug-resistant cancers. (C) 2012 Elsevier Inc. All rights reserved. C1 [Pitchakarn, Pornsiri; Pintha, Komsak; Limtrakul, Pornngarm] Chiang Mai Univ, Fac Med, Dept Biochem, Chiang Mai 50200, Thailand. [Ohnuma, Shinobu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pompimon, Wilart] Lampang Rajabhat Univ, Dept Chem, Lab Nat Prod, Fac Sci, Lampang 52100, Thailand. RP Limtrakul, P (reprint author), Chiang Mai Univ, Fac Med, Dept Biochem, Chiang Mai 50200, Thailand. EM plimtrak@med.cmu.ac.th FU National Research Council of Thailand; Royal Golden Jubilee Scholarship Ph.D. Program (R.G.J.); National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the National Research Council of Thailand, the Royal Golden Jubilee Scholarship Ph.D. Program (R.G.J.) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (S.O. and S.V.A.). We thank George Leiman for editorial assistance in preparation of the manuscript. NR 36 TC 14 Z9 15 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD JAN PY 2012 VL 23 IS 1 BP 76 EP 84 DI 10.1016/j.jnutbio.2010.11.005 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 867GQ UT WOS:000298443300009 PM 21414769 ER PT J AU Baracos, V Caserotti, P Earthman, CP Fields, D Gallagher, D Hall, KD Heymsfield, SB Muller, MJ Rosen, AN Pichard, C Redman, LM Shen, W Shepherd, JA Thomas, D AF Baracos, Vickie Caserotti, Paolo Earthman, Carrie P. Fields, David Gallagher, Dympna Hall, Kevin D. Heymsfield, Steven B. Mueller, Manfred J. Rosen, Antonella Napolitano Pichard, Claude Redman, Leanne M. Shen, Wei Shepherd, John A. Thomas, Diana TI Advances in the Science and Application of Body Composition Measurement SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article ID RESTING ENERGY-EXPENDITURE; X-RAY ABSORPTIOMETRY; FAT-FREE MASS; AIR DISPLACEMENT PLETHYSMOGRAPH; MAGNETIC-RESONANCE METHOD; METABOLIC-RATE; ADIPOSE-TISSUE; WEIGHT-LOSS; BIOIMPEDANCE SPECTROSCOPY; MUSCLE MASS C1 [Heymsfield, Steven B.; Redman, Leanne M.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Baracos, Vickie] Univ Alberta, Dept Oncol, Edmonton, AB, Canada. [Caserotti, Paolo] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Earthman, Carrie P.] Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN USA. [Fields, David] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Childrens Med Res Inst,Diabet & Metab Res Program, Oklahoma City, OK 73190 USA. [Gallagher, Dympna; Shen, Wei] Columbia Univ, New York Obes Res Ctr, St Lukes Roosevelt Hosp, New York, NY USA. [Gallagher, Dympna; Shen, Wei] Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. [Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Mueller, Manfred J.] Univ Kiel, Inst Human Nutr & Food Sci, Kiel, Germany. [Rosen, Antonella Napolitano] Cambridge Univ Hosp NHS Trust, Clin Unit Cambridge, GlaxoSmithKline, Cambridge, England. [Pichard, Claude] Univ Hosp Geneva, Dept Clin Nutr, Geneva, Switzerland. [Shepherd, John A.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Thomas, Diana] Montclair State Univ, Dept Math Sci, Montclair, NJ USA. RP Heymsfield, SB (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Steven.Heymsfield@pbrc.edu OI Baracos, Vickie/0000-0002-9609-1001; Gallagher, Dympna/0000-0003-1769-9754 FU National Institute of Diabetes and Digestive and Kidney Diseases [5U13DK064190] FX The 2011 A.S.P.E.N. Research Workshop, "Current Advances in the Science and Application of Body Composition Measurement," was supported by award number 5U13DK064190 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. NR 92 TC 21 Z9 21 U1 2 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD JAN PY 2012 VL 36 IS 1 BP 96 EP 107 DI 10.1177/0148607111417448 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 874XS UT WOS:000298992000013 PM 22235108 ER PT J AU O'Brien, K Font-Montgomery, E Lukose, L Bryant, J Piwnica-Worms, K Edwards, H Riney, L Garcia, A Daryanani, K Choyke, P Mohan, P Heller, T Gahl, WA Gunay-Aygun, M AF O'Brien, Kevin Font-Montgomery, Esperanza Lukose, Linda Bryant, Joy Piwnica-Worms, Katie Edwards, Hailey Riney, Lauren Garcia, Angelica Daryanani, Kailash Choyke, Peter Mohan, Parvathi Heller, Theo Gahl, William A. Gunay-Aygun, Meral TI Congenital Hepatic Fibrosis and Portal Hypertension in Autosomal Dominant Polycystic Kidney Disease SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease; congenital hepatic fibrosis; polycystic liver disease; portal hypertension ID LIVER-DISEASE; CYSTIC DISEASE; VOLUME; PATHOGENESIS; CHILDREN; ENCODES; PROTEIN; LENGTH; CILIA; WOMAN AB Objectives: Autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases are the most common hepatorenal fibrocystic diseases (ciliopathies). Characteristics of liver disease of these disorders are quite different. All of the patients with ARPKD have congenital hepatic fibrosis (CHF) often complicated by portal hypertension. In contrast, typical liver involvement in ADPKD is polycystic liver disease, although rare atypical cases with CHF are reported. Our goal was to describe the characteristics of CHF in ADPKD. Patients and Methods: As a part of an intramural study of the National Institutes of Health on ciliopathies (www.clinicaltrials.gov, trial NCT00068224), we evaluated 8 patients from 3 ADPKD families with CHF. We present their clinical, biochemical, imaging, and PKD1 and PKHD1 sequencing results. In addition, we tabulate the characteristics of 15 previously reported patients with ADPKD-CHF from 11 families. Results: In all of the 19 patients with ADPKD-CHF (9 boys, 10 girls), portal hypertension was the main manifestation of CHF; hepatocelllular function was preserved and liver enzymes were largely normal. In all of the 14 families, CHF was not inherited vertically, that is the parents of the index cases had PKD but did not have CHF-suggesting modifier gene(s). Our 3 families had pathogenic mutations in PKD1; sequencing of the PKHD1 gene as a potential modifier did not reveal any mutations. Conclusions: Characteristics of CHF in ADPKD are similar to CHF in ARPKD. ADPKD-CHF is caused by PKD1 mutations, with probable contribution from modifying gene(s). Given that both boys and girls are affected, these modifier(s) are likely located on autosomal chromosome(s) and less likely X-linked. C1 [O'Brien, Kevin; Font-Montgomery, Esperanza; Lukose, Linda; Bryant, Joy; Piwnica-Worms, Katie; Edwards, Hailey; Riney, Lauren; Garcia, Angelica; Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Daryanani, Kailash] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Mohan, Parvathi] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Heller, Theo] NIDDK, NIH, Bethesda, MD USA. RP Gunay-Aygun, M (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 10C103, Bethesda, MD 20892 USA. EM mgaygun@mail.nih.gov FU National Human Genome Research Institute; NIH Clinical Center FX This study was supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Clinical Center. NR 42 TC 5 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JAN PY 2012 VL 54 IS 1 BP 83 EP 89 DI 10.1097/MPG.0b013e318228330c PG 7 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 868UG UT WOS:000298550800016 PM 21694639 ER PT J AU Vos, MB Colvin, R Belt, P Molleston, JP Murray, KF Rosenthal, P Schwimmer, JB Tonascia, J Unalp, A Lavine, JE AF Vos, Miriam B. Colvin, Ryan Belt, Patricia Molleston, Jean P. Murray, Karen F. Rosenthal, Philip Schwimmer, Jeffrey B. Tonascia, James Unalp, Aynur Lavine, Joel E. CA NASH CRN Res Grp TI Correlation of Vitamin E, Uric Acid, and Diet Composition With Histologic Features of Pediatric NAFLD SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE nonalcoholic steatohepatitis; nutrition; sugar-sweetened beverages; vitamin C ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; FRUCTOSE CONSUMPTION; CHILDREN; ADOLESCENTS; OBESE; RISK; TRIAL; SUGAR; YOUTH AB Objectives: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease. Subjects and Methods: This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria. Results: No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased ballooning degeneration (P 0.05). Conclusions: Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated. C1 [Vos, Miriam B.] Emory Univ, Atlanta, GA 30322 USA. [Colvin, Ryan; Tonascia, James; Unalp, Aynur] Johns Hopkins Univ, Baltimore, MD USA. [Belt, Patricia] NIDDK, NIH, Bethesda, MD USA. [Molleston, Jean P.] Indiana Univ, Indianapolis, IN 46204 USA. [Murray, Karen F.] Univ Washington, Seattle, WA 98195 USA. [Rosenthal, Philip] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schwimmer, Jeffrey B.] Univ Calif San Diego, San Diego, CA 92103 USA. RP Lavine, JE (reprint author), Columbia Univ, Med Ctr, Morgan Stanley Childrens Hosp New York, 3959 Broadway,CHN7-702, New York, NY 10032 USA. EM jl3553@columbia.edu FU National Institute of Diabetes and Digestive Diseases (NIDDK) [U01DK061732, U01DK061713, U01DK061737, U01DK061718, U01DK061734, U01DK061738, U01DK061728, U01DK061731, U01DK061730]; National Institute of Child Health and Human Development (NICHD); National Institutes of Health General Clinical Research Centers or Clinical and Translational Science [UL1RR024989, M01RR000750, RR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR00188, M01RR020359]; NIH [K23DK080953]; Children's Digestive Health and Nutrition Foundation FX The NASH CRN is supported by the National Institute of Diabetes and Digestive Diseases (NIDDK) grants U01DK061732 (Case Western Reserve University), U01DK061713 (Duke University Medical Center), U01DK061737 (Indiana University), U01DK061718 (St Louis University), U01DK061734 (Columbia University), U01DK061738 (University of California, San Francisco), U01DK061728 (University of Washington), U01DK061731 (Virginia Commonwealth University), and U01DK061730 (Johns Hopkins University) and the National Institute of Child Health and Human Development (NICHD). Other grant support includes the following: National Institutes of Health General Clinical Research Centers or Clinical and Translational Science Awards: UL1RR024989, M01RR000750, RR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR00188, M01RR020359. M. B. Vos is supported by NIH K23DK080953 and the Children's Digestive Health and Nutrition Foundation/ Nestle Nutrition Award. NR 33 TC 47 Z9 49 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JAN PY 2012 VL 54 IS 1 BP 90 EP 96 DI 10.1097/MPG.0b013e318229da1a PG 7 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 868UG UT WOS:000298550800017 PM 22197855 ER PT J AU Hambidge, KM Mazariegos, M Kindem, M Wright, LL Cristobal-Perez, C Juarez-Garcia, L Westcott, JE Goco, N Krebs, NF AF Hambidge, K. Michael Mazariegos, Manolo Kindem, Mark Wright, Linda L. Cristobal-Perez, Christina Juarez-Garcia, Lucrecia Westcott, Jamie E. Goco, Norman Krebs, Nancy F. TI Infant Stunting Is Associated With Short Maternal Stature SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE infant growth; maternal height; stunting ID GROWTH; SUPPLEMENTATION; HEIGHT AB The objectives were to determine the range of maternal height associated with growth velocity of older infants and the magnitude of this association in an indigent population. Maternal height and infant length-for-age z scores (LAZ) were positively correlated at both 6 (n = 412, r = 0.324) and 12 (n = 388, r = 0.335) months (P < 0.0001) and for maternal heights from 131 to 164 cm. Maternal height is independently associated with infant LAZ and stunting (LAZ < -2) at both 6 and 12 months (P < 0.001) and with linear growth velocity from 6 to 12 months (P = 0.0023). C1 [Hambidge, K. Michael; Westcott, Jamie E.; Krebs, Nancy F.] Univ Colorado, Dept Pediat, Sect Nutr, Aurora, CO 80045 USA. [Mazariegos, Manolo; Cristobal-Perez, Christina; Juarez-Garcia, Lucrecia] Inst Nutr Cent Amer & Panama, Guatemala City, Guatemala. [Goco, Norman] Res Triangle Int, Res Triangle Pk, NC USA. [Wright, Linda L.] Natl Inst Child Hlth & Human Dev, NIH, Rockville, MD USA. RP Hambidge, KM (reprint author), Univ Colorado, Dept Pediat, Sect Nutr Res, 12700 E 19th Ave,Box C225, Aurora, CO 80045 USA. EM Michael.Hambidge@ucdenver.edu FU Global Network for Women's and Children's Health Research [NICHD U01 HD040657, U01 HD040636]; NIH [K24 RR018357] FX This work was supported by the Global Network for Women's and Children's Health Research (NICHD U01 HD040657 and U01 HD040636, and the Office of Dietary Supplements) and NIH grant K24 RR018357. NR 6 TC 6 Z9 6 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JAN PY 2012 VL 54 IS 1 BP 117 EP 119 DI 10.1097/MPG.0b013e3182331748 PG 3 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 868UG UT WOS:000298550800024 PM 21866055 ER PT J AU Salzer, WL Winick, NJ Wacker, P Lu, XM Devidas, M Shuster, JJ Mahoney, DH Lauer, SJ Camitta, BM AF Salzer, Wanda L. Winick, Naomi J. Wacker, Pierre Lu, Xiaomin Devidas, Meenakshi Shuster, Jonathan J. Mahoney, Donald H. Lauer, Stephen J. Camitta, Bruce M. TI Plasma Methotrexate, Red Blood Cell Methotrexate, and Red Blood Cell Folate Values and Outcome in Children With Precursor B-acute Lymphoblastic Leukemia A Report From the Children's Oncology Group SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE red blood cell methotrexate and folate; childhood acute lymphoblastic leukemia; methotrexate metabolism; red blood cell ID HIGH-DOSE METHOTREXATE; ACUTE LYMPHOCYTIC-LEUKEMIA; INTRAVENOUS METHOTREXATE; THERAPY; RISK; PHARMACOKINETICS; LEUCOVORIN; PHARMACODYNAMICS; MERCAPTOPURINE; IDENTIFICATION AB Plasma steady state methotrexate (MTX) level and red blood cell (RBC) MTX and folate concentrations were evaluated in 1124 children with newly diagnosed acute lymphoblastic leukemia enrolled in the Pediatric Oncology Group studies 9005 (lower risk; Regimens A and C) and 9006 (higher risk; Regimen A). These regimens included intermediate-dose MTX (1 g/m(2)) given as a 24 hours infusion every other week for 12 doses during intensification. Plasma MTX level was evaluated at the end of MTX infusions. RBC MTX and folate concentrations were measured at the end of intensification. The 5 year continuous complete remission was 76 +/- 1.4% versus 85 +/- 3.0% for those patients with steady state MTX levels less than or equal to and greater than 14 mu M, respectively (P=0.0125). Hispanic children had significantly reduced median steady state MTX levels, 8.7 mu M, compared with non-Hispanic children, 9.95 mu M (P=0.0015), but this did not correlate with a difference in outcome. Neither RBC MTX, RBC folate, nor the RBC MTX: folate ratio identified children at increased risk of failure. C1 [Salzer, Wanda L.] NCI, Bethesda, MD 20892 USA. [Winick, Naomi J.] Univ Texas SW Sch Med, Div Pediat Hematol Oncol, Dallas, TX USA. [Mahoney, Donald H.] Baylor Coll Med, Dept Pediat, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Wacker, Pierre] Univ Hosp Geneva, Dept Pediat, Hematol Oncol Unit, Geneva, Switzerland. [Lu, Xiaomin] Univ Florida, Dept Biostat, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. [Devidas, Meenakshi] Univ Florida, Dept Biostat, Coll Med, Gainesville, FL USA. [Shuster, Jonathan J.] Univ Florida, Coll Med, Dept Hlth Outcomes & Policy, Gainesville, FL USA. [Lauer, Stephen J.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Pediat, Midw Childrens Canc Ctr, Milwaukee, WI 53226 USA. RP Salzer, WL (reprint author), NCI IRB, NIH, Bldg 82,Room 215,MSC 8200, Bethesda, MD 20892 USA. EM salzerw@mail.nih.gov FU NIH [CA98543-08, CA29139]; COG FX Supported by NIH U10 grant CA98543-08 and CA29139. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm NR 35 TC 4 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD JAN PY 2012 VL 34 IS 1 BP E1 EP E7 DI 10.1097/MPH.0b013e31820ee239 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 873CY UT WOS:000298859700001 PM 21364468 ER PT J AU Cole, CR Hansen, NI Higgins, RD Bell, EF Shankaran, S Laptook, AR Walsh, MC Hale, EC Newman, NS Das, A Stoll, BJ AF Cole, Conrad R. Hansen, Nellie I. Higgins, Rosemary D. Bell, Edward F. Shankaran, Seetha Laptook, Abbot R. Walsh, Michele C. Hale, Ellen C. Newman, Nancy S. Das, Abhik Stoll, Barbara J. CA Child Hlth Human Dev Neonatal Res TI Bloodstream Infections in Very Low Birth Weight Infants with Intestinal Failure SO JOURNAL OF PEDIATRICS LA English DT Article ID SHORT-BOWEL SYNDROME; NEONATAL RESEARCH NETWORK; LATE-ONSET SEPSIS; PARENTERAL-NUTRITION; PRETERM INFANTS; INTENSIVE-CARE; MANAGEMENT; MORTALITY; OUTCOMES; CHILDREN AB Objective To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSIs) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC). Study design Infants weighing 401-1500 g at birth who survived for >72 hours and received care at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers were studied. The frequency of culture-positive BSI and pathogens were compared in infants with medically managed NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, the duration of parenteral nutrition (PN) and other outcomes were evaluated. Results A total of 932 infants were studied (IF, n = 78; surgical NEC without IF, n = 452; medical NEC, n = 402). The proportion with BSI after diagnosis of NEC was higher in the infants with IF than in those with surgical NEC (P = .007) or medical NEC (P < .001). Gram-positive pathogens were most frequent. Among infants with IF, an increased number of infections was associated with longer hospitalization and duration of PN (median stay: 172 for those with 0 infections, 188 days for those with 1 infection, and 260 days for those with >= 2 infections [P = .06]; median duration of PN: 90, 112, and 115 days, respectively [P = .003]) and decreased achievement of full feeds during hospitalization (87%, 67%, and 50%, respectively; P = .03). Conclusion Recurrent BSIs are common in very low birth weight infants with IF. Gram-positive bacteria were the most commonly identified organisms in these infants. (J Pediatr 2012;160:54-9). C1 [Cole, Conrad R.] Cincinnati Childrens Hosp, Med Ctr, Div Gastroenterol Hepatol & Nutr, Intestinal Rehabil Program, Cincinnati, OH 45229 USA. [Hansen, Nellie I.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Higgins, Rosemary D.] Eunice Kennedy Shiver Natl Inst Child Hlth & Huma, NIH, Bethesda, MD USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Shankaran, Seetha] Dept Pediat, Detroit, MI USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Walsh, Michele C.; Newman, Nancy S.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Hale, Ellen C.; Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. RP Cole, CR (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Gastroenterol Hepatol & Nutr, Intestinal Rehabil Program, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM conrad.cole@cchmc.org FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The Neonatal Research Network's Generic Database (2002-2005) and Follow-up Studies (2003-2007) were supported by grants from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Data collected at participating sites were transmitted to RTI International, the data-coordinating center for the network, which stored, managed, and analyzed the data for this study. The authors declare no conflicts of interest. NR 25 TC 14 Z9 16 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2012 VL 160 IS 1 BP 54 EP U102 DI 10.1016/j.jpeds.2011.06.034 PG 8 WC Pediatrics SC Pediatrics GA 863DM UT WOS:000298143000016 PM 21840538 ER PT J AU Hensler, JG Advani, T Burke, TF Cheng, K Rice, KC Koek, W AF Hensler, Julie G. Advani, Tushar Burke, Teresa F. Cheng, Kejun Rice, Kenner C. Koek, Wouter TI GABA(B) Receptor-Positive Modulators: Brain Region-Dependent Effects SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GAMMA-HYDROXYBUTYRIC ACID; CENTRAL-NERVOUS-SYSTEM; ALLOSTERIC MODULATOR; BINDING-SITES; RAT-BRAIN; IN-VIVO; GHB; AGONIST; CGP7930; MICE AB This study examined the positive modulatory properties of 2,6-di-tert- butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and (R, S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3-Hbenzofuran-2-one (rac-BHFF) at gamma-aminobutyric acid B (GABA(B)) receptors in different brain regions. Using quantitative autoradiography, we measured GABA(B) receptor-stimulated binding of guanosine 5'-O-(3-[35S] thiotriphosphate) ([S-35]GTP gamma S) to G proteins in medial prefrontal cortex (mPFC), hippocampus, and cerebellum. CGP7930 and rac-BHFF enhanced baclofen-stimulated [S-35]GTP gamma S binding similarly in mPFC and hippocampus, but were more effective in cerebellum. CGP7930 (100 mu M) increased [S-35]GTP gamma S binding stimulated by baclofen (30 mu M) from 29 to 241% above basal in mPFC and from 13 to 1530% above basal in cerebellum. Likewise, rac-BHFF (10 mu M) increased baclofen-stimulated [35S] GTP gamma S binding more in cerebellum (from 13 to 1778% above basal) than in mPFC (from 29 to 514% above basal). rac-BHFF (10 mu M) in combination with gamma-hydroxybutyrate (20 mM) increased [35S] GTP gamma S binding in cerebellum but not in mPFC. rac-BHFF also enhanced the effects of 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348). Consistent with its partial agonist properties, CGP35348 stimulated [35S] GTP gamma S binding in mPFC when given alone (to 18% above basal), but less extensively than baclofen (140% above basal), and antagonized baclofen when given together. CGP35348 (1 mM) in combination with rac-BHFF (100 mu M) produced an increase in [35S] GTP gamma S binding that was larger in cerebellum (from 61 to 1260% above basal) than in mPFC (from 18 to 118% above basal). Taken together, the results show that GABA B receptor-positive modulators enhance [35S] GTP gamma S binding stimulated by GABA(B) receptor agonists in a brain region-dependent manner. This regionally selective enhancement is further evidence of pharmacologically distinct GABA(B) receptor populations, possibly allowing for more selective therapeutic targeting of the GABA(B) system. C1 [Hensler, Julie G.; Burke, Teresa F.; Koek, Wouter] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Advani, Tushar; Koek, Wouter] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Hensler, JG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, MC 7764,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM hensler@uthscsa.edu FU National Institutes of Health National Institute on Drug Abuse [DA15692] FX This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant DA15692]. The research of the Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism was supported by the National Institutes of Health Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. NR 39 TC 13 Z9 13 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2012 VL 340 IS 1 BP 19 EP 26 DI 10.1124/jpet.111.186577 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866TZ UT WOS:000298408600003 PM 21954301 ER PT J AU Kaszas, K Keller, JM Coddou, C Mishra, SK Hoon, MA Stojilkovic, S Jacobson, KA Iadarola, MJ AF Kaszas, Krisztian Keller, Jason M. Coddou, Claudio Mishra, Santosh K. Hoon, Mark A. Stojilkovic, Stanko Jacobson, Kenneth A. Iadarola, Michael J. TI Small Molecule Positive Allosteric Modulation of TRPV1 Activation by Vanilloids and Acidic pH SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CAPSAICIN RECEPTOR; PROTON ACTIVATION; PAIN; RESINIFERATOXIN; NEURONS; CHANNEL; 1,4-DIHYDROPYRIDINES; PHOSPHORYLATION; CAPSAZEPINE; ANTAGONISTS AB Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a high-conductance, nonselective cation channel strongly expressed in nociceptive primary afferent neurons of the peripheral nervous system and functions as a multimodal nociceptor gated by temperatures greater than 43 degrees C, protons, and small-molecule vanilloid ligands such as capsaicin. The ability to respond to heat, low pH, vanilloids, and endovanilloids and altered sensitivity and expression in experimental inflammatory and neuropathic pain models made TRPV1 a major target for the development of novel, nonopioid analgesics and resulted in the discovery of potent antagonists. In human clinical trials, observations of hyperthermia and the potential for thermal damage by suppressing the ability to sense noxious heat suggested that full-scale blockade of TRPV1 function can be counterproductive and subtler pharmacological approaches are necessary. Here we show that the dihydropyridine derivative 4,5-diethyl-3-(2-methoxyethylthio)-2-methyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1477) behaves as a positive allosteric modulator of both proton and vanilloid activation of TRPV1. Under inflammatory-mimetic conditions of low pH (6.0) and protein kinase C phosphorylation, addition of MRS1477 further increased sensitivity of already sensitized TPRV1 toward capsaicin. MRS1477 does not affect inhibition by capsazepine or ruthenium red and remains effective in potentiating activation by pH in the presence of an orthosteric vanilloid antagonist. These results indicate a distinct site on TRPV1 for positive allosteric modulation that may bind endogenous compounds or novel pharmacological agents. Positive modulation of TRPV1 sensitivity suggests that it may be possible to produce a selective analgesia through calcium overload restricted to highly active nociceptive nerve endings at sites of tissue damage and inflammation. C1 [Kaszas, Krisztian; Keller, Jason M.; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Mishra, Santosh K.; Hoon, Mark A.] Natl Inst Dent & Craniofacial Res, Mol Genet Unit, Lab Sensory Biol, NIH, Bethesda, MD USA. [Coddou, Claudio; Stojilkovic, Stanko] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, NIH, Bethesda, MD USA. RP Iadarola, MJ (reprint author), Bldg 49,Room 1C08,49 Convent Dr, Bethesda, MD 20892 USA. EM miadarola@dir.nidcr.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health National Institute of Dental and Craniofacial Research, Division of Intramural Research; National Institutes of Health National Institute of Child Health and Human Development; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health National Institute of Mental Health [R03-MH089480-01A1] FX This work was supported by the National Institutes of Health National Institute of Dental and Craniofacial Research, Division of Intramural Research; the National Institutes of Health National Institute of Child Health and Human Development; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institutes of Health National Institute of Mental Health [Grant R03-MH089480-01A1]. NR 36 TC 20 Z9 20 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2012 VL 340 IS 1 BP 152 EP 160 DI 10.1124/jpet.111.183053 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866TZ UT WOS:000298408600017 PM 22005042 ER PT J AU Du, LL Gao, ZG Nithipatikom, K IJzerman, AP van Veldhoven, JPD Jacobson, KA Gross, GJ Auchampach, JA AF Du, Lili Gao, Zhan-Guo Nithipatikom, Kasem IJzerman, Adriaan P. van Veldhoven, Jacobus P. D. Jacobson, Kenneth A. Gross, Garrett J. Auchampach, John A. TI Protection from Myocardial Ischemia/Reperfusion Injury by a Positive Allosteric Modulator of the A(3) Adenosine Receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID AGONIST EFFICACY; DERIVATIVES; ENHANCERS; SERIES; DOGS; ACTIVATION; ISCHEMIA; BINDING; CELLS; HEART AB Adenosine is increased in ischemic tissues where it serves a protective role by activating adenosine receptors (ARs), including the A(3) AR subtype. We investigated the effect of N-{2-[(3,4-dichlorophenyl)amino] quinolin-4-yl}cyclohexanecarboxamide (LUF6096), a positive allosteric modulator of the A(3) AR, on infarct size in a barbital-anesthetized dog model of myocardial ischemia/reperfusion injury. Dogs were subjected to 60 min of coronary artery occlusion and 3 h of reperfusion. Infarct size was assessed by macrohistochemical staining. Three experimental groups were included in the study. Groups I and II received two doses of vehicle or LUF6096 (0.5 mg/kg i.v. bolus), one administered before ischemia and the other immediately before reperfusion. Group III received a single dose of LUF6096 (1 mg/kg i.v. bolus) immediately before reperfusion. In preliminary in vitro studies, LUF6096 was found to exert potent enhancing activity (EC50 114.3 +/- 15.9 nM) with the canine A(3) AR in a guanosine 5'-[gamma-[S-35]thio]triphosphate binding assay. LUF6096 increased the maximal efficacy of the partial A(3) AR agonist 2-chloro-N-6-(3-iodobenzyl) adenosine-5'-N-methylcarboxamide and the native agonist adenosine more than 2-fold while producing a slight decrease in potency. In the dog studies, administration of LUF6096 had no effect on any hemodynamic parameter measured. Pretreatment with LUF6096 before coronary occlusion and during reperfusion in group II dogs produced a marked reduction in infarct size (similar to 50% reduction) compared with group I vehicle-treated dogs. An equivalent reduction in infarct size was observed when LUF6096 was administered immediately before reperfusion in group III dogs. This is the first study to demonstrate efficacy of an A(3) AR allosteric enhancer in an in vivo model of infarction. C1 [Du, Lili; Nithipatikom, Kasem; Gross, Garrett J.; Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. [Du, Lili; Nithipatikom, Kasem; Gross, Garrett J.; Auchampach, John A.] Med Coll Wisconsin, Cardiovasc Ctr, Milwaukee, WI 53226 USA. [Gao, Zhan-Guo; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. [IJzerman, Adriaan P.; van Veldhoven, Jacobus P. D.] Leiden Univ, Div Med Chem, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands. RP Auchampach, JA (reprint author), Med Coll Wisconsin, Dept Pharmacol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM jauchamp@mcw.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health National Heart, Lung, and Blood Institute [R01-HL077707, R37-HL074314]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL077707, R37-HL074314] and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. NR 28 TC 12 Z9 12 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2012 VL 340 IS 1 BP 210 EP 217 DI 10.1124/jpet.111.187559 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866TZ UT WOS:000298408600024 PM 22011434 ER PT J AU Kim, P Jenkins, SE Connolly, ME Deveney, CM Fromm, SJ Brotman, MA Nelson, EE Pine, DS Leibenluft, E AF Kim, Pilyoung Jenkins, Sarah E. Connolly, Megan E. Deveney, Christen M. Fromm, Stephen J. Brotman, Melissa A. Nelson, Eric E. Pine, Daniel S. Leibenluft, Ellen TI Neural correlates of cognitive flexibility in children at risk for bipolar disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Bipolar disorder; Relatives; fMRI; Cognitive flexibility; Cognitive control ID SUBGENUAL PREFRONTAL CORTEX; RESPONSE FLEXIBILITY; 1ST-DEGREE RELATIVES; INHIBITORY CONTROL; MOOD DISORDERS; RATING-SCALE; I DISORDER; TASK; DEFICITS; FMRI AB Background: Youth with bipolar disorder (BD) show behavioral and neural deficits in cognitive flexibility; however, whether such deficits exist among youths at risk for BD has not been explored. Methods: The current fMRI study examined the neural basis of cognitive flexibility in BD youth (n = 28), unaffected youth at risk for BD (AR; n = 13), and healthy volunteer youth (HV; n = 21) by comparing brain activation patterns while participants performed the change task. On change trials, subjects must inhibit a prepotent response and execute an alternate one. Results: During successful change trials, both BD and AR youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to HV youth. During failed change trials, both BD and AR youth exhibited increased caudate activation relative to HV youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex (ACC) relative to the other two groups. Conclusions: Abnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself. Published by Elsevier Ltd. C1 [Kim, Pilyoung] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Kim, P (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, 9000 Rockville Pike,Bldg 15K,Rm 208, Bethesda, MD 20892 USA. EM pilyoung.kim@nih.gov RI Nelson, Eric/B-8980-2008; Brotman, Melissa/H-7409-2013 OI Nelson, Eric/0000-0002-3376-2453; FU National Institute of Mental Health, National Institutes of Health FX Funding for this study was provided exclusively by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. 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 18 Z9 18 U1 3 U2 23 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 JAN PY 2012 VL 46 IS 1 BP 22 EP 30 DI 10.1016/j.jpsychires.2011.09.015 PG 9 WC Psychiatry SC Psychiatry GA 868MR UT WOS:000298527900003 PM 22024484 ER PT J AU Roy, A Hodgkinson, CA DeLuca, V Goldman, D Enoch, MA AF Roy, Alec Hodgkinson, Colin A. DeLuca, Vincenzo Goldman, David Enoch, Mary-Anne TI Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE African Americans; Substance dependence; CTQ; CRH; CRHR1; CRHR2 ID MAJOR DEPRESSIVE DISORDER; PITUITARY-ADRENAL AXIS; ADULT DEPRESSION; ANTIDEPRESSANT TREATMENT; BINDING-PROTEIN; HUMAN BRAIN; CRHR1 GENE; QUESTIONNAIRE; STRESS; ABUSE AB Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Corticotropin releasing hormone (CRH) regulates the HPA axis and its actions are moderated by a high-affinity binding protein (CRHBP). We hypothesized that CRHBP variation and interaction with childhood trauma might influence suicidal behavior. Moreover, there might be an additive effect with FKPB5, another HPA axis gene previously associated with suicidality in this dataset. African Americans were recruited: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). A total of 474 participants (112 suicide attempters) completed the Childhood Trauma Questionnaire (CTQ). Haplotype-tagging SNPs were genotyped across CRHBP and, for completeness, across CRH, CRHR1 and CRHR2. FKBP5 genotypes were available. Three CRHBP SNPs rs6453267, rs7728378 and rs10474485 showed a nominally significant interaction with the continuous CTQ score to predict suicide attempt; rs7728378 remained significant after FOR correction. There was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 035-0.30 in carriers of either the FKBP5 rs3800373 major homozygote or the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes. Individuals without either major homozygote were resilient to the effects of childhood trauma (suicide attempt prevalence 0.24). Main effects of CRHBP rs6453267 and CRHR1 rs9900679, both unique to African ancestry, were detected. CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced childhood trauma. Published by Elsevier Ltd. C1 [Roy, Alec] New Jersey VA Hlth Care Syst, Dept Vet Affairs, Psychiat Serv, E Orange, NJ USA. [Hodgkinson, Colin A.; Goldman, David; Enoch, Mary-Anne] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [DeLuca, Vincenzo] Ctr Addict & Mental Hlth, Toronto, ON, Canada. RP Roy, A (reprint author), New Jersey Hlth Care Syst, Psychiat Serv 116A, 385 Tremont Ave, E Orange, NJ 07018 USA. EM alec.roy@va.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism, NIH; National Institute of Drug Abuse, NIH [RO1 DA 10336-02] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by grant RO1 DA 10336-02 to AR from the National Institute of Drug Abuse, NIH. NR 50 TC 48 Z9 52 U1 2 U2 11 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 JAN PY 2012 VL 46 IS 1 BP 72 EP 79 DI 10.1016/j.jpsychires.2011.09.009 PG 8 WC Psychiatry SC Psychiatry GA 868MR UT WOS:000298527900010 PM 21978546 ER PT J AU Kato, GJ AF Kato, Gregory J. TI Priapism in Sickle-Cell Disease: A Hematologist's Perspective SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Priapism; Ischemic Priapism; Stuttering Priapism; Erectile Dysfunction; Sickle Cell; Hematology and Priapism ID NITRIC-OXIDE BIOAVAILABILITY; PULMONARY-HYPERTENSION; THALASSEMIA-INTERMEDIA; RECURRENT PRIAPISM; STUTTERING PRIAPISM; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY; MEDIATED VASODILATION; EXCHANGE-TRANSFUSION; UNSTABLE HEMOGLOBIN; ORGAN DYSFUNCTION AB Introduction. Priapism is a familiar problem to hematologists, well known for its association with sickle-cell disease (SCD). It also occurs in a variety of other hematological illnesses, nearly all forms of congenital hemolytic anemia, including other hemoglobinopathies and red blood cell membranopathies and enzymopathies. Aim. Provide urologists with a comprehensive review of priapism in SCD, with an emphasis on the perspective of a practicing hematologist. Methods. Medline searches through July 2010 were conducted using the terms priapism, erectile dysfunction, and sickle cell. Main Outcome Measures. Expert opinion was based on review of the medical literature related to this subject matter. Results. In men with SCD, large epidemiological studies have linked the risk of priapism to clinical markers of the severity of intravascular hemolysis. Extracellular hemoglobin and arginase released during hemolysis has been implicated in reducing nitric oxide bioavailability, although the relevance of hemolysis to vascular dysfunction has been challenged by some scientists. Consistent with the role of impairment of the nitric oxide axis, mice genetically deficient in nitric oxide production have also been shown to develop priapic activity. Provocative new data indicate that hemolysis-linked dysregulation of adenosine signaling in the penis contributes to priapism in sickle cell mice. Serious questions have arisen regarding the efficacy of mainstays of textbook dogma for treatment of acute severe priapism, including intravenous fluids, alkalinization, and exchange transfusion, and there is increasing acceptance for early aspiration and irrigation of the corpus cavernosum. Conclusion. For patients with sickle cell with recurrent priapism, there is very limited evidence for a medical prophylaxis role for hydroxyurea, etilefrine, pseudoephedrine, leuprolide, sildenafil, and other agents. Recent publications have highlighted nitric oxide and adenosine signal transduction pathways as worthy of additional research. Research and clinical management of sickle-cell priapism is strengthened by multidisciplinary collaboration between hematologists and urologists. Kato GJ. Priapism in sickle-cell disease: A hematologist's perspective. J Sex Med 2012; 9: 70-78. C1 NHLBI, NIH, Sickle Cell Vasc Dis Sect, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, NIH, Sickle Cell Vasc Dis Sect, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health [1ZIAHL006014-01]; National Institutes of Health; Ikaria-INO Therapeutics FX Dr. Kato is supported by research funding from the Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health (1ZIAHL006014-01 and others). He has received research funding through a Cooperative Research and Development agreement between the National Institutes of Health and Ikaria-INO Therapeutics. He declares no conflicts of interest affecting any of the content of this manuscript. NR 99 TC 13 Z9 13 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1743-6095 J9 J SEX MED JI J. Sex. Med. PD JAN PY 2012 VL 9 IS 1 BP 70 EP 78 DI 10.1111/j.1743-6109.2011.02287.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 872HE UT WOS:000298799100009 PM 21554552 ER PT J AU Overhage, JM Ryan, PB Reich, CG Hartzema, AG Stang, PE AF Overhage, J. Marc Ryan, Patrick B. Reich, Christian G. Hartzema, Abraham G. Stang, Paul E. TI Validation of a common data model for active safety surveillance research SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CONTROLLED-TRIALS AB Objective Systematic analysis of observational medical databases for active safety surveillance is hindered by the variation in data models and coding systems. Data analysts often find robust clinical data models difficult to understand and ill suited to support their analytic approaches. Further, some models do not facilitate the computations required for systematic analysis across many interventions and outcomes for large datasets. Translating the data from these idiosyncratic data models to a common data model (CDM) could facilitate both the analysts' understanding and the suitability for large-scale systematic analysis. In addition to facilitating analysis, a suitable CDM has to faithfully represent the source observational database. Before beginning to use the Observational Medical Outcomes Partnership (OMOP) CDM and a related dictionary of standardized terminologies for a study of large-scale systematic active safety surveillance, the authors validated the model's suitability for this use by example. Validation by example To validate the OMOP CDM, the model was instantiated into a relational database, data from 10 different observational healthcare databases were loaded into separate instances, a comprehensive array of analytic methods that operate on the data model was created, and these methods were executed against the databases to measure performance. Conclusion There was acceptable representation of the data from 10 observational databases in the OMOP CDM using the standardized terminologies selected, and a range of analytic methods was developed and executed with sufficient performance to be useful for active safety surveillance. C1 [Overhage, J. Marc] Indiana Univ, Sch Med, Regenstrief Inst, Indianapolis, IN 46202 USA. [Overhage, J. Marc; Ryan, Patrick B.; Reich, Christian G.; Hartzema, Abraham G.; Stang, Paul E.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Ryan, Patrick B.; Stang, Paul E.] Res & Dev LLC, Dept Pharmaceut, Johnson & Johnson Inst, Titusville, NJ USA. [Ryan, Patrick B.] Univ N Carolina, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. RP Overhage, JM (reprint author), Indiana Univ, Sch Med, Regenstrief Inst, Indianapolis, IN 46202 USA. EM moverhage@regenstrief.org FU Foundation for the National Institutes of Health FX The authors thank and acknowledge the contributions of the OMOP distributed research partners in phases of this research, who are supported by a grant from the Foundation for the National Institutes of Health. NR 17 TC 58 Z9 58 U1 4 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JAN PY 2012 VL 19 IS 1 BP 54 EP 60 DI 10.1136/amiajnl-2011-000376 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 872YT UT WOS:000298848100008 PM 22037893 ER PT J AU Smith, PK Michler, RE Woo, YJ Alexander, JH Puskas, JD Parides, MK Hahn, RT Williams, JB Dent, JM Ferguson, TB Moquete, E Rose, EA Page, P Jeffries, NO O'Gara, PT Ascheim, DD AF Smith, Peter K. Michler, Robert E. Woo, Y. Joseph Alexander, John H. Puskas, John D. Parides, Michael K. Hahn, Rebecca T. Williams, Judson B. Dent, John M. Ferguson, T. Bruce, Jr. Moquete, Ellen Rose, Eric A. Page, Pierre Jeffries, Neal O. O'Gara, Patrick T. Ascheim, Deborah D. TI Design, rationale, and initiation of the Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial: A report from the Cardiothoracic Surgical Trials Network SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID LONG-TERM SURVIVAL; MYOCARDIAL-INFARCTION; HEART-FAILURE; REVASCULARIZATION; ECHOCARDIOGRAPHY; DISEASE; IMPACT AB Objective: Patients with coronary artery disease complicated by moderate ischemic mitral regurgitation have demonstrably poorer outcome than do patients with coronary artery disease but without mitral regurgitation. The optimal treatment of this condition has become increasingly controversial, and a randomized trial evaluating current practices is warranted. Methods: We describe the design and initial execution of the Cardiothoracic Surgical Trials Network Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial. Results: This is an ongoing prospective, multicenter, randomized, controlled clinical trial designed to test the safety and efficacy of mitral repair in addition to coronary artery bypass grafting in the treatment of moderate ischemic mitral regurgitation. Conclusions: The results of the Cardiothoracic Surgical Trials Network Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial will provide long-awaited information on controversial therapies for this morbid disease process. (J Thorac Cardiovasc Surg 2012;143:111-7) C1 [Parides, Michael K.; Moquete, Ellen; Rose, Eric A.; Ascheim, Deborah D.] Mt Sinai Sch Med, Dept Hlth Evidence & Policy, InCHOIR, New York, NY 10029 USA. [Smith, Peter K.; Williams, Judson B.] Duke Univ, Div Cardiovasc & Thorac Surg, Durham, NC USA. [Alexander, John H.] Duke Univ, Div Cardiol, Durham, NC USA. [Michler, Robert E.] Montefiore Einstein Heart Ctr, Dept Cardiovasc & Thorac Surg, New York, NY USA. [Woo, Y. Joseph] Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Puskas, John D.] Emory Univ, Div Cardiothorac Surg, Atlanta, GA 30322 USA. [Hahn, Rebecca T.] Columbia Univ, Med Ctr, Div Cardiol, New York, NY USA. [Dent, John M.] Univ Virginia, Div Cardiovasc, Charlottesville, VA USA. [Ferguson, T. Bruce, Jr.] E Carolina Univ, E Carolina Heart Inst, Dept Cardiovasc Sci, Greenville, NC USA. [Page, Pierre] Hop Sacre Coeur, Dept Surg, Montreal, PQ H4J 1C5, Canada. [Jeffries, Neal O.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Ascheim, DD (reprint author), Mt Sinai Sch Med, Dept Hlth Evidence & Policy, InCHOIR, 1 Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM deborah.ascheim@mssm.edu FU National Heart Lung and Blood Institute; Canadian Institute of Health Research; National Institute of Neurological Diseases and Stroke [7U01 HL088942] FX Supported by the National Heart Lung and Blood Institute, the Canadian Institute of Health Research, and the National Institute of Neurological Diseases and Stroke (grant no. 7U01 HL088942). NR 20 TC 14 Z9 15 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JAN PY 2012 VL 143 IS 1 BP 111 EP U175 DI 10.1016/j.jtcvs.2011.05.006 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 863GW UT WOS:000298151800018 PM 21788032 ER PT J AU Baillie, GJ Galiano, M Agapow, PM Myers, R Chiam, R Gall, A Palser, AL Watson, SJ Hedge, J Underwood, A Platt, S McLean, E Pebody, RG Rambaut, A Green, J Daniels, R Pybus, OG Kellam, P Zambon, M AF Baillie, Gregory J. Galiano, Monica Agapow, Paul-Michael Myers, Richard Chiam, Rachael Gall, Astrid Palser, Anne L. Watson, Simon J. Hedge, Jessica Underwood, Anthony Platt, Steven McLean, Estelle Pebody, Richard G. Rambaut, Andrew Green, Jonathan Daniels, Rod Pybus, Oliver G. Kellam, Paul Zambon, Maria TI Evolutionary Dynamics of Local Pandemic H1N1/2009 Influenza Virus Lineages Revealed by Whole-Genome Analysis SO JOURNAL OF VIROLOGY LA English DT Article ID A H1N1; ASSOCIATION; SENSITIVITY; DISEASE; D222G AB Virus gene sequencing and phylogenetics can be used to study the epidemiological dynamics of rapidly evolving viruses. With complete genome data, it becomes possible to identify and trace individual transmission chains of viruses such as influenza virus during the course of an epidemic. Here we sequenced 153 pandemic influenza H1N1/09 virus genomes from United Kingdom isolates from the first (127 isolates) and second (26 isolates) waves of the 2009 pandemic and used their sequences, dates of isolation, and geographical locations to infer the genetic epidemiology of the epidemic in the United Kingdom. We demonstrate that the epidemic in the United Kingdom was composed of many cocirculating lineages, among which at least 13 were exclusively or predominantly United Kingdom clusters. The estimated divergence times of two of the clusters predate the detection of pandemic H1N1/09 virus in the United Kingdom, suggesting that the pandemic H1N1/09 virus was already circulating in the United Kingdom before the first clinical case. Crucially, three clusters contain isolates from the second wave of infections in the United Kingdom, two of which represent chains of transmission that appear to have persisted within the United Kingdom between the first and second waves. This demonstrates that whole-genome analysis can track in fine detail the behavior of individual influenza virus lineages during the course of a single epidemic or pandemic. C1 [Baillie, Gregory J.; Chiam, Rachael; Gall, Astrid; Palser, Anne L.; Watson, Simon J.; Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge, England. [Galiano, Monica; Agapow, Paul-Michael; Myers, Richard; Underwood, Anthony; Platt, Steven; McLean, Estelle; Pebody, Richard G.; Green, Jonathan; Zambon, Maria] Hlth Protect Agcy, Ctr Infect, London, England. [Hedge, Jessica; Rambaut, Andrew] Inst Evolutionary Biol, Ashworth Labs, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Daniels, Rod] Natl Inst Med Res, Div Virol, London NW7 1AA, England. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. RP Kellam, P (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England. EM pk5@sanger.ac.uk RI pybus, oliver/B-2640-2012; Baillie, Gregory/F-9478-2013; Chiang, Vincent, Ming-Hsien/D-4312-2016; OI Baillie, Gregory/0000-0002-6130-250X; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863; Hedge, Jessica/0000-0002-4343-4146; Pybus, Oliver/0000-0002-8797-2667; Rambaut, Andrew/0000-0003-4337-3707; Pebody, Richard/0000-0002-9069-2885 FU Wellcome Trust; Health Protection Agency FX This work was supported by the Wellcome Trust and the Health Protection Agency. NR 25 TC 36 Z9 40 U1 1 U2 6 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 JAN PY 2012 VL 86 IS 1 BP 11 EP 18 DI 10.1128/JVI.05347-11 PG 8 WC Virology SC Virology GA 865YV UT WOS:000298347700002 PM 22013031 ER PT J AU Vaccari, M Boasso, A Fenizia, C Fuchs, D Hryniewicz, A Morgan, T Weiss, D Doster, MN Heraud, JM Shearer, GM Franchini, G AF Vaccari, Monica Boasso, Adriano Fenizia, Claudio Fuchs, Dietmar Hryniewicz, Anna Morgan, Tia Weiss, Deborah Doster, Melvin N. Heraud, Jean Michel Shearer, Gene M. Franchini, Genoveffa TI Fatal Pancreatitis in Simian Immunodeficiency Virus SIVmac251-Infected Macaques Treated with 2 ',3 '-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade SO JOURNAL OF VIROLOGY LA English DT Article ID TRYPTOPHAN CATABOLISM; IMMUNE-RESPONSES; DENDRITIC CELLS; ANTIRETROVIRAL THERAPY; MUCOSAL SITES; TGF-BETA; INFECTION; CD4(+); EXPRESSION; TOLERANCE AB Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4(+)-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIVmac251 and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART. C1 [Vaccari, Monica; Fenizia, Claudio; Hryniewicz, Anna; Morgan, Tia; Doster, Melvin N.; Heraud, Jean Michel; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. [Boasso, Adriano; Shearer, Gene M.] NCI, Expt Immunol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Fuchs, Dietmar] Innsbruck Med Univ, Div Biol Chem, Ludwig Boltzmann Inst AIDS Res, Bioctr, Innsbruck, Austria. [Weiss, Deborah] Adv BioSci Labs Inc, Kensington, MD USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI HERAUD, Jean-Michel/O-1464-2013; OI HERAUD, Jean-Michel/0000-0003-1107-0859; Boasso, Adriano/0000-0001-9673-6319 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 19 Z9 20 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 1 BP 108 EP 113 DI 10.1128/JVI.05609-11 PG 6 WC Virology SC Virology GA 865YV UT WOS:000298347700011 PM 22013040 ER PT J AU Hansman, GS Shahzad-ul-Hussan, S McLellan, JS Chuang, GY Georgiev, I Shimoike, T Katayama, K Bewley, CA Kwong, PD AF Hansman, Grant S. Shahzad-ul-Hussan, Syed McLellan, Jason S. Chuang, Gwo-Yu Georgiev, Ivelin Shimoike, Takashi Katayama, Kazuhiko Bewley, Carole A. Kwong, Peter D. TI Structural Basis for Norovirus Inhibition and Fucose Mimicry by Citrate SO JOURNAL OF VIROLOGY LA English DT Article ID BLOOD GROUP ANTIGENS; FOODBORNE VIRAL SURROGATES; TRANSFER DIFFERENCE NMR; NORWALK VIRUS; CRYSTALLOGRAPHIC STRUCTURE; PSEUDOMONAS-AERUGINOSA; BINDING-SPECIFICITY; CRYSTAL-STRUCTURE; IN-VITRO; STD NMR AB Human noroviruses bind with their capsid-protruding domains to histo-blood-group antigens (HBGAs), an interaction thought to direct their entry into cells. Although human noroviruses are the major cause of gastroenteritis outbreaks, development of antivirals has been lacking, mainly because human noroviruses cannot be cultivated. Here we use X-ray crystallography and saturation transfer difference nuclear magnetic resonance (STD NMR) to analyze the interaction of citrate with genogroup II (GII) noroviruses. Crystals of citrate in complex with the protruding domain from norovirus GII.10 Vietnam026 diffracted to 1.4 angstrom and showed a single citrate bound at the site of HBGA interaction. The citrate interaction was coordinated with a set of capsid interactions almost identical to that involved in recognizing the terminal HBGA fucose, the saccharide which forms the primary conserved interaction between HBGAs and GII noroviruses. Citrate and a water molecule formed a ring-like structure that mimicked the pyranoside ring of fucose. STD NMR showed the protruding domain to have weak affinity for citrate (460 mu M). This affinity, however, was similar to the affinities of the protruding domain for fucose (460 mu M) and H type 2 trisaccharide (390 mu M), an HBGA shown previously to be specifically recognized by human noroviruses. Importantly, competition STD NMR showed that citrate could compete with HBGA for norovirus binding. Together, the results suggest that citrate and other glycomimetics have the potential to block human noroviruses from binding to HBGAs. C1 [Hansman, Grant S.; Shahzad-ul-Hussan, Syed; McLellan, Jason S.; Chuang, Gwo-Yu; Georgiev, Ivelin; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hansman, Grant S.; Shimoike, Takashi; Katayama, Kazuhiko] Natl Inst Infect Dis, Dept Virol 2, Tokyo 2080011, Japan. [Shahzad-ul-Hussan, Syed; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov; pkwong@mail.nih.gov RI Hansman, Grant/K-7983-2013; OI Hansman, Grant/0000-0001-8735-4618 FU National Institutes of Health (NIDDK); Office of the Director, NIH; Japan Health Science Foundation; Ministry of Health, Labor, and Welfare of Japan; 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 of the National Institutes of Health (NIDDK, C.A.B; NIAID, P.D.K); the Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH (C.A.B.); a grant from The Japan Health Science Foundation; and by grants from the Ministry of Health, Labor, and Welfare of Japan. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. NR 55 TC 32 Z9 32 U1 1 U2 14 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 JAN PY 2012 VL 86 IS 1 BP 284 EP 292 DI 10.1128/JVI.05909-11 PG 9 WC Virology SC Virology GA 865YV UT WOS:000298347700027 PM 22031945 ER PT J AU Wolfe, CL Ojeda, S Moss, B AF Wolfe, Cindy L. Ojeda, Suany Moss, Bernard TI Transcriptional Repression and RNA Silencing Act Synergistically To Demonstrate the Function of the Eleventh Component of the Vaccinia Virus Entry-Fusion Complex SO JOURNAL OF VIROLOGY LA English DT Article ID OPEN READING FRAME; CELL-CELL FUSION; SURFACE HEPARAN-SULFATE; VIRION MEMBRANE-PROTEIN; MATURE VIRION; ENTRY/FUSION COMPLEX; HOST-CELLS; L1 PROTEIN; GENE; REPLICATION AB Poxviruses have an elaborate system for infecting cells comprising several proteins for attachment and a larger number dedicated to membrane fusion and entry. Thus far, 11 proteins have been identified as components of the vaccinia virus (VACV) entry-fusion complex (EFC), and 10 of these proteins have been shown to be required for entry. J5, the remaining functionally uncharacterized component of the complex, is conserved in all poxviruses, has a predicted C-terminal transmembrane domain, and is an N-terminally truncated paralog of two other EFC proteins. To determine the role of J5, we constructed a mutant that inducibly regulates J5 transcription. Although the virus yield was reduced only about 80% without inducer, the inability to isolate a J5 deletion mutant suggested an essential function. To enhance stringency, we employed RNA silencing alone and together with transcriptional repression of the inducible mutant. The yield of infectious virus was reduced 4-to 5-fold by repression, 2-fold by silencing, and 60-fold by the combination of the two. Virus particles made under the latter conditions appeared to contain a full complement of proteins excluding J5 but had very low infectivity. Further studies indicated that after binding to cells, J5-deficient virions had a defect in core entry and an inability to induce syncytium formation. In addition, we confirmed that J5 is associated with the EFC by affinity purification. These data indicate that J5 is a functional component of the EFC and highlights the advantage of combining transcriptional repression and RNA silencing for stringent reduction of gene expression. C1 [Wolfe, Cindy L.; Ojeda, Suany; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bmoss@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX The work was supported by funds from the Division of Intramural Research, NIAID, NIH. NR 49 TC 7 Z9 9 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 JAN PY 2012 VL 86 IS 1 BP 293 EP 301 DI 10.1128/JVI.05935-11 PG 9 WC Virology SC Virology GA 865YV UT WOS:000298347700028 PM 22013036 ER PT J AU Belov, GA Nair, V Hansen, BT Hoyt, FH Fischer, ER Ehrenfeld, E AF Belov, George A. Nair, Vinod Hansen, Bryan T. Hoyt, Forrest H. Fischer, Elizabeth R. Ehrenfeld, Ellie TI Complex Dynamic Development of Poliovirus Membranous Replication Complexes SO JOURNAL OF VIROLOGY LA English DT Article ID TOBACCO-MOSAIC-VIRUS; ENDOPLASMIC-RETICULUM; VIRAL-RNA; INTRACELLULAR-DISTRIBUTION; ELECTRON TOMOGRAPHY; SECRETORY PATHWAY; PLASMA-MEMBRANE; FINE STRUCTURE; BREFELDIN-A; PROTEIN AB Replication of all positive-strand RNA viruses is intimately associated with membranes. Here we utilize electron tomography and other methods to investigate the remodeling of membranes in poliovirus-infected cells. We found that the viral replication structures previously described as "vesicles" are in fact convoluted, branching chambers with complex and dynamic morphology. They are likely to originate from cis-Golgi membranes and are represented during the early stages of infection by single-walled connecting and branching tubular compartments. These early viral organelles gradually transform into double-membrane structures by extension of membranous walls and/or collapsing of the luminal cavity of the single-membrane structures. As the double-membrane regions develop, they enclose cytoplasmic material. At this stage, a continuous membranous structure may have double-and single-walled membrane morphology at adjacent cross-sections. In the late stages of the replication cycle, the structures are represented mostly by double-membrane vesicles. Viral replication proteins, double-stranded RNA species, and actively replicating RNA are associated with both double-and single-membrane structures. However, the exponential phase of viral RNA synthesis occurs when single-membrane formations are predominant in the cell. It has been shown previously that replication complexes of some other positive-strand RNA viruses form on membrane invaginations, which result from negative membrane curvature. Our data show that the remodeling of cellular membranes in poliovirus-infected cells produces structures with positive curvature of membranes. Thus, it is likely that there is a fundamental divergence in the requirements for the supporting cellular membrane-shaping machinery among different groups of positive-strand RNA viruses. C1 [Belov, George A.] Univ Maryland, Virginia Maryland Coll Vet Med, College Pk, MD 20742 USA. [Nair, Vinod; Hansen, Bryan T.; Hoyt, Forrest H.; Fischer, Elizabeth R.] NIAID, Res Technol Branch, Microscopy Unit, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Ehrenfeld, Ellie] NIAID, NIH, Rockville, MD 20852 USA. RP Belov, GA (reprint author), Univ Maryland, Virginia Maryland Coll Vet Med, College Pk, MD 20742 USA. EM gbelov@umd.edu RI Belov, George/B-4625-2008 OI Belov, George/0000-0002-0892-1731 FU National Institute of Allergy and Infectious Diseases, NIH FX This research was supported by the National Institute of Allergy and Infectious Diseases, NIH. NR 60 TC 78 Z9 78 U1 0 U2 15 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 JAN PY 2012 VL 86 IS 1 BP 302 EP 312 DI 10.1128/JVI.05937-11 PG 11 WC Virology SC Virology GA 865YV UT WOS:000298347700029 PM 22072780 ER PT J AU Cingoz, O Paprotka, T Delviks-Frankenberry, KA Wildt, S Hu, WS Pathak, VK Coffin, JM AF Cingoez, Oya Paprotka, Tobias Delviks-Frankenberry, Krista A. Wildt, Sheryl Hu, Wei-Shau Pathak, Vinay K. Coffin, John M. TI Characterization, Mapping, and Distribution of the Two XMRV Parental Proviruses SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; CHRONIC-FATIGUE-SYNDROME; MOUSE XENOTROPIC GAMMARETROVIRUSES; PROSTATE-CANCER; RETROVIRUS XMRV; NUDE-MICE; UNITED-STATES; NO EVIDENCE; CELL-LINE; HAPLOTYPE DIVERSITY AB Xenotropic murine leukemia virus-related virus (XMRV) was previously reported to be associated with human prostate cancer and chronic fatigue syndrome. Our groups recently showed that XMRV was created through recombination between two endogenous murine retroviruses, PreXMRV-1 and PreXMRV-2, during the passaging of a prostate tumor xenograft in nude mice. Here, multiple approaches that led to the identification of PreXMRV-2, as well as the distribution of both parental proviruses among different mouse species, are described. The chromosomal loci of both proviruses were determined in the mouse genome, and integration site information was used to analyze the distribution of both proviruses in 48 laboratory mouse strains and 46 wild-derived strains. The strain distributions of PreXMRV-1 and PreXMRV-2 are quite different, the former being found predominantly in Asian mice and the latter in European mice, making it unlikely that the two XMRV ancestors could have recombined independently in the wild to generate an infectious virus. XMRV was not present in any of the mouse strains tested, and among the wild-derived mouse strains analyzed, not a single mouse carried both parental proviruses. Interestingly, PreXMRV-1 and PreXMRV-2 were found together in three laboratory strains, Hsd nude, NU/NU, and C57BR/cd, consistent with previous data that the recombination event that led to the generation of XMRV could have occurred only in the laboratory. The three laboratory strains carried the Xpr1n receptor variant nonpermissive to XMRV and xenotropic murine leukemia virus (X-MLV) infection, suggesting that the xenografted human tumor cells were required for the resulting XMRV recombinant to infect and propagate. C1 [Cingoez, Oya; Coffin, John M.] Tufts Univ, Sackler Sch Grad Biomed Sci, Genet Program, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Paprotka, Tobias; Delviks-Frankenberry, Krista A.; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Wildt, Sheryl] Harlan Labs, Indianapolis, IN USA. RP Coffin, JM (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Genet Program, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. EM john.coffin@tufts.edu RI Delviks-Frankenberry, Krista/M-4822-2013 FU intramural Bench-to-Bedside Award; F.M. Kirby Foundation; NIH, National Cancer Institute, Center for Cancer Research; [R37 CA 089441] FX This work was supported by grant R37 CA 089441 to J.M.C. and in part by an intramural Bench-to-Bedside Award to V.K.P. J.M.C. was a Research Professor of the American Cancer Society, with support from the F.M. Kirby Foundation. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 67 TC 10 Z9 11 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 1 BP 328 EP 338 DI 10.1128/JVI.06022-11 PG 11 WC Virology SC Virology GA 865YV UT WOS:000298347700031 PM 22031947 ER PT J AU Bennett, RS Gresko, AK Nelson, JT Murphy, BR Whitehead, SS AF Bennett, R. S. Gresko, A. K. Nelson, J. T. Murphy, B. R. Whitehead, S. S. TI A Recombinant Chimeric La Crosse Virus Expressing the Surface Glycoproteins of Jamestown Canyon Virus Is Immunogenic and Protective against Challenge with either Parental Virus in Mice or Monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID CALIFORNIA ENCEPHALITIS GROUP; RESPIRATORY SYNCYTIAL VIRUS; GENOME SEQUENCE; NEUTRALIZING ANTIBODIES; AEDES-ALBOPICTUS; VACCINE; CDNA; RNA; BUNYAVIRUSES; PROTEINS AB La Crosse virus (LACV) and Jamestown Canyon virus (JCV), family Bunyaviridae, are mosquito-borne viruses that are endemic in North America and recognized as etiologic agents of encephalitis in humans. Both viruses belong to the California encephalitis virus serogroup, which causes 70 to 100 cases of encephalitis a year. As a first step in creating live attenuated viral vaccine candidates for this serogroup, we have generated a recombinant LACV expressing the attachment/fusion glycoproteins of JCV. The JCV/LACV chimeric virus contains full-length S and L segments derived from LACV. For the M segment, the open reading frame (ORF) of LACV is replaced with that derived from JCV and is flanked by the untranslated regions of LACV. The resulting chimeric virus retained the same robust growth kinetics in tissue culture as observed for either parent virus, and the virus remains highly infectious and immunogenic in mice. Although both LACV and JCV are highly neurovirulent in 21 day-old mice, with 50% lethal dose (LD(50)) values of 0.1 and 0.5 log(10) PFU, respectively, chimeric JCV/LACV is highly attenuated and does not cause disease even after intracerebral inoculation of 10(3) PFU. Parenteral vaccination of mice with 10(1) or 10(3) PFU of JCV/LACV protected against lethal challenge with LACV, JCV, and Tahyna virus (TAHV). The chimeric virus was infectious and immunogenic in rhesus monkeys and induced neutralizing antibodies to JCV, LACV, and TAHV. When vaccinated monkeys were challenged with JCV, they were protected against the development of viremia. Generation of highly attenuated yet immunogenic chimeric bunyaviruses could be an efficient general method for development of vaccines effective against these pathogenic viruses. C1 [Bennett, R. S.; Gresko, A. K.; Nelson, J. T.; Murphy, B. R.; Whitehead, S. S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Whitehead, SS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM swhitehead@niaid.nih.gov OI Bennett, Richard/0000-0002-7227-4831 FU NIAID Division of Intramural Research, National Institutes of Health, Bethesda, MD FX This work was supported with funds from the NIAID Division of Intramural Research, National Institutes of Health, Bethesda, MD. NR 31 TC 3 Z9 3 U1 3 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 1 BP 420 EP 426 DI 10.1128/JVI.02327-10 PG 7 WC Virology SC Virology GA 865YV UT WOS:000298347700040 PM 22013033 ER PT J AU Kobayashi, H Choyke, PL AF Kobayashi, Hisataka Choyke, Peter L. TI Recipe for a new imaging biomarker: carefully combine target, reagent, and technology SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID MOLECULES; PARTICLES; PROBES AB A careful combination of biological targeting moieties (C3 fragments), imaging reagents (a small particle of iron oxide), and appropriate technology (T2-weighted magnetic resonance imaging) is the key to the successful development of an imaging agent for glomerulonephritis. This recipe applies to virtually any molecular imaging probe for the kidney and throughout the body. However, each organ and disease requires a unique combination of these three components in order to achieve success. Kidney International (2012) 81, 129-131. doi:10.1038/ki.2011.374 C1 [Kobayashi, Hisataka; Choyke, Peter L.] 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,MSC 1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural NIH HHS NR 10 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JAN PY 2012 VL 81 IS 2 BP 129 EP 131 DI 10.1038/ki.2011.374 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 869XR UT WOS:000298633800002 PM 22205431 ER PT J AU Warren, CL Zhao, JF Glass, K Rishi, V Ansari, AZ Vinson, C AF Warren, Christopher L. Zhao, Jianfei Glass, Kimberly Rishi, Vikas Ansari, Aseem Z. Vinson, Charles TI Fabrication of duplex DNA microarrays incorporating methyl-5-cytosine SO LAB ON A CHIP LA English DT Article ID TRANSCRIPTION FACTORS; BINDING MOLECULES; CPG METHYLATION; SPECIFICITY; SITES; ARRAY AB We synthesized customized double-stranded DNA microarrays including methyl-5-cytosine at CpG dinucleotides and produced all 163,555 possible 8-mers (un-, hemi-, and di-methylated) to gain insight into how methylation affects transcription factor binding. An antibody to methyl-5-cytidine showed greater binding to the methylated DNA, demonstrating efficient incorporation of methyl-5-cytosine into the synthesized DNA. In contrast, binding of the transcription factor CREB was inhibited by CpG methylation. This platform represents a powerful new technology to evaluate the effect of DNA methylation on protein binding in any sequence context. C1 [Zhao, Jianfei; Rishi, Vikas; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Warren, Christopher L.] Univ Wisconsin, Sch Med & Publ Hlth, McArdle Lab Canc Res, Madison, WI 53706 USA. [Glass, Kimberly] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Ansari, Aseem Z.] Univ Wisconsin, Genome Ctr, Madison, WI 53706 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [GM069420]; March of Dimes; U.S. Department of Agriculture, Innovation and Economic Development Research Program; Vilas Associate and Shaw scholar awards; National Institutes of Health/National Library of Medicine [T15LM007359] FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. AZA was supported by grants from the National Institutes of Health (GM069420), March of Dimes, U.S. Department of Agriculture, Innovation and Economic Development Research Program, and Vilas Associate and Shaw scholar awards. CLW was supported by a National Institutes of Health/National Library of Medicine predoctoral fellowship (T15LM007359). NR 16 TC 4 Z9 4 U1 0 U2 4 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 J9 LAB CHIP JI Lab Chip PY 2012 VL 12 IS 2 BP 376 EP 380 DI 10.1039/c1lc20698b PG 5 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA 874NB UT WOS:000298964100019 PM 22139143 ER PT J AU Major, EO Nath, A AF Major, Eugene O. Nath, Avindra TI Neurological infections: risks of globalisation and new drugs SO LANCET NEUROLOGY LA English DT Editorial Material C1 [Major, Eugene O.; Nath, Avindra] NINDS, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD JAN PY 2012 VL 11 IS 1 BP 14 EP 15 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 868HG UT WOS:000298513700009 PM 22172615 ER PT J AU Rochowski, A Rosenberg, PS Alonzo, TA Gerbing, RB Lange, BJ Alter, BP AF Rochowski, Andrzej Rosenberg, Philip S. Alonzo, Todd A. Gerbing, Robert B. Lange, Beverly J. Alter, Blanche P. TI Estimation of the prevalence of Fanconi anemia among patients with de novo acute myelogenous leukemia who have poor recovery from chemotherapy SO LEUKEMIA RESEARCH LA English DT Article DE Fanconi anemia; Acute myelogenous leukemia; Prevalence ID CANCER AB We speculated that some individuals with de novo acute myelogenous leukemia (AML) may have undiagnosed Fanconi Anemia (FA). Data from patients enrolled on AML protocol CCG-2961, published FA cohort studies, SEER, and Bayes rule were used to estimate the probability of FA among all newly diagnosed AML cases, and among those who had no or delayed recovery of the absolute neutrophil count following initial chemotherapy. We determined that the probability of undiagnosed FA in patients in a treatment trial for newly diagnosed patients was around 0.18%, and around 0.83% in the subset who had poor marrow recovery. We suggest that FA or other inherited bone marrow failure syndromes be considered prior to treatment, or certainly among those with poor recovery. Published by Elsevier Ltd. C1 [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Lange, Beverly J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Gerbing, Robert B.] Childrens Oncol Grp, Arcadia, CA USA. [Alonzo, Todd A.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Rochowski, Andrzej] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Execut Plaza S,Room 7020, Rockville, MD 20852 USA. EM alterb@mail.nih.gov FU Children's National Medical Center; National Cancer Institute (NCI), National Institutes of Health (NIH) [U10 CA98543, U10 CA98413]; NIH; NCI FX This research was supported in part by Children's National Medical Center, the Children's Oncology Group Grants U10 CA98543 and U10 CA98413 from the National Cancer Institute (NCI), National Institutes of Health (NIH), and the Intramural Research Program of the NIH and the NCI. The authors gratefully thank an anonymous reviewer for detailed comments that led to significant improvements to our study. NR 5 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JAN PY 2012 VL 36 IS 1 BP 29 EP 31 DI 10.1016/j.leukres.2011.09.009 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 863FV UT WOS:000298149100023 PM 21974856 ER PT J AU van Gelderen, P de Zwart, JA Lee, J Sati, P Reich, DS Duyn, JH AF van Gelderen, Peter de Zwart, Jacco A. Lee, Jongho Sati, Pascal Reich, Daniel S. Duyn, Jeff H. TI Nonexponential T2*decay in white matter SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T2*relaxation; high field imaging; myelin water fraction; white matter imaging ID MAGNETIZATION-TRANSFER; MYELIN WATER; MULTIPLE-SCLEROSIS; HUMAN BRAIN; MRI; SENSITIVITY; SUSCEPTIBILITY; INHOMOGENEITY; RESONANCE; VOLUME AB Visualizing myelin in human brain may help the study of diseases such as multiple sclerosis. Previous studies based on T1 and T2 relaxation contrast have suggested the presence of a distinct water pool that may report directly on local myelin content. Recent work indicates that T2* contrast may offer particular advantages over T1 and T2 contrast, especially at high field. However, the complex mechanism underlying T2* relaxation may render interpretation difficult. To address this issue, T2* relaxation behavior in human brain was studied at 3 and 7 T. Multiple gradient echoes covering most of the decay curve were analyzed for deviations from mono-exponential behavior. The data confirm the previous finding of a distinct rapidly relaxing signal component (T2* similar to 6 ms), tentatively attributed to myelin water. However, in extension to previous findings, this rapidly relaxing component displayed a substantial resonance frequency shift, reaching 36 Hz in the corpus callosum at 7 T. The component's fractional amplitude and frequency shift appeared to depend on both field strength and fiber orientation, consistent with a mechanism originating from magnetic susceptibility effects. The findings suggest that T2* contrast at high field may be uniquely sensitive to tissue myelin content and that proper interpretation will require modeling of susceptibility-induced resonance frequency shifts. Magn Reson Med, 2011. (C) 2011 Wiley-Liss, Inc. C1 [van Gelderen, Peter; de Zwart, Jacco A.; Lee, Jongho; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Lee, Jongho] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Sati, Pascal; Reich, Daniel S.] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD USA. RP van Gelderen, P (reprint author), Bld 10,Rm B1D-725,10 Ctr Dr, Bethesda, MD 20892 USA. EM gelderen@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU National Institutes of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Neurological Disorders and Stroke. NR 24 TC 27 Z9 27 U1 0 U2 7 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 JAN PY 2012 VL 67 IS 1 BP 110 EP 117 DI 10.1002/mrm.22990 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 867VL UT WOS:000298482800013 PM 21630352 ER PT J AU Gabriel, KP McClain, JJ High, RR Schmid, KK Whitfield, GP Ainsworth, BE AF Gabriel, Kelley Pettee McClain, James J. High, Robin R. Schmid, Kendra K. Whitfield, Geoffrey P. Ainsworth, Barbara E. TI Patterns of Accelerometer-Derived Estimates of Inactivity in Middle-Age Women SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE AMBULATORY MONITORING; MEASUREMENT; VARIABILITY; WOMEN ID PHYSICAL-ACTIVITY MEASURES; TYPE-2 DIABETES-MELLITUS; SEDENTARY BEHAVIORS; UNITED-STATES; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; RISK; OBESITY; ASSOCIATIONS; CALIBRATION AB PETTEE GABRIEL, K., J. J. MCCLAIN, R. R. HIGH, K. K. SCHMID, G. P. WHITFIELD, and B. E. AINSWORTH. Patterns of Accelerometer-Derived Estimates of Inactivity in Middle-Age Women. Med. Sci. Sports Exerc., Vol. 44, No. 1, pp. 104-110, 2012. Purpose: The study's purpose was to characterize accelerometer-derived estimates of physical inactivity collected during five consecutive weeks in middle-age women. Methods: Data were obtained from 63 participants (95.5%) enrolled in the Evaluation of Physical Activity Measures in Middle-Age Women Study. Inactive time (min center dot d(-1)) was estimated as the sum of activity counts <100, and inactive-to-active transitions were defined as an interruption in which a period of inactivity was immediately followed by a minute or more above 100 counts. A repeated-measures ANOVA using PROC MIXED (SAS/STAT software, v. 9.2) was used to describe hourly, daily, and weekly variation in estimates of physical inactivity. Results: Participants were 52.7 +/- 5.5 yr, 85.7% non-Hispanic white, and 63.5% postmenopausal, with a body mass index of 26.7 +/- 5.1 kg center dot m(-2). Inactive time gradually increased as the day continued, particularly on weekend days. When compared with weekdays, average inactive time was lower on Saturday and Sunday (all P < 0.01 except for Saturday vs Monday, P < 0.10); Saturdays were not significantly different from Sundays. Breaks in inactive time were significantly lower on Sunday when compared with weekdays and Saturday (all P < 0.05), and fewer breaks were noted on Saturday when compared with Wednesday and Friday (both P < 0.01). After adjustment for total wear time or inactive time, most day-to-day differences were attenuated. Week-by-week differences in physical inactivity estimates were also not statistically significant. Conclusions: The results of this study suggest that inactive time increases as the day continues and that daily physical inactivity estimates are more stable after 1) adjustment for wear time or 2) when averaged over the week. Researchers should carefully consider the intended application of physical inactivity estimates before data collection and processing, analysis, and final data reporting. C1 [Gabriel, Kelley Pettee] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth Austin Reg Campus, Div Epidemiol Human Genet & Environm Sci, Austin, TX 78701 USA. [McClain, James J.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [High, Robin R.; Schmid, Kendra K.] Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE USA. [Ainsworth, Barbara E.] Arizona State Univ, Program Exercise & Wellness, Hlth Lifestyles Res Ctr, Mesa, AZ USA. RP Gabriel, KP (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth Austin Reg Campus, Div Epidemiol Human Genet & Environm Sci, Univ Texas Adm Bldg,1616 Guadalupe St,Suite 6-300, Austin, TX 78701 USA. EM Kelley.P.Gabriel@uth.tmc.edu FU American College of Sports Medicine Paffenbarger-Blair Endowment for Epidemiological Research on Physical Activity; Arizona State University FX This research was funded by the American College of Sports Medicine Paffenbarger-Blair Endowment for Epidemiological Research on Physical Activity that was awarded to Dr. Kelley Pettee Gabriel while working as a postdoctoral research associate at Arizona State University. NR 26 TC 6 Z9 6 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JAN PY 2012 VL 44 IS 1 BP 104 EP 110 DI 10.1249/MSS.0b013e318229056e PG 7 WC Sport Sciences SC Sport Sciences GA 866JT UT WOS:000298377400014 ER PT J AU Chen, KY Janz, KF Zhu, WM Brychta, RJ AF Chen, Kong Y. Janz, Kathleen F. Zhu, Weimo Brychta, Robert J. TI Redefining the Roles of Sensors in Objective Physical Activity Monitoring SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE TRANSDUCERS; DEVICES; MOTION SENSORS; PHYSIOLOGICAL SENSORS; CONTEXTUAL SENSORS ID GLOBAL POSITIONING SYSTEM; ARTIFICIAL NEURAL-NETWORK; HEART-RATE MONITOR; HEALTH SMART HOME; ENERGY-EXPENDITURE; STEP FREQUENCY; HUMAN MOVEMENT; ACCELEROMETRY; WALKING; VALIDITY AB CHEN, K. Y., K. F. JANZ, W. ZHU, and R. J. BRYCHTA. Redefining the Roles of Sensors in Objective Physical Activity Monitoring. Med. Sci. Sports Exerc., Vol. 44, No. 1S, pp. S13-S23, 2012. Background: Because physical activity researchers are increasingly using objective portable devices, this review describes the current state of the technology to assess physical activity, with a focus on specific sensors and sensor properties currently used in monitors and their strengths and weaknesses. Additional sensors and sensor properties desirable for activity measurement and best practices for users and developers also are discussed. Best Practices: We grouped current sensors into three broad categories for objectively measuring physical activity: associated body movement, physiology, and context. Desirable sensor properties for measuring physical activity and the importance of these properties in relationship to specific applications are addressed, and the specific roles of transducers and data acquisition systems within the monitoring devices are defined. Technical advancements in sensors, microcomputer processors, memory storage, batteries, wireless communication, and digital filters have made monitors more usable for subjects (smaller, more stable, and longer running time) and for researchers (less costly, higher time resolution and memory storage, shorter download time, and user-defined data features). Future Directions: Users and developers of physical activity monitors should learn about the basic properties of their sensors, such as range, accuracy, and precision, while considering the data acquisition/filtering steps that may be critical to data quality and may influence the desirable measurement outcome(s). C1 [Chen, Kong Y.; Brychta, Robert J.] NIDDK, Diabet Endocrinol & Obes Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Janz, Kathleen F.] Univ Iowa, Coll Liberal Arts & Sci, Dept Hlth & Human Physiol, Iowa City, IA USA. [Zhu, Weimo] Univ Illinois, Coll Appl Hlth Sci, Dept Kinesiol & Community Hlth, Urbana, IL 61801 USA. RP Chen, KY (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, Intramural Res Program, NIH, Bldg 10-CRC,Rm 6-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenkong@mail.nih.gov OI Chen, Kong/0000-0002-0306-1904 FU National Institute of Diabetes and Digestive and Kidney Diseases [1 Z01 DK071014] FX This work was partially supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (1 Z01 DK071014, K.Y.C. and R.J.B.). NR 61 TC 42 Z9 42 U1 4 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PY 2012 VL 44 SU 1 BP S13 EP S23 DI 10.1249/MSS.0b013e3182399bc8 PG 11 WC Sport Sciences SC Sport Sciences GA 871IR UT WOS:000298732000003 PM 22157770 ER PT J AU Freedson, P Bowles, HR Troiano, R Haskell, W AF Freedson, Patty Bowles, Heather R. Troiano, Richard Haskell, William TI Assessment of Physical Activity Using Wearable Monitors: Recommendations for Monitor Calibration and Use in the Field SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PHYSICAL ACTIVITY MEASUREMENT; WEARABLE ACCELEROMETERS; RECOMMENDATIONS FOR USING MONITORS ID ARTIFICIAL NEURAL-NETWORK; ENERGY-EXPENDITURE; AUSTRALIAN ADULTS; TIME; ACCELEROMETER; ASSOCIATIONS; COMPENDIUM AB FREEDSON, P., H. R. BOWLES, R. TROIANO, and W. HASKELL. Assessment of Physical Activity Using Wearable Monitors: Recommendations for Mornitor Calibration and Use in the Field. Med. Sci. Sports Exerc., Vol. 44, No. 1S, pp. S1-S4, 2012. This article provides recommendations for the use of wearable monitors for assessing physical activity. We have provided recommendations for measurement researchers, end users, and developers of activity monitors. We discuss new horizons and future directions in the field of objective measurement of physical activity and present challenges that remain for the future. These recommendations are based on the proceedings from the workshop "Objective Measurement of Physical Activity: Best Practices and Future Direction," held on July 20-21, 2009, and also on data and information presented since the workshop. C1 [Freedson, Patty] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Kinesiol, Amherst, MA 01003 USA. [Bowles, Heather R.; Troiano, Richard] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Haskell, William] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. RP Freedson, P (reprint author), Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Kinesiol, Totman Bldg, Amherst, MA 01003 USA. EM psf@kin.umass.edu OI Troiano, Richard/0000-0002-6807-989X FU NCI NIH HHS [R01 CA121005-04, R01 CA121005, U01 CA130783, U01 CA130783-02] NR 20 TC 68 Z9 68 U1 2 U2 24 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PY 2012 VL 44 SU 1 BP S1 EP S4 DI 10.1249/MSS.0b013e3182399b7e PG 4 WC Sport Sciences SC Sport Sciences GA 871IR UT WOS:000298732000001 PM 22157769 ER PT J AU Matthews, CE Hagstromer, M Pober, DM Bowles, HR AF Matthews, Charles E. Hagstromer, Maria Pober, David M. Bowles, Heather R. TI Best Practices for Using Physical Activity Monitors in Population-Based Research SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE BEHAVIOR; ENERGY EXPENDITURE; SEDENTARY; MEASUREMENT; HEALTH ID ACTIVITY ENERGY-EXPENDITURE; ARTIFICIAL NEURAL-NETWORK; ACCELEROMETER DATA; MEASUREMENT ERROR; UNITED-STATES; VALIDATION; INTENSITY; POSTURE; OBESITY; DESIGN AB MATTHEWS, C. E., M. HAGSTROMER, D. M. POBER, and H. R. BOWLES. Best Practices for Using Physical Activity Monitors in Population-Based Research. Med. Sci. Sports Exerc., Vol. 44, No. 1S, pp. S68-S76, 2012. The use of physical activity monitors in population-based research has increased dramatically in the past decade. In this report, we review the major purpose for using physical activity monitors in different types of population-based studies (i.e., surveillance, intervention, association studies) and discuss the strengths and weaknesses for the various behavioral outcomes derived from monitors for each study type. We also update and extend previous recommendations for use of these instruments in large-scale studies, particularly with respect to selecting monitor systems in the context of technological advances that have occurred in recent years. The current state of the science with respect to optimal measurement schedules for use of physical activity monitors is also discussed. A checklist and flowchart are provided so that investigators have more guidance when reporting key elements of monitor use in their studies. C1 [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Hagstromer, Maria] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Physiotherapy, Stockholm, Sweden. [Bowles, Heather R.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. RP Matthews, CE (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 3028, Rockville, MD 20892 USA. EM charles.matthews2@nih.gov RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Hagstromer, Maria/0000-0002-4607-8677 FU Intramural NIH HHS [Z99 CA999999] NR 40 TC 144 Z9 145 U1 4 U2 44 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PY 2012 VL 44 SU 1 BP S68 EP S76 DI 10.1249/MSS.0b013e3182399e5b PG 9 WC Sport Sciences SC Sport Sciences GA 871IR UT WOS:000298732000009 PM 22157777 ER PT J AU Welk, GJ McClain, J Ainsworth, BE AF Welk, Gregory J. McClain, James Ainsworth, Barbara E. TI Protocols for Evaluating Equivalency of Accelerometry-Based Activity Monitors SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACCELEROMETERS; ASSESSMENT; PHYSICAL ACTIVITY; ACTIVITY MONITORS ID KENZ LIFECORDER EX; PHYSICAL-ACTIVITY; ACTIGRAPH ACCELEROMETERS; ENERGY-EXPENDITURE; TECHNICAL RELIABILITY; CONVERGENT VALIDITY; RT3 ACCELEROMETER; VALIDATION; VARIABILITY; COMPENDIUM AB WELK, G. J., J. MCCLAIN, and B. E. AINSWORTH. Protocols for Evaluating Equivalency of Accelerometry-Based Activity Monitors. Med. Sci. Sports Exerc., Vol. 44, No. 1S, pp. S39-S49, 2012. A wide array of accelerometer-based activity monitors has been developed to facilitate objective monitoring of physical activity behaviors, but it has proven difficult to equate outputs from different monitors. On the surface, commercially available monitors seem to be performing the same basic task-monitoring total body acceleration. However, differences in sensor properties and internal data processing have made it difficult to directly compare output from different monitors. In recent years, many new competing technologies have been released into the market, compounding the challenge of evaluating monitor equivalency and the relative strengths and limitations of different monitors. To advance physical activity assessment and improve our ability to compare results across studies using different monitors, it is important to conduct functional equivalency studies in a standardized and systematic way. This article summarizes issues associated with monitor equivalency and proposes methods for standardization and quality control in future research. C1 [Welk, Gregory J.] Iowa State Univ, Coll Human Sci, Dept Kinesiol, Ames, IA USA. [McClain, James] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ainsworth, Barbara E.] Arizona State Univ, Coll Nursing & Hlth Innovat, Hlth Lifestyles Res Ctr, Phoenix, AZ USA. [Ainsworth, Barbara E.] Arizona State Univ, Coll Nursing & Hlth Innovat, Program Exercise & Wellness, Phoenix, AZ USA. RP Welk, GJ (reprint author), 257 Forker Bldg, Ames, IA 50011 USA. EM gwelk@iastate.edu NR 35 TC 46 Z9 47 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PY 2012 VL 44 SU 1 BP S39 EP S49 DI 10.1249/MSS.0b013e3182399d8f PG 11 WC Sport Sciences SC Sport Sciences GA 871IR UT WOS:000298732000006 PM 22157773 ER PT J AU Fischer, TV Folio, LR Backus, CE Bunger, R AF Fischer, Tatjana V. Folio, Les R. Backus, Christopher E. Bunger, Rolf TI Case Report Highlighting How Wound Path Identification on CT Can Help Identify Organ Damage in Abdominal Blast Injuries SO MILITARY MEDICINE LA English DT Article ID CARTESIAN POSITIONING SYSTEM AB Penetrating trauma is frequently encountered in forward deployed military combat hospitals. Abdominal blast injuries represent nearly 11% of combat injuries, and multiplanar computed tomography imaging is optimal for injury assessment and surgical planning. We describe a multiplanar approach to assessment of blast and ballistic injuries, which allows for more expeditious detection of in tracts and damage caused along the path. Precise delineation of the trajectory path and localization of retained fragments enables time-saving and detailed evaluation of associated tissue and vascular injury. For consistent and reproducible documentation of fragment locations in the body, we propose a localization scheme based on Cartesian coordinates to report 3-dimensional locations of fragments and demonstrating the application in three cases of abdominal blast injury. C1 [Fischer, Tatjana V.] Tech Univ Munich, D-80333 Munich, Germany. [Folio, Les R.] NIH, Bethesda, MD 20892 USA. [Backus, Christopher E.] David Grant Med Ctr, Travis AFB, CA 94535 USA. [Bunger, Rolf] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Fischer, TV (reprint author), Tech Univ Munich, Arcisstr 21, D-80333 Munich, Germany. NR 11 TC 3 Z9 4 U1 0 U2 3 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 JAN PY 2012 VL 177 IS 1 BP 101 EP 107 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 874RP UT WOS:000298976100023 PM 22338990 ER PT J AU Sarkar, TR Sharan, S Wang, J Pawar, SA Cantwell, CA Johnson, PF Morrison, DK Wang, JM Sterneck, E AF Sarkar, Tapasree Roy Sharan, Shikha Wang, Jun Pawar, Snehalata A. Cantwell, Carrie A. Johnson, Peter F. Morrison, Deborah K. Wang, Ju-Ming Sterneck, Esta TI Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBP delta Expression and Contributes to Transformation of Breast Tumor Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BINDING-PROTEIN-DELTA; CYCLIN D1; GENE-EXPRESSION; FAMILY KINASES; CANCER CELLS; SKI-606 BOSUTINIB; EPITHELIAL-CELLS; ABSENTIA HOMOLOG; GROWTH ARREST; TARGETING SRC AB The transcription factor CCAAT/enhancer-binding protein delta (C/EBP delta, CEBPD) is a tumor suppressor that is downregulated during breast cancer progression but may also promote metastasis. Here, we have investigated the mechanism(s) regulating C/EBP delta expression and its role in human breast cancer cells. We describe a novel pathway by which the tyrosine kinase Src downregulates C/EBP delta through the SIAH2 E3 ubiquitin ligase. Src phosphorylates SIAH2 in vitro and leads to tyrosine phosphorylation and activation of SIAH2 in breast tumor cell lines. SIAH2 interacts with C/EBP delta, but not C/EBP beta, and promotes its polyubiquitination and proteasomal degradation. Src/SIAH2-mediated inhibition of C/EBP delta expression supports elevated cydin D1 levels, phosphorylation of retinoblastoma protein (Rb), motility, invasive properties, and survival of transformed cells. Pharmacological inhibition of Src family kinases by SKI-606 (bosutinib) induces C/EBP delta expression in an SIAH2-dependent manner, which is necessary for "therapeutic" responses to SKI-606 in vitro. Ectopic expression of degradation-resistant mutants of C/EBP delta, which do not interact with SIAH2 and/or cannot be polyubiquitinated, prevents full transformation of MCF-10A cells by activated Src (Src truncated at amino acid 531 [Src-531]) in vitro. These data reveal that C/EBP delta expression can be regulated at the protein level by oncogenic Src kinase signals through SIAH2, thus contributing to breast epithelial cell transformation. C1 [Sarkar, Tapasree Roy; Sharan, Shikha; Wang, Jun; Pawar, Snehalata A.; Morrison, Deborah K.; Sterneck, Esta] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21701 USA. [Cantwell, Carrie A.; Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. [Wang, Ju-Ming] Natl Cheng Kung Univ, Coll Biosci & Biotechnol, Inst Bioinformat & Biosignal Transduct, Tainan 70101, Taiwan. RP Sterneck, E (reprint author), NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21701 USA. EM sternecg@mail.nih.gov FU NIH National Cancer Institute [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the NIH National Cancer Institute and in part with federal funds under contract number HHSN261200800001E. NR 74 TC 33 Z9 34 U1 2 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2012 VL 32 IS 2 BP 320 EP 332 DI 10.1128/MCB.05790-11 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 875HD UT WOS:000299020100008 PM 22037769 ER PT J AU Cui, YH Xiao, L Rao, JN Zou, TT Liu, L Chen, Y Turner, DJ Gorospe, M Wang, JY AF Cui, Yu-Hong Xiao, Lan Rao, Jaladanki N. Zou, Tongtong Liu, Lan Chen, Yu Turner, Douglas J. Gorospe, Myriam Wang, Jian-Ying TI miR-503 represses CUG-binding protein 1 translation by recruiting CUGBP1 mRNA to processing bodies SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; GU-RICH ELEMENTS; POLYAMINE DEPLETION; POSTTRANSCRIPTIONAL REGULATION; MYOTONIC-DYSTROPHY; P-BODIES; MICRORNA BIOGENESIS; HUR; APOPTOSIS; STABILITY AB microRNAs (miRNAs) and RNA-binding proteins (RBPs) jointly regulate gene expression at the posttranscriptional level and are involved in many aspects of cellular functions. The RBP CUG-binding protein 1 (CUGBP1) destabilizes and represses the translation of several target mRNAs, but the exact mechanism that regulates CUGBP1 abundance remains elusive. In this paper, we show that miR-503, computationally predicted to associate with three sites of the CUGBP1 mRNA, represses CUGBP1 expression. Overexpression of an miR-503 precursor (pre-miR-503) reduced the de novo synthesis of CUGBP1 protein, whereas inhibiting miR-503 by using an antisense RNA (antagomir) enhanced CUGBP1 biosynthesis and elevated its abundance; neither intervention changed total CUGBP1 mRNA levels. Studies using heterologous reporter constructs revealed a greater repressive effect of miR-503 through the CUGBP1 coding region sites than through the single CUGBP1 3'-untranslated region target site. CUGBP1 mRNA levels in processing bodies (P-bodies) increased in cells transfected with pre-miR-503, while silencing P-body resident proteins Ago2, RCK, or LSm4 decreased miR-503-mediated repression of CUGBP1 expression. Decreasing the levels of cellular polyamines reduced endogenous miR-503 levels and promoted CUGBP1 expression, an effect that was prevented by ectopic miR-503 overexpression. Repression of CUGBP1 by miR-503 in turn altered the expression of CUGBP1 target mRNAs and thus increased the sensitivity of intestinal epithelial cells to apoptosis. These findings identify miR-503 as both a novel regulator of CUGBP1 expression and a modulator of intestinal epithelial homoeostasis. C1 [Cui, Yu-Hong; Xiao, Lan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Chen, Yu; Turner, Douglas J.; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Cui, Yu-Hong; Xiao, Lan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Chen, Yu; Turner, Douglas J.; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU Department of Veterans Affairs; National Institutes of Health (NIH) [DK-57819, DK-61972, DK-68491]; National Institute on Aging FX We thank J. L. Martindale for experimental support. This work was supported by Merit Review Grants (to J.-Y. W. and J. N. R.) from the Department of Veterans Affairs and by National Institutes of Health (NIH) grants DK-57819, DK-61972, DK-68491 (to J.-Y. W.). J.-Y. W. is a Senior Research Career Scientist, Medical Research Service, U. S. Department of Veterans Affairs. M. G. is supported by the National Institute on Aging-Intramural Research Program, NIH. NR 59 TC 38 Z9 39 U1 1 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 1 PY 2012 VL 23 IS 1 BP 151 EP 162 DI 10.1091/mbc.E11-05-0456 PG 12 WC Cell Biology SC Cell Biology GA 870HY UT WOS:000298661200014 PM 22072795 ER PT J AU Andreotti, G Silverman, DT AF Andreotti, Gabriella Silverman, Debra T. TI Occupational risk factors and pancreatic cancer: A review of recent findings SO MOLECULAR CARCINOGENESIS LA English DT Article DE occupation; pancreatic cancer; epidemiology ID AGRICULTURAL PESTICIDE USE; N-NITROSAMINES; PHYSICAL-ACTIVITY; FOLLOW-UP; WORKERS; EXPOSURE; MORTALITY; METAANALYSIS; INDUSTRY; RUBBER AB Several occupational exposures have been linked to excess risk of pancreatic cancer; however, most associations are not well established. The objective of this review article is to report on the more recently published studies (1998-2010), and provide a summary of the most consistently reported occupational risk factors for pancreatic cancer, including exposure to chlorinated hydrocarbon compounds, pesticides, polycyclic aromatic hydrocarbons (PAHs), metals, nitrosamines, radiation, various airborne particles, and employment in sedentary occupations. We conclude that the strongest and most consistent findings linking occupational exposures with pancreatic cancer risk to date are for chlorinated hydrocarbons and PAHs. (C) 2011 Wiley Periodicals, Inc. C1 [Andreotti, Gabriella; Silverman, Debra T.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Andreotti, G (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8122,MSC 7240, Bethesda, MD 20892 USA. NR 60 TC 14 Z9 16 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JAN PY 2012 VL 51 IS 1 SI SI BP 98 EP 108 DI 10.1002/mc.20779 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 862NH UT WOS:000298098500009 PM 22162234 ER PT J AU Sanchez, GV Weinstein, SJ Stolzenberg-Solomon, RZ AF Sanchez, G. V. Weinstein, S. J. Stolzenberg-Solomon, R. Z. TI Is dietary fat, vitamin D, or folate associated with pancreatic cancer? SO MOLECULAR CARCINOGENESIS LA English DT Article DE pancreatic cancer; dietary fat; vitamin D; folate; nutritional risk factors ID FOLIC-ACID FORTIFICATION; FRANCISCO BAY AREA; MALE SMOKERS; 25-HYDROXYVITAMIN D; SCREENING TRIAL; INSULIN SENSITIVITY; COLORECTAL ADENOMAS; NETHERLANDS COHORT; UNITED-STATES; IN-VITRO AB Although potentially modifiable risk factors for pancreatic cancer include smoking, obesity, and diabetes, less is known about the extent to which diet affects cancer risk. Recent studies have demonstrated some consistency for dietary fat being associated with elevated pancreatic cancer risk, particularly from animal sources. However, less is known about which fatty acids pose the greatest risk. Vitamin D, due to its endogenous production following UV-B exposure, is a unique risk factor in that researchers have created several methods to assess its exposure in humans. Studies that measured vitamin D exposure differently have shown inconsistent results. Dietary studies suggest protective associations, whereas studies of circulating 25-hydroxyvitamin D status show null or positive associations with low or very high concentrations, respectively. Several, but not all epidemiologic studies provide evidence of an inverse relationship between total and/or dietary folate and risk of pancreatic cancer. Protective associations for circulating folate are more often observed among populations with inadequate status. This article reviews the current epidemiological and experimental evidence investigating the relationship of dietary fat, vitamin D, and folate with pancreatic cancer. Additionally the mechanisms by which these risk factors may contribute to cancer, the methodological challenges involved with assessing risk, and other obstacles encountered when ascertaining the magnitude and direction of these three exposures are discussed. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. C1 [Sanchez, G. V.; Weinstein, S. J.; Stolzenberg-Solomon, R. Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sanchez, G. V.] George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Stolzenberg-Solomon, RZ (reprint author), 6120 Execut Blvd,Suite 320, Bethesda, MD 20852 USA. FU Intramural NIH HHS [Z99 CA999999] NR 63 TC 10 Z9 10 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JAN PY 2012 VL 51 IS 1 SI SI BP 119 EP 127 DI 10.1002/mc.20833 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 862NH UT WOS:000298098500011 PM 22162236 ER PT J AU Anderson, KE Mongin, SJ Sinha, R Stolzenberg-Solomon, R Gross, MD Ziegler, RG Mabie, JE Risch, A Kazin, SS Church, TR AF Anderson, Kristin E. Mongin, Steven J. Sinha, Rashmi Stolzenberg-Solomon, Rachael Gross, Myron D. Ziegler, Regina G. Mabie, Jerome E. Risch, Adam Kazin, Sally S. Church, Timothy R. TI Pancreatic cancer risk: Associations with meat-derived carcinogen intake in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort SO MOLECULAR CARCINOGENESIS LA English DT Article DE pancreatic cancer; carcinogens; cohort; meat intake ID FOOD FREQUENCY QUESTIONNAIRE; HETEROCYCLIC AMINES; MUTAGENS; EXPOSURE; COOKING; MODULE AB Background Epidemiological studies report positive associations between high-temperature cooked meat intake and pancreatic cancer. We assessed associations between dietary intake of heterocyclic amines (HCAs) and benzo(a)pyrene (BaP)mutagens formed in meat cooked at high temperaturesand incident exocrine pancreatic cancer in a prospective cohort. Methods The 62 581 subjects randomized to screening in the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) who completed an initial dietary survey that assessed meat intake, cooking methods, and doneness preferences defined the cohort. Subjects were surveyed annually for incident cancers through 2007. A National Cancer Institute research database (CHARRED) was used to estimate HCA and BaP intake and a Mutagenic Activity Index (MAI) from survey data. Proportional hazard ratios (HRs) for risk of pancreatic cancer were estimated from multi-variate Cox regression models by quintile of intake, with the lowest quintile as the referent. Results During follow-up (median: 10 yr), 248 cases of exocrine pancreatic cancer were confirmed. Preferences for well and very well done meat were generally associated with increased risks. Significant elevations in pancreatic cancer risk were found in upper quintiles of MAI, and individual mutagens 2-amino3,4,8- trimethylimidazo[ 4,5-f] quinoxaline (DiMeIQx) and 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx). Compared to the lowest quintile of MAI, the third and fifth quintiles brought HRs of 1.86 (1.22, 2.85) and 1.87 (1.16, 3.02), respectively. These three exposures exhibited significant (P-trend: 0.01-0.03) positive trends in risk as their levels increased Conclusion Consuming well-done meat cooked at high temperatures, which contains high mutagen levels, appears to confer increased risk of pancreatic cancer. (C) 2011 Wiley Periodicals, Inc. C1 [Anderson, Kristin E.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Masonic Canc Ctr, Minneapolis, MN 55454 USA. [Mongin, Steven J.; Church, Timothy R.] Univ Minnesota, Div Environm Hlth Sci, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Sinha, Rashmi; Stolzenberg-Solomon, Rachael; Ziegler, Regina G.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD USA. [Gross, Myron D.] Univ Minnesota, Sch Med, Minneapolis, MN 55454 USA. [Mabie, Jerome E.; Risch, Adam; Kazin, Sally S.] Informat Management Serv Inc, Rockville, MD USA. RP Anderson, KE (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Masonic Canc Ctr, 1300 S 2nd St 300, Minneapolis, MN 55454 USA. RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Church, Timothy R./0000-0003-3292-5035 FU U.S. National Cancer Institute, National Institutes of Health, Department of Health and Human Services [N01-CN-25513 f]; National Institutes of Health [DA-13333] FX The authors wish to thank the PLCO centers and staff for making this study possible. In addition, we thank Tom Hickey, IMS, for suggestions regarding this analysis. We are also grateful to the men and women in PLCO study for their participation. This research was funded, in part, by contract number N01-CN-25513 from the U.S. National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and by National Institutes of Health grant (DA-13333) to the University of Minnesota. NR 24 TC 23 Z9 24 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JAN PY 2012 VL 51 IS 1 SI SI BP 128 EP 137 DI 10.1002/mc.20794 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 862NH UT WOS:000298098500012 PM 22162237 ER PT J AU Annamalai, B Mannangatti, P Arapulisamy, O Shippenberg, TS Jayanthi, LD Ramamoorthy, S AF Annamalai, Balasubramaniam Mannangatti, Padmanabhan Arapulisamy, Obulakshmi Shippenberg, Toni S. Jayanthi, Lankupalle D. Ramamoorthy, Sammanda TI Tyrosine Phosphorylation of the Human Serotonin Transporter: A Role in the Transporter Stability and Function SO MOLECULAR PHARMACOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; PLACENTAL CHORIOCARCINOMA CELLS; UP-REGULATION; MESSENGER-RNA; GROWTH-FACTOR; SYNTAXIN 1A; RECEPTOR; EXPRESSION; PLATELETS; COCAINE AB The serotonin (5-HT) transporter (SERT) regulates serotoninergic neurotransmission by clearing 5-HT released into the synaptic space. Phosphorylation of SERT on serine and threonine mediates SERT regulation. Whether tyrosine phosphorylation regulates SERT is unknown. Here, we tested the hypothesis that tyrosine-phosphorylation of SERT regulates 5-HT transport. In support of this, alkali-resistant P-32-labeled SERT was found in rat platelets, and Src-tyrosine kinase inhibitor 4-amino5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4,d]pyrimidine (PP2) decreased platelet SERT function and expression. In human placental trophoblast cells expressing SERT, PP2 reduced transporter function, expression, and stability. Although siRNA silencing of Src expression decreased SERT function and expression, coexpression of Src resulted in PP2-sensitive increases in SERT function and expression. PP2 treatment markedly decreased SERT protein stability. Compared with WT-SERT, SERT tyrosine mutants Y47F and Y142F exhibited reduced 5-HT transport despite their higher total and cell surface expression levels. Moreover, Src-coexpression increased total and cell surface expression of Y47F and Y142F SERT mutants without affecting their 5-HT transport capacity. It is noteworthy that Y47F and Y142F mutants exhibited higher protein stability compared with WT-SERT. However, similar to WT-SERT, PP2 treatment decreased the stability of Y47F and Y142F mutants. Furthermore, compared with WT-SERT, Y47F and Y142F mutants exhibited lower basal tyrosine phosphorylation and no further enhancement of tyrosine phosphorylation in response to Src coexpression. These results provide the first evidence that SERT tyrosine phosphorylation supports transporter protein stability and 5HT transport. C1 [Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Jayanthi, Lankupalle D.; Ramamoorthy, Sammanda] Med Univ S Carolina, Div Neurosci Res, Dept Neurosci, Charleston, SC 29425 USA. [Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Ramamoorthy, S (reprint author), Med Univ S Carolina, Div Neurosci Res, Dept Neurosci, 173 Ashley Ave,BSB 403, Charleston, SC 29425 USA. EM rama@musc.edu FU National Institutes of Health National Institute of Mental Health [MH62612]; National Institutes of Health National Institute of General Medical Sciences [GM081054]; National Institutes of Health National Institute on Drug Abuse FX This work was supported by the National Institutes of Health National Institute of Mental Health [Grant MH62612] (to S.R); the National Institutes of Health National Institute of General Medical Sciences [Grant GM081054] (to L.D.J.), and in part by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse (to. T.S.S). NR 41 TC 5 Z9 6 U1 1 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JAN PY 2012 VL 81 IS 1 BP 73 EP 85 DI 10.1124/mol.111.073171 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 866VF UT WOS:000298413500009 PM 21992875 ER PT J AU Papaleo, F Yang, F Garcia, S Chen, J Lu, B Crawley, JN Weinberger, DR AF Papaleo, F. Yang, F. Garcia, S. Chen, J. Lu, B. Crawley, J. N. Weinberger, D. R. TI Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways SO MOLECULAR PSYCHIATRY LA English DT Article DE dopamine; genes; mice; prefrontal cortex; schizophrenia; working memory ID WORKING-MEMORY; PREPULSE INHIBITION; GENETIC-VARIATION; D2 RECEPTOR; FUNCTIONAL CONNECTIVITY; HIPPOCAMPAL-FORMATION; SUSCEPTIBILITY GENE; PYRAMIDAL NEURONS; MESSENGER-RNA; 6P22.3 GENE AB Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin-1-deficient mice (dys-/-) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys-/- pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys-/- were also respectively more and less sensitive to D2 agonist-and antagonist-induced behavioral effects. Dys-/- had reduced expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and CaMKK beta in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys-/- behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis. Molecular Psychiatry (2012) 17, 85-98; doi:10.1038/mp.2010.106; published online 19 October 2010 C1 [Papaleo, F.] Italian Inst Technol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Weinberger, D. R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, IRP,NIH, Bethesda, MD 20892 USA. [Yang, F.] NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. [Crawley, J. N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Papaleo, F (reprint author), Italian Inst Technol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. EM francesco.papaleo@iit.it; weinberd@mail.nih.gov OI Papaleo, Francesco/0000-0002-6326-0657 FU NIH, National Institute of Mental Health FX We thank Q Tian, L Erickson, K Jenkins, J Aney and G Carr for technical assistance. This research was supported by the Intramural Program of the NIH, National Institute of Mental Health. NR 65 TC 45 Z9 48 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2012 VL 17 IS 1 BP 85 EP 98 DI 10.1038/mp.2010.106 PG 14 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 875EU UT WOS:000299014000013 PM 20956979 ER PT J AU Morgan, RA AF Morgan, Richard A. TI Live and Let Die: A New Suicide Gene Therapy Moves to the Clinic SO MOLECULAR THERAPY LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; SERIOUS ADVERSE EVENT; T-CELLS; LEUKEMIA; SAFETY C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Bldg 10,CRC Room 3-5940,10 Ctr Dr,MSC1201, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov NR 11 TC 11 Z9 11 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JAN PY 2012 VL 20 IS 1 BP 11 EP 13 DI 10.1038/mt.2011.273 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 875HV UT WOS:000299021900005 PM 22319780 ER PT J AU Xu, WQ Russ, JL Eiden, MV AF Xu, Wenqin Russ, Jill L. Eiden, Maribeth V. TI Evaluation of Residual Promoter Activity in gamma-Retroviral Self-inactivating (SIN) Vectors SO MOLECULAR THERAPY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; INTEGRATION SITE SELECTION; PACKAGING CELL-LINE; GENE-THERAPY; MOUSE MODEL; SCID-X1; DESIGN; VIRUS; GENOTOXICITY; EFFICIENCY AB Therapeutic gene delivery mediated by retroviral vectors has the advantage of stable integration into the host genome. A major safety concern for gene delivery achieved by murine leukemia virus (MLV)-based retroviral vectors is the activation of adjacent cellular genes including oncogenes following integration into the host genome. Self-inactivating (SIN) vectors lacking viral enhancers/promoters in their 3' long terminal repeat (LTR) have been proposed as a means of overcoming this safety concern. However the MLV-based SIN vectors currently used by laboratories to assess insertional mutagenesis, integration site selection, and the potency of transgene expression are not uniform in the composition of their 3' LTRs. We constructed a series of SIN vectors representative of the currently employed vectors, but lacking an internal promoter. Green fluorescent protein (GFP) was used as a reporter gene. Target cells exposed to these vectors were evaluated for number of integrants and GFP expression at the messenger RNA (mRNA) level and protein level. We found that viral promoter activity in the 3' LTR is not attenuated in many currently employed SIN vectors. These results suggest that the influence of strong residual promoter activity should be taken into consideration when interpreting experimental results obtained using SIN vectors in gene therapy research. C1 [Xu, Wenqin; Russ, Jill L.; Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, LCMR, NIH, Bethesda, MD 20892 USA. RP Eiden, MV (reprint author), NIMH, Sect Directed Gene Transfer, LCMR, NIH, 49 Convent Dr,Bldg 49,Room SA32, Bethesda, MD 20892 USA. EM eidenm@mail.nih.gov FU National Institute of Mental Health FX We are greatly indebted to James Nagle and Deborah Kauffman at National Institute of Neurological Disorders and Stroke sequencing facility (National Institutes of Health) for sequencing of plasmid and genomic DNA. We are grateful to Arlette Kouwenhoven for her expert technical assistance and helpful comments. We thank Laura Li for experimental help. National Institute of Mental Health intramural funding supported this work. The authors declared no conflict of interest. NR 33 TC 11 Z9 11 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JAN PY 2012 VL 20 IS 1 BP 84 EP 90 DI 10.1038/mt.2011.204 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 875HV UT WOS:000299021900014 PM 22008914 ER PT J AU Sips, M Sciaranghella, G Diefenbach, T Dugast, AS Berger, CT Liu, Q Kwon, D Ghebremichael, M Estes, JD Carrington, M Martin, JN Deeks, SG Hunt, PW Alter, G AF Sips, M. Sciaranghella, G. Diefenbach, T. Dugast, A-S Berger, C. T. Liu, Q. Kwon, D. Ghebremichael, M. Estes, J. D. Carrington, M. Martin, J. N. Deeks, S. G. Hunt, P. W. Alter, G. TI Altered distribution of mucosal NK cells during HIV infection SO MUCOSAL IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; INTRA-EPITHELIAL LYMPHOCYTES; CD4(+) T-CELLS; GASTROINTESTINAL-TRACT; INTRAEPITHELIAL LYMPHOCYTES; FUNCTIONAL-CHARACTERISTICS; LYMPHADENOPATHY SYNDROME; INTESTINAL EPITHELIUM; COLLAGEN DEPOSITION; CYTOLYTIC FUNCTION AB The human gut mucosa is a major site of human immunodeficiency virus (HIV) infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells have an important role in control of HIV infection, but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here, we show that two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (intraepithelial lymphocytes, IELs) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective killer immunoglobulin-like receptor/human leukocyte antigen genotypes. Both IEL and LP NK cells were significantly expanded in immunological non-responsive patients, who incompletely recovered CD4 + T cells on highly active antiretroviral therapy (HAART). These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4 + T-cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut. C1 [Sips, M.; Sciaranghella, G.; Diefenbach, T.; Dugast, A-S; Berger, C. T.; Liu, Q.; Kwon, D.; Ghebremichael, M.; Carrington, M.; Alter, G.] Harvard Univ & Massachusetts Inst Technol, Ragon Inst Massachusetts Gen Hosp, Boston, MA USA. [Estes, J. D.] Frederick Inc, NCI, AIDS & Canc Virus Program, Frederick, MD USA. [Carrington, M.] SAIC Frederick Inc, NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Martin, J. N.; Deeks, S. G.; Hunt, P. W.] Univ Calif San Francisco, Dept Med, Posit Hlth Program, San Francisco, CA USA. RP Alter, G (reprint author), Harvard Univ & Massachusetts Inst Technol, Ragon Inst Massachusetts Gen Hosp, Boston, MA USA. EM galter@partners.org RI Dugast, AnneSophie/L-9541-2015 FU NCI NIH HHS [HHSN261200800001E]; NIAID NIH HHS [K08 AI084546, P30 AI027763, R01 AI080289] NR 51 TC 24 Z9 24 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JAN PY 2012 VL 5 IS 1 BP 30 EP 40 DI 10.1038/mi.2011.40 PG 11 WC Immunology SC Immunology GA 866UP UT WOS:000298411100005 PM 21993602 ER PT J AU Bolton, DL Song, K Wilson, RL Kozlowski, PA Tomaras, GD Keele, BF Lovingood, RV Rao, S Roederer, M AF Bolton, D. L. Song, K. Wilson, R. L. Kozlowski, P. A. Tomaras, G. D. Keele, B. F. Lovingood, R. V. Rao, S. Roederer, M. TI Comparison of systemic and mucosal vaccination: impact on intravenous and rectal SIV challenge SO MUCOSAL IMMUNOLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL RESPONSES; RHESUS-MONKEYS; IMMUNE-RESPONSES; SIVMAC251 CHALLENGE; PROTECTIVE EFFICACY; VIRAL LOAD; INFECTION; CD4(+); MACAQUES AB Mucosal tissues are the primary route of transmission for most respiratory and sexually transmitted diseases, including human immunodeficiency virus. We aimed to generate strong mucosal immune responses to simian immunodeficiency virus (SIV) in rhesus macaques by targeting recombinant adenovirus serotype 5 (rAd5) to the lung. The immunogenicity and efficacy of aerosol (AE) vaccination was compared with intramuscular (IM) delivery in either an intravenous (IV) or intrarectal (IR) SIV(mac251) challenge model. Aerosolized rAd5 induced strong cellular responses in the lung and systemic humoral responses equivalent to IM. Strikingly, all immunization groups controlled acute viremia in the IV challenge model by 1-2 logs. By contrast, after IR challenge, only peak viremia was reduced by immunization, with no significant effect on SIV infection acquisition rate or mucosal CD4(+) T-cell preservation. Improved disease outcome was associated with pre-challenge cellular and humoral responses, while post-challenge T-cell responses were highly correlated with viremia control. The similar outcomes achieved by systemic and airway mucosal immunization support AE delivery as a safe, effective, and less invasive alternative to parenteral vaccination. C1 [Bolton, D. L.; Song, K.; Roederer, M.] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Wilson, R. L.; Kozlowski, P. A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA USA. [Tomaras, G. D.; Lovingood, R. V.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Keele, B. F.] SAIC Frederick Inc, NCI Frederick, AIDS & Canc Virus Program, Frederick, MD USA. [Rao, S.] Vaccine Res Ctr, Lab Anim Med, Bethesda, MD USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Roederer@nih.gov RI Tomaras, Georgia/J-5041-2016 FU National Institutes of Health [AI058896]; Louisiana Vaccine Center; South Louisiana Institute for Infectious Disease Research; Louisiana Board of Regents; National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN266200400088C] FX We thank M. Louder and Dr J Mascola for performing SIV Env neutralization assays and Dr J Lifson of SAIC-Frederick and Dr T Denny of Duke University for plasma viral load measurements. We thank Dr B. Lafont of the Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, for major histocompatibility complex haplotype sequencing. We also thank JP Todd and A Ault for assisting with animal immunizations, challenges, and sampling scheduling, as well as T Jenkins and A Dodson of Bioqual for animal care and handling. Adenovirus viral stocks were kindly provided by J Gall of GenVec. We thank Vicki C Ashley and R Glenn Overman for technical assistance with the antibody measurements and all members of the ImmunoTechnology Section for insightful discussions. This work was supported in part by the National Institutes of Health grant AI058896 (to PAK) and the Louisiana Vaccine Center and the South Louisiana Institute for Infectious Disease Research sponsored by the Louisiana Board of Regents, by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the National Cancer Institute, National Institutes of Health under contract HHSN266200400088C. NR 50 TC 20 Z9 20 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JAN PY 2012 VL 5 IS 1 BP 41 EP 52 DI 10.1038/mi.2011.45 PG 12 WC Immunology SC Immunology GA 866UP UT WOS:000298411100006 PM 22031182 ER PT J AU Nakano, H Free, ME Whitehead, GS Maruoka, S Wilson, RH Nakano, K Cook, DN AF Nakano, H. Free, M. E. Whitehead, G. S. Maruoka, S. Wilson, R. H. Nakano, K. Cook, D. N. TI Pulmonary CD103(+) dendritic cells prime Th2 responses to inhaled allergens SO MUCOSAL IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; THYMIC STROMAL LYMPHOPOIETIN; ANTIGEN-PRESENTING CELLS; HOUSE-DUST EXTRACTS; IN-VIVO; IMMUNE-RESPONSES; TYPE-2 RESPONSES; OX40 LIGAND; IFN-GAMMA; INDUCTION AB Allergic asthma stems largely from the actions of T helper 2 (Th2) cells, but the pathways that initiate Th2 responses to inhaled allergens are not fully understood. In the lung, there are two major subsets of dendritic cells (DCs), displaying CD11b or CD103. We found that after taking up inhaled ovalbumin in vivo, purified CD103(+) DCs from the lung or lung-draining lymph nodes primed Th2 differentiation ex vivo. Th2 induction by CD103(+) DCs was also seen when cockroach or house dust mite allergens were used. In contrast, CD11b hi DCs primed Th1 differentiation. Moreover, mice lacking CD103(+) DCs displayed diminished Th2 priming to various inhaled allergens and did not develop asthma-like responses following subsequent allergen challenge. Low-level antigen presentation by CD103(+) DCs was necessary, but not sufficient for Th2 priming. Together, these findings show that CD103(+) DCs have a significant role in priming Th2 responses to inhaled allergens. C1 [Nakano, H.; Free, M. E.; Whitehead, G. S.; Maruoka, S.; Wilson, R. H.; Nakano, K.; Cook, D. N.] NIEHS, Lab Resp Biol, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Cook, DN (reprint author), NIEHS, Lab Resp Biol, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM cookd@niehs.nih.gov FU National Institutes of Health (NIH); NIEHS FX We thank Maria Sifre and Carl Bortner for help with flow cytometry; Laura Miller, Ligon Perrow, Herman Price, and Dan Morgan for support with animal experiments; Andrew McKenzie (Medical Research Council, UK and Simon Hogan (University of Cincinnati) for providing IL-9-deficient mice; Brian Kelsall (NIH/NIAID) for advice on DC preparation; Jim Aloor for advice on LPS removal; and Michael Fessler (NIEHS) and Cheolho Cheong (Rockefeller University) for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the NIEHS. NR 53 TC 59 Z9 59 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JAN PY 2012 VL 5 IS 1 BP 53 EP 65 DI 10.1038/mi.2011.47 PG 13 WC Immunology SC Immunology GA 866UP UT WOS:000298411100007 PM 22012243 ER PT J AU Westbrook, AM Wei, B Hacke, K Xia, MH Braun, J Schiestl, RH AF Westbrook, Aya M. Wei, Bo Hacke, Katrin Xia, Menghang Braun, Jonathan Schiestl, Robert H. TI The role of tumour necrosis factor-alpha and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity SO MUTAGENESIS LA English DT Article ID NF-KAPPA-B; DNA-DAMAGE; TNF-ALPHA; COMET ASSAY; BOWEL-DISEASE; INTESTINAL INFLAMMATION; IN-VIVO; ENDOTHELIAL-CELLS; INDUCED COLITIS; MICE AB Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-alpha, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-alpha is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-alpha was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-alpha-induced DNA damage in the absence of other cell types. Furthermore, TNFR1(-/-)TNFR2(-/-) mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-alpha injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-kappa B inhibitors were also able to decrease damage induced by TNF-alpha injection in wild-type mice. When TNF-alpha administration was combined with interleukin (IL)-1 beta, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-alpha/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators. C1 [Wei, Bo; Hacke, Katrin; Braun, Jonathan; Schiestl, Robert H.] Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Westbrook, Aya M.; Schiestl, Robert H.] Univ Calif Los Angeles, Sch Publ Hlth, Mol Toxicol Interdept Program, Los Angeles, CA 90095 USA. [Schiestl, Robert H.] Univ Calif Los Angeles, Sch Med, Dept Radiat Oncol, Los Angeles, CA 90095 USA. [Xia, Menghang] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Schiestl, RH (reprint author), Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med, 650 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM rschiestl@mednet.ucla.edu FU National Institutes of Health [DK46763, AI078885]; the Crohn's and Colitis Foundation of America; University of California, Los Angeles National Institute of Environmental Health Sciences FX National Institutes of Health (DK46763 to J.B., AI078885 to J.B. and R.S); the Crohn's and Colitis Foundation of America grant to (B.W.); University of California, Los Angeles National Institute of Environmental Health Sciences training grant in Molecular Toxicology to (A.W.). NR 55 TC 13 Z9 15 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD JAN PY 2012 VL 27 IS 1 BP 77 EP 86 DI 10.1093/mutage/ger063 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 866MP UT WOS:000298385400008 PM 21980144 ER PT J AU Choi, KY Liu, G Lee, S Chen, XY AF Choi, Ki Young Liu, Gang Lee, Seulki Chen, Xiaoyuan TI Theranostic nanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives SO NANOSCALE LA English DT Review ID GLYCOL CHITOSAN NANOPARTICLES; IRON-OXIDE NANOPARTICLES; WALLED CARBON NANOTUBES; TUMOR-BEARING MICE; RECEPTOR-MEDIATED ENDOCYTOSIS; VISIBLE DRUG-DELIVERY; IN-VIVO; CONTROLLED-RELEASE; TARGETED DELIVERY; MULTIFUNCTIONAL NANOPARTICLES AB Theranostics is a concept which refers to the integration of imaging and therapy. As an evolving new field, it is related to but different from traditional imaging and therapeutics. It embraces multiple techniques to arrive at a comprehensive diagnostic, in vivo molecular images and an individualized treatment regimen. More recently, there is a trend of tangling these efforts with emerging materials and nanotechnologies, in an attempt to develop novel platforms and methodologies to tackle practical issues in clinics. In this article, topics of rationally designed nanoparticles for the simultaneous imaging and therapy of cancer will be discussed. Several exemplary nanoparticle platforms such as polymeric nanoparticles, gold nanomaterials, carbon nanotubes, magnetic nanoparticles and silica nanoparticles will be elaborated on and future challenges of nanoparticle-based systems will be discussed. C1 [Choi, Ki Young; Liu, Gang; Lee, Seulki; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn NIBIB, Lab Mol Imaging & Nanomed LOMIN, Natl Inst Hlth NIH, Bethesda, MD 20892 USA. RP Lee, S (reprint author), Natl Inst Biomed Imaging & Bioengn NIBIB, Lab Mol Imaging & Nanomed LOMIN, Natl Inst Hlth NIH, Bethesda, MD 20892 USA. EM Seulki.Lee@nih.gov; Shawn.Chen@nih.gov RI CHOI, KI YOUNG/Q-7177-2016 FU National Institutes of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); NIH [K99/R00] FX This work was supported by the Intramural Research Program (IRP) of the National Institutes of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). S. L. is partially supported by the NIH Pathway to Independence (K99/R00) Award. NR 128 TC 179 Z9 182 U1 31 U2 205 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 J9 NANOSCALE JI Nanoscale PY 2012 VL 4 IS 2 BP 330 EP 342 DI 10.1039/c1nr11277e PG 13 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 873AZ UT WOS:000298854300001 PM 22134683 ER PT J AU Wang, HC Falck, JR Hall, TMT Shears, SB AF Wang, Huanchen Falck, J. R. Hall, Traci M. Tanaka Shears, Stephen B. TI Structural basis for an inositol pyrophosphate kinase surmounting phosphate crowding SO NATURE CHEMICAL BIOLOGY LA English DT Article ID HEXAKISPHOSPHATE KINASE; CRYSTAL-STRUCTURE; DIPHOSPHOINOSITOL PENTAKISPHOSPHATE; 1,4,5-TRISPHOSPHATE 3-KINASE; CELLS; SPECIFICITY; ENZYMES; BINDING; IDENTIFICATION; POLYPHOSPHATES AB Inositol pyrophosphates (such as IP7 and IP8) are multifunctional signaling molecules that regulate diverse cellular activities. Inositol pyrophosphates have 'high-energy' phosphoanhydride bonds, so their enzymatic synthesis requires that a substantial energy barrier to the transition state be overcome. Additionally, inositol pyrophosphate kinases can show stringent ligand specificity, despite the need to accommodate the steric bulk and intense electronegativity of nature's most concentrated three-dimensional array of phosphate groups. Here we examine how these catalytic challenges are met by describing the structure and reaction cycle of an inositol pyrophosphate kinase at the atomic level. We obtained crystal structures of the kinase domain of human PPIP5K2 complexed with nucleotide cofactors and either substrates, product or a MgF3- transition-state mimic. We describe the enzyme's conformational dynamics, its unprecedented topological presentation of nucleotide and inositol phosphate, and the charge balance that facilitates partly associative in-line phosphoryl transfer. C1 [Wang, Huanchen; Shears, Stephen B.] NIEHS, Inositol Signaling Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Falck, J. R.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Hall, Traci M. Tanaka] NIEHS, Macromol Struct Grp, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, HC (reprint author), NIEHS, Inositol Signaling Grp, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wangh7@niehs.nih.gov OI Falck, John/0000-0002-9219-7845 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Institutes of Health; National Institute of Environmental Health Sciences (NIEHS) FX Data were collected at the Southeast Regional Collaborative Access Team 22-ID/22-BM beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. The use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences (NIEHS). We are grateful to L. C. Pedersen for advice and support. We also thank H. Ke for his assistance in writing the manuscript. Expression vectors were prepared by the NIEHS Protein Expression Core Facility. NR 40 TC 44 Z9 47 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JAN PY 2012 VL 8 IS 1 BP 111 EP 116 DI 10.1038/nchembio.733 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866VL UT WOS:000298414100019 PM 22119861 ER PT J AU Wang, ZM Jacobs, KB Yeager, M Hutchinson, A Sampson, J Chatterjee, N Albanes, D Berndt, SI Chung, CC Diver, WR Gapstur, SM Teras, LR Haiman, CA Henderson, BE Stram, D Deng, X Hsing, AW Virtamo, J Eberle, MA Stone, JL Purdue, MP Taylor, P Tucker, M Chanock, SJ AF Wang, Zhaoming Jacobs, Kevin B. Yeager, Meredith Hutchinson, Amy Sampson, Joshua Chatterjee, Nilanjan Albanes, Demetrius Berndt, Sonja I. Chung, Charles C. Diver, W. Ryan Gapstur, Susan M. Teras, Lauren R. Haiman, Christopher A. Henderson, Brian E. Stram, Daniel Deng, Xiang Hsing, Ann W. Virtamo, Jarmo Eberle, Michael A. Stone, Jennifer L. Purdue, Mark P. Taylor, Phil Tucker, Margaret Chanock, Stephen J. TI Improved imputation of common and uncommon SNPs with a new reference set SO NATURE GENETICS LA English DT Letter ID BASE-LINE CHARACTERISTICS; GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; COHORT; MAP C1 [Wang, Zhaoming; Jacobs, Kevin B.; Yeager, Meredith; Hutchinson, Amy; Sampson, Joshua; Chatterjee, Nilanjan; Albanes, Demetrius; Berndt, Sonja I.; Chung, Charles C.; Deng, Xiang; Hsing, Ann W.; Purdue, Mark P.; Taylor, Phil; Tucker, Margaret; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Jacobs, Kevin B.; Yeager, Meredith; Hutchinson, Amy; Deng, Xiang] Natl Canc Inst NCI Frederick, Core Genotyping Facil, SAIC Frederick, Frederick, MD USA. [Diver, W. Ryan; Gapstur, Susan M.; Teras, Lauren R.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Haiman, Christopher A.; Henderson, Brian E.; Stram, Daniel] Univ So Calif, Dept Prevent Med, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Eberle, Michael A.; Stone, Jennifer L.] Illumina, San Diego, CA USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 NR 11 TC 24 Z9 24 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JAN PY 2012 VL 44 IS 1 BP 6 EP 7 DI 10.1038/ng.1044 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 870JA UT WOS:000298664000003 ER PT J AU Tschop, MH Speakman, JR Arch, JRS Auwerx, J Bruning, JC Chan, L Eckel, RH Farese, RV Galgani, JE Hambly, C Herman, MA Horvath, TL Kahn, BB Kozma, SC Maratos-Flier, E Muller, TD Munzberg, H Pfluger, PT Plum, L Reitman, ML Rahmouni, K Shulman, GI Thomas, G Kahn, CR Ravussin, E AF Tschoep, Matthias H. Speakman, John R. Arch, Jonathan R. S. Auwerx, Johan Bruening, Jens C. Chan, Lawrence Eckel, Robert H. Farese, Robert V., Jr. Galgani, Jose E. Hambly, Catherine Herman, Mark A. Horvath, Tamas L. Kahn, Barbara B. Kozma, Sara C. Maratos-Flier, Eleftheria Mueller, Timo D. Muenzberg, Heike Pfluger, Paul T. Plum, Leona Reitman, Marc L. Rahmouni, Kamal Shulman, Gerald I. Thomas, George Kahn, C. Ronald Ravussin, Eric TI A guide to analysis of mouse energy metabolism SO NATURE METHODS LA English DT Article ID CHRONIC SOCIAL STRESS; DIET-INDUCED OBESITY; FAT-FREE MASS; BODY-COMPOSITION; LABORATORY MICE; FOOD-INTAKE; EXPENDITURE; TISSUE; AGE; BEHAVIOR AB We present a consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof. We hope this guide will facilitate comparisons across studies and minimize spurious interpretations of data. We recommend that division of energy expenditure data by either body weight or lean body weight and that presentation of group effects as histograms should be replaced by plotting individual data and analyzing both group and body-composition effects using analysis of covariance (ANCOVA). The epidemic of obesity has generated a large C1 [Muenzberg, Heike; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Tschoep, Matthias H.; Mueller, Timo D.; Pfluger, Paul T.] Tech Univ Munich, Dept Med, Helmholz Ctr Munich, Inst Diabet & Obes, Munich, Germany. [Speakman, John R.; Hambly, Catherine] Univ Aberdeen, Inst Biol & Environm Sci, Aberdeen, Scotland. [Speakman, John R.] Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China. [Arch, Jonathan R. S.] Univ Buckingham, Clore Lab, Buckingham, England. [Auwerx, Johan] Ecole Polytech Fed Lausanne, Lausanne, Switzerland. [Bruening, Jens C.] Max Planck Inst Neurol Res, D-50931 Cologne, Germany. [Chan, Lawrence] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Chan, Lawrence] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Eckel, Robert H.] Univ Colorado Denver Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Aurora, CO USA. [Farese, Robert V., Jr.] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94143 USA. [Galgani, Jose E.] Univ Chile, Fac Med, Dept Nutr, Santiago 7, Chile. [Herman, Mark A.; Kahn, Barbara B.; Maratos-Flier, Eleftheria] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Horvath, Tamas L.] Yale Univ, Sch Med, Comparat Med Sect, Program Integrat Cell Signaling & Neurobiol Met, New Haven, CT 06510 USA. [Kozma, Sara C.; Thomas, George] Univ Cincinnati, Coll Med, Dept Canc & Cell Biol, Metab Dis Inst, Cincinnati, OH USA. [Plum, Leona] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY USA. [Plum, Leona] Columbia Univ, Dept Med, New York, NY USA. [Reitman, Marc L.] NIDDKD, Diabet Endocrinol & Obes Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Rahmouni, Kamal] Univ Iowa Carver Coll Med, Ctr Funct Genom Hypertens, Dept Internal Med, Iowa City, IA USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. RP Ravussin, E (reprint author), Pennington Biomed Res Ctr, Baton Rouge, LA USA. EM c.ronald.kahn@joslin.harvard.edu; e.ravussin@pbrc.edu RI Herman, Mark/H-3232-2012; Reitman, Marc/B-4448-2013; John, Speakman/A-9494-2008; Tschoep, Matthias/I-5443-2014; Thomas, George/K-9235-2014; OI Reitman, Marc/0000-0002-0426-9475; John, Speakman/0000-0002-2457-1823; Thomas, George/0000-0003-3518-8149; Tschoep, Matthias/0000-0002-4744-371X FU Biotechnology and Biological Sciences Research Council [BB/G009953/1]; NHLBI NIH HHS [R01 HL051586]; NIDDK NIH HHS [R01 DK056084, R01 DK040936, R01 DK082659, R37 DK031036, R37 DK043051, U24 DK059635] NR 56 TC 216 Z9 216 U1 3 U2 49 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD JAN PY 2012 VL 9 IS 1 BP 57 EP 63 DI 10.1038/NMETH.1806 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 870KB UT WOS:000298667000028 PM 22205519 ER PT J AU Kim, J Zhao, T Petralia, RS Yu, Y Peng, HC Myers, E Magee, JC AF Kim, Jinhyun Zhao, Ting Petralia, Ronald S. Yu, Yang Peng, Hanchuan Myers, Eugene Magee, Jeffrey C. TI mGRASP enables mapping mammalian synaptic connectivity with light microscopy SO NATURE METHODS LA English DT Article ID CA1 PYRAMIDAL CELLS; CIRCUIT; BRAIN; EXPRESSION; NEUREXINS; SYNAPSES; PROTEINS; NEURONS; SINGLE; ARCHITECTURE AB The GFP reconstitution across synaptic partners (GRASP) technique, based on functional complementation between two nonfluorescent GFP fragments, can be used to detect the location of synapses quickly, accurately and with high spatial resolution. The method has been previously applied in the nematode and the fruit fly but requires substantial modification for use in the mammalian brain. We developed mammalian GRASP (mGRASP) by optimizing transmembrane split-GFP carriers for mammalian synapses. Using in silico protein design, we engineered chimeric synaptic mGRASP fragments that were efficiently delivered to synaptic locations and reconstituted GFP fluorescence in vivo. Furthermore, by integrating molecular and cellular approaches with a computational strategy for the three-dimensional reconstruction of neurons, we applied mGRASP to both long-range circuits and local microcircuits in the mouse hippocampus and thalamocortical regions, analyzing synaptic distribution in single neurons and in dendritic compartments. C1 [Kim, Jinhyun; Zhao, Ting; Yu, Yang; Peng, Hanchuan; Myers, Eugene; Magee, Jeffrey C.] Howard Hughes Med Inst, Ashburn, VA USA. [Kim, Jinhyun] Korea Inst Sci & Technol, Ctr Funct Connect, Seoul, South Korea. [Zhao, Ting] Zhejiang Univ, Qiushi Acad Adv Studies, Hangzhou 310003, Zhejiang, Peoples R China. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Kim, J (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus, Ashburn, VA USA. EM kimj@kist.re.kr; mageej@janelia.hhmi.org RI Zhao, Ting/C-9500-2014; Yu, Yang/D-4071-2015 OI Yu, Yang/0000-0002-4340-430X FU Howard Hughes Medical Institute, US National Institute on Deafness and other Communication Disorders; World Class Institute of National Research Foundation of Korea; Ministry of Education, Science and Technology of Korea FX We thank A. Losonczy for valuable discussions and preliminary physiological experiments, R. Sprengel for valuable discussions and help with the 2A-peptide, C. Bargmann (Rockefeller University) the ace-4-CD4spGFP1-10 and rig-3p-CD4spGFP11 expression constructs11, K. Swartz for simulation of molecular length, B. V. Zemelman (University of Texas at Austin) for the sst-Cre and GAD-Cre mouse lines and Y.-X. Wang for help with the immuno-silver-gold study. This work was supported by Howard Hughes Medical Institute, US National Institute on Deafness and other Communication Disorders intramural research program, as well as the World Class Institute Program of the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology of Korea. NR 37 TC 69 Z9 70 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD JAN PY 2012 VL 9 IS 1 BP 96 EP U139 DI 10.1038/NMETH.1784 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 870KB UT WOS:000298667000037 PM 22138823 ER PT J AU Simons, SB Caruana, DA Zhao, ML Dudek, SM AF Simons, Stephen B. Caruana, Douglas A. Zhao, Meilan Dudek, Serena M. TI Caffeine-induced synaptic potentiation in hippocampal CA2 neurons SO NATURE NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; ADENOSINE; RECEPTOR; PLASTICITY; TRANSMISSION; ANTAGONISTS; MEMORY; RATS AB Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A(1) adenosine receptors (A(1)Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. We found that physiological doses of caffeine in vivo or A(1)R antagonists in vitro induced robust, long-lasting potentiation of synaptic transmission in rat CA2 without affecting other regions of the hippocampus. C1 [Simons, Stephen B.; Caruana, Douglas A.; Zhao, Meilan; Dudek, Serena M.] Natl Inst Environm Hlth Sci, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Dudek, SM (reprint author), Natl Inst Environm Hlth Sci, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov OI Dudek, Serena M./0000-0003-4094-8368 FU US National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES 100221] FX We thank D. Armstrong and members of the Dudek laboratory for their input on the manuscript. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES 100221). NR 15 TC 23 Z9 23 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JAN PY 2012 VL 15 IS 1 BP 23 EP 25 DI 10.1038/nn.2962 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 866VO UT WOS:000298414400009 PM 22101644 ER PT J AU Hammer, JA Sellers, JR AF Hammer, John A., III Sellers, James R. TI Walking to work: roles for class V myosins as cargo transporters SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review AB Cells use molecular motors, such as myosins, to move, position and segregate their organelles. Class V myosins possess biochemical and structural properties that should make them ideal actin-based cargo transporters. Indeed, studies show that class V myosins function as cargo transporters in yeast, moving a range of organelles, such as the vacuole, peroxisomes and secretory vesicles. There is also increasing evidence in vertebrate cells that class V myosins not only tether organelles to actin but also can serve as short-range, point-to-point organelle transporters, usually following long-range, microtubule-dependent organelle transport. C1 [Hammer, John A., III] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. [Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov; sellersj@nhlbi.nih.gov OI Hammer, John/0000-0002-2496-5179 NR 146 TC 95 Z9 96 U1 8 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JAN PY 2012 VL 13 IS 1 BP 13 EP 26 DI 10.1038/nrm3248 PG 14 WC Cell Biology SC Cell Biology GA 866LG UT WOS:000298381700013 PM 22146746 ER PT J AU Heilig, M AF Heilig, Markus TI Our focus on the pharmacogenetics of CRF1 antagonists is simply because they are in clinical development SO NATURE REVIEWS NEUROSCIENCE LA English DT Letter C1 Natl Inst Alcohol Abuse & Alcoholism, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov NR 7 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JAN PY 2012 VL 13 IS 1 DI 10.1038/nrn3110-c2 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 865PQ UT WOS:000298323200015 ER PT J AU Gleichmann, M Zhang, YQ Wood, WH Becker, KG Mughal, MR Pazin, MJ van Praag, H Kobilo, T Zonderman, AB Troncoso, JC Markesbery, WR Mattson, MP AF Gleichmann, Marc Zhang, Yongqing Wood, William H., III Becker, Kevin G. Mughal, Mohamed R. Pazin, Michael J. van Praag, Henriette Kobilo, Tali Zonderman, Alan B. Troncoso, Juan C. Markesbery, William R. Mattson, Mark P. TI Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Aging; GABA; Activity; Homeostatic disinhibition; Interneuron; Calcium; Synaptic scaling ID GENE-EXPRESSION; SYNAPTIC PLASTICITY; AMYLOID DEPOSITION; TRANSGENIC MODEL; MOUSE MODEL; DNA-DAMAGE; STEM-CELLS; IN-VIVO; A-BETA; SOMATOSTATIN AB Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer's disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca(2+) signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca(2+)-mediated degeneration. Published by Elsevier Inc. C1 [Gleichmann, Marc; Mughal, Mohamed R.; van Praag, Henriette; Kobilo, Tali; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Zhang, Yongqing; Wood, William H., III; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, Intramural Res Program,Biomed Res Ctr, Baltimore, MD 21224 USA. [Pazin, Michael J.] NIA, Lab Cellular & Mol Biol, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Res Resources Branch, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. [Markesbery, William R.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, 5th Floor,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; van Praag, Henriette/F-3939-2015; OI van Praag, Henriette/0000-0002-5727-434X; Becker, Kevin/0000-0002-6794-6656; Zonderman, Alan B/0000-0002-6523-4778; Pazin, Michael/0000-0002-7561-3640 FU National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. We thank Dr Jenq-Lin Yang for assistance with the comet assay. Brain samples from young control individuals age 20-40 were obtained from the NICHD, Brain and Tissue Bank for Developmental Disorders at the University of Maryland, those from old individuals were provided by the Baltimore Longitudinal Study on Aging. Brain samples from Alzheimer patients and age matched controls were provided from the University of Kentucky Alzheimer's Disease Center Autopsy Program. NR 56 TC 2 Z9 3 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2012 VL 33 IS 1 AR 205.e1 DI 10.1016/j.neurobiolaging.2010.08.012 PG 18 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 860FR UT WOS:000297934700046 PM 20947216 ER PT J AU Majounie, E Traynor, BJ Chio, A Restagno, G Mandrioli, J Benatar, M Taylor, JP Singleton, AB AF Majounie, Elisa Traynor, Bryan J. Chio, Adriano Restagno, Gabriella Mandrioli, Jessica Benatar, Michael Taylor, J. Paul Singleton, Andrew B. TI Mutational analysis of the VCP gene in Parkinson's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE VCP; Parkinson's disease AB Mutations in the valosin-containing protein gene (VCP) have been identified in neurological disorders (inclusion body myopathy-early Paget's disease of the bone-frontotemporal dementia and amyotrophic lateral sclerosis) and are thought to play a role in the clearance of abnormally folded proteins. Parkinsonism has been noted in kindreds with VCP mutations. Based on this, we hypothesized that mutations in VCP may also contribute to idiopathic Parkinson's disease (PD). We screened the coding region of the VCP gene in a large cohort of 768 late-onset PD cases (average age at onset, 70 years), both sporadic and with positive family history. We identified a number of rare single nucleotide changes, including a variant previously described to be pathogenic, but no clear disease-causing variants. We conclude that mutations in VCP are not a common cause for idiopathic PD. Published by Elsevier Inc. C1 [Majounie, Elisa; Traynor, Bryan J.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Restagno, Gabriella] ASO OIRM S Anna, Dept Clin Pathol, Mol Genet Unit, Turin, Italy. [Mandrioli, Jessica] St Agostino Estense Hosp, Dept Neurosci, Modena, Italy. [Mandrioli, Jessica] Univ Modena, I-41100 Modena, Italy. [Benatar, Michael] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Taylor, J. Paul] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. RP Majounie, E (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM Elisa.Majounie@nih.gov RI Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010; OI Chio, Adriano/0000-0001-9579-5341 FU Intramural NIH HHS [ZIA AG000957-08] NR 0 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2012 VL 33 IS 1 AR 209.e1 DI 10.1016/j.neurobiolaging.2011.07.011 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 860FR UT WOS:000297934700055 PM 21920633 ER PT J AU Mok, K Traynor, BJ Schymick, J Tienari, PJ Laaksovirta, H Peuralinna, T Myllykangas, L Chio, A Shatunov, A Boeve, BF Boxer, AL DeJesus-Hernandez, M Mackenzie, IR Waite, A Williams, N Morris, HR Simon-Sanchez, J van Swieten, JC Heutink, P Restagno, G Mora, G Morrison, KE Shaw, PJ Rollinson, PS Al-Chalabi, A Rademakers, R Pickering-Brown, S Orrell, RW Nalls, MA Hardy, J AF Mok, Kin Traynor, Bryan J. Schymick, Jennifer Tienari, Pentti J. Laaksovirta, Hannu Peuralinna, Terhi Myllykangas, Liisa Chio, Adriano Shatunov, Aleksey Boeve, Bradley F. Boxer, Adam L. DeJesus-Hernandez, Mariely Mackenzie, Ian R. Waite, Adrian Williams, Nigel Morris, Huw R. Simon-Sanchez, Javier van Swieten, John C. Heutink, Peter Restagno, Gabriella Mora, Gabriele Morrison, Karen E. Shaw, Pamela J. Rollinson, Pamela Sara Al-Chalabi, Ammar Rademakers, Rosa Pickering-Brown, Stuart Orrell, Richard W. Nalls, Michael A. Hardy, John TI The chromosome 9 ALS and FTD locus is probably derived from a single founder SO NEUROBIOLOGY OF AGING LA English DT Article DE Genetics; Amyotrophic lateral sclerosis; Frontotemporal dementia; Finland ID AMYOTROPHIC-LATERAL-SCLEROSIS; GENOME-WIDE ASSOCIATION; FRONTOTEMPORAL LOBAR DEGENERATION; DEMENTIA; SUSCEPTIBILITY; POPULATIONS; COMMON AB We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease. (C) 2012 Elsevier Inc. All rights reserved. C1 [Mok, Kin; Orrell, Richard W.; Hardy, John] UCL Inst Neurol, Reta Lila Weston Res Labs, Dept Mol Neurosci, London, England. [Mok, Kin; Orrell, Richard W.; Hardy, John] UCL Inst Neurol, Reta Lila Weston Res Labs, Dept Clin Neurosci, London, England. [Traynor, Bryan J.; Schymick, Jennifer; Laaksovirta, Hannu; Nalls, Michael A.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.; Schymick, Jennifer; Laaksovirta, Hannu] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Tienari, Pentti J.; Laaksovirta, Hannu; Peuralinna, Terhi] Univ Helsinki, Dept Neurol, Helsinki Univ Cent Hosp, Mol Neurol Res Program, Helsinki, Finland. [Myllykangas, Liisa] Univ Helsinki, Dept Pathol, Haartman Inst, Helsinki, Finland. [Myllykangas, Liisa] HUSLAB, Helsinki, Finland. [Myllykangas, Liisa] Folkhalsan Inst Genet, Helsinki, Finland. [Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Chio, Adriano] Azienda Osped Univ San Giovanni Battista, Turin, Italy. [Shatunov, Aleksey] Kings Coll London, Inst Psychiat, Med Res Council Ctr Neurodegenerat Res, London WC2R 2LS, England. [Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Boxer, Adam L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [DeJesus-Hernandez, Mariely; Rademakers, Rosa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Mackenzie, Ian R.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Waite, Adrian; Williams, Nigel; Morris, Huw R.; Al-Chalabi, Ammar] Cardiff Univ, Sch Med, Med Res Council Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Simon-Sanchez, Javier; van Swieten, John C.; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [van Swieten, John C.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Restagno, Gabriella] Azienda Osped OIRM St Anna, Mol Genet Lab, Turin, Italy. [Mora, Gabriele] IRCCS Sci Inst Milan, Fdn Salvatore Mangeri, Milan, Italy. [Morrison, Karen E.] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Morrison, Karen E.] Queen Elizabeth Hosp, Univ Hosp Birmingham NHS Fdn Trust, Birmingham B15 2TH, W Midlands, England. [Shaw, Pamela J.] Univ Sheffield, Dept Neurosci, Sheffield Inst Translat Neurosci, SITraN, Sheffield, S Yorkshire, England. [Rollinson, Pamela Sara; Pickering-Brown, Stuart] Univ Manchester, Fac Human & Med Sci, Neurodegenerat & Mental Hlth Res Grp, Manchester, Lancs, England. RP Hardy, J (reprint author), UCL Inst Neurol, Reta Lila Weston Res Labs, Dept Mol Neurosci, London, England. EM jhardy@ion.ucl.ac.uk RI Tienari, Pentti/A-4893-2012; Al-Chalabi, Ammar/E-5361-2010; Pickering-Brown, Stuart/D-4008-2009; Hardy, John/C-2451-2009; Morris, Huw/B-8527-2008; Shatunov, Aleksey/E-6946-2011; Mok, Kin/F-5860-2012; Traynor, Bryan/G-5690-2010; Orrell, Richard/L-2123-2013; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Pickering-Brown, Stuart/0000-0003-1561-6054; Morris, Huw/0000-0002-5473-3774; Chio, Adriano/0000-0001-9579-5341 FU National Institute on Aging [Z01-AG000949-02]; NIH [R01AG031278, R01AG038791]; National Institute on Neurological Disorders and Stroke; NIH/NIA [R01 AG26251]; European Community [259867]; Motor Neurone Disease Association of Great Britain; ALS Association; Angel Fund; ALS Therapy Alliance; Wellcome Trust; Reta Lila Weston Foundation; MRC; Microsoft Research Foundation; Helsinki University Central Hospital; Finnish Academy; Ministero della Salute; Progetti Finalizzati; Fondazione Vialli e Mauro for ALS; Federazione Italiana Giuoco Calcio; Hersenstichting Nederland; NIHR specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM); Institute of Psychiatry, King's College London; NIHR FX This work was supported in part by the Intramural Research Programs of the NIH, the National Institute on Aging (Z01-AG000949-02), and the National Institute on Neurological Disorders and Stroke. Extramural NIH grants R01AG031278, R01AG038791 supported some family assessments: NIH/NIA grant R01 AG26251 (RR) funded some analytical work. The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259867. The authors thank the Motor Neurone Disease Association of Great Britain for several grants relating to this work (RWO, AAC, PJS, HM), the ALS Association, The Angel Fund, the ALS Therapy Alliance, and the Wellcome Trust (PJS) for support. This work was also funded by the Reta Lila Weston Foundation, and by an MRC returning scientist (JH) and fellowship (SPB) award, by Microsoft Research Foundation, the ALS Association, Helsinki University Central Hospital, and the Finnish Academy. This work was also funded by Ministero della Salute, Progetti Finalizzati 2007, Fondazione Vialli e Mauro for ALS, and Federazione Italiana Giuoco Calcio. The authors also thank the Hersenstichting Nederland (www.hersenstichting.nl) for supporting this work. The authors thank the NIHR specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry, King's College London as well as the NIHR-funded UCL/UCLH Comprehensive Biomedical Research Centre. NR 21 TC 51 Z9 51 U1 0 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2012 VL 33 IS 1 AR 209.e3 DI 10.1016/j.neurobiolaging.2011.08.005 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 860FR UT WOS:000297934700056 PM 21925771 ER PT J AU Addolorato, G Leggio, L Hopf, FW Diana, M Bonci, A AF Addolorato, Giovanni Leggio, Lorenzo Hopf, F. Woodward Diana, Marco Bonci, Antonello TI Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE alcoholism; addiction; pharmacotherapy; GABA; ion channels; transcranial magnetic stimulation ID RANDOMIZED CONTROLLED-TRIAL; ETHANOL WITHDRAWAL SYNDROME; PLACEBO-CONTROLLED TRIAL; COCAINE-DEPENDENT INDIVIDUALS; DIHYDROPYRIDINE BINDING-SITES; NUCLEUS-ACCUMBENS SHELL; VENTRAL TEGMENTAL AREA; PREFERRING AA RATS; HIGH-DOSE BACLOFEN; ADD-ON GABAPENTIN AB Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism. Neuropsychopharmacology Reviews (2012) 37, 163-177; doi: 10.1038/npp.2011.216; published online 26 October 2011 C1 [Bonci, Antonello] NIDA Intramural Res Program, Baltimore, MD USA. [Bonci, Antonello] UCSF, Dept Neurol, San Francisco, CA USA. [Bonci, Antonello] Johns Hopkins Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Addolorato, Giovanni; Leggio, Lorenzo] Univ Cattolica Sacro Cuore, Inst Internal Med, Rome, Italy. [Leggio, Lorenzo] Brown Univ, Sch Med, Dept Behav & Social Sci, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Hopf, F. Woodward] Univ Calif San Francisco, Dept Neurol, Ernest Gallo Clin & Res Ctr, San Francisco, CA USA. [Diana, Marco] Univ Sassari, Dept Drug Sci, G Minardi Cognit Neurosci Lab, I-07100 Sassari, Italy. RP Bonci, A (reprint author), NIDA Intramural Res Program, Baltimore, MD USA. EM antonello.bonci@nih.gov RI Diana, Marco/D-1475-2011; Leggio, Lorenzo/M-2972-2016; OI Diana, Marco/0000-0002-6561-5642; Addolorato, Giovanni/0000-0002-1522-9946 NR 213 TC 30 Z9 30 U1 6 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 163 EP 177 DI 10.1038/npp.2011.216 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500009 PM 22030714 ER PT J AU Brady, LS Insel, TR AF Brady, Linda S. Insel, Thomas R. TI Translating Discoveries into Medicine: Psychiatric Drug Development in 2011 SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID PLURIPOTENT STEM-CELLS; DISORDERS; MODEL C1 [Brady, Linda S.] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. RP Brady, LS (reprint author), NIMH, Div Neurosci & Basic Behav Sci, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM lbrady@mail.nih.gov NR 10 TC 11 Z9 11 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 281 EP 283 DI 10.1038/npp.2011.106 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500016 PM 22157856 ER PT J AU Buckholtz, NS Ryan, LM Petanceska, S Refolo, LM AF Buckholtz, Neil S. Ryan, Laurie M. Petanceska, Suzana Refolo, Lorenzo M. TI NIA Commentary: Translational Issues in Alzheimer's Disease Drug Development SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material C1 [Buckholtz, Neil S.; Ryan, Laurie M.; Petanceska, Suzana; Refolo, Lorenzo M.] NIA, Div Neurosci, Bethesda, MD 20892 USA. RP Buckholtz, NS (reprint author), NIA, Div Neurosci, 7201 Wisconsin Ave,Suite 350, Bethesda, MD 20892 USA. EM buckholn@nia.nih.gov NR 7 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 284 EP 286 DI 10.1038/npp.2011.116 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500017 PM 22157857 ER PT J AU Heemskerk, J Farkas, R Kaufmann, P AF Heemskerk, Jill Farkas, Rebecca Kaufmann, Petra TI Neuroscience Networking: Linking Discovery to Drugs SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material AB Discoveries in the pre-clinical neurosciences have set the stage for bringing new therapies to patients affected by neurological disorders. The National Institute of Neurological Disorders and Stroke (NINDS) is dedicated to promoting the development of new therapies through its funding programs that range from basic neuroscience to translational research and finally clinical research to test the most promising new therapies in patients. In an effort to accelerate the translation of new discoveries to clinical practice, NINDS is piloting novel organizational strategies. In translational research, NINDS is taking the lead on the establishment of a 'virtual pharma' structure, through which researchers will partner with the NIH to accelerate the progress of drug development from early hit discovery through phase 1 clinical trials. In clinical research, the new Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) aims to promote the efficient implementation of scientifically sound, biomarker-informed phase 2 clinical trials that can be initiated by academic or industry investigators. Neuropsychopharmacology Reviews (2012) 37, 287-289; doi: 10.1038/npp.2011.177 C1 [Heemskerk, Jill; Farkas, Rebecca; Kaufmann, Petra] NINDS, Off Translat Res, NIH, Bethesda, MD 20892 USA. RP Heemskerk, J (reprint author), NINDS, Off Translat Res, NIH, 6001 Executive Blvd,NSC 2229, Bethesda, MD 20892 USA. EM jill.heemskerk@nih.gov NR 3 TC 7 Z9 7 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 287 EP 289 DI 10.1038/npp.2011.177 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500018 PM 22157858 ER PT J AU Volkow, ND Skolnick, P AF Volkow, Nora D. Skolnick, Phil TI New Medications for Substance Use Disorders: Challenges and Opportunities SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID ABUSE AB An increased understanding of the biological mechanisms underlying the process of addiction has led to unique molecular targets and strategies for pharmacotherapies against addiction. However, the successful translation of these discoveries will require: 1) a more active engagement of the pharmaceutical sector, 2) partnership with regulatory agencies to arrive at meaningful outcomes for medication approval and 3) a greater involvement of the healthcare system in the screening and treatment of substance use disorders. Neuropsychopharmacology Reviews (2012) 37, 290-292; doi: 10.1038/npp.2011.84 C1 [Volkow, Nora D.; Skolnick, Phil] NIDA, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 7 TC 29 Z9 29 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 290 EP 292 DI 10.1038/npp.2011.84 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500019 PM 22157859 ER PT J AU Edwards, E AF Edwards, Emmeline TI The Role of Complementary, Alternative, and Integrative Medicine in Personalized Health Care SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID DEPRESSION; PLACEBO; BRAIN; PAIN C1 NIH, Div Extramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Edwards, E (reprint author), NIH, Div Extramural Res, Natl Ctr Complementary & Alternat Med, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM edwardse@mail.nih.gov NR 7 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 293 EP 295 DI 10.1038/npp.2011.92 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500020 PM 22157860 ER PT J AU Babineau, BA Yang, M Crawley, JN AF Babineau, Brooke A. Yang, Mu Crawley, Jacqueline N. TI Mainstreaming Mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID AUTISM; DEFICITS C1 [Babineau, Brooke A.; Yang, Mu; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Babineau, BA (reprint author), NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. EM crawleyj@mail.nih.gov FU Intramural NIH HHS NR 6 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 1 BP 300 EP 301 DI 10.1038/npp.2011.168 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865EK UT WOS:000298293500026 PM 22157866 ER PT J AU Anton, RF Litten, RZ Falk, DE Palumbo, JM Bartus, RT Robinson, RL Kranzler, HR Kosten, TR Meyer, RE O'Brien, CP Mann, K Meulien, D AF Anton, Raymond F. Litten, Raye Z. Falk, Daniel E. Palumbo, Joseph M. Bartus, Raymond T. Robinson, Rebecca L. Kranzler, Henry R. Kosten, Thomas R. Meyer, Roger E. O'Brien, Charles P. Mann, Karl Meulien, Didier CA ACTIVE Workgrp TI The Alcohol Clinical Trials Initiative (ACTIVE): Purpose and Goals for Assessing Important and Salient Issues for Medications Development in Alcohol Use Disorders SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE addiction and substance abuse; clinical pharmacology/clinical trials; alcohol and alcoholism; drug discovery/development; neuropharmacology ID RANDOMIZED CONTROLLED-TRIAL; BEHAVIORAL-INTERVENTIONS; DEPENDENCE; NALTREXONE; HEALTH; COMORBIDITY; RELIABILITY; TOPIRAMATE; EFFICACY; COMBINE AB Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future. Neuropsychopharmacology (2012) 37, 402-411; doi:10.1038/npp.2011.182; published online 7 September 2011 C1 [Anton, Raymond F.] Med Univ S Carolina, Inst Psychiat, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. [Litten, Raye Z.; Falk, Daniel E.] NIAAA, Rockville, MD 20852 USA. [Palumbo, Joseph M.] Johnson & Johnson Pharmaceut Res & Dev LLC, Titusville, NJ USA. [Bartus, Raymond T.] Ceregene, San Diego, CA USA. [Robinson, Rebecca L.] Eli Lilly, Indianapolis, IN USA. [Kranzler, Henry R.; O'Brien, Charles P.] Univ Penn, Philadelphia, PA 19104 USA. [Kosten, Thomas R.] Baylor Coll Med MIC, Houston, TX USA. [Meyer, Roger E.] Best Practice Management, Bethesda, MD USA. [Mann, Karl] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Meulien, Didier] Lundbeck, Paris, France. RP Anton, RF (reprint author), Med Univ S Carolina, Inst Psychiat, Ctr Drug & Alcohol Programs, 67 President St,MSC 861, Charleston, SC 29425 USA. EM antonr@musc.edu FU Abbott Laboratories; Alkermes; Eli Lilly; GlaxoSmithKline; Johnson and Johnson Pharmaceuticals; Lundbeck; Schering Plough; Merck; Hythiam; STTR from NIDA; Johnson and Johnson; Pfizer; Forest; Astra Zeneca; Daishi Sumitomo; Sanofi-Aventis; Hoffman La Roche; United BioSource; Takeda Pharmaceuticals; Northwestern University FX The ACTIVE workgroup has been, and is, supported by the following pharmaceutical companies through funding to the ACNP. The support provided covers the cost of meetings, honoraria for academic participants, and administrative support to ACNP. Staff members of government agencies receive no support for their participation. The FDA, NIAAA, and NIDA have provided in kind support for staff participation and data analysis. Travel expenses for industry representatives to attend ACTIVE meetings are supported by their respective companies. Those pharmaceutical companies are: Abbott Laboratories, Alkermes, Eli Lilly, GlaxoSmithKline, Johnson and Johnson Pharmaceuticals, Lundbeck, Schering Plough. Over the past 3 years, Dr RF Anton reports has been a consultant for Eli Lilly, Merck, Johnson and Johnson, GlaxoSmithKline, Organon and Alkermes; served as a scientific advisory board member for Eli Lilly and Johnson and Johnson; and received grant support from Eli Lilly, Merck, and Hythiam. He owns stock in Johnson and Johnson. He also is an officer and stockholder in Alcomed (funded by an STTR from NIDA). JM Palumbo, is a full time employee of Johnson and Johnson Pharmaceutical Research and Development, LLC. At the time of the submission of this paper, Johnson and Johnson does not sell or promote any therapeutic agent indicated for the treatment of alcoholism. A member of Dr Palumbo's immediate family is employed by Actelion Clinical Research. Dr Palumbo declares no conflicts of interest that pertain to this publication. Dr RT Bartus is an officer of Ceregene and receives salary, compensation and stock options. He formerly worked for Alkermes and retains stock options in that company. RL Robinson is an employee and minor stockholder of Eli Lilly. Over the past 3 years, Dr HR Kranzler has been paid a consultant for Alkermes, GlaxoSmithKline and Gilead and has received research support from Merck. Over the past 3 years, Dr TR Kosten has received compensation for professional services from Reckitt Benckiser, Catalyst Pharma, Titan Pharma, Gerson Lerman, and Alkermes. Over the past 3 years, Dr RE Meyer received principal compensation from Best Practice Project Management. This company received support from the following companies in connection with a consensus development meeting on suicidality (Johnson and Johnson, Schering Plough, Pfizer, Forest, Astra Zeneca, Daishi Sumitomo, Sanofi-Aventis, Hoffman La Roche and United BioSource), as well as support for consulting from Takeda Pharmaceuticals. He has current and projected support from Forest for an investigator-initiated grant as a subcontractor from Northwestern University to Best Practice Project Management. During the past 3 years, Dr CP O'Brien has served as a consultant to Alkermes, Reckitt-Benckiser, Catalyst, Abbott, Embera, and Gilead. During the past 3 years, Dr K Mann has received compensation for professional services from Alkermes, Lundbeck, Johnson and Johnson, Pfizer, Merck, and Norgine. Over the past 3 years, Dr D Meulien declares that, except for income received from his primary employer Lundbeck, he has not received financial support or compensation from any individual or corporate entity for research or professional service and has no personal financial holdings that could be perceived as constituting a potential conflict of interest. The remaining authors declare no conflict of interest. The views expressed in this paper are those of the authors.; No official endorsement by the US Department of Veterans Affairs, US Food and Drug Administration, US National Institutes of Health, or ay of the pharmaceutical companies that provided grants to the American College of Neuropsychopharmaclogy should be inferred. NR 25 TC 8 Z9 8 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 2 BP 402 EP 411 DI 10.1038/npp.2011.182 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865WV UT WOS:000298342500011 PM 21900883 ER PT J AU Gilman, JM Ramchandani, VA Crouss, T Hommer, DW AF Gilman, Jodi M. Ramchandani, Vijay A. Crouss, Tess Hommer, Daniel W. TI Subjective and Neural Responses to Intravenous Alcohol in Young Adults with Light and Heavy Drinking Patterns SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE alcohol; fMRI; reward; tolerance; alcoholism; nucleus accumbens ID NUCLEUS-ACCUMBENS; HIGH-RISK; DOPAMINE RELEASE; FAMILY-HISTORY; HUMAN BRAIN; REWARD ANTICIPATION; STRIATAL DOPAMINE; SOCIAL DRINKERS; HEART-RATE; ETHANOL AB Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals' vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized. We performed a double-blind, placebo-controlled, randomized crossover alcohol challenge study comparing functional magnetic resonance imaging and subjective response to intravenously administered 6% v/v ethanol to a target blood alcohol concentration of 0.08% or placebo between HDs and social drinkers (SDs). During the imaging, we presented emotional cues in order to measure how emotion modulated the effects of alcohol on the brain's reward circuitry. We found that, at equivalent blood alcohol concentrations, HDs reported lower subjective alcohol effects than SDs. Alcohol significantly activated the nucleus accumbens in SDs, but not in HDs. Self-reported ratings of intoxication correlated with striatal activation, suggesting that activation may reflect subjective experience of intoxication. Fearful faces significantly activated the amygdala in the SDs only, and this activation was attenuated by alcohol. This study shows that HDs not only experience reduced subjective effects of alcohol, but also demonstrate a blunted response to alcohol in the brain's reward system. Our findings indicate that reduced subjective and neural response to alcohol in HDs may be suggestive of either the development of tolerance to alcohol, or of pre-existing decreased sensitivity to alcohol's effects. Neuropsychopharmacology (2012) 37, 467-477; doi:10.1038/npp.2011.206; published online 28 September 2011 C1 [Gilman, Jodi M.; Ramchandani, Vijay A.; Crouss, Tess; Hommer, Daniel W.] NIAAA, Sect Brain Elect & Imaging, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Gilman, JM (reprint author), NIAAA, Sect Brain Elect & Imaging, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,Bldg 10 CRC Hatfield Clin Res Ctr,Room, Bethesda, MD 20892 USA. EM gilmanj@mail.nih.gov FU NIDA NIH HHS [K01 DA034093] NR 70 TC 27 Z9 27 U1 6 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 2 BP 467 EP 477 DI 10.1038/npp.2011.206 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865WV UT WOS:000298342500017 PM 21956438 ER PT J AU Marenco, S Stein, JL Savostyanova, AA Sambataro, F Tan, HY Goldman, AL Verchinski, BA Barnett, AS Dickinson, D Apud, JA Callicott, JH Meyer-Lindenberg, A Weinberger, DR AF Marenco, Stefano Stein, Jason L. Savostyanova, Antonina A. Sambataro, Fabio Tan, Hao-Yang Goldman, Aaron L. Verchinski, Beth A. Barnett, Alan S. Dickinson, Dwight Apud, Jose A. Callicott, Joseph H. Meyer-Lindenberg, Andreas Weinberger, Daniel R. TI Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE diffusion tensor imaging (DTI); probabilistic tractography; medio-dorsal nucleus; prefrontal cortex; working memory; reproducibility ID DORSOLATERAL PREFRONTAL CORTEX; WHITE-MATTER INTEGRITY; MEDIODORSAL THALAMIC NUCLEUS; DIFFUSION TRACTOGRAPHY; NEURON NUMBER; 1ST-EPISODE SCHIZOPHRENIA; LONGITUDINAL FASCICULUS; ONSET SCHIZOPHRENIA; BIPOLAR DISORDER; WORKING-MEMORY AB The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age-and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC. Neuropsychopharmacology (2012) 37, 499-507; doi:10.1038/npp.2011.215; published online 28 September 2011 C1 [Marenco, Stefano; Stein, Jason L.; Savostyanova, Antonina A.; Tan, Hao-Yang; Goldman, Aaron L.; Verchinski, Beth A.; Barnett, Alan S.; Dickinson, Dwight; Apud, Jose A.; Callicott, Joseph H.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program, Bethesda, MD 20892 USA. [Sambataro, Fabio] Italian Inst Technol, Brain Ctr Motor & Social Cognit, Parma, Italy. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-6800 Mannheim, Germany. RP Marenco, S (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program, 10 Ctr Dr,Bldg 10,Room 4S235, Bethesda, MD 20892 USA. EM marencos@mail.nih.gov RI Sambataro, Fabio/E-3426-2010; Marenco, Stefano/A-2409-2008; Farmer, Antonina/M-8914-2013; Meyer-Lindenberg, Andreas/H-1076-2011; OI Sambataro, Fabio/0000-0003-2102-416X; Marenco, Stefano/0000-0002-2488-2365; Farmer, Antonina/0000-0002-3305-8300; Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Callicott, Joseph/0000-0003-1298-3334; Stein, Jason/0000-0003-4829-0513 FU NIMH IRP FX This study was entirely funded by the NIMH IRP. The material in this paper was presented in abstract form at the annual meeting of the American College of Neuro-Psycho-Pharmacology in Boca Raton, FL (9-13 December 2007), at the meeting of the Society for Biological Psychiatry in Washington, DC (1-3 May 2008), and at the meeting of the International Schizophrenia Research Society in Venice, Italy (21-25 June 2008). 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). We thank Fengyu Zhang (NIMH) for statistical advice, Tim Behrens and Saad Jbadi (Oxford) for guidance on probabilistic tractography, and Dharshan Chandramohan for help in the revision process. NR 76 TC 55 Z9 56 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 2 BP 499 EP 507 DI 10.1038/npp.2011.215 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865WV UT WOS:000298342500020 PM 21956440 ER PT J AU Zuo, LJ Gelernter, J Zhang, CK Zhao, HY Lu, LG Kranzler, HR Malison, RT Li, CSR Wang, F Zhang, XY Deng, HW Krystal, JH Zhang, FY Luo, XG AF Zuo, Lingjun Gelernter, Joel Zhang, Clarence K. Zhao, Hongyu Lu, Lingeng Kranzler, Henry R. Malison, Robert T. Li, Chiang-Shan R. Wang, Fei Zhang, Xiang-Yang Deng, Hong-Wen Krystal, John H. Zhang, Fengyu Luo, Xingguang TI Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE risk region; alcohol dependence; cis-eQTL; GWAS ID DRUG-DEPENDENCE; POLYMORPHISM; GENE; DETERMINANTS; CONSUMPTION; SERVER; RISK; DRD2; LOCI AB Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant gene-KIAA0040-that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of -log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369 <= r <= 0.824; 2.8 x 10(-9)<= p <= 0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 x 10(-11)<= p <= 1.5 x 10(-6)) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system. Neuropsychopharmacology (2012) 37, 557-566; doi:10.1038/npp.2011.229; published online 28 September 2011 C1 [Zuo, Lingjun; Gelernter, Joel; Malison, Robert T.; Li, Chiang-Shan R.; Wang, Fei; Krystal, John H.; Luo, Xingguang] Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. [Gelernter, Joel] Yale Univ, Sch Med, Dept Genet, West Haven, CT 06516 USA. [Gelernter, Joel] Yale Univ, Sch Med, Dept Neurobiol, West Haven, CT 06516 USA. [Gelernter, Joel; Krystal, John H.] VA Connecticut Healthcare Syst, Alcohol Res Ctr, West Haven, CT USA. [Zhang, Clarence K.; Zhao, Hongyu; Lu, Lingeng] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Kranzler, Henry R.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Philadelphia VAMC, MIRECC, Philadelphia, PA USA. [Malison, Robert T.] Connecticut Mental Hlth Ctr, Clin Neurosci Res Unit, New Haven, CT USA. [Zhang, Xiang-Yang] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Deng, Hong-Wen] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Biostat, New Orleans, LA USA. [Krystal, John H.] Yale New Haven Med Ctr, New Haven, CT 06504 USA. [Zhang, Fengyu] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Zuo, LJ (reprint author), Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. EM Lingjun.Zuo@yale.edu; Xingguang.Luo@yale.edu RI Li, Chiang-Shan/J-2813-2016; OI Li, Chiang-Shan/0000-0002-9393-1212; Deng, Hong-Wen/0000-0002-0387-8818 FU National Institute on Drug Abuse (NIDA) [K01 DA029643, K24 DA017899, K02 DA026990]; National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01 AA016015, R21 AA020319, K24 AA013736, R01 AA11330, R01 AA017535, P50 AA012870]; National Alliance for Research on Schizophrenia and Depression (NARSAD) [17616]; Department of Veterans Affairs; VA Alcohol Research Center; VA National Center for PTSD; Depression REAP; National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) [U01 HG004422, U01HG004438]; GENEVA Coordinating Center [U01 HG004446]; National Institute on Alcohol Abuse and Alcoholism [U10 AA008401]; National Institute on Drug Abuse [R01 DA013423]; National Cancer Institute [P01 CA089392]; NIH [HHSN268200782096C]; ACNP Alcohol Clinical Trials Initiative (ACTIVE); ACTIVE FX This work was supported in part by National Institute on Drug Abuse (NIDA) Grants K01 DA029643, K24 DA017899, and K02 DA026990, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Grants R01 AA016015, R21 AA020319, K24 AA013736, R01 AA11330, R01 AA017535, and P50 AA012870, and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Award 17616 (to LZ). It also received support from the Department of Veterans Affairs through its support of the VA Alcohol Research Center, the VA National Center for PTSD, and the Depression REAP. We thank NIH GWAS Data Repository, the Contributing Investigator(s) (Drs Bierut and Edenberg) who contributed the phenotype and genotype data (SAGE and COGA) from his/her original study, and the primary funding organization that supported the contributing study. Funding support for SAGE and COGA was provided through the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) Grant U01 HG004422 and U01HG004438; the GENEVA Coordinating Center (U01 HG004446); the National Institute on Alcohol Abuse and Alcoholism (U10 AA008401); the National Institute on Drug Abuse (R01 DA013423); the National Cancer Institute (P01 CA089392); and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research or at deCODE.; Dr Kranzler has been a paid consultant for Alkermes, GlaxoSmithKline, and Gilead. He serves as a member of an Advisory Board for Lundbeck. He also reports associations with Eli Lilly, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson, as these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and Dr Kranzler receives support from ACTIVE. NR 31 TC 37 Z9 38 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2012 VL 37 IS 2 BP 557 EP 566 DI 10.1038/npp.2011.229 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 865WV UT WOS:000298342500025 PM 21956439 ER PT J AU Ravasi, L Tokugawa, J Nakayama, T Seidel, J Sokoloff, L Eckelman, WC Kiesewetter, DO AF Ravasi, Laura Tokugawa, Joji Nakayama, Toshiyuki Seidel, Jurgen Sokoloff, Louis Eckelman, William C. Kiesewetter, Dale O. TI Imaging of the muscarinic acetylcholine neuroreceptor in rats with the M2 selective agonist [F-18]FP-TZTP SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Muscarinic receptor; Small animal PET scanner; Distribution ratios; Alzheimer's disease; agonist ID ANIMAL PET SCANNER; IN-VIVO; MASS-SPECTROMETRY; BRAIN; BINDING; SENSITIVITY; METABOLITES; LIGAND AB Introduction: [F-18]FP-TZTP is an M2 muscarinic subtype selective receptor-binding radiotracer used in vivo to image human and nonhuman primate brain following both bolus injection and infusion. In order to carry out repeated studies in rodents, the techniques developed for primates must be transferred to rodents with the same precision. This includes obtaining a metabolite-corrected input function. Methods: We compared bolus injection with constant infusion in rats that were awake or under isoflurane anesthesia. Brain plasma and brain blood distribution ratios were calculated by dividing brain F-18 concentrations, determined in vivo by positron emission tomography imaging with the Advanced Technology Laboratory Animal Scanner, ex vivo by direct counting in excised brain tissue or by quantitative autoradiography by the plasma or whole blood concentrations that had been corrected for metabolite contents. Results: Blood volume constraints prevented adequate blood sampling to define a precise input function after bolus injection, thus preventing full kinetic analysis. Constant infusion, however, required fewer blood samples to define the input function, allowing calculation of distribution ratios, but complete equilibrium between plasma and tissue had not yet been reached after 120 min. Conclusion: Our results showed that the blood clearance and metabolism were too rapid to obtain a reproducible input function after bolus injection. The equilibrium distribution ratios did not lead to precise biochemical parameters, but the constant infusion was more suitable, in that distribution ratios between tissue and plasma were statistically more precise. Constant infusion is the better approach for studying [F-18] FP-TZTP by small animal imaging. Published by Elsevier Inc. C1 [Tokugawa, Joji; Kiesewetter, Dale O.] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Ravasi, Laura; Eckelman, William C.; Kiesewetter, Dale O.] CC NIH, PET Dept, Bethesda, MD USA. [Ravasi, Laura] Hop Roger Salengro CHRU Lille, Serv Med Nucl & Imagerie Fonct, EA 1046, Lille, France. [Eckelman, William C.] Mol Tracer LLC, Bethesda, MD USA. [Nakayama, Toshiyuki; Sokoloff, Louis] NIMH NIH, LCM, Bethesda, MD USA. [Seidel, Jurgen] NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. RP Kiesewetter, DO (reprint author), NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM dk7k@nih.gov FU NIH (NIBIB, NIMH and CC) FX This work was supported in part by the Intramural Research Program of the NIH (NIBIB, NIMH and CC). The authors thank the cyclotron staff, especially Bik-Kee Vuong, for the radiolabeled tracer production and Dr. Ying Ma for his technical advice on the metabolite extraction. We are especially grateful to Dr. Kazuaki Shimoji for his excellent teaching and training skills with respect to surgical methodology. NR 21 TC 2 Z9 2 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JAN PY 2012 VL 39 IS 1 BP 45 EP 55 DI 10.1016/j.nucmedbio.2011.06.003 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 874DS UT WOS:000298936200006 PM 21831648 ER PT J AU Jenkins, JF Calzone, KA AF Jenkins, Jean F. Calzone, Kathleen A. TI Are Nursing Faculty Ready to Integrate Genomic Content Into Curricula? SO NURSE EDUCATOR LA English DT Article ID OPINION LEADERS; GENETICS; INNOVATIONS; DIFFUSION; HEALTH AB Genomics is an emerging field with newly developed expectations for all healthcare professionals. Nursing faculty are critical to preparing the future nursing workforce in genomics but faculty knowledge, receptivity, and interest in learning more about this subject were unknown. The authors discuss the process used to assess nursing faculty's readiness to change as a way to substantiate the need for faculty training. C1 [Jenkins, Jean F.] NHGRI, NIH, Bethesda, MD 20892 USA. [Calzone, Kathleen A.] NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Jenkins, JF (reprint author), NHGRI, NIH, Bldg 31,Rm 4B09, Bethesda, MD 20892 USA. EM jean.jenkins@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Genetics Branch; National Human Genome Research Institute FX This research was supported by the Intramural Research Programs of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Genetics Branch, and National Human Genome Research Institute. NR 12 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-3624 EI 1538-9855 J9 NURS EDUC JI Nurs. Educ. PD JAN-FEB PY 2012 VL 37 IS 1 BP 25 EP 29 DI 10.1097/NNE.0b013e31823836ec PG 5 WC Nursing SC Nursing GA 863FJ UT WOS:000298147900012 PM 22158000 ER PT J AU Kalupahana, NS Massiera, F Quignard-Boulange, A Ailhaud, G Voy, BH Wasserman, DH Moustaid-Moussa, N AF Kalupahana, Nishan S. Massiera, Florence Quignard-Boulange, Annie Ailhaud, Gerard Voy, Brynn H. Wasserman, David H. Moustaid-Moussa, Naima TI Overproduction of Angiotensinogen from Adipose Tissue Induces Adipose Inflammation, Glucose Intolerance, and Insulin Resistance SO OBESITY LA English DT Article ID DIET-INDUCED OBESITY; MONOCYTE CHEMOATTRACTANT PROTEIN-1; INCREASED ENERGY-EXPENDITURE; CONVERTING-ENZYME; INDEPENDENT MECHANISM; DIABETES-MELLITUS; HUMAN ADIPOCYTES; GENE-EXPRESSION; BLOOD-PRESSURE; MUSCLE-CELLS AB Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-kappa B (NF-kappa B) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NF kappa B-dependent increases in WAT inflammation. C1 [Kalupahana, Nishan S.; Voy, Brynn H.; Moustaid-Moussa, Naima] Univ Tennessee, Obes Res Ctr, Knoxville, TN 37996 USA. [Kalupahana, Nishan S.; Voy, Brynn H.; Moustaid-Moussa, Naima] Univ Tennessee, Dept Anim Sci, Knoxville, TN 37901 USA. [Kalupahana, Nishan S.] Univ Tennessee, Dept Nutr, Knoxville, TN 37996 USA. [Massiera, Florence; Ailhaud, Gerard] Univ Nice Sophia Antipolis, CNRS, IBDC, UMR, Nice, France. [Massiera, Florence] CEPRODI SA, Paris, France. [Quignard-Boulange, Annie] INRA AgroParisTech, Nutr Physiol & Ingest Behav, Paris, France. [Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN USA. RP Moustaid-Moussa, N (reprint author), Univ Tennessee, Obes Res Ctr, Knoxville, TN 37996 USA. EM moustaid@utk.edu RI e-, a/F-9947-2012 FU American Heart Association [0755626B, 09PRE2260238]; USDA-NIFA NRI [2005-35200-15224]; Department of Animal Science and UT AgResearch; UT Obesity Research Center; Vanderbilt Mouse Metabolic Phenotyping Center [U24 DK059637] FX This project was supported by American Heart Association Grant In Aid # 0755626B, USDA-NIFA NRI award 2005-35200-15224, Department of Animal Science and UT AgResearch (N.M.-M.), American Heart Association predoctoral fellowship 09PRE2260238, UT Obesity Research Center (N.S.K.), and Vanderbilt Mouse Metabolic Phenotyping Center U24 DK059637 (D.H.W.). We would like to thank Taryn Stewart and Dr. Morvarid Bejnood for their assistance in the in vivo studies. NR 40 TC 25 Z9 27 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD JAN PY 2012 VL 20 IS 1 BP 48 EP 56 DI 10.1038/oby.2011.299 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 866SB UT WOS:000298401400004 PM 21979391 ER PT J AU Spong, CY AF Spong, Catherine Y. TI What Is New in Maternal-Fetal Medicine? Best Articles From the Past Year SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material C1 NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. RP Spong, CY (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. EM spongc@exchange.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2012 VL 119 IS 1 BP 168 EP 170 DI 10.1097/AOG.0b013e31823df148 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 869YN UT WOS:000298636400022 PM 22183224 ER PT J AU Gabbe, SG Landon, MB Warren-Boulton, E Fradkin, J AF Gabbe, Steven G. Landon, Mark B. Warren-Boulton, Elizabeth Fradkin, Judith TI Promoting Health After Gestational Diabetes A National Diabetes Education Program Call to Action SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PREGNANCY; MELLITUS; PREVALENCE; WOMEN; HYPERGLYCEMIA; PREVENTION; METFORMIN; OBESITY AB The National Diabetes Education Program joins the American College of Obstetricians and Gynecologists (the College) to promote opportunities for obstetrician-gynecologists (ob-gyns) and other primary care providers to better meet the long-term health needs of women with prior gestational diabetes mellitus (GDM) and their children. Up to one third of GDM women may have diabetes or prediabetes postpartum, yet only about half of these women are tested postpartum, and about a quarter are tested 6-12 weeks postpartum. Women with GDM face a lifelong increased risk for subsequent diabetes, primarily type 2 diabetes mellitus. Timely testing for prediabetes may provide an opportunity for ob-gyns to prevent or delay the onset of type 2 diabetes mellitus through diet, physical activity, weight management, and pharmacologic intervention. The College and the American Diabetes Association recommend testing women with a history of GDM at 6-12 weeks postpartum. If the postpartum test is normal, retest every 3 years and at the first prenatal visit in a subsequent pregnancy. If prediabetes is diagnosed, test annually. Because children of GDM pregnancies face an increased risk for obesity and type 2 diabetes mellitus, families need support to develop healthy eating and physical activity behaviors. Current criteria indicate that GDM occurs in 2% to 10% of all pregnancies. If new GDM diagnostic criteria are used, the frequency of GDM may increase to about 18% of pregnancies annually. The projected increase in the number of women with GDM and the potential subsequent associated risks underscore the need for proactive long-term primary care treatment of the mother and her children. (Obstet Gynecol 2012;119:171-6) DOI: 10.1097/AOG.0b013e3182393208 C1 Ohio State Univ, Med Ctr, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Hager Sharp Inc, Washington, DC USA. Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Gabbe, SG (reprint author), Ohio State Univ, OSU Med Ctr, 200 Meiling Hall,370 W 9th Ave, Columbus, OH 43210 USA. EM steven.gabbe@osumc.edu FU Intramural NIH HHS [Z99 DK999999] NR 24 TC 29 Z9 31 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2012 VL 119 IS 1 BP 171 EP 176 DI 10.1097/AOG.0b013e3182393208 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 869YN UT WOS:000298636400023 PM 22183225 ER PT J AU Spong, CY Saade, G Mercer, B D'Alton, M Blackwell, S Kilpatrick, SJ AF Spong, Catherine Y. Saade, George Mercer, Brian D'Alton, Mary Blackwell, Sean Kilpatrick, Sarah J. TI Concept of Gestational Age in "Completed Weeks": Lost in Translation Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Saade, George] Univ Texas Med Branch Galveston, Dept Obstet & Gynecol, Galveston, TX USA. [Mercer, Brian] Case Western Reserve Univ, MetroHlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [D'Alton, Mary] Columbia Presbyterian Med Ctr, Dept Obstet & Gynecol, New York, NY USA. [Blackwell, Sean] Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX USA. [Kilpatrick, Sarah J.] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Los Angeles, CA 90048 USA. RP Spong, CY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2012 VL 119 IS 1 BP 184 EP 184 DI 10.1097/AOG.0b013e31823f012c PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 869YN UT WOS:000298636400031 ER PT J AU Reddy, UM Bettegowda, VR Dias, T Yamada-Kushnir, T Ko, CW Willinger, M AF Reddy, Uma M. Bettegowda, Vani R. Dias, Todd Yamada-Kushnir, Tomoko Ko, Chia-Wen Willinger, Marian TI Concept of Gestational Age in "Completed Weeks": Lost in Translation Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. March Dimes, White Plains, NY USA. US FDA, Silver Spring, MD USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2012 VL 119 IS 1 BP 185 EP 185 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 869YN UT WOS:000298636400032 ER PT J AU Li, L Pan, ZM Gao, K Zhang, W Luo, Y Yao, ZQ Liang, XQ Tang, BJ Li, QQ AF Li, Li Pan, Zhongmian Gao, Kun Zhang, Wei Luo, Yuan Yao, Zhongqiang Liang, Xinqiang Tang, Bujian Li, Qingdi Quentin TI Impact of post-operative hormone replacement therapy on life quality and prognosis in patients with ovarian malignancy SO ONCOLOGY LETTERS LA English DT Article DE hormone replacement therapy; ovarian malignancy; life quality; prognosis ID OF-LIFE; GYNECOLOGICAL CANCER; SURVIVAL; ESTROGEN; ETIOLOGY; ONCOLOGY; BREAST; CELLS AB The present study aimed to assess the impact of post-surgical hormone replacement therapy (HRT) on life quality and prognosis in women with ovarian malignancy. HRT (Premarin, Nilestriol and medroxyprogesterone) was administered following surgery in 31 patients with ovarian cancer. A total of 44 ovarian cancer patients of similar age, clinical stage and pathological features did not receive HRT following surgery. The expression of estrogen receptor (ER)-alpha, ER beta and progesterone receptor (PR) in cancer tissues was detected by immunohistochemical staining. Serum levels of calcitonin (CT) and transforming growth factor (TGF)-alpha were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Data were analyzed using Kaplan-Meier survival curves, a log-rank test and a Cox scale risk model. Quality of life was assessed in the patient groups and in healthy post-menopausal women (control) based on a questionnaire developed by the European Organization of Research and Treatment of Cancer (EORTC-C30), as well as our own specific questionnaire. A log-rank test revealed no difference in survival between the patients with and without HRT (p>0.05), and a Cox model showed that HRT was not an independent prognostic factor. The accumulated survival rate did not differ significantly based on the expression of ER alpha, ER beta or PR in patients with or without HRT (p>0.05). The serum TGF alpha levels prior to and following surgery were not significantly different in either of the two patient groups (p>0.05). Serum CT levels were higher in patients without HRT at 1.5 years following surgery (p<0.05), but no significant difference was found in the serum CT levels of patients receiving HRT. The HRT and non-HRT groups differed significantly with regard to the body and emotional functional sub-scales of the EORTC-C30 (p<0.05) and the sex quality and autonomic nerve maladjustment categories of our specific questionnaire (p<0.05). Findings of this study showed that HRT administered following surgery exhibited no apparent negative effect on prognosis in patients with ovarian cancer, regardless of ER alpha, ER beta or PR expression in cancer tissues, and had no effect on serum transforming growth factor (TGF)-alpha levels. Post-surgical HRT aided in the stabilization of serum CT levels and improved the quality of life in these patients. C1 [Li, Qingdi Quentin] NIAID, NIH, Bethesda, MD 20892 USA. [Li, Li; Pan, Zhongmian; Gao, Kun; Tang, Bujian] Guangxi Med Univ, Dept Gynecol Oncol, Canc Hosp, Nanning 530021, Guangxi, Peoples R China. [Luo, Yuan; Yao, Zhongqiang] Guangxi Med Univ, Dept Pathol, Canc Hosp, Nanning 530021, Guangxi, Peoples R China. [Zhang, Wei; Liang, Xinqiang] Guangxi Med Univ, Dept Lab Res, Canc Hosp, Nanning 530021, Guangxi, Peoples R China. RP Li, QQ (reprint author), NIAID, NIH, Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM lili_temp@hotmail.com; liquenti@mail.nih.gov FU Provincial Research Project Funding of Guangxi, China [GSR 9817101] FX This study was supported by a grant from the Provincial Research Project Funding of Guangxi, China (No. GSR 9817101). NR 28 TC 3 Z9 5 U1 1 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 J9 ONCOL LETT JI Oncol. Lett. PD JAN PY 2012 VL 3 IS 1 BP 244 EP 249 DI 10.3892/ol.2011.461 PG 6 WC Oncology SC Oncology GA 862WL UT WOS:000298124700045 ER PT J AU Bartolomei, S AF Bartolomei, Sonja TI Handbook of Cancer Chemotherapy, 8th edition SO ONCOLOGY NURSING FORUM LA English DT Book Review C1 [Bartolomei, Sonja] NIH, Bethesda, MD 20892 USA. RP Bartolomei, S (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD JAN PY 2012 VL 39 IS 1 BP 111 EP 111 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 873RW UT WOS:000298901700014 ER PT J AU Funamizu, N Kamata, Y Misawa, T Uwagawa, T Lacy, CR Yanaga, K Manome, Y AF Funamizu, Naotake Kamata, Yuko Misawa, Takeyuki Uwagawa, Tadashi Lacy, Curtis Ray Yanaga, Katsuhiko Manome, Yoshinobu TI Hydroxyurea Decreases Gemcitabine Resistance in Pancreatic Carcinoma Cells With Highly Expressed Ribonucleotide Reductase SO PANCREAS LA English DT Article DE gemcitabine; pancreatic carcinoma; chemoresistance; ribonucleotide reductase; mesenchymal phenotype ID EQUILIBRATIVE NUCLEOSIDE TRANSPORTER-1; DEOXYCYTIDINE KINASE GENE; INTEGRIN-LINKED KINASE; PHASE-III TRIAL; CANCER-PATIENTS; SURVIVAL; SUBUNIT; OVEREXPRESSION; SENSITIVITY; PHENOTYPE AB Objectives: This study aimed to determine whether the treatment of pancreatic carcinoma can be defined on the basis of the expression of genes involved in gemcitabine metabolism and whether combination treatment is more effective than conventional treatment. Methods: Four pancreatic carcinoma cell lines (Panc-1, MIAPaCa-2, BxPC-3, and Capan-2) were used to determine the patterns of gemcitabine-metabolizing genes and mesenchymal marker gene expressions using quantitative real-time polymerase chain reaction. Chemosensitivity and cell proliferation were measured using colorimetric assay. Gemcitabine was combined with hydroxyurea or small interfering RNA targeting ribonucleotide reductase to assess changes in chemoresistance. Results: Panc-1 and MIAPaCa-2 cell lines were profoundly chemoresistant and expressed genes corresponding to cells with distinct mesenchymal phenotypes. In addition, Panc-1 highly expressed ribonucleotide reductase and showed a 4-fold increase in gemcitabine sensitivity after treatment with hydroxyurea. Conclusions: Combination treatment tailored to cells with highly expressed ribonucleotide reductase was more effective than treatment with gemcitabine alone. Moreover, phenotype and gemcitabine metabolism may independently confer chemoresistance. C1 [Funamizu, Naotake] Jikei Univ, Sch Med, Dept Mol Cell Biol, Inst DNA Med,Minato Ku, Tokyo 1058461, Japan. [Funamizu, Naotake; Misawa, Takeyuki; Uwagawa, Tadashi; Yanaga, Katsuhiko] Jikei Univ, Sch Med, Dept Surg, Tokyo 1058461, Japan. [Kamata, Yuko] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Lacy, Curtis Ray] Jikei Univ, Sch Med, Dept Oncol, Inst DNA Med, Tokyo 1058461, Japan. RP Funamizu, N (reprint author), Jikei Univ, Sch Med, Dept Mol Cell Biol, Inst DNA Med,Minato Ku, 3-25-8 Nishi Shinbashi, Tokyo 1058461, Japan. EM funamizujikei@yahoo.co.jp NR 39 TC 5 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD JAN PY 2012 VL 41 IS 1 BP 107 EP 113 DI 10.1097/MPA.0b013e318224b5fb PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 866JE UT WOS:000298375900014 PM 21926937 ER PT J AU Lee, HS Park, JW Chertov, O Colantonio, S Simpson, JT Fivash, MJ Yoo, CW Lee, GK Zo, JI Kim, HT Kim, HK AF Lee, Hee Seok Park, Jun Won Chertov, Oleg Colantonio, Simona Simpson, John T. Fivash, Matthew J. Yoo, Chong Woo Lee, Geon Kook Zo, Jae Ill Kim, Heung Tae Kim, Hark Kyun TI Matrix-assisted laser desorption/ionization mass spectrometry reveals decreased calcylcin expression in small cell lung cancer SO PATHOLOGY INTERNATIONAL LA English DT Article DE calcyclin; cancer; lung; mass spectrometry; small cell ID PULMONARY ADENOCARCINOMA; COMPARATIVE PROTEOMICS; SAMPLE PREPARATION; TUMOR-MARKERS; CARCINOMA; GENES AB To date, most of the proteomic analyses on lung cancer tissue samples have been performed using surgical specimens, which are obtained after a diagnosis is made. To determine if a proteomic signature obtained from bronchoscopic biopsy samples could be found to assist with diagnosis, 50 lung cancer bronchoscopic biopsy samples and 13 adjacent normal lung tissue samples were analyzed using histology-directed, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Lung tissue samples were cryosectioned, and sinapinic acid was robotically deposited on areas of each tissue section enriched in epithelial cells, either tumor or normal. Mass spectra were acquired using a MALDI-time of flight instrument. Small cell lung cancers (SCLCs) demonstrated clearly different protein profiles from normal lung tissue and from non-small cell lung cancers (NSCLCs). Calcyclin (m/z= 10 094.7) was identified to be underexpressed in small cell lung cancers, as compared with non-small cell lung cancers and normal lung tissue. An immunohistochemistry study using 152 NSCLCs and 21 SCLCs confirmed significantly reduced calcyclin stain in SCLCs. Thus, protein profiles obtained from bronchoscopic biopsy samples via MALDI MS distinguish cancerous epithelium from normal lung tissue and between NSCLCs and SCLCs. C1 [Kim, Heung Tae] Natl Canc Ctr, Ctr Lung Canc, Goyang 411769, South Korea. [Chertov, Oleg; Colantonio, Simona; Simpson, John T.] SAIC Frederick Inc, Prot Chem Lab, Adv Technol Program, Frederick, MD USA. [Fivash, Matthew J.] NCI, Data Management Syst Inc, Frederick, MD 21701 USA. RP Kim, HT (reprint author), Natl Canc Ctr, Ctr Lung Canc, Goyang 411769, South Korea. EM htkim@ncc.re.kr; hkim@ncc.re.kr FU Converging Research Center through the Ministry of Education, Science and Technology of Korea [2010K001121]; Korean National Cancer Center [1110500]; National Cancer Institute, National Institutes of Health [HH5N261200800001E] FX The work was supported by Converging Research Center Program through the Ministry of Education, Science and Technology of Korea (2010K001121); by Korean National Cancer Center Grant 1110500; and by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HH5N261200800001E. The authors thank Mr Young Duc Kim (SAIC/NCI-Frederick) and Ms Jeong Hwa Lee (Konkuk University) for technical help. NR 25 TC 4 Z9 5 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1320-5463 J9 PATHOL INT JI Pathol. Int. PD JAN PY 2012 VL 62 IS 1 BP 28 EP 35 DI 10.1111/j.1440-1827.2011.02783.x PG 8 WC Pathology SC Pathology GA 867US UT WOS:000298480900004 PM 22192801 ER PT J AU Beutler, JA AF Beutler, John A. TI Early years of the journal SO PHARMACEUTICAL BIOLOGY LA English DT Editorial Material DE History; pharmacognosy; journals AB A brief account of the journal from 1961 to 1991. C1 NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. RP Beutler, JA (reprint author), NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. EM beutlerj@mail.nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 0 TC 0 Z9 0 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD JAN PY 2012 VL 50 IS 1 BP 6 EP 7 DI 10.3109/13880209.2011.601315 PG 2 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 866KS UT WOS:000298380200002 PM 22181341 ER PT J AU Herrinton, LJ Liu, LY Abramson, O Jaffe, ES AF Herrinton, Lisa J. Liu, Liyan Abramson, Oren Jaffe, Elaine S. TI The incidence of hepatosplenic T-cell lymphoma in a large managed care organization, with reference to anti-tumor necrosis factor therapy, Northern California, 2000-2006 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE hepatosplenic T-cell lymphoma; Crohn's disease; HIV/AIDS; incidence; epidemiology; autoimmunity ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; INFLIXIMAB USE; PATIENT; AZATHIOPRINE; ENTITY AB Background Hepatosplenic T-cell lymphoma (HSTCL), a rare and rapidly progressive subtype of peripheral T-cell lymphoma, has been reported following TNF-alpha-blocker therapy. To better understand this relationship, we conducted an epidemiologic study in the Kaiser Permanente membership. Methods The retrospective cohort study was conducted among Northern California members of all ages. The Kaiser Permanente Cancer Registry, supplemented with review of medical charts and pathology slides, was used to identify and confirm cases of HSTCL. Medical histories were obtained, and we computed the standardized incidence rate for the 7-year period 2000-2006, when immunohistochemical staining was fully established throughout the health plan for diagnosing lymphoma. Results Six cases were diagnosed during 2000-2006, for an annual age-standardized incidence rate of 0.3 (95% CI, 0.11-0.65) per million person-years. One case had a prior diagnosis of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS); another had a prior diagnosis of Crohn's disease treated with steroids, thiopurine and infliximab. Conclusion Prior cases of HIV/AIDS-linked HSTCL are uncommon in the existing literature. Multiple case reports of HSTCL in the setting of Crohn's disease treated with anti-TNF plus thiopurine have been published, but HSTCL is rare, making epidemiologic assessments difficult. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Herrinton, Lisa J.; Liu, Liyan] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Abramson, Oren] Kaiser Permanente No Calif, Dept Pediat Gastroenterol, Oakland, CA 94612 USA. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Herrinton, LJ (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM lisa.herrinton@kp.org OI Jaffe, Elaine/0000-0003-4632-0301 FU Centocor Research & Development, Inc. FX This project was funded through a contract with Centocor Research & Development, Inc., which provided the sponsor with a 30-day comment period, but no right to suppress the manuscript. Dr Herrinton has also had research contracts in the past 3 years with Proctor & Gamble and with Genentech. NR 14 TC 9 Z9 9 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 IS 1 BP 49 EP 52 DI 10.1002/pds.2216 PG 4 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 874UK UT WOS:000298983400006 PM 21823196 ER PT J AU Hildenbrand, HL Smith, ACM AF Hildenbrand, Hanna L. Smith, Ann C. M. TI Analysis of the Sensory Profile in Children with Smith-Magenis Syndrome SO PHYSICAL & OCCUPATIONAL THERAPY IN PEDIATRICS LA English DT Article DE sensory processing; sensory profile caregiver questionnaire; sensory modulation; Smith-Magenis syndrome ID SYNDROME DEL 17P11.2; BEHAVIORAL-PHENOTYPE; MALADAPTIVE BEHAVIOR; SPECTRUM; AUTISM; ABILITIES; GENOTYPE; DISORDER; FEATURES; ADULTS AB This study systematically assessed sensory processing in 34 children, aged 3-14 years, with Smith-Magenis syndrome (SMS) using the Sensory Profile Caregiver Questionnaire. Scores for the SMS cohort were significantly different from scores of the national sample of children with and without disabilities in all Sensory Profile categories and quadrants (p < .001). No main effects of age or gender were found, but an interaction effect of age by gender was found in Modulation of Sensory Input Affecting Emotional Responses, in which older females presented with the lowest scores. A significant decline over time was found in the Seeking pattern, reflecting increased vulnerability (p < .05). Nonsignificant trends suggest more vulnerabilities for older versus younger children, especially older females. The neurobehavioral phenotype in children with SMS is expanded by this description of sensory processing. How children with SMS experience and respond to everyday sensations informs multidisciplinary team decisions. C1 [Hildenbrand, Hanna L.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Smith, Ann C. M.] NIH, Off Clin Director, Human Genome Res Inst, Bethesda, MD 20892 USA. RP Hildenbrand, HL (reprint author), NIH, Dept Rehabil Med, 10 Ctr Dr,MSC 1604,Bldg 10CRC,Room 1-1469NE, Bethesda, MD 20892 USA. EM hhildenbrand@cc.nih.gov RI SMITH, ANN C.M./C-1122-2008 FU National Institutes of Health (NIH), National Human Genome Research Institute (NHGRI); NIH Clinical Center FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Human Genome Research Institute (NHGRI), and a Bench-to-Bedside Award from the NIH Clinical Center to the Medical Genetics Branch of the NHGRI. The authors would like to thank Donna Krasnewich, MD, Wendy Introne, MD, and Bonnie Hodsdon, OTR/L, NIH Chief OT who supported our work on this study; Joanne E. Flanagan, MS, OTR/L for initial work on this study; Rebecca Morse, MA, for assistance with data entry; Elizabeth K. Rasch, PT, PhD, for data analysis; Captain Rebecca A. Parks, MS, OTR/L, BCP, FAOTA, and Maryanne Sacco-Peterson, MA, OTR/L, for internal reviewing; and the families who participated in this research. NR 43 TC 2 Z9 2 U1 2 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0194-2638 EI 1541-3144 J9 PHYS OCCUP THER PEDI JI Phys. Occup. Ther. Pediatr. PY 2012 VL 32 IS 1 BP 48 EP 65 DI 10.3109/01942638.2011.572152 PG 18 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA 874AK UT WOS:000298927200006 PM 21599572 ER PT J AU Stout, NL Pfalzer, LA Springer, B Levy, E McGarvey, CL Danoff, JV Gerber, LH Soballe, PW AF Stout, Nicole L. Pfalzer, Lucinda A. Springer, Barbara Levy, Ellen McGarvey, Charles L. Danoff, Jerome V. Gerber, Lynn H. Soballe, Peter W. TI Breast Cancer-Related Lymphedema: Comparing Direct Costs of a Prospective Surveillance Model and a Traditional Model of Care SO PHYSICAL THERAPY LA English DT Editorial Material ID QUALITY-OF-LIFE; PREOPERATIVE ASSESSMENT ENABLES; AXILLARY NODE DISSECTION; CLINICAL-TRIALS; RADICAL-MASTECTOMY; SHOULDER FUNCTION; EARLY-DIAGNOSIS; ARM EDEMA; SURGERY; REHABILITATION AB Secondary prevention involves monitoring and screening to prevent negative sequelae from chronic diseases such as cancer. Breast cancer treatment sequelae, such as lymphedema, may occur early or late and often negatively affect function. Secondary prevention through prospective physical therapy surveillance aids in early identification and treatment of breast cancer-related lymphedema (BCRL). Early intervention may reduce the need for intensive rehabilitation and may be cost saving. This perspective article compares a prospective surveillance model with a traditional model of impairment-based care and examines direct treatment costs associated with each program. Intervention and supply costs were estimated based on the Medicare 2009 physician fee schedule for 2 groups: (1) a prospective surveillance model group (PSM group) and (2) a traditional model group (TM group). The PSM group comprised all women with breast cancer who were receiving interval prospective surveillance, assuming that one third would develop early-stage BCRL. The prospective surveillance model includes the cost of screening all women plus the cost of intervention for early-stage BCRL. The TM group comprised women referred for BCRL treatment using a traditional model of referral based on late-stage lymphedema. The traditional model cost includes the direct cost of treating patients with advanced-stage lymphedema. The cost to manage early-stage BCRL per patient per year using a prospective surveillance model is $636.19. The cost to manage late-stage BCRL per patient per year using a traditional model is $3,124.92. The prospective surveillance model is emerging as the standard of care in breast cancer treatment and is a potential cost-saving mechanism for BCRL treatment. Further analysis of indirect costs and utility is necessary to assess cost-effectiveness. A shift in the paradigm of physical therapy toward a prospective surveillance model is warranted. C1 [Stout, Nicole L.] Natl Naval Med Ctr, Breast Care Ctr, Bethesda, MD 20814 USA. [Pfalzer, Lucinda A.] Univ Michigan, Dept Phys Therapy, Flint, MI 48503 USA. [Springer, Barbara] Off Surg Gen, Proponency Off Rehabil & Reintegrat, Falls Church, VA USA. [Levy, Ellen] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [McGarvey, Charles L.] CLM Consulting, Rockville, MD USA. [Danoff, Jerome V.] NIH, Dept Rehabil Med, Washington, DC USA. [Danoff, Jerome V.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Gerber, Lynn H.] George Mason Univ, Fairfax, VA 22030 USA. [Soballe, Peter W.] USN Hosp, San Diego, CA 92134 USA. RP Stout, NL (reprint author), Natl Naval Med Ctr, Breast Care Ctr, 8901 Wisconsin Ave,Bldg 10,4 W, Bethesda, MD 20814 USA. EM nicole.stout@med.navy.mil FU Intramural NIH HHS NR 82 TC 33 Z9 33 U1 2 U2 8 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 EI 1538-6724 J9 PHYS THER JI Phys. Ther. PD JAN PY 2012 VL 92 IS 1 BP 152 EP 163 DI 10.2522/ptj.20100167 PG 12 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 870AS UT WOS:000298642100014 PM 21921254 ER PT J AU Meyer, TE Chu, LW Li, QZ Yu, K Rosenberg, PS Menashe, I Chokkalingam, AP Quraishi, SM Huang, WY Weiss, JM Kaaks, R Hayes, RB Chanock, SJ Hsing, AW AF Meyer, Tamra E. Chu, Lisa W. Li, Qizhai Yu, Kai Rosenberg, Philip S. Menashe, Idan Chokkalingam, Anand P. Quraishi, Sabah M. Huang, Wen-Yi Weiss, Jocelyn M. Kaaks, Rudolf Hayes, Richard B. Chanock, Stephen J. Hsing, Ann W. TI The association between inflammation-related genes and serum androgen levels in men: The prostate, lung, colorectal, and ovarian study SO PROSTATE LA English DT Article DE inflammation; androgens; genes; testosterone; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; RESPONSE ELEMENTS; MATRIX METALLOPROTEINASES; CANCER; CELLS; MMP-2; MACROPHAGES; EXPRESSION; RECEPTORS; PROMOTER AB BACKGROUND Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes. METHODS. In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5a-androstane-3a, 17b-diol glucuronide [3adiol G], and 4-androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based P values were generated using an adaptive rank truncated product (ARTP) method. RESULTS. Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value < 0.1) in both SNP and genebased tests. Specifically, T was associated with common variants in MMP2 and CD14, with the most significant SNPs being rs893226G > T in MMP2 and rs3822356T > C in CD14 (FDR q-value 0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione. CONCLUSION. These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk. Prostate 72: 65-71, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Meyer, Tamra E.] NCI, Div Canc Epidemiol & Genet, EPS, NIH, Rockville, MD 20852 USA. [Li, Qizhai] CAS, Acad Math & Syst Sci, Guangzhou, Guangdong, Peoples R China. [Chokkalingam, Anand P.] Univ Calif Berkeley, Sch Publ Hlth, Dept Epidemiol, Berkeley, CA 94720 USA. [Kaaks, Rudolf] German Natl Canc Ctr, Div Canc Epidemiol, Heidelberg, Germany. RP Meyer, TE (reprint author), NCI, Div Canc Epidemiol & Genet, EPS, NIH, 6120 Execut Blvd,Rm 5032, Rockville, MD 20852 USA. EM tamra.e.meyer@us.army.mil OI Hayes, Richard/0000-0002-0918-661X FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services FX Grant sponsor: Funding: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services. NR 25 TC 5 Z9 5 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD JAN PY 2012 VL 72 IS 1 BP 65 EP 71 DI 10.1002/pros.21407 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 869HM UT WOS:000298588900008 PM 21520164 ER PT J AU Wilkinson, AV Barrera, SL McBride, CM Snyder, DC Sloane, R Meneses, KM Pekmezi, D Kraus, WE Demark-Wahnefried, W AF Wilkinson, Anna V. Barrera, Stephanie L. McBride, Colleen M. Snyder, Denise C. Sloane, Richard Meneses, Karen M. Pekmezi, Dorothy Kraus, William E. Demark-Wahnefried, Wendy TI Extant health behaviors and uptake of standardized vs tailored health messages among cancer survivors enrolled in the FRESH START trial: a comparison of fighting-spirits vs fatalists SO PSYCHO-ONCOLOGY LA English DT Article DE coping; personality traits; diet; exercise; interventions; cancer survivors ID BREAST-CANCER; YOUNG-WOMEN; EXERCISE; DIET; ADJUSTMENT; SCALE; MAC AB Objective: Cancer coping styles have been associated with several cancer-related outcomes. We examined whether baseline lifestyle behaviors differed between cancer survivors with fatalistic vs fighting-spirit coping styles, and whether there was differential response to two diet-exercise mailed-print interventions, one standardized and another individually tailored. Methods: Baseline differences by coping style are presented for 628 breast and prostate cancer survivors who participated in the FRESH START trial, along with multivariable analyses on rates of uptake by coping style and arm assignment for those completing the 2-year trial. Results: At baseline, several differences were observed between fighting-spirits and fatalists, with the former significantly more likely to be white, younger, leaner, more-educated and at risk for depression, and less likely to consume 51fruits and vegetables (F& V)/ day (p-valueso < 0.05). Improvements in physical activity were observed, with fighting-spirits exhibiting the greatest gains from baseline to Year-1, regardless of intervention type; but by Year-2, these differences diminished as fatalists gained ground. Moreover, fatalists who received standardized intervention material also charted steady improvements in F& V intake over the study period; by Year-2, 58.1% of fatalists achieved the 5-a-day goal vs 44.6% of fighting-spirits (p-valueo<0.05). Conclusions: Lifestyle behaviors and health message uptake differs by cancer coping style. Although tailored interventions appear most effective and minimize differential uptake, standardized interventions also can improve behaviors, though fighting-spirits may require additional boosters to maintain change. Copyright r 2010 John Wiley & Sons, Ltd. C1 [Wilkinson, Anna V.; Snyder, Denise C.; Sloane, Richard] Univ Texas Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Austin, TX USA. [Wilkinson, Anna V.; Barrera, Stephanie L.; Demark-Wahnefried, Wendy] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [McBride, Colleen M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Demark-Wahnefried, Wendy] Duke Univ Sch Nursing, Durham, NC USA. [Meneses, Karen M.; Pekmezi, Dorothy; Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Program Canc Control & Populat Sci, Birmingham Comprehens Canc Ctr, Birmingham, AL USA. [Kraus, William E.] Duke Univ Med Ctr, Dept Med, Durham, NC USA. RP Wilkinson, AV (reprint author), 1616 Guadalupe,Suite 6-300, Austin, TX 78701 USA. EM anna.v.wilkinson@uth.tmc.edu OI Kraus, William E/0000-0003-1930-9684 FU National Institutes of Health [CA81191, CA74000, CA63782, CA126988, M01-RR-30]; American Institute of Cancer Research; Susan G. Komen Foundation FX Support from the National Institutes of Health (CA81191, CA74000, CA63782, CA126988 and M01-RR-30), the American Institute of Cancer Research and the Susan G. Komen Foundation. NR 20 TC 4 Z9 4 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JAN PY 2012 VL 21 IS 1 BP 108 EP 113 DI 10.1002/pon.1870 PG 6 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 871ME UT WOS:000298741400013 PM 21061408 ER PT J AU Bienvenu, OJ Samuels, JF Wuyek, LA Liang, KY Wang, Y Grados, MA Cullen, BA Riddle, MA Greenberg, BD Rasmussen, SA Fyer, AJ Pinto, A Rauch, SL Pauls, DL McCracken, JT Piacentini, J Murphy, DL Knowles, JA Nestadt, G AF Bienvenu, O. J. Samuels, J. F. Wuyek, L. A. Liang, K-Y. Wang, Y. Grados, M. A. Cullen, B. A. Riddle, M. A. Greenberg, B. D. Rasmussen, S. A. Fyer, A. J. Pinto, A. Rauch, S. L. Pauls, D. L. McCracken, J. T. Piacentini, J. Murphy, D. L. Knowles, J. A. Nestadt, G. TI Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Anxiety disorders; genetic epidemiology; obsessive-compulsive disorder; obsessive-compulsive personality disorder; obsessive-compulsive spectrum ID HOPKINS OCD FAMILY; DSM-V; PERSONALITY-DISORDERS; MAJOR DEPRESSION; PANIC DISORDER; COMORBIDITY; RELATIVES; HYPOCHONDRIASIS; PROBANDS; LA AB Background. Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. Method. Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). Results. Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. Conclusions. On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV. C1 [Bienvenu, O. J.; Samuels, J. F.; Wuyek, L. A.; Wang, Y.; Grados, M. A.; Cullen, B. A.; Riddle, M. A.; Nestadt, G.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Baltimore, MD 21287 USA. [Liang, K-Y.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Greenberg, B. D.; Rasmussen, S. A.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Fyer, A. J.; Pinto, A.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Fyer, A. J.; Pinto, A.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Rauch, S. L.; Pauls, D. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rauch, S. L.; Pauls, D. L.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Murphy, D. L.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Knowles, J. A.] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. RP Bienvenu, OJ (reprint author), Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Meyer 115,600 N Wolfe St, Baltimore, MD 21287 USA. EM jbienven@jhmi.edu RI Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU American Psychiatric Association; National Institutes of Health [MH50125, RR00052, NS42609, MH64543, MH80221, MH66284] FX This study was commissioned and funded by the American Psychiatric Association to support the work of the DSM-5 Anxiety, Obsessive-Compulsive Spectrum, Post-Traumatic, and Dissociative Disorders Work Group. National Institutes of Health grants MH50125, RR00052, NS42609, MH64543, MH80221 and MH66284 also supported this work. NR 43 TC 62 Z9 63 U1 6 U2 37 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD JAN PY 2012 VL 42 IS 1 BP 1 EP 13 DI 10.1017/S0033291711000742 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 874MG UT WOS:000298961600001 PM 21733222 ER PT J AU Hall, FS Centeno, M Perona, MTG Adair, J Dobner, PR Uhl, GR AF Hall, F. Scott Centeno, Marjorie Perona, Maria T. G. Adair, Jordan Dobner, Paul R. Uhl, George R. TI Effects of neurotensin gene knockout in mice on the behavioral effects of cocaine SO PSYCHOPHARMACOLOGY LA English DT Article DE Neurotensin; Cocaine; Gene knockout; Transgenic; Conditioned place preference; Conditioned locomotion ID VENTRAL TEGMENTAL AREA; CONDITIONED PLACE PREFERENCE; RAT PREFRONTAL CORTEX; STRIATAL FOS EXPRESSION; BRAIN DOPAMINE SYSTEMS; NUCLEUS-ACCUMBENS; ENDOGENOUS NEUROTENSIN; RECEPTOR ANTAGONIST; ANTIPSYCHOTIC-DRUGS; D-AMPHETAMINE AB The neuropeptide neurotensin (NT), which has been implicated in the modulation of dopamine signaling, is expressed in a subset of dopamine neurons and antagonism of the NT receptor has been reported to reduce psychostimulant-induced behavior. Gene knockout (KO) of the neurotensin/neuromedin N precursor provides an approach to delineating possible roles of endogenous NT in psychostimulant-induced responses. Involvement of NT in cocaine responses was examined by comparing acute and conditioned locomotor responses, conditioned place preference, and sensitization in wild-type (WT), heterozygous, and homozygous NT KO mice. NT KO mice did not differ from their WT or heterozygous littermates in either baseline or acute cocaine-stimulated locomotor activity. The locomotor stimulant effects of cocaine were slightly prolonged in these mice under some, but not all, experimental conditions. The rewarding effects of cocaine as assessed in the conditioned place preference and conditioned locomotion paradigms were also similar between genotypes at all cocaine doses tested. These results suggest that endogenous NT is not involved in cocaine-mediated behaviors in most circumstances, but under some conditions, a slight prolongation of the effects of cocaine was observed in the absence of endogenous NT. C1 [Hall, F. Scott; Centeno, Marjorie; Perona, Maria T. G.; Adair, Jordan; Uhl, George R.] NIDA, NIH DHHS, Mol Neurobiol Branch, Baltimore, MD 21224 USA. [Dobner, Paul R.] Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Program Neurosci, Worcester, MA 01655 USA. RP Hall, FS (reprint author), NIDA, NIH DHHS, Mol Neurobiol Branch, 333 Cassell Dr, Baltimore, MD 21224 USA. EM shall@intra.nida.nih.gov RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU National Institute on Drug Abuse (NIH) FX This research was supported financially by the National Institute on Drug Abuse Intramural Research Program (NIH). NR 62 TC 3 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2012 VL 219 IS 1 BP 35 EP 45 DI 10.1007/s00213-011-2370-9 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 870BX UT WOS:000298645200004 PM 21720755 ER PT J AU Brielmaier, J McDonald, CG Smith, R AF Brielmaier, Jennifer McDonald, Craig G. Smith, Robert F. TI Effects of acute stress on acquisition of nicotine conditioned place preference in adolescent rats: a role for corticotropin-releasing factor 1 receptors SO PSYCHOPHARMACOLOGY LA English DT Article DE Nicotine; Adolescence; Stress; Reward; Conditioned place preference; Corticotropin-releasing factor; CP-154,526 ID VENTRAL TEGMENTAL AREA; ACCUMBENS SHELL DOPAMINE; SOCIAL-INTERACTION TEST; NUCLEUS-ACCUMBENS; UNCONTROLLABLE STRESS; FACTOR CRF; PLASMA-CORTICOSTERONE; BEHAVIORAL-RESPONSES; INDUCED POTENTIATION; MESOLIMBIC SYSTEM AB Studies indicate that adolescence is a time of increased sensitivity to the rewarding effects of nicotine, and that stress is associated with an increased risk for smoking initiation in this age group. It is possible that stress leads to increased nicotine use in adolescence by augmenting its rewarding properties. Corticotropin-releasing factor type 1 receptors (CRF-R1) mediate physiological and behavioral stress responses. They may also mediate stress-induced potentiation of activity in multiple neural substrates implicated in nicotine reward. The aim of the present study was to determine the effect of acute stressor exposure on single trial nicotine conditioned place preference (CPP) in adolescent male rats using a biased CPP procedure and the role of CRF-R1 in this effect. A single episode of intermittent footshock administered 24 h before the start of place conditioning dose-dependently facilitated acquisition of CPP to nicotine (0.2, 0.4, and 0.6 mg/kg). Pretreatment with CP-154,526 (20 mg/kg), a selective CRF-R1 antagonist, 30 min before footshock exposure significantly attenuated the effect of prior stress to facilitate nicotine CPP acquisition. CP-154,526 pretreatment had no effect in animals conditioned with a nicotine dose that produced CPP under non-stress conditions, suggesting a specific role for CRF-R1 following stress. Taken together, the results suggest that during adolescence, nicotine reward is enhanced by recent stressor exposure in a manner that involves signaling at CRF-R1. Information from studies such as this may be used to inform efforts to prevent and treat adolescent nicotine dependence. C1 [Brielmaier, Jennifer; McDonald, Craig G.; Smith, Robert F.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Brielmaier, Jennifer] NIMH, Intramural Res Program, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Brielmaier, J (reprint author), NIMH, Intramural Res Program, Lab Behav Neurosci, Porter Neurosci Res Ctr Bldg 35 Room 1 C909,MSC 3, Bethesda, MD 20892 USA. EM brielmaierjm@mail.nih.gov RI McDonald, Craig/H-7390-2013 FU Virginia Foundation for Healthy Youth; American Psychological Association FX This research was supported by a grant from the Virginia Foundation for Healthy Youth to R. F. Smith and a grant from the American Psychological Association to J. Brielmaier. CP-154,526 was generously donated by Pfizer. The authors certify that they have no actual or potential conflicts of interest in relation to this article, nor do they have a financial relationship with either of the organizations that sponsored the research. The authors have full control of all primary data and agree to allow the journal to review the data if requested. The authors thank Drs. Theodore Dumas and Katherine McKnight for their valuable advice. NR 82 TC 24 Z9 24 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2012 VL 219 IS 1 BP 73 EP 82 DI 10.1007/s00213-011-2378-1 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 870BX UT WOS:000298645200007 PM 21720754 ER PT J AU Collins, GT Cunningham, AR Chen, JY Wang, SM Newman, AH Woods, JH AF Collins, Gregory T. Cunningham, Alyssa R. Chen, Jianyong Wang, Shaomeng Newman, Amy H. Woods, James H. TI Effects of pramipexole on the reinforcing effectiveness of stimuli that were previously paired with cocaine reinforcement in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Cocaine; Conditioned; Dopamine receptor; Drug abuse; Operant; Self-administration; Reinforcement ID DOPAMINE D3 RECEPTOR; IMPULSE CONTROL DISORDERS; ABUSE THERAPEUTIC AGENTS; PARKINSONS-DISEASE; CONDITIONED REINFORCEMENT; SEEKING BEHAVIOR; D-3 RECEPTOR; DYSREGULATION SYNDROME; REPETITIVE BEHAVIORS; AGONIST QUINPIROLE AB Dopamine D(2)-like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS). To evaluate the extent to which the pramipexole-maintained and pramipexole-induced responding are influenced by cocaine-paired stimuli. Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenter-administered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D(2)- (l-741,626) and D(3)-preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated. When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dose-dependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D(2) and D(3) antagonists differentially affected pramipexole-induced PR responding, with l-741,626 and PG01037 producing rightward, and downward shifts in the dose-response curve for CS-maintained responding, respectively. These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole. C1 [Collins, Gregory T.; Cunningham, Alyssa R.; Wang, Shaomeng; Woods, James H.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Chen, Jianyong; Wang, Shaomeng] Univ Michigan, Sch Med, Dept Internal Med & Med Chem, Ann Arbor, MI 48109 USA. [Newman, Amy H.] NIDA, NIH, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Collins, GT (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM collinsg@umich.edu RI Collins, Gregory/K-3125-2012 FU NIDA [DA 024897, DA 020669]; NIDA-IRP FX This research was supported by NIDA grants DA 024897, DA 020669, as well as the NIDA-IRP. NR 60 TC 16 Z9 16 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2012 VL 219 IS 1 BP 123 EP 135 DI 10.1007/s00213-011-2382-5 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 870BX UT WOS:000298645200011 PM 21701814 ER PT J AU Fernando, ABP Economidou, D Theobald, DE Zou, MF Newman, AH Spoelder, M Caprioli, D Moreno, M Hipolito, L Aspinall, AT Robbins, TW Dalley, JW AF Fernando, Anushka B. P. Economidou, Daina Theobald, David E. Zou, Mu-Fa Newman, Amy H. Spoelder, Marcia Caprioli, Daniele Moreno, Margarita Hipolito, Lucia Aspinall, Albert T. Robbins, Trevor W. Dalley, Jeffrey W. TI Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists SO PSYCHOPHARMACOLOGY LA English DT Article DE Impulsivity; Dopamine; Noradrenaline; Five-choice serial reaction time task; Quinpirole; Sumanirole; GBR-12909; Atomoxetine; Guanfacine; Methylphenidate ID DEFICIT-HYPERACTIVITY DISORDER; REACTION-TIME-TASK; IN-SITU HYBRIDIZATION; DEFICIT/HYPERACTIVITY DISORDER; NUCLEUS-ACCUMBENS; BEHAVIORAL PHARMACOLOGY; TERMINAL AUTORECEPTORS; CLINICAL-IMPLICATIONS; TRAIT IMPULSIVITY; PREFRONTAL CORTEX AB Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear. The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT). We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive 'HI' and low impulsive 'LI', respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner. Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats. These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT. C1 [Fernando, Anushka B. P.; Economidou, Daina; Theobald, David E.; Spoelder, Marcia; Caprioli, Daniele; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Fernando, Anushka B. P.; Economidou, Daina; Theobald, David E.; Spoelder, Marcia; Caprioli, Daniele; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. [Zou, Mu-Fa; Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Moreno, Margarita] Univ Almeria, Dept Neurosci & Hlth Sci, Almeria, Spain. [Hipolito, Lucia] Univ Valencia, Dept Farm & Technol Farmaceut, Valencia, Spain. [Aspinall, Albert T.] Univ St Andrews, St Marys Coll, Sch Psychol, St Andrews KY16 9JP, Fife, Scotland. [Dalley, Jeffrey W.] Univ Cambridge, Addenbrookes Hosp, Dept Psychiat, Cambridge CB2 2QQ, England. RP Dalley, JW (reprint author), Univ Cambridge, Behav & Clin Neurosci Inst, Downing St, Cambridge CB2 3EB, England. EM jwd20@cam.ac.uk RI Hipolito, Lucia/E-5006-2015; Moreno, Margarita/K-9869-2014 OI Hipolito, Lucia/0000-0002-6834-5748; Moreno, Margarita/0000-0001-7336-6167 FU Wellcome Trust [089589/z/09/z]; MRC [G0701500]; Jose Castillejo Fellowship; Ministerio de Ciencia e Innovacion of Spain [PSI2009-08626]; RCUK; British Pharmacological Society; NIDA-IRP, NIH FX This study was supported by the Wellcome Trust Programme grant to TWR, JWD, Barry J. Everitt, Angela C. Roberts and Barbara J. Sahakian (089589/z/09/z) and by an MRC grant to JWD, TWR, Barry J. Everitt, Tim D Fryer, Franklin I. Aigbirhio and Jean-Claude Baron (G0701500). MM was supported by the Jose Castillejo Fellowship and PSI2009-08626 grant from Ministerio de Ciencia e Innovacion of Spain. AF was supported by an MRC studentship, and ESJR was supported by an RCUK Academic Fellowship and British Pharmacological Society Integrative Pharmacology award. AHN and MFZ were supported by the NIDA-IRP, NIH. NR 58 TC 53 Z9 54 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2012 VL 219 IS 2 SI SI BP 341 EP 352 DI 10.1007/s00213-011-2408-z PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 870BZ UT WOS:000298645400008 PM 21761147 ER PT J AU Robinson, OJ Cools, R Sahakian, BJ AF Robinson, Oliver J. Cools, Roshan Sahakian, Barbara J. TI Tryptophan depletion disinhibits punishment but not reward prediction: implications for resilience SO PSYCHOPHARMACOLOGY LA English DT Article DE Serotonin; Inhibition; Reward; Punishment; Resilience ID 5-HYDROXYINDOLEACETIC ACID; BEHAVIORAL-INHIBITION; CEREBROSPINAL-FLUID; HEALTHY FEMALES; NEGATIVE MOOD; SEROTONIN; DOPAMINE; VOLUNTEERS; THREAT AB Rationale We have previously shown that tryptophan depletion enhances punishment but not reward prediction (Cools et al. in Neuropsychopharmacology 33:2291-2299, 2008b). This provided evidence for a valence-specific role of serotonin (which declines under depleted tryptophan) in aversive processing. Recent theoretical (Dayan and Huys in PLoS Comput Biol 4:e4, 2008) and experimental (Crockett et al. in J Neurosci 29:11993-11999, 2009) approaches have, however, further specified this role by showing that serotonin is critical for punishment-induced inhibition. Objectives We sought to examine the role of serotonin in punishment-induced inhibition. We also examined the impact of induced mood on this effect to assess whether effects of tryptophan depletion on affective inhibition are moderated by mood. Methods Healthy females consumed a balanced amino acid mixture with (N = 20) or without (N = 21) the serotonin precursor tryptophan. Each subject completed either negative or neutral mood induction. All subjects completed the reward and punishment reversal learning task adopted in the previous study. Results We demonstrate a punishment prediction impairment in individuals who consumed tryptophan which was absent in individuals who were depleted of tryptophan. This effect was impervious to mood state. Conclusions Our results suggest that serotonin promotes the inhibition of responses to punishing outcomes. This may lead to reduced punishment prediction accuracy in the presence of tryptophan and may contribute to resilience to affective disorders. Reduction of serotonin via tryptophan depletion then removes this inhibition. As such, we highlight a mechanism by which reduced serotonin can contribute to disorders of impulsivity and compulsivity as well as disorders of emotion. C1 [Robinson, Oliver J.] NIMH, NIH, Bethesda, MD 20892 USA. [Cools, Roshan] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Ctr Cognit Neuroimaging,Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Robinson, Oliver J.; Sahakian, Barbara J.] Univ Cambridge, Addenbrookes Hosp, Dept Psychiat, Cambridge CB2 2QQ, England. [Robinson, Oliver J.; Sahakian, Barbara J.] Univ Cambridge, Addenbrookes Hosp, MRC Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 2QQ, England. RP Robinson, OJ (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM oliver.j.robinson@gmail.com RI Robinson, Oliver/B-3646-2011; Cools, Roshan/D-1905-2010 OI Robinson, Oliver/0000-0002-3100-1132; FU Medical Research Council [G0001354, G1000183]; Wellcome Trust [093875] NR 31 TC 22 Z9 22 U1 2 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2012 VL 219 IS 2 SI SI BP 599 EP 605 DI 10.1007/s00213-011-2410-5 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 870BZ UT WOS:000298645400030 PM 21769566 ER PT J AU Fertuck, EA Keilp, J Song, I Morris, MC Wilson, ST Brodsky, BS Stanley, B AF Fertuck, Eric A. Keilp, John Song, Inkyung Morris, Melissa C. Wilson, Scott T. Brodsky, Beth S. Stanley, Barbara TI Higher Executive Control and Visual Memory Performance Predict Treatment Completion in Borderline Personality Disorder SO PSYCHOTHERAPY AND PSYCHOSOMATICS LA English DT Article DE Borderline personality disorder; Neuropsychology; Treatment retention; Treatment completion; Treatment adherence; Psychotherapy; Executive function; Memory; Executive control ID MAJOR DEPRESSION; SCHIZOPHRENIA; RETENTION; SYSTEMS; IMPACT; CARE AB Background: Non-completion of a prescribed course of treatment occurs in 20-60% of individuals diagnosed with borderline personality disorder (BPD). While symptom severity, personality traits and environmental factors have been implicated as predictors of treatment non-completion (TNC), there have been no studies of neuropsychological predictors in this population. Methods: From a randomized controlled trial, a subsample of 31, unmedicated outpatients diagnosed with BPD with recent self-injurious behavior was assessed on 5 neuropsychological domains. Patients were also assessed for general IQ, demographic and other salient clinical variables. Patients were randomized to one of four treatment conditions, which lasted up to 1 year. Number of weeks in treatment (WIT) up to 1 year was utilized as the index of TNC. Results: Thirty-three percent of the subsample (n = 12) did not complete 1 year of treatment. However, more WIT were predicted by better baseline executive control (Trails B; p < 0.01) and visual memory performance (Benton visual retention; p < 0.001); other neuropsychological domains did not predict WIT. Conclusion: In the treatment of outpatients with BPD, better executive control and visual memory performance predict more WIT. Assessing and addressing these neurocognitive factors in treatment may reduce TNC in this high-risk population. Copyright (C) 2011 S. Karger AG, Basel C1 [Fertuck, Eric A.] CUNY, Dept Psychol, Subprogram Clin Psychol, New York, NY 10021 USA. [Stanley, Barbara] CUNY, Dept Psychol, John Jay Coll, New York, NY 10021 USA. [Fertuck, Eric A.; Keilp, John; Morris, Melissa C.; Wilson, Scott T.; Brodsky, Beth S.; Stanley, Barbara] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, New York, NY USA. [Song, Inkyung] Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL USA. RP Fertuck, EA (reprint author), CUNY City Coll, Dept Psychol, 160 Convent Ave, New York, NY 10031 USA. EM efertuck@ccny.cuny.edu RI Stanley, Barbara/J-8736-2013; OI Song, Inkyung/0000-0003-2778-651X FU NIMH [K23 MH077044, R01 MH061017, MH62665]; NIAAA [P20 AA015630] FX This study was supported in part by grants from NIMH (K23 MH077044) to E. F., and NIMH (R01 MH061017 and MH62665) and NIAAA (P20 AA015630) to B. S. Eli Lilly provided the fluoxetine and placebos for this study at no cost. The authors have no financial involvement (including employment, fees, share ownership) or affiliation with any organization whose financial interests may be affected by the material in the manuscript. NR 41 TC 8 Z9 8 U1 1 U2 10 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0033-3190 J9 PSYCHOTHER PSYCHOSOM JI Psychother. Psychosom. PY 2012 VL 81 IS 1 BP 38 EP 43 DI 10.1159/000329700 PG 6 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 866TJ UT WOS:000298406200006 PM 22116411 ER PT J AU Coleman, CN Whitcomb, RC Miller, CW Noska, MA AF Coleman, C. Norman Whitcomb, Robert C., Jr. Miller, Charles W. Noska, Michael A. TI Commentary on the Combined Disaster in Japan SO RADIATION RESEARCH LA English DT Editorial Material C1 [Coleman, C. Norman] NCI, Radiat Res Program, Bethesda, MD 20892 USA. [Coleman, C. Norman] Off Assistant Secretary Preparedness & Response, Bethesda, MD USA. [Whitcomb, Robert C., Jr.; Miller, Charles W.] Ctr Dis Control & Prevent, Radiat Studies Branch, Atlanta, GA USA. [Noska, Michael A.] US Dept HHS, US FDA, Silver Spring, MD USA. RP Coleman, CN (reprint author), Execut Plaza N,6130 Execut Blvd,Rm 6014, Rockville, MD 20852 USA. EM ccoleman@mail.nih.gov FU Intramural CDC HHS [CC999999] NR 5 TC 1 Z9 1 U1 1 U2 1 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 JAN PY 2012 VL 177 IS 1 BP 15 EP 17 DI 10.1667/RRXX40.1 PG 3 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 874FA UT WOS:000298939600002 PM 22103272 ER PT J AU Thierry-Chef, I Simon, SL Weinstock, RM Kwon, D Linet, MS AF Thierry-Chef, Isabelle Simon, Steven L. Weinstock, Robert M. Kwon, Deukwoo Linet, Martha S. TI Reconstruction of Absorbed Doses to Fibroglandular Tissue of the Breast of Women Undergoing Mammography (1960 to the Present) SO RADIATION RESEARCH LA English DT Article ID FIELD DIGITAL MAMMOGRAPHY; SCREEN-FILM MAMMOGRAPHY; DETECTION DEMONSTRATION PROJECT; X-RAY TRENDS; IMAGE QUALITY; CANCER-DETECTION; UNITED-STATES; MAGNIFICATION MAMMOGRAPHY; NATIONWIDE EVALUATION; ROENTGEN EXPOSURE AB Thierry-Chef, I., Simon, S. L., Weinstock, R. M., Kwon, D. and Linet, M. S. Reconstruction of Absorbed Doses to Fibroglandular Tissue of the Breast of Women Undergoing Mammography (1960 to the Present). Radial. Res. 177, 92-108 (2012). The assessment of potential benefits versus harms from mammographic examinations as described in the controversial breast cancer screening recommendations of the U.S. Preventive Task Force included limited consideration of absorbed dose to the fibroglandular tissue of the breast (glandular tissue dose), the tissue at risk for breast cancer. Epidemiological studies on cancer risks associated with diagnostic radiological examinations often lack accurate information on glandular tissue dose, and there is a clear need for better estimates of these doses. Our objective was to develop a quantitative summary of glandular tissue doses from mammography by considering sources of variation over time in key parameters, including imaging protocols, X-ray target materials, voltage, filtration, incident air kerma, compressed breast thickness, and breast composition. We estimated the minimum, maximum and mean values for glandular tissue dose for populations of exposed women within 5-year periods from 1960 to the present, with the minimum to maximum range likely including 90% to 95% of the entirety of the dose range from mammography in North America and Europe. Glandular tissue dose from a single view in mammography is presently about 2 mGy, about one-sixth the dose in the 1960s. The ratio of our estimates of maximum to minimum glandular tissue doses for average-size breasts was about 100 in the 1960s compared to a ratio of about 5 in recent years. Findings from our analysis provide quantitative information on glandular tissue doses from mammographic examinations that can be used in epidemiological studies of breast cancer. (C) 2012 by Radiation Research Society C1 [Thierry-Chef, Isabelle] Int Agcy Res Canc, F-69372 Lyon 08, France. [Simon, Steven L.; Kwon, Deukwoo; Linet, Martha S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Thierry-Chef, I (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM thierrychefi@iarc.fr FU European Commission under EURATOM [FP6-012926]; U.S. National Cancer Institute FX The authors are grateful to Mrs. Monika Moissonnier and Mr. Brian Moroz for their assistance in completing calculations to derive conversion coefficients and to Mrs. Moissonnier for her assistance in the development and management of the database of literature data. The authors are also appreciative of the assistance of Dr. J. M. Boone of UC Davis in providing some otherwise unavailable X-ray spectra. Dr. Marvin Rosenstein is also warmly thanked for his valuable comments on the manuscript, especially on the use of appropriate radiation dose quantities. This work was partly financed by the European Commission under the EURATOM 6th Framework Programme as part of the GENE-RAD-RISK project (project number FP6-012926) and funded in part by the intramural research program of the U.S. National Cancer Institute. NR 124 TC 7 Z9 7 U1 0 U2 3 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 JAN PY 2012 VL 177 IS 1 BP 92 EP 108 DI 10.1667/RR2241.1 PG 17 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 874FA UT WOS:000298939600011 PM 21988547 ER PT J AU Haneuse, S Buist, DSM Miglioretti, DL Anderson, ML Carney, PA Onega, T Geller, BM Kerlikowske, K Rosenberg, RD Yankaskas, BC Elmore, JG Taplin, SH Smith, RA Sickles, EA AF Haneuse, Sebastien Buist, Diana S. M. Miglioretti, Diana L. Anderson, Melissa L. Carney, Patricia A. Onega, Tracy Geller, Berta M. Kerlikowske, Karla Rosenberg, Robert D. Yankaskas, Bonnie C. Elmore, Joann G. Taplin, Stephen H. Smith, Robert A. Sickles, Edward A. TI Mammographic Interpretive Volume and Diagnostic Mammogram Interpretation Performance in Community Practice SO RADIOLOGY LA English DT Article ID SCREENING MAMMOGRAPHY; BREAST-CANCER; ACCURACY; WOMEN; RADIOLOGISTS; POPULATION; FACILITIES AB Purpose: To investigate the association between radiologist interpretive volume and diagnostic mammography performance in community-based settings. Materials and Methods: This study received institutional review board approval and was HIPAA compliant. A total of 117 136 diagnostic mammograms that were interpreted by 107 radiologists between 2002 and 2006 in the Breast Cancer Surveillance Consortium were included. Logistic regression analysis was used to estimate the adjusted effect on sensitivity and the rates of false-positive findings and cancer detection of four volume measures: annual diagnostic volume, screening volume, total volume, and diagnostic focus (percentage of total volume that is diagnostic). Analyses were stratified by the indication for imaging: additional imaging after screening mammography or evaluation of a breast concern or problem. Results: Diagnostic volume was associated with sensitivity; the odds of a true-positive finding rose until a diagnostic volume of 1000 mammograms was reached; thereafter, they either leveled off (P < .001 for additional imaging) or decreased (P = .049 for breast concerns or problems) with further volume increases. Diagnostic focus was associated with false-positive rate; the odds of a false-positive finding increased until a diagnostic focus of 20% was reached and decreased thereafter (P < .024 for additional imaging and P,.001 for breast concerns or problems with no self-reported lump). Neither total volume nor screening volume was consistently associated with diagnostic performance. Conclusion: Interpretive volume and diagnostic performance have complex multifaceted relationships. Our results suggest that diagnostic interpretive volume is a key determinant in the development of thresholds for considering a diagnostic mammogram to be abnormal. Current volume regulations do not distinguish between screening and diagnostic mammography, and doing so would likely be challenging.(C) RSNA, 2011 C1 [Haneuse, Sebastien] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Buist, Diana S. M.; Miglioretti, Diana L.; Anderson, Melissa L.] Grp Hlth Res Inst, Seattle, WA USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Onega, Tracy] Norris Cotton Canc Ctr, Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Geller, Berta M.] Univ Vermont, Coll Med, Dept Family Med, Burlington, VT USA. [Geller, Berta M.] Univ Vermont, Coll Med, Dept Radiol, Burlington, VT USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. [Sickles, Edward A.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Rosenberg, Robert D.] Univ New Mexico, Hlth Sci Ctr, Dept Radiol, Albuquerque, NM 87131 USA. [Yankaskas, Bonnie C.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Elmore, Joann G.] Univ Washington, Harborview Med Ctr, Sch Med, Dept Med, Seattle, WA 98104 USA. [Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Rockville, MD USA. [Smith, Robert A.] Amer Canc Soc, Canc Control Sci Dept, Atlanta, GA 30329 USA. RP Haneuse, S (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. EM shaneuse@hsph.harvard.edu FU American Cancer Society; Longaberger Company's Horizon of Hope Campaign [SIRGS-07-271-01, SIRGS-07-272-01, SIRGS-07-274-01, SIRGS-07-275-01, SIRGS-06-281-01, ACS A1-07-362]; Agency for Healthcare Research and Quality [HS-10591]; Breast Cancer Stamp Fund; National Cancer Institute [1R01 CA107623, 1K05 CA104699, U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX From the Department of Biostatistics, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115 (S.H.); Group Health Research Institute, Seattle, Wash (D.S.M.B., D.L.M., M.L.A.); Department of Biostatistics, University of Washington, Seattle, Wash (D.L.M.); Departments of Family Medicine and Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Ore (P.A.C.); Department of Community and Family Medicine, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH (T.O.); Departments of Family Medicine and Radiology, University of Vermont, College of Medicine, Burlington, Vt (B.M.G.); Department of Medicine (K.K.), Department of Epidemiology and Biostatistics (K.K.), General Internal Medicine Section, Department of Veterans Affairs (K.K.), and Department of Radiology (E.A.S.), University of California, San Francisco, Calif; Department of Radiology, University of New Mexico, Health Sciences Center, Albuquerque, NM (R.D.R.); Department of Radiology, University of North Carolina, Chapel Hill, NC (B.C.Y.); Department of Medicine, University of Washington School of Medicine, Harborview Medical Center, Seattle, Wash (J.G.E.); Division of Cancer Control and Population Science, Applied Research Program, National Cancer Institute, Rockville, Md (S.H.T.); and Cancer Control Science Department, American Cancer Society, Atlanta, Ga (R.A.S.). Received June 7, 2011; revision requested July 24; revision received July 27; accepted August 3; final version accepted August 15. Supported by the American Cancer Society, the Longaberger Company's Horizon of Hope Campaign (SIRGS-07-271-01, SIRGS-07-272-01, SIRGS-07-274-01, SIRGS-07-275-01, SIRGS-06-281-01, ACS A1-07-362), the Agency for Healthcare Research and Quality (HS-10591), and the Breast Cancer Stamp Fund. Address correspondence to S. H. (e-mail: shaneuse@hsph.harvard.edu); This research was supported by the National Cancer Institute (grants 1R01 CA107623, 1K05 CA104699, U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040). NR 24 TC 8 Z9 8 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2012 VL 262 IS 1 BP 69 EP 79 DI 10.1148/radiol.11111026 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 869PY UT WOS:000298611500010 PM 22106351 ER PT J AU Yao, B Bagnato, F Matsuura, E Merkle, H van Gelderen, P Cantor, FK Duyn, JH AF Yao, Bing Bagnato, Francesca Matsuura, Eiji Merkle, Hellmut van Gelderen, Peter Cantor, Fredric K. Duyn, Jeff H. TI Chronic Multiple Sclerosis Lesions: Characterization with High-Field-Strength MR Imaging SO RADIOLOGY LA English DT Article ID MAGNETIZATION-TRANSFER RATIO; GRADIENT-ECHO MRI; WHITE-MATTER; BRAIN IRON; FORMALIN FIXATION; T-2 RELAXATION; PHASE-CONTRAST; TESLA; DISABILITY; EVOLUTION AB Purpose: To elucidate the mechanism of magnetic resonance (MR) imaging contrast in multiple sclerosis (MS) lesion appearance by using susceptibility-weighted imaging and to assess with histologic correlation the role of iron and myelin in generating this MR imaging contrast. Materials and Methods: Each patient provided written consent to a human subject protocol approved by an institutional review board. High-spatial-resolution susceptibility-weighted 7.0-T MR images were obtained in 21 patients with MS. Contrast patterns in quantitative phase and R2* images, derived from 7.0-T data, were investigated in 220 areas defined as chronic MS lesions on conventional T2-weighted fluid-attenuated inversion recovery, T2-weighted, and T1-weighted spin-echo images. The presence of positive or negative phase shifts (ie, decreased or increased MR frequency, respectively) was assessed in each lesion. In addition, postmortem MR imaging was performed at 7.0 T and 11.7 T, and its results were correlated with those of immunohistochemical staining specific for myelin, iron, and ferritin. Results: The majority (133 [ 60.5%] of 220) of the identified lesions had a normal phase and reduced R2*. A substantial fraction of the lesions (84 [ 38.2%] of 220) had negative phase shift, either uniformly or at their rim, and a variety of appearances on R2* maps. These two lesion contrast patterns were reproduced in the postmortem MR imaging study. Comparison with histologic findings showed that, while R2* reduction corresponded to severe loss of both iron and myelin, negative phase shift corresponded to focal iron deposits with myelin loss. Conclusion: Combined analysis of 7.0-T R2* and phase data may help in characterizing the pathologic features of MS lesions. The observed R2* decreases suggest profound myelin loss, whereas negative phase shifts suggest a focal iron accumulation. (C) RSNA, 2011 C1 [Yao, Bing; Merkle, Hellmut; van Gelderen, Peter; Duyn, Jeff H.] NIH, Adv MRI Sect, Bethesda, MD 20892 USA. [Matsuura, Eiji; Cantor, Fredric K.] NIH, Lab Funct Mol Imaging, Bethesda, MD 20892 USA. [Matsuura, Eiji; Cantor, Fredric K.] NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Bagnato, Francesca] Vanderbilt Univ, Inst Imaging Sci, Dept Radiol, Nashville, TN USA. RP Yao, B (reprint author), NIH, Adv MRI Sect, 10 Ctr Dr,Bldg 10,Room B1D728,MSC 1065, Bethesda, MD 20892 USA. EM yaob@mail.nih.gov RI MATSUURA, EIJI/E-1231-2013 OI MATSUURA, EIJI/0000-0001-8215-8853 FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This research was supported by the intramural program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 40 TC 50 Z9 52 U1 1 U2 5 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2012 VL 262 IS 1 BP 206 EP 215 DI 10.1148/radiol.11110601 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 869PY UT WOS:000298611500025 PM 22084205 ER PT J AU Vupputuri, S Parks, CG Nylander-French, LA Owen-Smith, A Hogan, SL Sandler, DP AF Vupputuri, Suma Parks, Christine G. Nylander-French, Leena A. Owen-Smith, Ashli Hogan, Susan L. Sandler, Dale P. TI Occupational Silica Exposure and Chronic Kidney Disease SO RENAL FAILURE LA English DT Article DE chronic kidney disease; silica; case-control; epidemiology; occupational exposure ID STAGE RENAL-DISEASE; CRYSTALLINE SILICA; UNITED-STATES; GRANITE WORKERS; RISK-FACTORS; ASSOCIATION; PROXY; GLOMERULONEPHRITIS; ARTHRITIS; FAILURE AB Introduction: Occupational exposure to silica may be associated with chronic kidney disease (CKD). Most studies have been conducted in occupational cohorts with high levels of exposure but small numbers of cases. We analyzed data from a population-based case-control study of occupational silica exposure and CKD. Methods: Cases were hospital patients with newly diagnosed CKD, and community controls were selected using random digit dialing and frequency matched by age, gender, race, and proximity to the hospital. Silica exposure estimates were assigned by industrial hygiene review of lifetime job history data and weighted for certainty and intensity. Conditional logistic regression was used to estimate the odds ratios (ORs) for CKD conditioned on demographic, lifestyle, and clinical variables. Results: The mean age of participants was 63 years (range 30-83 years); 59% were male and 55% were white. Any silica exposure (compared with none) was associated with a 40% increased risk of CKD [OR = 1.40, 95% confidence interval (CI): 1.04, 1.89] in a multivariable adjusted model. The mean cumulative duration of silica exposure was significantly higher in exposed cases than in exposed controls (33.4 vs. 24.8 years, respectively). Overall, compared with nonexposed participants, the ORs (95% CI) for those below and above the median duration of silica exposure were 1.20 (0.77, 1.86) and 1.76 (1.14, 2.71), respectively. Conclusions: We found a positive relationship between occupational silica exposure and CKD. A dose-response trend of increasing CKD risk with increasing duration of silica exposure was observed and was particularly strong among nonwhites. C1 [Vupputuri, Suma; Owen-Smith, Ashli] Kaiser Permanente Georgia, Ctr Hlth Res SE, Atlanta, GA 30305 USA. [Parks, Christine G.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Nylander-French, Leena A.] Univ N Carolina, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Hogan, Susan L.] Univ N Carolina, UNC Kidney Ctr, Chapel Hill, NC USA. [Hogan, Susan L.] Univ N Carolina, Div Nephrol & Hypertens, Chapel Hill, NC USA. RP Vupputuri, S (reprint author), Kaiser Permanente Georgia, Ctr Hlth Res SE, 3495 Piedmont Rd,Bldg 11,Suite 101, Atlanta, GA 30305 USA. EM suma.vupputuri@kp.org OI Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences [Z01-ES-049028] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-049028). NR 31 TC 11 Z9 11 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0886-022X J9 RENAL FAILURE JI Ren. Fail. PY 2012 VL 34 IS 1 BP 40 EP 46 DI 10.3109/0886022X.2011.623496 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 863SU UT WOS:000298189000008 PM 22032652 ER PT J AU Than, NG AF Than, Nandor Gabor TI PP13, Decidual Zones of Necrosis, and Spiral Artery Remodeling-Preeclampsia Revisited? SO REPRODUCTIVE SCIENCES LA English DT Editorial Material ID TROPHOBLAST INVASION; PLACENTAL BED; PREGNANCY C1 [Than, Nandor Gabor] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Than, Nandor Gabor] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Than, NG (reprint author), Wayne State Univ, Sch Med, 3990 John R, Detroit, MI 48201 USA. EM nthan@med.wayne.edu NR 10 TC 3 Z9 3 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD JAN PY 2012 VL 19 IS 1 BP 14 EP 15 DI 10.1177/1933719111431678 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 873BG UT WOS:000298855000002 PM 22228738 ER PT J AU Strang, JF Kenworthy, L Daniolos, P Case, L Wills, MC Martin, A Wallace, GL AF Strang, John F. Kenworthy, Lauren Daniolos, Peter Case, Laura Wills, Meagan C. Martin, Alex Wallace, Gregory L. TI Depression and anxiety symptoms in children and adolescents with autism spectrum disorders without intellectual disability SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Autism; Children; Adolescents; Depression; Anxiety; IQ ID PERVASIVE DEVELOPMENTAL DISORDERS; ASPERGER-SYNDROME; DIAGNOSTIC INTERVIEW; PSYCHIATRIC-DISORDERS; COMORBIDITY; PREVALENCE; PARENT; FRIENDSHIP; VERSION; PEOPLE AB Recent studies have shown that rates of depression and anxiety symptoms are elevated among individuals with autism spectrum disorders (ASDs) of various ages and IQs and that depression/anxiety symptoms are associated with higher IQ and fewer ASD symptoms. In this study which examined correlates of depression and anxiety symptoms in the full school-age range of children and adolescents (age 6-18) with ASDs and IQs >= 70 (n = 95), we also observed elevated rates of depression/anxiety symptoms, but we did not find higher IQ or fewer ASD symptoms among individuals with ASDs and depression or anxiety symptoms. These findings indicate an increased risk for depression/anxiety symptoms in children and adolescents with ASDs without intellectual disability, regardless of age, IQ, or ASD symptoms. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Strang, John F.; Kenworthy, Lauren; Daniolos, Peter; Wills, Meagan C.] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Rockville, MD 20850 USA. [Case, Laura; Martin, Alex; Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Strang, JF (reprint author), Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, 15245 Shady Grove Rd,Suite 350, Rockville, MD 20850 USA. EM jstrang@cnmc.org RI martin, alex/B-6176-2009; OI Case, Laura/0000-0003-3730-2451; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [ZIA MH002920-03]; NCRR NIH HHS [M01 RR013297]; NIMH NIH HHS [U54 MH066417] NR 35 TC 59 Z9 59 U1 9 U2 47 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 EI 1878-0237 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD JAN-MAR PY 2012 VL 6 IS 1 BP 406 EP 412 DI 10.1016/j.rasd.2011.06.015 PG 7 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 858TU UT WOS:000297826400048 PM 22615713 ER PT J AU Guyer, AE Choate, VR Pine, DS Nelson, EE AF Guyer, Amanda E. Choate, Victoria R. Pine, Daniel S. Nelson, Eric E. TI Neural circuitry underlying affective response to peer feedback in adolescence SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE adolescence; cognitive flexibility; peer feedback; social reward ID ORBITOFRONTAL CORTEX; SOCIAL COGNITION; BIOLOGICAL MOTION; PREFRONTAL CORTEX; ROMANTIC LOVE; REWARD VALUE; CHILDREN; ANXIETY; BRAIN; PERCEPTION AB Peer feedback affects adolescents' behaviors, cognitions and emotions. We examined neural circuitry underlying adolescents' emotional response to peer feedback using a functional neuroimaging paradigm whereby, 36 adolescents (aged 9-17 years) believed they would interact with unknown peers postscan. Neural activity was expected to vary based on adolescents' perceptions of peers and feedback type. Ventrolateral prefrontal cortex (vlPFC) activity was found when adolescents indicated how they felt following feedback (acceptance or rejection) from peers of low vs high interest. Greater activation in both cortical (e.g. superior temporal gyrus, insula, anterior cingulate) and subcortical (e.g. striatum, thalamus) regions emerged in response to acceptance vs rejection feedback. Response to acceptance also varied by age and gender in similar regions (e.g. superior temporal gyrus, fusiform, insula), with greater age-related increases in activation to acceptance vs rejection for females than males. Affective response to rejection vs acceptance did not yield significantly greater neural activity in any region. vlPFC response suggests cognitive flexibility in reappraising initial perceptions of peers following feedback. Striatal response suggests that acceptance is a potent social reward for adolescents, an interpretation supported by more positive self-reported affective response to acceptance than rejection from high- but not low-interest peers. C1 [Guyer, Amanda E.] Univ Calif Davis, Ctr Mind & Brain, Dept Human & Community Dev, Davis, CA 95618 USA. [Choate, Victoria R.; Pine, Daniel S.; Nelson, Eric E.] NIMH, Dept Hlth & Human Serv, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. RP Guyer, AE (reprint author), Univ Calif Davis, Ctr Mind & Brain, Dept Human & Community Dev, 267 Cousteau Pl, Davis, CA 95618 USA. EM aeguyer@ucdavis.edu RI Nelson, Eric/B-8980-2008 OI Nelson, Eric/0000-0002-3376-2453 FU National Institutes of Health; National Institutes of Health Career Development [K99/R00 MH080076] FX The authors greatly appreciate the time given to us by the children and families involved in the study. In addition, the authors give special thanks to Harvey Iwamoto for task programming. The National Institute of Mental Health Intramural Research Program of the National Institutes of Health and National Institutes of Health Career Development (grant K99/R00 MH080076 to A.E.G.). NR 62 TC 43 Z9 43 U1 4 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JAN PY 2012 VL 7 IS 1 SI SI BP 81 EP 92 DI 10.1093/scan/nsr043 PG 12 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 873OA UT WOS:000298891400008 PM 21828112 ER PT J AU Silk, JS Stroud, LR Siegle, GJ Dahl, RE Lee, KH Nelson, EE AF Silk, Jennifer S. Stroud, Laura R. Siegle, Greg J. Dahl, Ronald E. Lee, Kyung Hwa Nelson, Eric E. TI Peer acceptance and rejection through the eyes of youth: pupillary, eyetracking and ecological data from the Chatroom Interact task SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE adolescence; social interaction; peer rejection; pupil dilation; eyetracking; ecological momentary assessment ID EMOTIONAL INFORMATION; ROMANTIC RELATIONSHIPS; FACIAL EXPRESSIONS; SOCIAL EXCLUSION; ADOLESCENCE; CHILDREN; BRAIN; DEPRESSION; AGE; PERSPECTIVE AB We developed an ecologically valid virtual peer interaction paradigm-the Chatroom Interact Task in which 60 pre-adolescents and adolescents (ages 9-17 years) were led to believe that they were interacting with other youth in a simulated internet chatroom. Youth received rejection and acceptance feedback from virtual peers. Findings revealed increased pupil dilation, an index of increased activity in cognitive and affective processing regions of the brain, to rejection compared to acceptance trials, which was greater for older youth. Data from a cell-phone Ecological Momentary Assessment (EMA) protocol completed following the task indicated that increased pupillary reactivity to rejection trials was associated with lower feelings of social connectedness with peers in daily life. Eyetracking analyses revealed attentional biases toward acceptance feedback and away from rejection feedback. Biases toward acceptance feedback were stronger for older youth. Avoidance of rejection feedback was strongest among youth with increased pupillary reactivity to rejection, even in the seconds leading up to and following rejection feedback. These findings suggest that adolescents are sensitive to rejection feedback and seek to anticipate and avoid attending to rejection stimuli. Furthermore, the salience of social rejection and acceptance feedback appears to increase during adolescence. C1 [Silk, Jennifer S.; Siegle, Greg J.; Dahl, Ronald E.] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15260 USA. [Silk, Jennifer S.; Siegle, Greg J.; Dahl, Ronald E.; Lee, Kyung Hwa] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Stroud, Laura R.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02903 USA. [Dahl, Ronald E.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Nelson, Eric E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Silk, JS (reprint author), Univ Pittsburgh, Dept Psychiat, Sch Med, 3811 Ohara St, Pittsburgh, PA 15260 USA. EM silkj@upmc.edu RI Nelson, Eric/B-8980-2008; OI Nelson, Eric/0000-0002-3376-2453; Silk, Jennifer/0000-0002-8638-4337 FU National Institute of Drug Abuse [R21DA024144]; Staunton Farm Foundation; Clinical and Translational Science Institute at the University of Pittsburgh (NIH/NCRR/CTSA) [UL1 RR024153]; NIMH FX The authors are grateful to Daniel Pine, M. D. for his input and assistance on this project, Marcie McCullough and Katie Burkhouse for their assistance in data acquisition, Wessyl Kelly for her assistance with data analysis, Harvey Iwamoto for task-related computer programming, and Ruth Stroud and Jennifer Sears for assistance with photography. The authors also thank the participants and their families. This research was supported by a National Institute of Drug Abuse grant R21DA024144 (J.S.S./R.E.D., PI's), the Staunton Farm Foundation, the Clinical and Translational Science Institute at the University of Pittsburgh (NIH/NCRR/CTSA Grant UL1 RR024153) and the NIMH intramural research program NR 59 TC 36 Z9 36 U1 5 U2 47 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JAN PY 2012 VL 7 IS 1 SI SI BP 93 EP 105 DI 10.1093/scan/nsr044 PG 13 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 873OA UT WOS:000298891400009 PM 21775386 ER PT J AU Rao, M Ahrlund-Richter, L Kaufman, DS AF Rao, Mahendra Ahrlund-Richter, Lars Kaufman, Dan S. TI Concise Review: Cord Blood Banking, Transplantation and Induced Pluripotent Stem Cell: Success and Opportunities SO STEM CELLS LA English DT Review DE Hematopoietic stem cell transplantation; Hematologic malignancies; Bone marrow; Cord blood ID HEMATOLOGIC MALIGNANCY; UNRELATED DONORS; BONE-MARROW; LEUKEMIA; ADULTS; MECHANISMS; GENERATION; HISTORY AB Hematopoietic cell transplantation (HCT) has become a standard practice to treat a number of malignant and nonmalignant hematologic diseases. Bone marrow, mobilized peripheral blood, and umbilical cord blood can all serve as primary sources of cells for HCT. The number of cord blood units currently stored is large, although it represents only a fraction of potential collections. With much of the collection being sequestered in private banks for possible autologous use, there is a reason to expect that public banks may not be able to provide for the demand in coming years as use of cord blood for treatment of patients with diseases such as leukemia and lymphoma continues to increase. We suggest that a possible solution to encourage private banks to share their valuable units is to apply recent methodologies to generate induced pluripotent stem cells from cord cells and to optimize techniques to generate hematopoietic lineages from them. This strategy would allow us to take advantage of the units already collected under appropriate regulatory guidelines, to access a pristine cell that can be converted to a pluripotent cell at a much higher efficiency and in a shorter time period than other cells. The ability to potentially replenish a used cord unit with new cells, as well as extend the potential utility of cord blood for additional therapeutic applications, should allow banks to develop an appropriate business model for both private and public cord blood banks to flourish. STEM CELLS 2012;30:5560 C1 [Rao, Mahendra] NIH, Natl Ctr Regenerat Med, Bethesda, MD 20892 USA. [Ahrlund-Richter, Lars] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden. [Kaufman, Dan S.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Kaufman, Dan S.] Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA. RP Rao, M (reprint author), NIH, Natl Ctr Regenerat Med, Bldg 10, Bethesda, MD 20892 USA. EM mahendra.rao@nih.gov RI Ahrlund-Richter, Lars/C-6226-2012 FU CIRM; Maryland TEDCO; NIH/NHLBI FX This work was supported by CIRM and Maryland TEDCO grants (M. R.), and the NIH/NHLBI (D.S.K.). NR 41 TC 37 Z9 37 U1 5 U2 29 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JAN PY 2012 VL 30 IS 1 SI SI BP 55 EP 60 DI 10.1002/stem.770 PG 6 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 869LC UT WOS:000298598400010 PM 22069231 ER PT J AU Nemeth, K Key, S Bottlik, G Masszi, T Mezey, E Karpati, S AF Nemeth, Krisztian Key, Sharon Bottlik, Gyula Masszi, Tamas Mezey, Eva Karpati, Sarolta TI Analyses of Donor-Derived Keratinocytes in Hairy and Nonhairy Skin Biopsies of Female Patients Following Allogeneic Male Bone Marrow Transplantation SO STEM CELLS AND DEVELOPMENT LA English DT Article ID STEM-CELL TRANSPLANTATION; EPITHELIAL-CELLS; IN-VIVO; NICHE; BULGE; CD34; PHAGOCYTOSIS; FINGERNAILS; ENGRAFTMENT; EXPRESSION AB Skin samples taken from 6 female patients receiving allogeneic bone marrow transplants (BMT) from male siblings (n = 5) or from unrelated human leukocyte antigen (HLA)-matched male donor (n = 1) due to hematological malignancies were studied for the presence of donor cells. One nontransplanted male and 1 female control that received female BM were used as further controls of the technique. Skin biopsies were taken from the scalp and the back from each patient 12-16 years after the successful BMT. We have found donor chimerism in all of the 6 patients in both of their biopsies. Using single and double immunostainings in combination with Y chromosome hybridization, we observed that there are cytokeratin-expressing donor-derived cells in the epidermis of all the 6 patients, the numbers being slightly higher in the scalp (0.37%-1.78%) than in the back (0.32%-1.08%) biopsies. The indication for BMT, and the age of the patient did not seem to have any effect on the numbers found. A few of the double-labeled cells also stained for Ki67, a marker of cellular proliferation, suggesting that the engrafted cells were able to further divide in the epidermis. In 2 patients we observed patches of donor keratinocytes within the epidermis, suggesting a clonal origin. We conclude that in agreement with some and in contrast to other published studies, BM-derived circulating cells are able to engraft in the human skin and to further proliferate there and thus contribute to tissue renewal. These data raise the possibility to use BM cells in regenerative medicine to help in extended injuries, large surface burns, or lack of skin due to other reasons. C1 [Nemeth, Krisztian; Key, Sharon; Mezey, Eva] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. [Nemeth, Krisztian; Bottlik, Gyula; Karpati, Sarolta] Semmelweis Univ, Dept Dermatovenereol & Dermatooncol, Budapest, Hungary. [Masszi, Tamas] Szent Laszlo Hosp, Dept Hematol & Stem Cell Transplantat, Budapest, Hungary. RP Mezey, E (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. EM mezeye@mail.nih.gov OI Masszi, Tamas/0000-0002-9038-302X FU Division of Intramural Research program of NIDCR; NIH; DHHS FX The authors appreciate the help provided by G. Szombath, M. Sardy, and M. Krepuska in coordinating the biopsies and contributing technical help. This research was supported by the Division of Intramural Research program of NIDCR, in the Intramural Research Program, NIH, DHHS. NR 25 TC 3 Z9 3 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JAN PY 2012 VL 21 IS 1 BP 152 EP 157 DI 10.1089/scd.2010.0593 PG 6 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 875DC UT WOS:000299009500015 PM 21288071 ER PT J AU ter Bogt, TFM Gabhainn, SN Simons-Morton, BG Ferreira, M Hublet, A Godeau, E Kuntsche, E Richter, M AF ter Bogt, Tom F. M. Gabhainn, Saoirse Nic Simons-Morton, Bruce G. Ferreira, Mafalda Hublet, Anne Godeau, Emmanuelle Kuntsche, Emmanuel Richter, Matthias CA HBSC Risk Behav HBSC Peer Culture Focus Grp TI Dance Is the New Metal: Adolescent Music Preferences and Substance Use Across Europe SO SUBSTANCE USE & MISUSE LA English DT Article DE pop; rock; urban; dance; highbrow; heavy metal; hip-hop; techno; adolescent; substance use ID CANNABIS USE; MENTAL-HEALTH; HEAVY-METAL; RAP MUSIC; BEHAVIOR; ALCOHOL; LIFE; QUESTIONNAIRE; CHILDREN; GENDER AB This study examined relationships between music preferences and substance use (tobacco, alcohol, cannabis) among 18,103 fifteen-year-olds from 10 European countries. In 2005-2006, across Europe, preferences for mainstream Pop (pop chart music) and Highbrow (classical music and jazz) were negatively associated with substance use, while preferences for Dance (house/trance and techno/hardhouse) were associated positively with substance use. In three countries, links were identified between liking Rock (rock, heavy metal punk/hardcore, and gothic) and substance use; associations between Urban (hip-hop and R&B) and substance use were mixed. No substantial gender differences emerged in these patterns, and controlling for relevant covariates did not attenuate the predictive value of substance use. The findings are consistent with the conclusion that music is a robust marker of adolescent substance use. C1 [ter Bogt, Tom F. M.] Univ Utrecht, Dept Interdisciplinary Social Sci, Utrecht, Netherlands. [Gabhainn, Saoirse Nic] Natl Univ Ireland Galway, Hlth Promot Res Ctr, Galway, Ireland. [Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Ferreira, Mafalda] Univ Tecn Lisboa, Fac Human Kinet, P-1100 Lisbon, Portugal. [Hublet, Anne] Univ Ghent, Fac Med, Dept Publ Hlth, B-9000 Ghent, Belgium. [Godeau, Emmanuelle] Univ Toulouse 3, INSERM, UMR 1027, F-31062 Toulouse, France. [Godeau, Emmanuelle] Serv Med Rectorat Toulouse, Toulouse, France. [Kuntsche, Emmanuel; Richter, Matthias] Swiss Inst Prevent Alcohol & Drug Problems SIPA, Res Dept, Lausanne, Switzerland. [Kuntsche, Emmanuel; Richter, Matthias] Radboud Univ Nijmegen, Inst Behav Sci, Nijmegen, Netherlands. Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. RP ter Bogt, TFM (reprint author), Univ Utrecht, Dept Interdisciplinary Social Sci, Utrecht, Netherlands. EM t.f.m.terbogt@uu.nl OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD002525-15] NR 47 TC 7 Z9 7 U1 2 U2 37 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PY 2012 VL 47 IS 2 BP 130 EP 142 DI 10.3109/10826084.2012.637438 PG 13 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 873BQ UT WOS:000298856200003 PM 22217067 ER PT J AU Sun, Y Tokar, EJ Waalkes, MP AF Sun, Yang Tokar, Erik J. Waalkes, Michael P. TI Overabundance of Putative Cancer Stem Cells in Human Skin Keratinocyte Cells Malignantly Transformed by Arsenic SO TOXICOLOGICAL SCIENCES LA English DT Article DE arsenic; skin cancer; cancer stem cell ID HAIR FOLLICLE BULGE; CHRONIC STIMULATION; GROWTH-FACTORS; ANIMAL-MODEL; MOUSE SKIN; EXPRESSION; PHENOTYPE; DIFFERENTIATION; NEOPLASIA; CARCINOMA AB Arsenic is a human skin carcinogen. Cancer is probably a disease driven by stem cells (SCs), and SCs are likely a key target during arsenic oncogenesis. In utero arsenic exposure predisposes mice to skin cancers that overproduce cancer SCs (CSCs) and have distorted CSC signaling and population dynamics. Therefore, we hypothesized CSC accumulation may occur during arsenic-induced malignant transformation in vitro of human skin keratinocytes. Thus, the HaCaT cell line, malignantly transformed by arsenite (100nM, 30 weeks; termed As-TM cells) in prior work, was further studied for the quantity and nature of SCs after this transformation. SCs were isolated from passage-matched control and As-TM cells by a magnetic bead system that enriches for CD34-positive cells. There were 2.5 times more SCs isolated from As-TM cells than control. Holoclone production from As-TM putative CSCs was 2.5-fold higher by 1 week and 3.5-fold higher by 2 weeks than control SCs. Potential malignant phenotype was assessed in isolated SC/CSCs. Transcript level of SC/CSC markers were elevated in both isolated As-TM CSCs and control SCs compared with parental cells, but compared with control SCs, As-TM putative CSCs had elevated CD34, K5, K14, K15, and K19 transcripts and dramatically stronger staining for p63, Rac1, K5, Notch1, and K19. As-TM putative CSCs also showed markedly elevated MMP-9 secretion and colony formation, indicators of cancer phenotype, even compared with total population of As-TM cells. Thus, malignant phenotype is particularly pronounced in CSCs after arsenic-induced transformation of human skin cells and occurs concurrently with a potential overproduction of these cells. C1 [Sun, Yang; Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Natl Toxicol Program Lab, Inorgan Toxicol Grp, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Natl Toxicol Program Lab, Inorgan Toxicol Grp, Div Natl Toxicol Program, Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX This work was supported in part by the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS) and by the Intramural Research program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. This article may be the work product of an employee or group of employees of the NIEHS, NIH, however, the statements contained herein do not necessarily represent the statements, opinions, or conclusions of the NIEHS, NIH of the U.S. Government. The content of this publication does not necessarily reflect the views or the policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 48 TC 23 Z9 25 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JAN PY 2012 VL 125 IS 1 BP 20 EP 29 DI 10.1093/toxsci/kfr282 PG 10 WC Toxicology SC Toxicology GA 871JP UT WOS:000298734400004 PM 22011395 ER PT J AU Porter, A Fischer, MJ Brooks, D Bruce, M Charleston, J Cleveland, WH Dowie, D Faulkner, M Gassman, J Greene, T Hiremath, L Kendrick, C Kusek, JW Thornley-Brown, D Wang, XL Norris, K Unruh, M Lash, J AF Porter, Anna Fischer, Michael J. Brooks, Deborah Bruce, Marino Charleston, Jeanne Cleveland, William H. Dowie, Donna Faulkner, Marquetta Gassman, Jennifer Greene, Tom Hiremath, Leena Kendrick, Cindy Kusek, John W. Thornley-Brown, Denyse Wang, Xuelei Norris, Keith Unruh, Mark Lash, James TI Quality of life and psychosocial factors in African Americans with hypertensive chronic kidney disease SO TRANSLATIONAL RESEARCH LA English DT Article ID HEMODIALYSIS-PATIENTS; DIALYSIS PATIENTS; SOCIAL SUPPORT; MORTALITY; HEALTH; SURVIVAL; HOSPITALIZATION; ASSOCIATION; PREDICTOR; OUTCOMES AB Health-related quality of life (HRQOL) is poorly understood in patients with chronic kidney disease (CKD) prior to end-stage renal disease. The association between psychosocial measures and HRQOL has not been fully explored in CKD, especially in African Americans. We performed a cross-sectional analysis of HRQOL and its association with sociodemographic and psychosocial factors in African Americans with hypertensive CKD. There were 639 participants in the African American Study of Kidney Disease and Hypertension Cohort Study. The Short Form-36 was used to measure HRQOL. The Diener Satisfaction with Life Scale measured life satisfaction, the Beck Depression Inventory-II assessed depression, the Coping Skills Inventory-Short Form measured coping, and the Interpersonal Support Evaluation List-16 was used to measure social support. The mean participant age was 60 years at enrollment, and men comprised 61% of participants. Forty-two percent reported a house-hold income less than $15,000/year. Higher levels of social support, coping skills, and life satisfaction were associated with higher HRQOL, whereas unemployment and depression were associated with lower HRQOL (P < 0.05). A significant positive association between higher estimated glomerular filtration rate (eGFR) was observed with the Physical Health Composite (PHC) score (P = 0.004) but not in the Mental Health Composite (MHC) score (P = 0.24). Unemployment was associated with lower HRQOL, and lower eGFR was associated with lower PHC. African Americans with hypertensive CKD with better social support and coping skills had higher HRQOL. This study demonstrates an association between CKD and low HRQOL, and it highlights the need for longitudinal studies to examine this association in the future. (Translational Research 2012;159:4-11) C1 [Porter, Anna] Univ Illinois, Dept Med, Nephrol Sect, Chicago, IL 60612 USA. [Porter, Anna] Jesse Brown VA Med Ctr, Chicago, IL USA. Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. Johns Hopkins Univ, Baltimore, MD USA. Morehouse Sch Med, Multidisciplinary Res Ctr, Atlanta, GA 30310 USA. Columbia Univ, Dept Med, Harlem Hosp Med Ctr, New York, NY USA. Meharry Med Coll, Dept Med, Nashville, TN 37208 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. Ohio State Univ, Dept Med, Med Ctr, Columbus, OH 43210 USA. NIDDK, NIH, Bethesda, MD USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Charles R Drew Univ, Dept Med, Los Angeles, CA USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Porter, A (reprint author), Univ Illinois, Dept Med, Nephrol Sect, 820 S Wood St,M-C 793, Chicago, IL 60612 USA. EM aporte3@uic.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Center on Minority Health and Health Disparities [NCMHD] [M01 RR-00080, M01 RR-00071, M0100032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, RR029887, DK 2818-02]; National Institutes of Health; King Pharmaceuticals; Pfizer Inc; AstraZeneca Pharmaceuticals; Glaxo Smith Kline; Forest Laboratories; Pharmacia; Upjohn FX Supported by grants to each clinical center and the coordinating center from the National Institute of Diabetes and Digestive and Kidney Diseases (to A.A.S.K.) by the Office of Research in Minority Health (now the National Center on Minority Health and Health Disparities [NCMHD]) (to A.A.S.K.); Grants M01 RR-00080, M01 RR-00071, M0100032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, RR029887, and DK 2818-02 from the National Institutes of Health; and by monetary support and donations of antihypertensive medications to each clinical center by King Pharmaceuticals, Pfizer Inc, AstraZeneca Pharmaceuticals, Glaxo Smith Kline, Forest Laboratories, Pharmacia, and Upjohn. NR 31 TC 13 Z9 13 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 J9 TRANSL RES JI Transl. Res. PD JAN PY 2012 VL 159 IS 1 BP 4 EP 11 DI 10.1016/j.trsl.2011.09.004 PG 8 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 867KD UT WOS:000298452400002 PM 22153804 ER PT J AU Trivedi, H Turkbey, B Rastinehad, AR Benjamin, CJ Bernardo, M Pohida, T Shah, V Merino, MJ Wood, BJ Linehan, WM Venkatesan, AM Choyke, PL Pinto, PA AF Trivedi, Hari Turkbey, Baris Rastinehad, Ardeshir R. Benjamin, Compton J. Bernardo, Marcelino Pohida, Thomas Shah, Vijay Merino, Maria J. Wood, Bradford J. Linehan, W. Marston Venkatesan, Aradhana M. Choyke, Peter L. Pinto, Peter A. TI Use of Patient-specific MRI-based Prostate Mold for Validation of Multiparametric MRI in Localization of Prostate Cancer SO UROLOGY LA English DT Article ID 3 T; HISTOPATHOLOGY; SPECIMENS; BIOPSIES; IMAGES AB OBJECTIVE To demonstrate the use of a patient-specific magnetic resonance imaging (MRI)-based prostate mold to generate histologic sections that directly correlate to axial MRI slices in a patient with anteriorly located prostate cancer. Anteriorly located prostate cancer has traditionally been difficult to detect on digital rectal examination and transrectal ultrasound-guided biopsy. Multiparametric MRI has potential as a valuable tool for the diagnosis and focal treatment of prostate cancer. A significant difficulty to date has been accurate correlation between the magnetic resonance images and histopathologic specimens. METHODS A patient-specific mold from a preoperative T(2)-weighted MRI scan was created to hold and shape the prostate specimen. Slots for slicing were positioned at 6-mm increments coplanar to the axial MRI slices. After surgical excision, the specimen was inked to maintain the orientation and fixed in formalin. The seminal vesicles were excised, and the prostate was oriented in the mold such that the color-coding matched the anatomic labels on the mold. The specimen was sliced with a single blade and the resultant 6-mm tissue blocks were used for histologic analysis. RESULTS Preoperative multiparametric MRI revealed a lesion in the right anterior transition zone that was positive on T(2)-weighed MRI, apparent diffusion coefficient maps of diffusion-weighted MRI, magnetic resonance spectroscopy, and dynamic contrast-enhanced MRI. The histologic sections obtained using the mold demonstrated a similar Gleason score 6 (3 + 3) lesion in the right anterior transition zone, correlating with the MRI findings. CONCLUSION The use of patient-specific prostate molds to register the MRI findings with the histopathologic specimen in prostate cancer could offer several benefits compared with current specimen processing techniques. This technique might further validate MRI as an accurate tool for prostate cancer localization and staging. UROLOGY 79: 233-239, 2012. (C) 2012 Published by Elsevier Inc. C1 [Pinto, Peter A.] NCI, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Mol Imaging Program,Urol Oncol Branch,NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Mol Imaging Program,Urol Oncol Branch,NIH, 10 Ctr Dr,MSC 1210,Bldg 10,Room 2-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X FU National Institutes of Health, National Cancer Institute; Center for Cancer Research; National Institutes of Health; Pfizer, Inc. FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. This research was supported in part through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health and Pfizer, Inc. (by a grant to the Foundation for National Institutes of Health from Pfizer, Inc.). NR 15 TC 29 Z9 29 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD JAN PY 2012 VL 79 IS 1 BP 233 EP 239 DI 10.1016/j.urology.2011.10.002 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 870LO UT WOS:000298671000057 PM 22202553 ER PT J AU Blair, RJR AF Blair, R. J. R. TI Considering anger from a cognitive neuroscience perspective SO WILEY INTERDISCIPLINARY REVIEWS-COGNITIVE SCIENCE LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; BORDERLINE PERSONALITY-DISORDER; CALLOUS-UNEMOTIONAL TRAITS; ANTERIOR CINGULATE CORTEX; EVENT-RELATED FMRI; RESPONSE REVERSAL; DECISION-MAKING; ORBITOFRONTAL CORTEX; FEARFUL FACES AB The goal of this paper is to consider anger from a cognitive neuroscience perspective. Five main claims are made: first, reactive aggression is the ultimate behavioral expression of anger and thus we can begin to understand anger by understanding reactive aggression. Second, neural systems implicated in reactive aggression (amygdala, hypothalamus, and periaqueductal gray; the basic threat system) are critically implicated in anger. Factors such as exposure to extreme threat that increase the responsiveness of these systems, should be (and are in the context of posttraumatic stress disorder), associated with increased anger. Third, regions of frontal cortex implicated in regulating the basic threat system, when dysfunctional (e. g., in the context of lesions) should be associated with increased anger. Fourth, frustration occurs when an individual continues to do an action in the expectation of a reward but does not actually receive that reward, and is associated with anger. Individuals who show impairment in the ability to alter behavioral responding when actions no longer receive their expected rewards should be (and are in the context of psychopathy) associated with increased anger. Fifth, someone not doing what another person wants them to do (particularly if this thwarts the person's goal) is frustrating and consequently anger inducing. The response to such a frustrating social event relies on the neural architecture implicated in changing behavioral responses in nonsocial frustrating situations. (C) 2011 John Wiley & Sons, Ltd. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov FU Intramural NIH HHS [Z01 MH002860-03] NR 89 TC 24 Z9 25 U1 8 U2 27 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1939-5078 J9 WIRES COGN SCI JI Wiley Interdiscip. Rev.-Cogn. Sci. PD JAN-FEB PY 2012 VL 3 IS 1 BP 65 EP 74 DI 10.1002/wcs.154 PG 10 WC Psychology, Experimental SC Psychology GA 863PI UT WOS:000298177500005 PM 22267973 ER PT J AU Aschebrook-Kilfoy, B Ward, MH Gierach, GL Schatzkin, A Hollenbeck, AR Sinha, R Cross, AJ AF Aschebrook-Kilfoy, Briseis Ward, Mary H. Gierach, Gretchen L. Schatzkin, Arthur Hollenbeck, Albert R. Sinha, Rashmi Cross, Amanda J. TI Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE epithelial; nitrate and nitrite; ovarian cancer ID N-NITROSO COMPOUNDS; RETIRED-PERSONS DIET; DRINKING-WATER; UNITED-STATES; RISK-FACTORS; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; WOMEN; FOOD; EPIDEMIOLOGY AB Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50-71 years at the time of the baseline questionnaire in 1995-1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01-1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05-1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies. European Journal of Cancer Prevention 21:65-72 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Aschebrook-Kilfoy, Briseis] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH,DHHS,DCEG, Rockville, MD 20852 USA. [Gierach, Gretchen L.] NCI, Hormonal & Reprod Epidemiol Branch, DCEG, NIH, Rockville, MD 20852 USA. [Schatzkin, Arthur; Sinha, Rashmi; Cross, Amanda J.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Aschebrook-Kilfoy, B (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH,DHHS,DCEG, 6120 Execut Blvd,EPS 8111, Rockville, MD 20852 USA. EM kilfoyb@mail.nih.gov RI Aschebrook-Kilfoy, Briseis/A-2537-2012; Sinha, Rashmi/G-7446-2015; Gierach, Gretchen/E-1817-2016 OI Sinha, Rashmi/0000-0002-2466-7462; Gierach, Gretchen/0000-0002-0165-5522 FU Department of Health and Human Service of the National Cancer Institute, National Institutes of Health FX This research was supported (in part) by the Department of Health and Human Service, Intramural Research Program of the National Cancer Institute, National Institutes of Health. 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. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this study were collected by the Florida Cancer Data System under contract to the Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected 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. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. NR 34 TC 13 Z9 13 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JAN PY 2012 VL 21 IS 1 BP 65 EP 72 DI 10.1097/CEJ.0b013e328347622f PG 8 WC Oncology SC Oncology GA 862UK UT WOS:000298119400009 PM 21934624 ER PT J AU Seidman, JC Richard, SA Viboud, C Miller, MA AF Seidman, Jessica C. Richard, Stephanie A. Viboud, Cecile Miller, Mark A. TI Quantitative review of antibody response to inactivated seasonal influenza vaccines SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Review DE antibody response; immunogenicity; influenza; vaccine ID NURSING-HOME RESIDENTS; H3N2 VIRUS-VACCINES; LOW ANTIGENIC DRIFT; HEALTHY-ADULTS; ELDERLY POPULATION; IMMUNE-RESPONSE; SUBUNIT VACCINE; UNITED-STATES; SPLIT VACCINE; YOUNG-ADULTS AB Background Seasonal influenza epidemics are associated with significant morbidity and mortality each year, particularly amongst young children and the elderly. Seasonal influenza vaccines have been available for decades, yet influenza remains a major public health threat in the US, sparking interest in studies evaluating the effectiveness of vaccination. Objectives We sought to identify determinants of serological responses to inactivated seasonal influenza vaccines including number of doses, adjuvant, and subject characteristics. Methods We reviewed 60 articles published between 1987 and 2006. We used weighted multiple logistic regression and random-effects models to evaluate how seroconversion and seroprotection rates varied with host and vaccine factors. Results Both children and seniors tended to have poorer immune responses compared to adults whereas use of adjuvant and a second vaccine dose tended to improve immune response. Pre-vaccination serological status had a large impact on the immune response to vaccination. We found substantial heterogeneity among studies, even with similar population settings and vaccination regimen. Conclusions Future studies should stratify their results by pre-vaccination serological status in an effort to produce more precise summary estimates of vaccine response. C1 [Seidman, Jessica C.; Richard, Stephanie A.; Viboud, Cecile; Miller, Mark A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Seidman, JC (reprint author), NIH, Fogarty Int Ctr, Bldg 16,Room 202,16 Ctr Dr, Bethesda, MD 20892 USA. EM seidmanj@mail.nih.gov FU Fogarty International Center at the National Institutes of Health FX This study was funded by the intramural program at the Fogarty International Center at the National Institutes of Health. NR 101 TC 12 Z9 13 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1750-2640 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD JAN PY 2012 VL 6 IS 1 BP 52 EP 62 DI 10.1111/j.1750-2659.2011.00268.x PG 11 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 861JK UT WOS:000298015000008 PM 21668661 ER PT J AU Padilla-Banks, E Jefferson, WN Myers, PH Goulding, DR Williams, CJ AF Padilla-Banks, Elizabeth Jefferson, Wendy N. Myers, Page H. Goulding, David R. Williams, Carmen J. TI Neonatal phytoestrogen exposure causes hypospadias in female mice SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Letter C1 [Williams, Carmen J.] NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Myers, Page H.; Goulding, David R.] NIEHS, Environm Dis & Med Program, Comparat Med Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Williams, CJ (reprint author), NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH,DHHS, POB 12233,MD E4-05, Res Triangle Pk, NC 27709 USA. EM williamsc5@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102405-04]; NIEHS NIH HHS [Z01-ES102405] NR 4 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD JAN PY 2012 VL 79 IS 1 BP 3 EP 3 DI 10.1002/mrd.21395 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 862KI UT WOS:000298089200001 PM 21990138 ER PT J AU Israel, B Garner, ST Thakare, M Elder, D Abney, T Azadi, P Beach, JW Price, JC Ahmed, H Capomacchia, AC AF Israel, Bridg'ette Garner, Solomon T. Thakare, Mohan Elder, Deborah Abney, Trinia Azadi, Parastoo Beach, J. Warren Price, James C. Ahmed, Hisham Capomacchia, Anthony C. TI Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs SO PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY LA English DT Article ID SHED SNAKE SKIN; IN-VITRO; POLYMERIC PRODRUGS; INSULIN-RESISTANCE; CHIMERA DRUG; RAT; PHARMACOKINETICS; BIOAVAILABILITY; PERMEABILITY; CHONDROCYTES AB The current investigation reports skin permeation of three novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with an NSAID, either ketoprofen or ibuprofen. They were evaluated for transdermal permeation using shed snakeskin, and to our knowledge represent the first MPs synthesized for this purpose, although they also could be used for subcutaneous delivery. MPs are defined as two active drug compounds usually connected by an ester linkage. Glucosamine administration has been linked to damaged cartilage repair, and pain relief in joints afflicted with osteoarthritis. NSAIDs are commonly used orally in transdermal creams or gels for joint pain relief. Two novel compounds we report (MP1 and MP2) covalently link ibuprofen and ketoprofen directly to the amide nitrogen of n-acetyl-glucosamine (NAG); the other compound (MP3) covalently links ibuprofen to the amide nitrogen, using a short chain acetyl linker. Permeability studies show that the ketoprofen mutual prodrug (MP2) permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. The ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; all three mutual prodrugs may be candidates for subcutaneous injection.