FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Grimes, WN Zhang, J Tian, H Graydon, CW Hoon, M Rieke, F Diamond, JS AF Grimes, William N. Zhang, Jun Tian, Hua Graydon, Cole W. Hoon, Mrinalini Rieke, Fred Diamond, Jeffrey S. TI Complex inhibitory microcircuitry regulates retinal signaling near visual threshold SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE amacrine; feedback; GABA; retina; microcircuit ID ROD BIPOLAR CELLS; RECEPTOR-MEDIATED INHIBITION; ACTIVATED POTASSIUM CHANNEL; ACCUMULATING AMACRINE CELLS; MAMMALIAN RIBBON SYNAPSE; RAT RETINA; GABA(C) RECEPTORS; HORIZONTAL CELLS; RABBIT RETINA; MOUSE RETINA AB Neuronal microcircuits, small, localized signaling motifs involving two or more neurons, underlie signal processing and computation in the brain. Compartmentalized signaling within a neuron may enable it to participate in multiple, independent microcircuits. Each A17 amacrine cell in the mammalian retina contains within its dendrites hundreds of synaptic feedback microcircuits that operate independently to modulate feedforward signaling in the inner retina. Each of these microcircuits comprises a small (<1 mu m) synaptic varicosity that typically receives one excitatory synapse from a presynaptic rod bipolar cell (RBC) and returns two reciprocal inhibitory synapses back onto the same RBC terminal. Feedback inhibition from the A17 sculpts the feedforward signal from the RBC to the AII, a critical component of the circuitry mediating night vision. Here, we show that the two inhibitory synapses from the A17 to the RBC express kinetically distinct populations of GABA receptors: rapidly activating GABA(A)Rs are enriched at one synapse while more slowly activating GABA(C)Rs are enriched at the other. Anatomical and electrophysiological data suggest that macromolecular complexes of voltage-gated (Ca-v) channels and Ca2+-activated K+ channels help to regulate GABA release from A17 varicosities and limit GABA(C)R activation under certain conditions. Finally, we find that selective elimination of A17-mediated feedback inhibition reduces the signal to noise ratio of responses to dim flashes recorded in the feedforward pathway (i.e., the AII amacrine cell). We conclude that A17-mediated feedback inhibition improves the signal to noise ratio of RBC-AII transmission near visual threshold, thereby improving visual sensitivity at night. C1 [Grimes, William N.; Zhang, Jun; Tian, Hua; Graydon, Cole W.; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, Bethesda, MD 20892 USA. [Grimes, William N.; Rieke, Fred] Univ Washington, Howard Hughes Med Inst, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Hoon, Mrinalini] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. RP Grimes, WN (reprint author), NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35,Rm 3E-621, Bethesda, MD 20892 USA. EM diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU NINDS Intramural Research Program; Howard Hughes Medical Institute; National Eye Institute [EY-10699] FX This work was supported by the NINDS Intramural Research Program (to J. S. Diamond) and the Howard Hughes Medical Institute (to F. Rieke). M. Hoon was supported by National Eye Institute Grant EY-10699 (to R. Wong). NR 69 TC 2 Z9 2 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL 1 PY 2015 VL 114 IS 1 BP 341 EP 353 DI 10.1152/jn.00017.2015 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CM9EV UT WOS:000358010600031 PM 25972578 ER PT J AU Nicolasjilwan, M Hu, Y Yan, CH Meerzaman, D Holder, CA Gutman, D Jain, R Colen, R Rubin, DL Zinn, PO Hwang, SN Raghavan, P Hammoud, DA Scarpace, LM Mikkelsen, T Chen, J Gevaert, O Buetow, K Freymann, J Kirby, J Flanders, AE Wintermark, M AF Nicolasjilwan, Manal Hu, Ying Yan, Chunhua Meerzaman, Daoud Holder, Chad A. Gutman, David Jain, Rajan Colen, Rivka Rubin, Daniel L. Zinn, Pascal O. Hwang, Scott N. Raghavan, Prashant Hammoud, Dima A. Scarpace, Lisa M. Mikkelsen, Tom Chen, James Gevaert, Olivier Buetow, Kenneth Freymann, John Kirby, Justin Flanders, Adam E. Wintermark, Max CA TCGA Glioma Phenotype Res Grp TI Addition of MR imaging features and genetic biomarkers strengthens glioblastoma survival prediction in TCGA patients SO JOURNAL OF NEURORADIOLOGY LA English DT Article DE Glioblastoma; Magnetic resonance imaging; Genetics; Survival; Prognosis ID RADIATION; PROGRESSION; THERAPY; GLIOMA; ASTROCYTOMA; MULTIFORME; MATTER; CARE AB Purpose: The purpose of our study was to assess whether a model combining clinical factors, MR imaging features, and genomics would better predict overall survival of patients with glioblastoma (GBM) than either individual data type. Methods: The study was conducted leveraging The Cancer Genome Atlas (TCGA) effort supported by the National Institutes of Health. Six neuroradiologists reviewed MRI images from The Cancer Imaging Archive (http://cancerimagingarchive.net) of 102 GBM patients using the VASARI scoring system. The patients' clinical and genetic data were obtained from the TCGA website (http://www.cancergenome.nih.gov/). Patient outcome was measured in terms of overall survival time. The association between different categories of biomarkers and survival was evaluated using Cox analysis. Results: The features that were significantly associated with survival were: (1) clinical factors: chemotherapy; (2) imaging: proportion of tumor contrast enhancement on MRI; and (3) genomics: HRAS copy number variation. The combination of these three biomarkers resulted in an incremental increase in the strength of prediction of survival, with the model that included clinical, imaging, and genetic variables having the highest predictive accuracy (area under the curve 0.679 +/- 0.068, Akaike's information criterion 566.7, P < 0.001). Conclusion: A combination of clinical factors, imaging features, and HRAS copy number variation best predicts survival of patients with GBM. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Nicolasjilwan, Manal; Raghavan, Prashant; Wintermark, Max] Univ Virginia Hlth Syst, Div Neuroradiol, Charlottesville, VA USA. [Hu, Ying; Yan, Chunhua; Meerzaman, Daoud] NCI, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. [Holder, Chad A.] Emory Univ, Sch Med, Dept Radiol & Imaging Sci, Div Neuroradiol, Atlanta, GA USA. [Gutman, David] Emory Univ, Dept Biomed Informat, Atlanta, GA 30322 USA. [Jain, Rajan] Henry Ford Hosp, Dept Radiol, Detroit, MI 48202 USA. [Jain, Rajan; Scarpace, Lisa M.; Mikkelsen, Tom] Dept Neurosurg, Detroit, MI USA. [Colen, Rivka] Univ Texas MD Anderson Canc Ctr, Div Neuroradiol, Houston, TX 77030 USA. [Rubin, Daniel L.] Stanford Univ, Dept Radiol & Med, Biomed Informat Res, Stanford, CA 94305 USA. [Zinn, Pascal O.] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. [Hwang, Scott N.] St Jude Childrens Res Hosp, Neuroradiol Sect, Memphis, TN 38105 USA. [Hammoud, Dima A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Chen, James] Univ Calif San Diego, Div Neuroradiol, San Diego, CA 92103 USA. [Gevaert, Olivier] Stanford Univ, Ctr Canc Syst Biol, Stanford, CA 94305 USA. [Gevaert, Olivier] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Buetow, Kenneth] Arizona State Univ Life Sci, Tempe, AZ USA. [Freymann, John; Kirby, Justin] SAIC Frederick Inc, Frederick, MD USA. [Flanders, Adam E.] Thomas Jefferson Univ Hosp, Div Neuroradiol, Philadelphia, PA 19107 USA. [Wintermark, Max] CHU Vaudois, Dept Radiol, CH-1011 Lausanne, Switzerland. RP Wintermark, M (reprint author), Dept Radiol & Med Imaging, Div Neuroradiol, POB 800170, Charlottesville, VA 22908 USA. EM max.wintermark@gmail.com OI Gevaert, Olivier/0000-0002-9965-5466; Hwang, Scott/0000-0002-6496-2087; Wintermark, Max/0000-0002-6726-3951 NR 30 TC 15 Z9 16 U1 1 U2 10 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 0150-9861 EI 1773-0406 J9 J NEURORADIOLOGY JI J. Neuroradiol. PD JUL PY 2015 VL 42 IS 4 BP 212 EP 221 DI 10.1016/j.neurad.2014.02.006 PG 10 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CN0NA UT WOS:000358109400004 PM 24997477 ER PT J AU Kennedy, AE Kamdar, KY Lupo, PJ Okcu, MF Scheurer, ME Dorak, MT AF Kennedy, Amy E. Kamdar, Kala Y. Lupo, Philip J. Okcu, Mehmet F. Scheurer, Michael E. Dorak, Mehmet T. TI Birth Characteristics and Childhood Leukemia Risk: Correlations With Genetic Markers SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE genetic associations; childhood acute lymphoblastic leukemia; genetic predisposition to disease; birth characteristics ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MAJOR HISTOCOMPATIBILITY COMPLEX; ADULT CANCER INCIDENCE; PRENATAL ORIGIN; CARDIOVASCULAR-DISEASE; WEIGHT; ASSOCIATION; SUSCEPTIBILITY; METAANALYSIS; POPULATION AB Birth characteristics such as birth order, birth weight, birth defects, and Down syndrome showed some of the first risk associations with childhood leukemia. Examinations of correlations between birth characteristics and leukemia risk markers have been limited to birth weight-related genetic polymorphisms. We integrated information on nongenetic and genetic markers by evaluating the relationship of birth characteristics, genetic markers for childhood acute lymphoblastic leukemia (ALL) susceptibility, and ALL risk together. The multiethnic study consisted of cases with childhood ALL (n=161) and healthy controls (n=261). Birth characteristic data were collected through questionnaires, and genotyping was achieved by TaqMan SNP Genotyping Assays. We observed risk associations for birth weight over 4000 g (odds ratios [OR]=1.93; 95% confidence interval [CI], 1.16-3.19), birth length (OR=1.18 per inch; 95% CI, 1.01-1.38), and with gestational age (OR=1.10 per week; 95% CI, 1.00-1.21). Only the HFE tag single-nucleotide polymorphism (SNP) rs9366637 showed an inverse correlation with a birth characteristic, gestational age, with a gene-dosage effect (P=0.005), and in interaction with a transferrin receptor rs3817672 genotype (P-interaction=0.05). This correlation translated into a strong association for rs9366637 with preterm birth (OR=5.0; 95% CI, 1.19-20.9). Our study provides evidence for the involvement of prenatal events in the development of childhood ALL. The inverse correlation of rs9366637 with gestational age has implications on the design of HFE association studies in birth weight and childhood conditions using full-term newborns as controls. C1 [Kennedy, Amy E.; Dorak, Mehmet T.] Florida Int Univ, Dept Epidemiol, Robert Stempel Coll Publ Hlth & Social Work, Miami, FL 33199 USA. [Kamdar, Kala Y.; Lupo, Philip J.; Okcu, Mehmet F.; Scheurer, Michael E.] Baylor Coll Med, Dept Pediat, Hematol Oncol Sect, Houston, TX 77030 USA. RP Kennedy, AE (reprint author), NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr,Room 4E114,MSC 9763, Rockville, MD 20850 USA. EM amy.kennedy@nih.gov OI Lupo, Philip/0000-0003-0978-5863; Kennedy, Amy/0000-0001-9589-5510 NR 50 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1077-4114 EI 1536-3678 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD JUL PY 2015 VL 37 IS 5 BP e301 EP e307 DI 10.1097/MPH.0000000000000347 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CM4MM UT WOS:000357658800006 PM 25955080 ER PT J AU Meyer, DM Begtrup, K Grotta, JC AF Meyer, Dawn M. Begtrup, Kamilla Grotta, James C. CA Recombinant Activated Factor VII I TI Is the ICH score a valid predictor of mortality in intracerebral hemorrhage? SO JOURNAL OF THE AMERICAN ASSOCIATION OF NURSE PRACTITIONERS LA English DT Article DE Vascular disease; patient outcomes; critical care; neurology ID GRADING SCALE; MORBIDITY; CARE AB PurposeThe intracerebral hemorrhage (ICH) score utilizes a 0- to 6-point scoring system to predict 30-day mortality in ICH patients. The purpose of this analysis was to (a) validate the ICH score in an international, heterogeneous population of ICH patients; and (b) assess the usefulness of a 72-h ICH score. Data sourcesAnalyses were based on data from 399 patients in the Novo Nordisk trial F7ICH-1371. The ICH score's ability to predict mortality was determined by calculating the sensitivity, specificity, and positive predictive value (PPV). ConclusionsBoth the baseline and 72-h ICH score had high specificity but low sensitivity resulting in an overall PPV of 57%-76%. Specificity of the ICH score was higher in the baseline ICH score (95%) as compared to the 72-h score (89%). Sensitivity of the ICH score was higher in the 72-h ICH score (75%) as compared to the baseline score (36%). Implications for practiceThe baseline ICH score provides reasonable PPV while the 72-h score provides higher sensitivity. ICH scores obtained at baseline and/or 72 h are valid and may help practitioners to more accurately predict 30-day mortality in ICH patients. C1 [Meyer, Dawn M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Begtrup, Kamilla] Novo Nordisk AS, DK-2880 Bagsvaerd, Denmark. [Grotta, James C.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Recombinant Activated Factor VII I] NINDS, NIH, Bethesda, MD 20892 USA. RP Meyer, DM (reprint author), Univ Calif San Diego, Dept Neurosci, 200 West Arbor Srive, San Diego, CA 92103 USA. EM dmmeyer@ucsd.edu NR 15 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2327-6886 EI 2327-6924 J9 J AM ASSOC NURSE PRA JI J. Am. Assoc. Nurs. Pract. PD JUL PY 2015 VL 27 IS 7 BP 351 EP 355 DI 10.1002/2327-6924.12198 PG 5 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA CM8LJ UT WOS:000357952100002 PM 25619130 ER PT J AU Tempero, M AF Tempero, Margaret TI Express Scripts? Really? SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, Med, New York, NY 10065 USA. [Tempero, Margaret] UCSF Pancreas Ctr, San Francisco, CA USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm, Bethesda, MD 20892 USA. [Tempero, Margaret] Mayo Clin, Rochester, MN USA. [Tempero, Margaret] UAB Minnesota, Minneapolis, MN USA. [Tempero, Margaret] UNMC Eppley Canc Center, Omaha, NE USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA USA. [Tempero, Margaret] UCSF, Res Programs, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, Med, New York, NY 10065 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2015 VL 13 IS 7 BP 827 EP 827 PG 1 WC Oncology SC Oncology GA CM7UI UT WOS:000357901600001 PM 26150575 ER PT J AU Laudisio, A Bandinelli, S Gemma, A Ferrucci, L Incalzi, RA AF Laudisio, Alice Bandinelli, Stefania Gemma, Antonella Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Associations of Heart Rate With Inflammatory Markers Are Modulated by Gender and Obesity in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Heart rate; Inflammation; Elderly; Body mass index; Epidemiology ID CARDIAC TRANSPLANTATION; MORTALITY; INTERLEUKIN-6; CENTERS; DECLINE; FRAILTY; EVENTS; WOMEN; MASS AB Background. Faster resting heart rate (HR), which is associated with inflammation and elevated cortisol levels, is a risk factor for excess cardiovascular morbidity and mortality. Obesity is associated with increased cardiovascular morbidity and mortality, inflammation, and elevated cortisol levels. The aim of the present study was to evaluate the interaction of Body Mass Index (BMI) with inflammation and cortisol in modulating HR in older subjects. Methods. We analyzed data of 895 participants aged 65+ enrolled in the "InCHIANTI" study, in sinus rhythm, and not taking beta blockers or digoxin. Linear regression was performed to assess the adjusted association between HR, IL-6, and cortisol levels. The model was also analyzed stratifying for BMI tertiles. Logistic regression was adopted for evaluating the association of HR exceeding the mean value with Il-6 and serum cortisol. Results. According to multivariable linear regression, IL-6 and cortisol levels were associated with HR (B=1.42, 95% CI=0.43-2.42; p=.005 and B=.34, 95% CI=0.17-.51; p<.0001, respectively). The association was significant only among women in the highest BMI tertile (B=4.16, 95% CI=1.40-6.91; p=.003 for IL-6 and B=.57, 95% CI=0.14-1.01; p=.010 for cortisol). Logistic regression confirmed that IL-6 and cortisol levels were associated with HR above the mean value in the highest BMI tertile (OR=2.13, 95% CI=1.15-3.97; p=.009 and OR=1.14, 95% CI=1.03-1.25; p=.009, respectively). Conclusions. Faster HR is associated with proinflammatory state in elderly patients; this association seems to be limited to women with higher BMI. C1 [Laudisio, Alice; Incalzi, Raffaele Antonelli] Campus Biomed Univ, Dept Geriatr, I-00128 Rome, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Gemma, Antonella] Azienda Sanit Locale Roma E, Dept Homecare Serv, Rome, Italy. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. RP Laudisio, A (reprint author), Campus Biomed Univ, Dept Geriatr, Via Alvaro del Portillo 200, I-00128 Rome, Italy. EM lavoralice@gmail.com OI Antonelli Incalzi, Raffaele/0000-0003-2100-2075 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002] FX The InCHIANTI study baseline (1998-2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-Up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-Ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract N01-AG-5-0002). NR 26 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2015 VL 70 IS 7 BP 899 EP 904 DI 10.1093/gerona/glu211 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CM7MW UT WOS:000357878900015 PM 25429009 ER PT J AU Gamaldo, AA McNeely, JM Shah, MT Evans, MK Zonderman, AB AF Gamaldo, Alyssa A. McNeely, Jessica M. Shah, Mauli T. Evans, Michele K. Zonderman, Alan B. TI Racial Differences in Self-Reports of Short Sleep Duration in an Urban-Dwelling Environment SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Aging; Race; Sleep duration ID ALL-CAUSE MORTALITY; SOCIOECONOMIC-STATUS; NATIONAL-HEALTH; US ADULTS; ASSOCIATION; INSOMNIA; NEIGHBORHOOD; METAANALYSIS; RACE; PREVALENCE AB Objectives. To explore whether there are differences in sleep duration between blacks and whites residing in similar urban neighborhoods and examine whether the relationship between sleep durations and sociodemographic and/or health indices are consistent for blacks and whites. Methods. A total of 1,207 participants from the Healthy Aging in Neighborhoods of Disparities across the Life Span study (age: mean = 47, standard deviation = 8.74). Sleep duration was assessed by a self-report of hours of nightly sleep in the past month. Sociodemographic measures included age, sex, education, poverty status, and perceived neighborhood disorder. Health status was assessed using measures of vigilance, depression, perceived stress, coronary artery disease, diabetes, blood pressure, and inflammation. Results. There were no significant racial group differences in sleep duration. Whites, however, were more likely than blacks to report sleep durations of <6/6-7 hr compared with >7 hr with increasing stress and education levels. Blacks were more likely than whites to report short sleep durations (i.e., 6-7 hr vs. >7 hr of sleep) with increasing inflammation levels. Discussion. Although racial disparities in sleep duration are minimized when the environment is equivalent between blacks and whites, the underlying demographic and health explanations for short sleep durations may vary between whites and blacks. C1 [Gamaldo, Alyssa A.; McNeely, Jessica M.; Shah, Mauli T.; Evans, Michele K.; Zonderman, Alan B.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gamaldo, Alyssa A.] Univ S Florida, Sch Aging Studies, Tampa, FL 33612 USA. [McNeely, Jessica M.; Shah, Mauli T.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. RP Gamaldo, AA (reprint author), Univ S Florida, Sch Aging Studies, 13301 Bruce B Downs Blvd, Tampa, FL 33612 USA. EM agamaldo@usf.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 47 TC 4 Z9 4 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 EI 1758-5368 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD JUL PY 2015 VL 70 IS 4 BP 568 EP 575 DI 10.1093/geronb/gbt117 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA CM7NC UT WOS:000357879600007 PM 24285771 ER PT J AU Xu, ZY Bagci, U Mansoor, A Kramer-Marek, G Luna, B Kubler, A Dey, B Foster, B Papadakis, GZ Camp, JV Jonsson, CB Bishai, WR Jain, S Udupa, JK Mollura, DJ AF Xu, Ziyue Bagci, Ulas Mansoor, Awais Kramer-Marek, Gabriela Luna, Brian Kubler, Andre Dey, Bappaditya Foster, Brent Papadakis, Georgios Z. Camp, Jeremy V. Jonsson, Colleen B. Bishai, William R. Jain, Sanjay Udupa, Jayaram K. Mollura, Daniel J. TI Computer-aided pulmonary image analysis in small animal models SO MEDICAL PHYSICS LA English DT Article DE lung segmentation; CT; fuzzy connectedness; machine learning; airway lumen segmentation; small animal model ID HUMAN AIRWAY TREE; CT IMAGES; MICRO-CT; FUZZY CONNECTEDNESS; INFLUENZA-VIRUS; GROUND-GLASS; LUNG; SEGMENTATION; CLASSIFICATION; QUANTIFICATION AB Purpose: To develop an automated pulmonary image analysis framework for infectious lung diseases in small animal models. Methods: The authors describe a novel pathological lung and airway segmentation method for small animals. The proposed framework includes identification of abnormal imaging patterns pertaining to infectious lung diseases. First, the authors' system estimates an expected lung volume by utilizing a regression function between total lung capacity and approximated rib cage volume. A significant difference between the expected lung volume and the initial lung segmentation indicates the presence of severe pathology, and invokes a machine learning based abnormal imaging pattern detection system next. The final stage of the proposed framework is the automatic extraction of airway tree for which new affinity relationships within the fuzzy connectedness image segmentation framework are proposed by combining Hessian and gray-scale morphological reconstruction filters. Results: 133 CT scans were collected from four different studies encompassing a wide spectrum of pulmonary abnormalities pertaining to two commonly used small animal models (ferret and rabbit). Sensitivity and specificity were greater than 90% for pathological lung segmentation (average dice similarity coefficient > 0.9). While qualitative visual assessments of airway tree extraction were performed by the participating expert radiologists, for quantitative evaluation the authors validated the proposed airway extraction method by using publicly available EXACT'09 data set. Conclusions: The authors developed a comprehensive computer-aided pulmonary image analysis framework for preclinical research applications. The proposed framework consists of automatic pathological lung segmentation and accurate airway tree extraction. The framework has high sensitivity and specificity; therefore, it can contribute advances in preclinical research in pulmonary diseases. C1 [Xu, Ziyue; Mansoor, Awais; Mollura, Daniel J.] NIH, CIDI, Radiol & Imaging Sci, Bethesda, MD 32892 USA. [Bagci, Ulas] Univ Cent Florida, CRCV, Orlando, FL 32816 USA. [Kramer-Marek, Gabriela] Inst Canc Res, London SW7 3RP, England. [Luna, Brian] Univ Calif Irvine, Microfluid Lab Automat, Irvine, CA 92697 USA. [Kubler, Andre] Univ London Imperial Coll Sci Technol & Med, Dept Med, London SW7 2AZ, England. [Dey, Bappaditya; Bishai, William R.; Jain, Sanjay] Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD 21231 USA. [Foster, Brent] Univ Calif Davis, Dept Biomed Engn, Sacramento, CA 95817 USA. [Papadakis, Georgios Z.] NIH, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Camp, Jeremy V.] Univ Louisville, Dept Microbiol & Immunol, Louisville, KY 40202 USA. [Jonsson, Colleen B.] Univ Tennessee, Natl Inst Math & Biol Synth, Knoxville, TN 37996 USA. [Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Udupa, Jayaram K.] Univ Penn, Dept Radiol, Med Image Proc Grp, Philadelphia, PA 19104 USA. RP Bagci, U (reprint author), Univ Cent Florida, CRCV, Orlando, FL 32816 USA. EM ulasbagci@gmail.com OI Luna, PhD, Brian/0000-0001-6718-4551; Bagci, Ulas/0000-0001-7379-6829 FU NIBIB NIH HHS [R01 EB020539] NR 45 TC 2 Z9 2 U1 3 U2 10 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2015 VL 42 IS 7 BP 3896 EP 3910 DI 10.1118/1.4921618 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CM4WN UT WOS:000357686400012 PM 26133591 ER PT J AU Gordon, IK Lu, J Graves, CA Huntoon, K Frerich, JM Hanson, RH Wang, XP Hong, CS Ho, W Feldman, MJ Ikejiri, B Bisht, K Chen, XYS Tandle, A Yang, CZ Arscott, WT Ye, D Heiss, JD Lonser, RR Camphausen, K Zhuang, ZP AF Gordon, Ira K. Lu, Jie Graves, Christian A. Huntoon, Kristin Frerich, Jason M. Hanson, Ryan H. Wang, Xiaoping Hong, Christopher S. Ho, Winson Feldman, Michael J. Ikejiri, Barbara Bisht, Kheem Chen, Xiaoyuan S. Tandle, Anita Yang, Chunzhang Arscott, W. Tristram Ye, Donald Heiss, John D. Lonser, Russell R. Camphausen, Kevin Zhuang, Zhengping TI Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DNA-DAMAGE; ADJUVANT TEMOZOLOMIDE; PP2A; CHECKPOINT; REPAIR; CELLS; IRRADIATION; CONCOMITANT; ACTIVATION; SUPPRESSOR AB Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiotherapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiotherapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of postradiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiotherapy maintained increased gamma-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared with radiotherapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA-damage response pathway activity. (C) 2015 AACR. C1 [Gordon, Ira K.; Graves, Christian A.; Hanson, Ryan H.; Bisht, Kheem; Tandle, Anita; Arscott, W. Tristram; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lu, Jie; Chen, Xiaoyuan S.; Ye, Donald] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. [Huntoon, Kristin; Frerich, Jason M.; Wang, Xiaoping; Hong, Christopher S.; Ho, Winson; Feldman, Michael J.; Ikejiri, Barbara; Yang, Chunzhang; Heiss, John D.; Lonser, Russell R.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 3D20, Bethesda, MD 20892 USA. EM zhuangP@ninds.nih.gov OI Heiss, John/0000-0002-3890-0165 FU Intramural Research Program at the National Institute of Neurological Disorders and Stroke; National Cancer Institute at the NIH; NIH Medical Research Scholars Program; NIH FX All co-authors were supported by the Intramural Research Program at the National Institute of Neurological Disorders and Stroke and National Cancer Institute at the NIH. K. Huntoon, J.M. Frerich, M.J. Feldman, and D. Ye were additionally supported by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, Inc., the Doris Duke Charitable Foundation, Alexandria Real Estate Equities, Inc., and Mr. and Mrs. Joel S. Marcus and the Howard Hughes Medical Research Institute, as well as other private donors. For a complete list, please visit http://fnih.org/work/education-training-O/medical-research-scholars-prog ram NR 28 TC 4 Z9 4 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2015 VL 14 IS 7 BP 1540 EP 1547 DI 10.1158/1535-7163.MCT-14-0614 PG 8 WC Oncology SC Oncology GA CM9UZ UT WOS:000358055900003 PM 25939762 ER PT J AU Sherris, D Dennis, PA Wilson, W Kawabata, S Yu, CR Gravina, GL Mancini, A Festuccia, C AF Sherris, David Dennis, Philip A. Wilson, Willie, III Kawabata, Shigeru Yu, Chunrong Gravina, Giovanni Luca Mancini, Andrea Festuccia, Claudio TI Differentiation of PI3K/Akt/mTOR inhibition in cancer models using dual dissociative TORC1/TORC2 (P529), single dissociative TORC1 (rapalogs) and catalytic inhibitors (PI3K/Akt, PI3K/mTOR) SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Sherris, David] RestorGenex Pharmaceut Inc, Jamaica Plain, MA USA. [Dennis, Philip A.; Wilson, Willie, III; Kawabata, Shigeru] NCI, Navy Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Yu, Chunrong] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Gravina, Giovanni Luca; Mancini, Andrea; Festuccia, Claudio] Univ Aquila, I-67100 Laquila, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2015 VL 14 IS 7 SU S MA A23 DI 10.1158/1538-8514.PI3K14-A23 PG 2 WC Oncology SC Oncology GA CN1EF UT WOS:000358159200019 ER PT J AU Staudt, LM AF Staudt, Louis M. TI The therapeutic potential of PI (3) inhibition in lymphoma SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Staudt, Louis M.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2015 VL 14 IS 7 SU S MA IA17 DI 10.1158/1538-8514.PI3K14-IA17 PG 1 WC Oncology SC Oncology GA CN1EF UT WOS:000358159200101 ER PT J AU Warnke, C Stettner, M Lehmensiek, V Dehmel, T Mausberg, AK von Geldern, G Gold, R Kumpfel, T Hohlfeld, R Maurer, M Stangel, M Straeten, V Limmroth, V Weber, T Kleinschnitz, C Wattjes, MP Svenningsson, A Olsson, T Hartung, HP Hermsen, D Tumani, H Adams, O Kieseier, BC AF Warnke, Clemens Stettner, Mark Lehmensiek, Vera Dehmel, Thomas Mausberg, Anne K. von Geldern, Gloria Gold, Ralf Kuempfel, Tania Hohlfeld, Reinhard Maeurer, Mathias Stangel, Martin Straeten, Vera Limmroth, Volker Weber, Thomas Kleinschnitz, Christoph Wattjes, Mike P. Svenningsson, Anders Olsson, Tomas Hartung, Hans-Peter Hermsen, Derik Tumani, Hayrettin Adams, Ortwin Kieseier, Bernd C. TI Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Progressive multifocal leukoencephalopathy; JC virus; natalizumab; Tysabri; multiple sclerosis; disease-modifying therapies; immunosuppression ID MULTIPLE-SCLEROSIS PATIENTS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; TRANSCRIPTIONAL EXPRESSION PROFILES; JC VIRUS; CEREBROSPINAL-FLUID; PROGENITOR CELLS; DISEASE; CD34(+); SUBPOPULATIONS; ADHESION AB Background: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML). Objective: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37). Methods: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid. Results: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid. Conclusions: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML. C1 [Warnke, Clemens; Stettner, Mark; Dehmel, Thomas; Mausberg, Anne K.; Hartung, Hans-Peter; Kieseier, Bernd C.] Univ Dusseldorf, Dept Neurol, Fac Med, Dusseldorf, Germany. [Lehmensiek, Vera; Tumani, Hayrettin] Univ Ulm, Dept Neurol, D-89069 Ulm, Germany. [von Geldern, Gloria] NINDS, NIH, Bethesda, MD 20892 USA. [Gold, Ralf] Ruhr Univ Bochum, Dept Neurol, Bochum, Germany. [Kuempfel, Tania; Hohlfeld, Reinhard] Univ Munich, Inst Clin Neuroimmunol, Munich, Germany. [Kuempfel, Tania; Hohlfeld, Reinhard] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Maeurer, Mathias] Caritas Hosp, Dept Neurol, Bad Mergentheim, Germany. [Stangel, Martin] Hannover Med Sch, Dept Neurol, Clin Neuroimmunol & Neurochem, Hannover, Germany. [Straeten, Vera] Johannes Wesling Hosp Minden, Dept Neurol, Minden, Germany. [Limmroth, Volker] Merheim Hosp, Dept Neurol, Cologne, Germany. [Weber, Thomas] Marienhosp Hamburg, Dept Neurol, Hamburg, Germany. [Kleinschnitz, Christoph] Univ Hosp Wuerzburg, Dept Neurol, Wurzburg, Germany. [Wattjes, Mike P.] Vrije Univ Amsterdam, Med Ctr, MS Ctr Amsterdam, Amsterdam, Netherlands. [Wattjes, Mike P.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol Nucl Med & PET Res, Amsterdam, Netherlands. [Svenningsson, Anders] Umea Univ Hosp, Dept Pharmacol & Clin Neurosci, S-90185 Umea, Sweden. [Olsson, Tomas] Karolinska Inst, Ctr Mol Med, Dept Neurol, Stockholm, Sweden. [Hermsen, Derik] Univ Hosp Duesseldorf, Inst Clin Chem, Dusseldorf, Germany. [Hermsen, Derik] Univ Hosp Duesseldorf, Diagnost Lab, Dusseldorf, Germany. [Adams, Ortwin] Univ Dusseldorf, Fac Med, Inst Virol, Dusseldorf, Germany. RP Warnke, C (reprint author), Dept Neurol, Moorenstr 5, D-40225 Dusseldorf, Germany. EM clemens.warnke@med.uni-duesseldorf.de OI Svenningsson, Anders/0000-0003-0663-2220 FU Research Commission of Heinrich Heine University, Duesseldorf [HHU]; German Ministry for Education and Research (BMBF); German Ministry for Education and Research (German Competence Network MS [KKNMS], Natalizumab Pharmacovigilance Study) [BCK]; European Committee for Treatment and Research; Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program [115303]; European Federation of Pharmaceutical Industries and Associations; Walter and Ilse Rose Foundation; German Research Foundation [DFG CRC TRR128, Z2]; BMBF (KKNMS); Niedersachsen Research Network on Neuroinfectiology of the Ministry of Science and Culture of Lower Saxony FX This work was supported by a local faculty grant (Research Commission of Heinrich Heine University, Duesseldorf [HHU]; OA) and a grant from the German Ministry for Education and Research (BMBF; German Competence Network MS [KKNMS], Natalizumab Pharmacovigilance Study, 01GI1002; BCK.). CW was supported by a European Committee for Treatment and Research in MS fellowship stipend. The research leading to these results received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115303, resources of which are composed of a financial contribution from the European Union's Seventh; Framework Program (FP7=2007-2013) and European Federation of Pharmaceutical Industries and Associations companies' in-kind contribution (to HPH, BCK, CW). The MS Center at the Department of Neurology, HHU is supported by the Walter and Ilse Rose Foundation. RH was supported by the German Research Foundation (DFG CRC TRR128, Z2) and BMBF (KKNMS). MSta is supported by the Niedersachsen Research Network on Neuroinfectiology of the Ministry of Science and Culture of Lower Saxony and the BMBF (KKNMS). We highly appreciate the excellent technical support by Tatjana Males. NR 40 TC 11 Z9 11 U1 1 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD JUL PY 2015 VL 21 IS 8 BP 1036 EP 1044 DI 10.1177/1352458514556296 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CM5OX UT WOS:000357738700011 PM 25392339 ER PT J AU Madan, RA Dahut, WL AF Madan, Ravi A. Dahut, William L. TI Charting a course in metastatic castration-sensitive prostate cancer SO NATURE REVIEWS UROLOGY LA English DT Editorial Material ID ANDROGEN DEPRIVATION; BONE-SCINTIGRAPHY; PET/CT C1 [Madan, Ravi A.; Dahut, William L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Madan, RA (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,10-12n226, Bethesda, MD 20892 USA. EM madanr@mail.nih.gov NR 7 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD JUL PY 2015 VL 12 IS 7 BP 368 EP 369 DI 10.1038/nrurol.2015.144 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CM4IF UT WOS:000357647300004 PM 26077994 ER PT J AU Marrazzo, JM Ramjee, G Richardson, BA Gomez, K Mgodi, N Nair, G Palanee, T Nakabiito, C van der Straten, A Noguchi, L Hendrix, CW Dai, JY Ganesh, S Mkhize, B Taljaard, M Parikh, UM Piper, J Masse, B Grossman, C Rooney, J Schwartz, JL Watts, H Marzinke, MA Hillier, SL McGowan, IM Chirenje, ZM AF Marrazzo, Jeanne M. Ramjee, Gita Richardson, Barbra A. Gomez, Kailazarid Mgodi, Nyaradzo Nair, Gonasagrie Palanee, Thesla Nakabiito, Clemensia van der Straten, Ariane Noguchi, Lisa Hendrix, Craig W. Dai, James Y. Ganesh, Shayhana Mkhize, Baningi Taljaard, Marthinette Parikh, Urvi M. Piper, Jeanna Masse, Benoit Grossman, Cynthia Rooney, James Schwartz, Jill L. Watts, Heather Marzinke, Mark A. Hillier, Sharon L. McGowan, Ian M. Chirenje, Z. Mike CA VOICE Study Team TI Tenofovir-Based Preexposure Prophylaxis for HIV Infection Among African Women SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Reproductive-age African women and others at high risk of acquiring human immunodeficiency virus type 1 (HIV-1) infection need effective interventions to prevent acquisition of this virus. Previous studies have demonstrated that daily oral pre-exposure prophylaxis with tenofovir disoproxil fumarate (TDF) alone or TDF combined with emtricitabine (FTC) (TDF-FTC) reduces the risk of HIV transmission by at least 50% in men who have sex with men, heterosexuals, and injection-drug users (with greater effectiveness in subjects with high adherence to the regimen). However, daily tenofovir (TFV)-based regimens were found to be ineffective in preventing HIV-1 acquisition among women in the Preexposure Prophylaxis Trial for HIV Prevention among African Women (FEM-PrEP) when adherence to the regimen was less than 40%. The Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial was a randomized, placebo-controlled trial that assessed the effectiveness of daily treatment with oral TDF, oral TDF-FTC, or 1% TFV vaginal gel in preventing sexually acquired HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. Adverse effects of the regimens were also assessed. Monthly HIV tests and quarterly blood testing were performed. From September 2009 through June 2011, 12,320 women were screened at 15 sites in South Africa, Uganda, and Zimbabwe. Of these, 5029 were enrolled in the study and randomized. Retention in the trial was excellent; 91% of women completed follow-up visits. The primary effectiveness end point, HIV-1 infection, was identified by seroconversion and assessed in a modified intention-to-treat population. There were 312 HIV-1 infections among study participants; the incidence of infection was 5.7 per 100 person-years. None of the TFV-based regimens were effective in reducing HIV-1 transmission: effectiveness was -49.0% for TDF alone (hazard ratio [HR] for infection, 1.49; 95% confidence interval [CI], 0.97-2.29), -4.4% for TDF-FTC (HR, 1.04; 95% CI, 0.73-1.49), and 14.5% for TFV gel (HR, 0.85; 95% CI, 0.61-1.21). Adherence appeared to be high (86%) based on women's returns of empty pill boxes and gel applicators. However, measurable drug plasma levels in random samples were only 30% for TDF, 29% for TDF-FTC, and 25% for TFV gel. Independent predictors of adherence included being married, being older than 25 years, and being multiparous. There were elevated serum creatinine levels more frequently among participants who received oral TDF-FTC compared with oral placebo (1.3% vs 0.2%, P = 0.004). No significant differences were noted in the frequencies of other adverse events. Consistent with the findings of other studies, these data show that TDF-based regimens proven to prevent HIV infection are ineffective when adherence is poor. C1 [Marrazzo, Jeanne M.] Univ Washington, Seattle, WA 98195 USA. [Richardson, Barbra A.; Dai, James Y.; Masse, Benoit] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Ramjee, Gita; Ganesh, Shayhana] MRC, HIV Prevent Res Unit, London, England. [Nair, Gonasagrie] Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. [Palanee, Thesla] Witwatersrand Reprod Hlth & HIV Res Inst, Johannesburg, South Africa. [Mkhize, Baningi] Perinatal HIV Res Unit, Johannesburg, South Africa. [Taljaard, Marthinette] AURUM Inst, Klerksdorp, South Africa. [Gomez, Kailazarid] FHI 360, Durham, NC USA. [Mgodi, Nyaradzo; Chirenje, Z. Mike] Univ California San Francisco, Univ Zimbabwe, Res Programme, Harare, Zimbabwe. [Nakabiito, Clemensia] Johns Hopkins Univ Res Collaborat, Makerere Univ, Kampala, Uganda. [van der Straten, Ariane] RTI Int, Womens Global Hlth Imperat, San Francisco, CA USA. [Noguchi, Lisa; Parikh, Urvi M.; Hillier, Sharon L.; McGowan, Ian M.] Univ Pittsburgh, Med Ctr, Magee Womens Res Inst, Pittsburgh, PA USA. [Hendrix, Craig W.; Marzinke, Mark A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Piper, Jeanna] NIAID, Div Aids, Bethesda, MD USA. [Grossman, Cynthia] NIMH, Bethesda, MD USA. [Watts, Heather] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Rooney, James] NIH, Bethesda, MD 20892 USA. [Rooney, James] Gilead Sci, Foster City, CA USA. [Schwartz, Jill L.] CONRAD, Arlington, VA USA. [Masse, Benoit] Univ Montreal, Univ St Justine, Ctr Hosp, Montreal, PQ, Canada. RP Marrazzo, JM (reprint author), Univ Washington, Seattle, WA 98195 USA. RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Masse, Benoit/0000-0002-4944-8098; Marrazzo, Jeanne/0000-0002-9277-7364 NR 0 TC 0 Z9 0 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUL PY 2015 VL 70 IS 7 BP 444 EP 446 DI 10.1097/01.ogx.0000466878.37011.6f PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CM5OO UT WOS:000357737800011 ER PT J AU Brun, SN Markant, SL Esparza, LA Garcia, G Terry, D Huang, JM Pavlyukov, MS Li, XN Grant, GA Crawford, JR Levy, ML Conway, EM Smith, LH Nakano, I Berezov, A Greene, MI Wang, Q Wechsler-Reya, RJ AF Brun, S. N. Markant, S. L. Esparza, L. A. Garcia, G. Terry, D. Huang, J-M Pavlyukov, M. S. Li, X-N Grant, G. A. Crawford, J. R. Levy, M. L. Conway, E. M. Smith, L. H. Nakano, I. Berezov, A. Greene, M. I. Wang, Q. Wechsler-Reya, R. J. TI Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma SO ONCOGENE LA English DT Article ID CELL LUNG-CANCER; PHASE-II; PEDIATRIC MEDULLOBLASTOMA; MALIGNANT GLIOMA; DRUG-RESISTANCE; MOUSE MODELS; EXPRESSION; YM155; APOPTOSIS; INHIBITOR AB Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease. C1 [Brun, S. N.; Markant, S. L.; Esparza, L. A.; Wechsler-Reya, R. J.] NCI, Sanford Burnham Med Res Inst, Designated Canc Ctr, Initiat & Maintenance Program, La Jolla, CA 92037 USA. [Brun, S. N.; Markant, S. L.; Esparza, L. A.; Wechsler-Reya, R. J.] Sanford Consortium Regenerat Med, La Jolla, CA USA. [Brun, S. N.; Markant, S. L.; Wechsler-Reya, R. J.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC USA. [Garcia, G.] SBMRI, Histopathol Core, La Jolla, CA USA. [Terry, D.; Smith, L. H.] SBMRI, Conrad Prebys Ctr Chem Genom, Lake Nona, FL USA. [Huang, J-M; Wang, Q.] Samuel Oschin Comprehens Canc Inst, Cedars Sinai Womens Canc Program, Los Angeles, CA USA. [Pavlyukov, M. S.; Nakano, I.] Ohio State Univ, Dept Neurol Surg, Columbus, OH 43210 USA. [Pavlyukov, M. S.; Nakano, I.] Ohio State Univ, James Comprehens Canc Ctr, Columbus, OH 43210 USA. [Li, X-N] Baylor Coll Med, Texas Childrens Canc Ctr, Brain Tumor Program, Houston, TX 77030 USA. [Li, X-N] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Grant, G. A.] Stanford Univ, Lucile Packard Childrens Hosp, Dept Neurosurg, Stanford, CA 94305 USA. [Crawford, J. R.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Crawford, J. R.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Crawford, J. R.; Levy, M. L.] Rady Childrens Hosp, San Diego, CA USA. [Levy, M. L.] Univ Calif San Diego, Dept Neurosurg, La Jolla, CA 92093 USA. [Conway, E. M.] Univ British Columbia, Ctr Blood Res, Dept Med, Div Hematol, Vancouver, BC V5Z 1M9, Canada. [Smith, L. H.] Sanford Burnham Med Res Inst, Cardiopathobiol Program, Lake Nona, FL USA. [Berezov, A.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Greene, M. I.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Wechsler-Reya, RJ (reprint author), NCI, Sanford Burnham Med Res Inst, Designated Canc Ctr, Initiat & Maintenance Program, 2880 Torrey Pines Scen Dr, La Jolla, CA 92037 USA. EM rwreya@sanfordburnham.org RI Wang, Qiang/N-7310-2015 OI Wang, Qiang/0000-0001-9409-0251 FU Canadian Institutes for Health Research (CIHR); Natural Sciences and Engineering Research Council of Canada (NSERC); NCI [5P30CA030199, R01 CA122759]; Cedars-Sinai/Sanford-Burnham Grant Program for Cancer Research; Research Leadership Award from the California Institute for Regenerative Medicine [CIRM LA1-01747]; [5R01CA08948] FX We appreciate the support of the Sanford-Burnham Shared Resources, including Amy Cortez, Jonna Hurtado and Yoav Altman (Flow Cytometry); Robbin Newlin (Histopathology); Danielle McAnally, Michael Vicchiarelli and Arianna Mangravita-Novo (Chemical Genomics); Lili Lacarra, Adriana Charbono and Kenny Venegas (Animal facility); and Anthony Pinkerton and members of the Medicinal Chemistry Resource for generation of S12 and LLP3. We are also grateful to Ana Miletic-Sedy and Robert Rickert for sharing Survivinfl/fl mice; and to Robert Margolis for helpful discussions. We thank the Flanders Institute for Biotechnology (VIB), Belgium, for allowing us to use the Survivinfl/fl mice. EMC is supported by grants from the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC). He holds a Tier 1 Canada Research Chair (CRC) in Endothelial Cell Biology. MIG is supported by Grant 5R01CA08948. This work was supported by NCI award number 5P30CA030199 and R01 CA122759 and by the Cedars-Sinai/Sanford-Burnham Grant Program for Cancer Research. RWR is the recipient of a Research Leadership Award from the California Institute for Regenerative Medicine (CIRM LA1-01747). NR 68 TC 7 Z9 7 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUL PY 2015 VL 34 IS 29 BP 3770 EP 3779 DI 10.1038/onc.2014.304 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CM9BV UT WOS:000358001600003 PM 25241898 ER PT J AU Gerber, LH Shah, J Rosenberger, W Armstrong, K Turo, D Otto, P Heimur, J Thaker, N Sikdar, S AF Gerber, Lynn H. Shah, Jay Rosenberger, William Armstrong, Kathryn Turo, Diego Otto, Paul Heimur, Juliana Thaker, Nikki Sikdar, Siddhartha TI Dry Needling Alters Trigger Points in the Upper Trapezius Muscle and Reduces Pain in Subjects With Chronic Myofascial Pain SO PM&R LA English DT Article ID OF-THE-LITERATURE; MUSCULOSKELETAL PAIN; MANAGEMENT; PREVALENCE; NECK AB Objective: To determine whether dry needling of an active myofascial trigger point (MTrP) reduces pain and alters the status of the trigger point to either a non-spontaneously tender nodule or its resolution. Design: A prospective, nonrandomized, controlled, interventional clinical study. Setting: University campus. Participants: A total of 56 subjects with neck or shoulder girdle pain of more than 3 months duration and active MTrPs were recruited from a campus-wide volunteer sample. Of these, 52 completed the study (23 male and 33 female). Their mean age was 35.8 years. Interventions: Three weekly dry needling treatments of a single active MTrP. Main Outcome Measures: Primary Outcomes: Baseline and posttreatment evaluations of pain using a verbal analogue scale, the Brief Pain Inventory, and the status of the MTrP as determined by digital palpation. Trigger points were rated as active (spontaneously painful), latent (requiring palpation to reproduce the characteristic pain), or resolved (no palpable nodule). Secondary Outcomes: Profile of Mood States, Oswestry Disability Index, and Short Form 36 scores, and cervical range of motion. Results: Primary outcomes: A total of 41 subjects had a change in trigger point status from active to latent or resolved, and 11 subjects had no change (P < .001). Reduction in all pain scores was significant (P < .001). Secondary outcomes: Significant improvement in posttreatment cervical rotational asymmetry in subjects as follows: unilateral/bilateral MTrPs (P = .001 and P = 21, respectively); in pain pressure threshold in subjects with unilateral/bilateral MTrPs, (P = .006 and P = .012, respectively); improvement in the SF-36 mental health and physical functioning subscale scores (P = .019 and P = .03), respectively; and a decrease in the Oswestry Disability Index score (P = .003). Conclusions: Dry needling reduces pain and changes MTrP status. Change in trigger point status is associated with a statistically and clinically significant reduction in pain. Reduction of pain is associated with improved mood, function, and level of disability. C1 [Gerber, Lynn H.] George Mason Univ, CCID, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Shah, Jay; Heimur, Juliana; Thaker, Nikki] Natl Inst Hlth, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. [Rosenberger, William] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Armstrong, Kathryn] George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Turo, Diego; Otto, Paul; Sikdar, Siddhartha] George Mason Univ, Dept Bioengn, Fairfax, VA 22030 USA. RP Gerber, LH (reprint author), George Mason Univ, CCID, Ctr Study Chron Illness & Disabil, 4400 Univ Dr, Fairfax, VA 22030 USA. EM ngerber1@gmu.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health [1R01AR057348] FX Funding for this study was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (grant #1R01AR057348). NR 50 TC 10 Z9 10 U1 5 U2 31 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD JUL PY 2015 VL 7 IS 7 BP 711 EP 720 DI 10.1016/j.pmrj.2015.01.020 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CN0PF UT WOS:000358115100004 PM 25661462 ER PT J AU Shah, JP Thaker, N Heimur, J Aredo, JV Sikdar, S Gerber, L AF Shah, Jay P. Thaker, Nikki Heimur, Juliana Aredo, Jacqueline V. Sikdar, Siddhartha Gerber, Lynn TI Myofascial Trigger Points Then and Now: A Historical and Scientific Perspective SO PM&R LA English DT Review ID END-PLATE-NOISE; RAT DORSAL-HORN; PAIN SYNDROME; SKELETAL-MUSCLE; REFERRED PAIN; NECK PAIN; IN-VIVO; MANAGEMENT; SENSITIZATION; FIBROMYALGIA AB The intent of this article is to discuss the evolving role of the myofascial trigger point (MTrP) in myofascial pain syndrome (MPS) from both a historical and scientific perspective. MTrPs are hard, discrete, palpable nodules in a taut band of skeletal muscle that may be spontaneously painful (i.e., active) or painful only on compression (i.e., latent). MPS is a term used to describe a pain condition that can be acute or, more commonly, chronic and involves the muscle and its surrounding connective tissue (e.g. fascia). According to Travell and Simons, MTrPs are central to the syndromed-but are they necessary? Although the clinical study of muscle pain and MTrPs has proliferated over the past two centuries, the scientific literature often seems disjointed and confusing. Unfortunately, much of the terminology, theories, concepts, and diagnostic criteria are inconsistent, incomplete, or controversial. To address these deficiencies, investigators have recently applied clinical, imaging (of skeletal muscle and brain), and biochemical analyses to systematically and objectively study the MTrP and its role in MPS. Data suggest that the soft tissue milieu around the MTrP, neurogenic inflammation, sensitization, and limbic system dysfunction may all play a role in the initiation, amplification, and perpetuation of MPS. The authors chronicle the advances that have led to the current understanding of MTrP pathophysiology and its relationship to MPS, and review the contributions of clinicians and researchers who have influenced and expanded our contemporary level of clinical knowledge and practice. C1 [Shah, Jay P.; Thaker, Nikki; Heimur, Juliana; Aredo, Jacqueline V.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Sikdar, Siddhartha] George Mason Univ, Volgenau Sch Engn, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Sikdar, Siddhartha] George Mason Univ, Volgenau Sch Engn, Dept Bioengn, Fairfax, VA 22030 USA. [Gerber, Lynn] George Mason Univ, Coll Hlth & Human Serv, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. RP Shah, JP (reprint author), NIH, Dept Rehabil Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jshah@mail.cc.nih.gov FU National Institutes of Health [1R01-AR057348] FX grant, National Institutes of Health #1R01-AR057348 (money to institution) NR 95 TC 12 Z9 12 U1 7 U2 36 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD JUL PY 2015 VL 7 IS 7 BP 746 EP 761 DI 10.1016/j.pmrj.2015.01.024 PG 16 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CN0PF UT WOS:000358115100008 PM 25724849 ER PT J AU Dore, GA Waldstein, SR Evans, MK Zonderman, AB AF Dore, Gregory A. Waldstein, Shari R. Evans, Michele K. Zonderman, Alan B. TI Associations Between Diabetes and Cognitive Function in Socioeconomically Diverse African American and White Men and Women SO PSYCHOSOMATIC MEDICINE LA English DT Article ID RETINAL MICROVASCULAR ABNORMALITIES; HEALTH LITERACY; MATTER LESIONS; RISK-FACTORS; ETHNICITY; DEMENTIA; DECLINE; RACE; DISPARITIES; DYSFUNCTION AB Objectives To examine whether race and poverty (income <125% of the federal poverty limit), modifies associations between diabetes and cognition in a biracial, urban-dwelling sample. Methods Cross-sectional data for 2066 participants (mean age = 47.6 years, 56.8% women, 56.2% African American, 38.6% below poverty) from the first wave of the Healthy Aging in Neighborhoods of Diversity across the Life Span study were used for analyses. Eleven tests measured cognitive function. Interactions among diabetes, race, and poverty status with cognition were assessed in multiple regression analyses. Results Significant interactions among diabetes, race, and poverty status were observed. Among African Americans below poverty, diabetic individuals performed lower than nondiabetic individuals on California Verbal Learning Test Free Recall Short Delay (z = -0.444 [0.123] versus z = -0.137 [0.045]) and Long Delay (z = -0.299 [0.123] versus z = -0.130 [0.045]), Digit Span Backward (z = -0.347 [0.109] versus z = -0.072 [0.041]), and the Brief Test of Attention (z = -0.452 [-0.099] versus z = -0.099 [0.047]), and higher on Category Fluency (z = 0.114 [0.117] versus z = -0.118 [0.044]). No consistent differences between diabetic and nondiabetic individuals were found for African American and white participants above poverty. Conclusions Diabetes was associated with poorer verbal memory, working memory, and attention among African Americans living in poverty. Diabetic African Americans below poverty may have increased risk of cognitive deficit at a younger age. Improving health literacy, doctor-patient communication, and multidisciplinary medical care for impoverished individuals may reduce differences. Additional research is needed to clarify mechanisms underlying these associations. C1 [Dore, Gregory A.; Zonderman, Alan B.] NIA, Behav Epidemiol, NIH, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, NIH, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. [Waldstein, Shari R.] Univ Maryland, Dept Psychol, Baltimore, MD 21201 USA. RP Dore, GA (reprint author), Biomed Res Ctr, Room 04B119,251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM gregory.dore@nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging Intramural Research Program; National Institute on Aging [1 RO1 AG034161] FX This research was supported by the National Institute on Aging Intramural Research Program and a grant from the National Institute on Aging (1 RO1 AG034161) to Shari R. Waldstein. The authors have no conflicts of interest to declare. NR 43 TC 5 Z9 5 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUL-AUG PY 2015 VL 77 IS 6 BP 643 EP 652 DI 10.1097/PSY.0000000000000196 PG 10 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CM5KI UT WOS:000357726300005 PM 26163817 ER PT J AU Sproull, M Kramp, T Tandle, A Shankavaram, U Camphausen, K AF Sproull, Mary Kramp, Tamalee Tandle, Anita Shankavaram, Uma Camphausen, Kevin TI Serum Amyloid A as a Biomarker for Radiation Exposure SO RADIATION RESEARCH LA English DT Article ID BODY IRRADIATION MODEL; C-REACTIVE PROTEIN; ACUTE-PHASE REACTANT; IONIZING-RADIATION; INFLAMMATORY RESPONSE; MEDICAL-MANAGEMENT; RADIOLOGICAL EVENT; BLOOD-PROTEINS; SAA; BIODOSIMETRY AB There is a need for minimally invasive biomarkers that can accurately and quickly quantify radiation exposure. Radiation-responsive proteins have applications in clinical medicine and for mass population screenings after a nuclear or radiological incident where the level of radiation exposure and exposure pattern complicate medical triage for first responders. In this study, we evaluated the efficacy of the acute phase protein serum amyloid A (SAA) as a biomarker for radiation exposure using plasma from irradiated mice. Ten-week-old female C57BL6 mice received a 1-8 Gy single whole-body or partial-body dose from a Pantak X-ray source at a dose rate of 2.28 Gy/min. Plasma was collected bymandibular or cardiac puncture at 6, 24, 48 and 72 h or 1-3 weeks postirradiation. SAA levels were determined using a commercially available ELISA assay. Data was pooled to generate SAA mu g/ml threshold values correlating plasma SAA levels with radiation dose. SAA levels were statistically significant over control at all exposures between 2 and 8 Gy at 24 h postirradiation but not at 6, 48 and 72 h or 1-3 weeks postirradiation. SAA levels at 1 Gy were not significantly elevated over control at all time points. Total-body-irradiated (TBI) SAA levels at 24 h were used to generate a dose prediction model that successfully differentiated TBI mice into dose received cohorts of control/1 Gy and >= 2 Gy groups with a high degree of accuracy in a blind study. Dose prediction of partial-body exposures based on the TBI model correlated increasing predictive accuracy with percentage of body exposure to radiation. Our findings indicate that plasma SAA levels might be a useful biomarker for radiation exposure in a variety of total-and partial-body irradiation settings. (C) 2015 by Radiation Research Society C1 [Sproull, Mary; Kramp, Tamalee; Tandle, Anita; Shankavaram, Uma; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr 3B42, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU Radiation and Nuclear Countermeasures Program [Y2-OD-0332-01 NIAID]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported in part by funding from the Radiation and Nuclear Countermeasures Program, grant no. Y2-OD-0332-01 NIAID and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 43 TC 3 Z9 3 U1 0 U2 5 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2015 VL 184 IS 1 BP 14 EP 23 DI 10.1667/RR13927.1 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA CM8NA UT WOS:000357957100003 PM 26114330 ER PT J AU Kleinman, S Glynn, SA AF Kleinman, Steven Glynn, Simone A. TI Database research in transfusion medicine: The power of large numbers SO TRANSFUSION LA English DT Editorial Material ID BLOOD-CELL TRANSFUSION; HOSPITALIZED-PATIENTS; NATIONAL HEART; DONORS; OUTCOMES; RISK; SURVIVAL; LUNG; EPIDEMIOLOGY; NETHERLANDS C1 [Kleinman, Steven] UBC Sch Med, Victoria, BC, Canada. [Glynn, Simone A.] NHLBI, Blood Epidemiol & Clin Therapeut Branch, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. RP Kleinman, S (reprint author), UBC Sch Med, Victoria, BC, Canada. EM skleinman@shaw.ca NR 27 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 IS 7 BP 1591 EP 1595 DI 10.1111/trf.13139 PG 5 WC Hematology SC Hematology GA CM8LQ UT WOS:000357953000001 PM 26172144 ER PT J AU Holm, DK Moessner, BK Engle, RE Zaaijer, HL Georgsen, J Purcell, RH Christensen, PB AF Holm, Dorte K. Moessner, Belinda K. Engle, Ronald E. Zaaijer, Hans L. Georgsen, Jorgen Purcell, Robert H. Christensen, Peer B. TI Declining prevalence of hepatitis E antibodies among Danish blood donors SO TRANSFUSION LA English DT Article ID E VIRUS HEV; TRANSFUSION-ASSOCIATED HEPATITIS; NATIONAL-HEALTH; ANTI-HEV; FRANCE; SEROPREVALENCE; TRANSMISSION; INFECTION; RISK; EPIDEMIOLOGY AB BACKGROUNDThe increasing incidence of reported hepatitis E cases in Europe has focused attention on hepatitis E virus (HEV) and the risk of transfusion-transmitted hepatitis E. The aim of this study was to investigate the prevalence of antibodies to HEV (anti-HEV) among Danish blood donors in 2013 and to compare it to previous studies in Denmark. In addition we wanted to compare the relative reactivity of two different assays. STUDY DESIGN AND METHODSSamples from 504 blood donors were collected and analyzed for anti-HEV with an in-house assay developed at the National Institutes of Health (NIH). In addition the samples were analyzed with the Wantai anti-HEV assay. Demographic information and possible HEV exposure was collected by self-administered questionnaire. RESULTSUsing the NIH assay the prevalence of anti-HEV among Danish blood donors was 10.7% and with the Wantai assay the prevalence of anti-HEV was 19.8% (p<0.001). In both cases the presence of anti-HEV was significantly correlated with increasing age. In addition, anti-HEV as measured by the Wantai test was significantly associated with contact with children (p=0.01), but in multivariate analysis only age was associated with anti-HEV in both assays. By the NIH assay, the prevalence had declined from 20.6% in 2003 to 10.7% in 2013. CONCLUSIONSAnti-HEV prevalence had decreased by half among Danish blood donors over 10 years, but was still highly prevalent. The difference in reactivity of the two assays demonstrates the importance of using the same assay when comparing the anti-HEV prevalence in populations over time. C1 [Holm, Dorte K.; Georgsen, Jorgen] Odense Univ Hosp, Dept Clin Immunol, DK-5000 Odense C, Denmark. [Moessner, Belinda K.; Christensen, Peer B.] Odense Univ Hosp, Dept Infect Dis, DK-5000 Odense C, Denmark. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Zaaijer, Hans L.] Sanquin Blood Supply Fdn, Dept Blood Borne Infect, Amsterdam, Netherlands. RP Holm, DK (reprint author), Odense Univ Hosp, Dept Clin Immunol, Sdr Blvd 29, DK-5000 Odense C, Denmark. EM dorte.holm@rsyd.dk RI Christensen, Peer/B-8042-2015 FU National Institute of Allergy and Infectious Diseases, NIH FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 32 TC 13 Z9 13 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 IS 7 BP 1662 EP 1667 DI 10.1111/trf.13028 PG 6 WC Hematology SC Hematology GA CM8LQ UT WOS:000357953000012 PM 25819381 ER PT J AU Flegel, WA AF Flegel, Willy A. TI Pathogenesis and mechanisms of antibody-mediated hemolysis SO TRANSFUSION LA English DT Article ID BLOOD-GROUP ANTIGENS; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; MONOCYTE-MACROPHAGE INTERACTION; TRANSFUSION REACTIONS; GROUP-A; CLINICAL-SIGNIFICANCE; HUMAN ERYTHROCYTES; RED-CELLS; MONONUCLEAR PHAGOCYTES; INFLAMMATORY RESPONSE AB BACKGROUNDThe clinical consequences of antibodies to red blood cells (RBCs) have been studied for a century. Most clinically relevant antibodies can be detected by sensitive in vitro assays. Several mechanisms of antibody-mediated hemolysis are well understood. Such hemolysis after transfusion is reliably avoided in a donor-recipient pair, if one individual is negative for the cognate antigen to which the other has the antibody. STUDY DESIGN AND RESULTSMechanisms of antibody-mediated hemolysis were reviewed based on a presentation at the Strategies to Address Hemolytic Complications of Immune Globulin Infusions Workshop addressing intravenous immunoglobulin (IVIG) and ABO antibodies. The presented topics included the rates of intravascular and extravascular hemolysis; immunoglobulin (Ig)M and IgG isoagglutinins; auto- and alloantibodies; antibody specificity; A, B, A,B, and A1 antigens; A1 versus A2 phenotypes; monocytes-macrophages, other immune cells, and complement; monocyte monolayer assay; antibody-dependent cell-mediated cytotoxicity; and transfusion reactions due to ABO and other antibodies. CONCLUSIONSeveral clinically relevant questions remained unresolved, and diagnostic tools were lacking to routinely and reliably predict the clinical consequences of RBC antibodies. Most hemolytic transfusion reactions associated with IVIG were due to ABO antibodies. Reducing the titers of such antibodies in IVIG may lower the frequency of this kind of adverse event. The only way to stop these events is to have no anti-A or anti-B in the IVIG products. C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM waf@nih.gov FU Intramural Research Program of the NIH Clinical Center FX This work was supported by the Intramural Research Program of the NIH Clinical Center. NR 101 TC 2 Z9 2 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 SU 2 SI SI BP S47 EP S58 DI 10.1111/trf.13147 PG 12 WC Hematology SC Hematology GA CM9FE UT WOS:000358011800009 PM 26174897 ER PT J AU Klein, HG Schreiber, GB AF Klein, Harvey G. Schreiber, George B. TI Special Issue: Hemolysis Supplement Strategies to Address Hemolytic Complications of Immune Globulin Infusions SO TRANSFUSION LA English DT Editorial Material C1 [Klein, Harvey G.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20814 USA. [Schreiber, George B.] Plasma Prot Therapeut Assoc, Brussels, Belgium. RP Klein, HG (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 SU 2 SI SI BP S1 EP S1 DI 10.1111/trf.13249 PG 1 WC Hematology SC Hematology GA CM9FE UT WOS:000358011800002 PM 26174886 ER PT J AU Key, TJ Appleby, PN Reeves, GK Travis, RC Brinton, LA Dallal, CM Helzlsouer, KJ Hoffman-Bolton, J Visvanathan, K Dorgan, JF Falk, RT Gapstur, SM Gaudet, MM Kaaks, R Riboli, E Rinaldi, S Key, T Manjer, J Hallmans, G Giles, GG Le Marchand, L Kolonel, LN Henderson, BE Tworoger, SS Hankinson, SE Zeleniuch-Jacquotte, A Koenig, K Krogh, V Sieri, S Muti, P Ziegler, RG Schairer, C Fuhrman, BJ Barrett-Connor, E Laughlin, GA Grant, EJ Cologne, J Ohishi, W Hida, A Cauley, JA Fourkala, EO Rohan, TE Strickler, HD Gunter, MJ AF Key, T. J. Appleby, P. N. Reeves, G. K. Travis, R. C. Brinton, L. A. Dallal, C. M. Helzlsouer, K. J. Hoffman-Bolton, J. Visvanathan, K. Dorgan, J. F. Falk, R. T. Gapstur, S. M. Gaudet, M. M. Kaaks, R. Riboli, E. Rinaldi, S. Key, T. Manjer, J. Hallmans, G. Giles, G. G. Le Marchand, L. Kolonel, L. N. Henderson, B. E. Tworoger, S. S. Hankinson, S. E. Zeleniuch-Jacquotte, A. Koenig, K. Krogh, V. Sieri, S. Muti, P. Ziegler, R. G. Schairer, C. Fuhrman, B. J. Barrett-Connor, E. Laughlin, G. A. Grant, E. J. Cologne, J. Ohishi, W. Hida, A. Cauley, J. A. Fourkala, E.-O. Rohan, T. E. Strickler, H. D. Gunter, M. J. CA Endogenous Hormones & Breast TI Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies SO STEROIDS LA English DT Article; Proceedings Paper CT Workshop on Measuring Extrogen Exposure and Metabolism - Summary of the Presentations CY MAR 20-21, 2014 CL Bethesda, MD DE Breast cancer; Estradiol; Body mass index; Extraction immunoassay; Direct immunoassay; Mass spectrometry ID ESTROGEN METABOLISM; SERUM ESTRADIOL; TESTOSTERONE; ANDROGEN; SHBG AB Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study. (C) 2014 The Authors. Published by Elsevier Inc. C1 [Key, T. J.; Appleby, P. N.; Reeves, G. K.; Travis, R. C.; Key, T.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Brinton, L. A.] Natl Canc Inst, Hormonal & Reproduct Epidemiol Branch, Bethesda, MD USA. [Dallal, C. M.] Univ Maryland, Sch Publ Hlth, Dept Epidemiol & Biostat, College Pk, MD USA. [Helzlsouer, K. J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Hoffman-Bolton, J.; Visvanathan, K.] Johns Hopkins Univ, George W Comstock Ctr Public Hlth Res & Prevent, Hagerstown, MD USA. [Dorgan, J. F.] Univ Maryland, Sch Med, Baltimore, MD USA. [Falk, R. T.] Natl Canc Inst, Div Canc Epidemiol & Genet, Hormonal & Reproduct Epidemiol Branch, Bethesda, MD USA. [Gapstur, S. M.; Gaudet, M. M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA USA. [Kaaks, R.] DKFZ, Heidelberg, Germany. [Riboli, E.; Gunter, M. J.] Imperial Coll, Sch Publ Hlth, London, England. [Rinaldi, S.] Int Agcy Res Canc, Lyon, France. [Manjer, J.] Malmo Univ Hosp, Dept Surg, Malmo, Sweden. [Hallmans, G.] Umea Univ Hosp, Dept Clin Med & Publ Hlth, Umea, Sweden. [Giles, G. G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Le Marchand, L.; Kolonel, L. N.] Univ Hawaii Canc Ctr, Epidemiol Program, Honolulu, HI USA. [Henderson, B. E.] Univ So Calif, Los Angeles, CA USA. [Tworoger, S. S.; Hankinson, S. E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA. [Tworoger, S. S.; Hankinson, S. E.] Harvard Med Sch, Boston, MA USA. [Tworoger, S. S.; Hankinson, S. E.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hankinson, S. E.] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA USA. [Zeleniuch-Jacquotte, A.; Koenig, K.] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Krogh, V.; Sieri, S.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Muti, P.] McMaster Univ, Dept Oncol, Hamilton, ON, Canada. [Ziegler, R. G.; Schairer, C.] Natl Canc Inst, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD USA. [Fuhrman, B. J.] Univ Arkansas Med Sci, Fay W Boozman Coll Publ Hlth, Dept Epidemiol, Little Rock, AR USA. [Barrett-Connor, E.; Laughlin, G. A.] Univ Calif San Diego, Dept Family & Prevent Med, Div Epidemiol, San Diego, CA USA. [Grant, E. J.] Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Nagasaki, Japan. [Cologne, J.] Radiat Effects Res Fdn, Dept Stat, Hiroshima, Nagasaki, Japan. [Ohishi, W.; Hida, A.] Radiat Effects Res Fdn, Dept Clin Studies, Hiroshima, Nagasaki, Japan. [Cauley, J. A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA USA. [Fourkala, E.-O.] UCL, Inst Womens Hlth, Womens Canc, London, England. [Rohan, T. E.; Strickler, H. D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. RP Key, TJ (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Endogenous Hormones & Breast Canc Collaborat Grp, Richard Doll Bldg,Roosevelt Dr, Oxford OX3 7LF, England. EM tim.key@ceu.ox.ac.uk RI Cauley, Jane/N-4836-2015; Krogh, Vittorio/K-2628-2016; Sieri, Sabina/K-4667-2016; OI Cauley, Jane/0000-0003-0752-4408; Krogh, Vittorio/0000-0003-0122-8624; Sieri, Sabina/0000-0001-5201-172X; Fuhrman, Barbara/0000-0002-1777-9888; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Cancer Research UK [C570/A5028]; National Cancer Institute [R01 CA098661, P30 CA016087]; National Institute of Environmental Health Sciences [ES000260]; National Institute for Health Research University College London Hospitals Biomedical Research Centre FX The central pooling and analysis of these data was supported by Cancer Research UK (C570/A5028). Details of funding for the original studies are in the relevant publications. The NYU WHS was supported by National Cancer Institute Grants R01 CA098661 and P30 CA016087 and National Institute of Environmental Health Sciences center grant ES000260.; UKCTOCS researchers were supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. NR 31 TC 6 Z9 6 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD JUL PY 2015 VL 99 SI SI BP 49 EP 55 DI 10.1016/j.steroids.2014.09.001 PN A PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CL5FH UT WOS:000356984700009 PM 25304359 ER PT J AU Armstrong, JJ Andrew, MK Mitnitski, A Launer, LJ White, LR Rockwood, K AF Armstrong, Joshua J. Andrew, Melissa K. Mitnitski, Arnold Launer, Lenore J. White, Lon R. Rockwood, Kenneth TI Social vulnerability and survival across levels of frailty in the Honolulu-Asia Aging Study SO AGE AND AGEING LA English DT Article DE social vulnerability; frailty; frailty index; aged ID COMPREHENSIVE GERIATRIC ASSESSMENT; ELDERLY-PEOPLE; OLDER-ADULTS; HEALTH; MORTALITY; INDEX; PREVALENCE; DEFICITS; OUTCOMES; DECLINE AB Methods: in secondary analysis of the Honolulu-Asia Aging Study (HAAS), participants (n = 3,271) were aged 72-93 years at baseline. A frailty index (FI) created using 58 potential health deficits to quantify participants' frailty level at baseline, with four frailty strata: 0.0 < FI a parts per thousand currency sign 0.1 (n = 1,074); 0.1 < FI a parts per thousand currency sign 0.20 (n = 1,549); 0.2 < FI a parts per thousand currency sign 0.30 (n = 472); FI > 0.3 (n = 176). Similarly, a social vulnerability index was created using 19 self-reported social deficits. Cox proportional hazard modelling was employed to estimate the impact of social vulnerability across the four levels of frailty, accounting for age, smoking, alcohol use and variation in health deficits within each frailty level. Results: for the fittest participants, social vulnerability was associated with mortality (hazards ratio (HR) = 1.04, 95% confidence interval (CI) = 1.01, 1.07; P value = 0.008). Similarly, for those considered at risk for frailty, each social deficit was associated with a 5% increased risk of mortality. For frail individuals, the Cox regression analyses indicated that social vulnerability was not significantly associated with mortality (0.2 < FI a parts per thousand currency sign 0.3: HR = 1.016, 95% CI = 0.98, 1.06; P value = 0.442; FI > 0.3: HR = 0.98, 95% CI = 0.93, 1.04). Conclusions: for the fittest and at-risk HAAS participants, the accumulation of social deficits was associated with significant increases in mortality risk. For frail individuals (FI > 0.20), the estimation of mortality risk may depend more so on intrinsic factors related to their health. C1 [Armstrong, Joshua J.] Dalhousie Univ, Geriatr Med Res, Halifax, NS B3H 2E1, Canada. [Andrew, Melissa K.; Mitnitski, Arnold; Rockwood, Kenneth] Dalhousie Univ, Dept Med, Halifax, NS B3H 2E1, Canada. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [White, Lon R.] Pacific Hlth Res & Educ Inst, Dept Med, Honolulu, HI USA. RP Andrew, MK (reprint author), Dalhousie Univ, Ctr Hlth Care Elderly, QEII Hlth Sci Ctr, Capital Dist Hlth Author, 5955 Vet Mem Lane, Halifax, NS B3H 2E1, Canada. EM mandrew@dal.ca FU Alzheimer Society of Canada; Canadian Institutes of Health Research; Dalhousie Medical Research Foundation FX J.A. is supported by a post-doctoral fellowship award from the Alzheimer Society of Canada. A.M. is supported by an operating grant from the Canadian Institutes of Health Research. K.R. was supported by the Dalhousie Medical Research Foundation who provides career funding as the Kathryn Allen Weldon Professor of Alzheimer Research Chair. Funding bodies played no role in the design, execution, analysis, interpretation of data or writing of the study. NR 21 TC 7 Z9 7 U1 5 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 EI 1468-2834 J9 AGE AGEING JI Age Ageing PD JUL PY 2015 VL 44 IS 4 BP 709 EP 712 DI 10.1093/ageing/afv016 PG 4 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CM1DK UT WOS:000357420400033 PM 25758407 ER PT J AU Hashemian, M Poustchi, H Ahnet, CC Boffetta, P Dawsey, SM Brennan, PJ Pharoah, P Etemadi, A Kamangar, F Sharafkhah, M Hekmatdoost, A Malekzadeh, R AF Hashemian, Maryam Poustchi, Hossein Ahnet, Christian C. Boffetta, Paolo Dawsey, Sanford M. Brennan, Paul J. Pharoah, Paul Etemadi, Arash Kamangar, Farin Sharafkhah, Maryam Hekmatdoost, Azita Malekzadeh, Reza TI Dietary intake of minerals and risk of esophageal squamous cell carcinoma: results from the Golestan Cohort Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE esophageal cancer; minerals; calcium; zinc; selenium; magnesium; copper; manganese ID FOOD FREQUENCY QUESTIONNAIRE; SELENIUM SUPPLEMENTATION; CANCER STATISTICS; COLON-CANCER; DNA-DAMAGE; ZINC; CALCIUM; IRAN; CARCINOGENESIS; POPULATION AB Background: Dietary factors have been hypothesized to affect the risk of esophageal cancer via different mechanisms, but the intake of minerals is understudied and the evidence is conflicting. Objective: The objective was to evaluate the associations of dietary intake of minerals with risk of esophageal squamous cell carcinoma (ESCC). Design: We used data from the Golestan Cohort Study, which was launched in a high-risk region for esophageal cancer in Iran. Participants were enrolled in 2004-2008 and were followed to 2014. Intakes of minerals were assessed with a validated food-frequency questionnaire. A Cox proportional hazards model was used to estimate HRs and 95% Cls of ESCC for dietary intakes of selected minerals. Results: We identified 201 ESCC cases among 47,405 subjects. Calcium intake was significantly inversely associated with the risk of ESCC (HR per 100-mg/d increase: 0.88; 95% CI: 0.81, 0.96; P 0.005; quartile 4 vs. quartile 1 HR: 0.49; 95% CI: 0.29, 0.82; Ptrend = 0.013). Zinc intake was also inversely associated with ESCC, but the quartile association did not reach significance (HR per 1-mg/d increase: 0.87; 95% CI: 0.77, 0.98; P = 0.027; quartile 4 vs. quartile I HR: 0.56; 95% CI: 0.28, 1.12; P-trend = 0.097). The relations between dietary intakes of selenium, magnesium, and copper and risk of ESCC were nonlinear (P-nonlinear trend = 0.001, 0.016, and 0.029, respectively). There was no relation between dietary intake of manganese and the risk of ESCC. Conclusion: The results suggest that higher intakes of calcium and zinc are associated with a lower risk of ESCC in a high-risk region of Iran. C1 [Hashemian, Maryam] Shahid Beheshti Univ Med Sci, Int Branch, Tehran, Iran. [Hekmatdoost, Azita] Shahid Beheshti Univ Med Sci, Natl Nutr & Food Technol Res Inst, Fac Nutr & Food Technol, Dept Clin Nutr, Tehran, Iran. [Hekmatdoost, Azita] Shahid Beheshti Univ Med Sci, Natl Nutr & Food Technol Res Inst, Fac Nutr & Food Technol, Dept Dietet, Tehran, Iran. [Poustchi, Hossein; Sharafkhah, Maryam] Univ Tehran Med Sci, Digest Dis Res Inst, Liver & Pancreatobiliary Dis Res Ctr, Tehran, Iran. [Etemadi, Arash; Kamangar, Farin; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [Ahnet, Christian C.; Dawsey, Sanford M.; Etemadi, Arash; Kamangar, Farin] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Brennan, Paul J.] Int Agcy Res Canc, F-69372 Lyon, France. [Pharoah, Paul] Univ Cambridge, Dept Oncol, Canc Res UK, Cambridge, England. RP Hekmatdoost, A (reprint author), Shahid Beheshti Univ Med Sci, Natl Nutr & Food Technol Res Inst, Fac Nutr & Food Technol, Dept Clin Nutr, Tehran, Iran. EM a_hekmat2000@yahoo.com; malek@ams.ac.ir RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016 OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072 FU Tehran University of Medical Sciences, Cancer Research UK; Intramural Research Program of the US National Cancer Institute at the NIH; International Agency for Research on Cancer FX Supported by Tehran University of Medical Sciences, Cancer Research UK, the Intramural Research Program of the US National Cancer Institute at the NIH, and through various collaborative research agreements with the International Agency for Research on Cancer. NR 49 TC 6 Z9 7 U1 0 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2015 VL 102 IS 1 BP 102 EP + DI 10.3945/ajcn.115.107847 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM1FD UT WOS:000357425500015 PM 26016858 ER PT J AU Wentzensen, N Eldridge, RC AF Wentzensen, Nicolas Eldridge, Ronald C. TI Invited Commentary: Clinical Utility of Prediction Models for Rare Outcomes-The Example of Pancreatic Cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE absolute risk; clinical relevance; rare endpoints; risk prediction; risk stratification; translational epidemiology AB Translating relative risk estimates into absolute risks is important in evaluating the potential clinical and public health relevance of etiologic discoveries. Predicting high absolute risk is challenging, particularly for rare endpoints such as pancreatic cancer. Recent efforts to develop risk prediction models for pancreatic cancer have found moderate risk levels for very small parts of the population. A new approach in which clinical symptoms and medication use are evaluated in addition to information on risk factors is presented by Risch et al. in this issue of the Journal (Am J Epidemiol. 2015;182(1):26-34). The authors estimated absolute risks based on the relative risks obtained from their case-control study. Their absolute risk estimates were higher than those from previous approaches but remained restricted to a very small proportion of the general population. In the present commentary, we address issues of absolute risk stratification (particularly for rare diseases), specific analytic methods, and how actionable information will differ based on the disease and possible intervention. We suggest that moving from cancer-specific models to broader models used to predict risk for multiple outcomes can make risk prediction for rare diseases more effective. When considering translational goals, it is important to estimate absolute risk at the early stages of etiologic research. The results can be sobering but allow focusing on the most promising goals. C1 [Wentzensen, Nicolas; Eldridge, Ronald C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7-E114, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov FU Intramural NIH HHS NR 8 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2015 VL 182 IS 1 BP 35 EP 38 DI 10.1093/aje/kwv028 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM1DQ UT WOS:000357421100005 PM 26049862 ER PT J AU Lin, GM Colangelo, LA Lloyd-Jones, DM Redline, S Yeboah, J Heckbert, SR Nazarian, S Alonso, A Bluemke, DA Punjabi, NM Szklo, M Liu, K AF Lin, Gen-Min Colangelo, Laura A. Lloyd-Jones, Donald M. Redline, Susan Yeboah, Joseph Heckbert, Susan R. Nazarian, Saman Alonso, Alvaro Bluemke, David A. Punjabi, Naresh M. Szklo, Moyses Liu, Kiang TI Association of Sleep Apnea and Snoring With Incident Atrial Fibrillation in the Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE atrial fibrillation; longitudinal studies; sleep apnea; snoring ID ALL-CAUSE MORTALITY; NOCTURNAL ARRHYTHMIAS; CARDIOVASCULAR-DISEASE; AFRICAN-AMERICANS; HEART HEALTH; RISK-FACTORS; OBESITY; WOMEN; PREVALENCE; MEN AB The association between sleep apnea and atrial fibrillation (AF) has not been examined in a multiethnic adult population in prospective community-based studies. We prospectively (2000-2011) investigated the associations of physician-diagnosed sleep apnea (PDSA), which is considered more severe sleep apnea, and self-reported habitual snoring without PDSA (HS), a surrogate for mild sleep apnea, with incident AF in white, black, and Hispanic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease at baseline (2000-2002). Cox proportional hazards models were used to assess the associations, with adjustment for socioeconomic status, traditional vascular disease risk factors, race/ethnicity, body mass index, diabetes, chronic kidney disease, alcohol intake, and lipid-lowering therapy. Out of 4,395 respondents to a sleep questionnaire administered in MESA, 181 reported PDSA, 1,086 reported HS, and 3,128 reported neither HS nor PDSA (unaffected). Over an average 8.5-year follow-up period, 212 AF events were identified. As compared with unaffected participants, PDSA was associated with incident AF in the multivariable analysis, but HS was not (PDSA: hazard ratio = 1.76, 95% confidence interval: 1.03, 3.02; HS: hazard ratio = 1.02, 95% confidence interval: 0.72, 1.44). PDSA, a marker of more severe sleep apnea, was associated with higher risk of incident AF in this analysis of MESA data. C1 [Lin, Gen-Min; Colangelo, Laura A.; Lloyd-Jones, Donald M.; Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Lin, Gen-Min] Hualien Armed Forces Gen Hosp, Dept Med, Hualien, Taiwan. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Dept Med, Sch Med, Boston, MA 02115 USA. [Redline, Susan] Beth Israel Deaconess Med Sch, Boston, MA USA. [Yeboah, Joseph] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Heckbert, Susan R.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Nazarian, Saman] Johns Hopkins Univ, Sch Med, Div Cardiol, Sect Cardiac Electrophysiol, Baltimore, MD USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Punjabi, Naresh M.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. [Szklo, Moyses] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Lin, GM (reprint author), Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, 680 North Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM farmer507@yahoo.com.tw RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167]; National Heart, Lung, and Blood Institute [R21HL121348]; Ministry of Defense, Taiwan FX This research was supported by National Institutes of Health contracts N01-HC-95159 through N01-HC-95167 and grant R21HL121348 from the National Heart, Lung, and Blood Institute. G.-M.L. was supported by a scholarship grant from the Ministry of Defense, Taiwan. NR 42 TC 7 Z9 7 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2015 VL 182 IS 1 BP 49 EP 57 DI 10.1093/aje/kwv004 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM1DQ UT WOS:000357421100008 PM 25977516 ER PT J AU Brehm, JM Ramratnam, SK Tse, SM Croteau-Chonka, DC Pino-Yanes, M Rosas-Salazar, C Litonjua, AA Raby, BA Boutaoui, N Han, YY Chen, W Forno, E Marsland, AL Nugent, NR Eng, C Colon-Semidey, A Alvarez, M Acosta-Perez, E Spear, ML Martinez, FD Avila, L Weiss, ST Soto-Quiros, M Ober, C Nicolae, DL Barnes, KC Lemanske, RF Strunk, RC Liu, A London, SJ Gilliland, F Sleiman, P March, M Hakonarson, H Duan, QL Kolls, JK Fritz, GK Hu, DL Fani, N Stevens, JS Almli, LM Burchard, EG Shin, J McQuaid, EL Ressler, K Canino, G Celedon, JC AF Brehm, John M. Ramratnam, Sima K. Tse, Sze Man Croteau-Chonka, Damien C. Pino-Yanes, Maria Rosas-Salazar, Christian Litonjua, Augusto A. Raby, Benjamin A. Boutaoui, Nadia Han, Yueh-Ying Chen, Wei Forno, Erick Marsland, Anna L. Nugent, Nicole R. Eng, Celeste Colon-Semidey, Angel Alvarez, Maria Acosta-Perez, Edna Spear, Melissa L. Martinez, Fernando D. Avila, Lydiana Weiss, Scott T. Soto-Quiros, Manuel Ober, Carole Nicolae, Dan L. Barnes, Kathleen C. Lemanske, Robert F., Jr. Strunk, Robert C. Liu, Andrew London, Stephanie J. Gilliland, Frank Sleiman, Patrick March, Michael Hakonarson, Hakon Duan, Qing Ling Kolls, Jay K. Fritz, Gregory K. Hu, Donglei Fani, Negar Stevens, Jennifer S. Almli, Lynn M. Burchard, Esteban G. Shin, Jaemin McQuaid, Elizabeth L. Ressler, Kerry Canino, Glorisa Celedon, Juan C. TI Stress and Bronchodilator Response in Children with Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE asthma; Puerto Ricans; bronchodilator response; stress ID PUERTO-RICAN CHILDREN; ADCYAP1R1 GENOTYPE; CHILDHOOD ASTHMA; DIAGNOSTIC-ACCURACY; MANAGEMENT PROGRAM; VIOLENCE EXPOSURE; GENE POLYMORPHISM; PAC1 RECEPTOR; DISORDER; SYMPTOMS AB Rationale: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). Objectives: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. Methods: This was a cross-sectional study of stress-and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. Measurements and Main Results: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the beta(2)-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). Conclusions: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children. C1 [Brehm, John M.; Ramratnam, Sima K.; Rosas-Salazar, Christian; Boutaoui, Nadia; Han, Yueh-Ying; Chen, Wei; Forno, Erick; Kolls, Jay K.; Celedon, Juan C.] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Div Pulm Med Allergy & Immunol, Pittsburgh, PA USA. [Marsland, Anna L.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Tse, Sze Man; Croteau-Chonka, Damien C.; Litonjua, Augusto A.; Raby, Benjamin A.; Weiss, Scott T.; Duan, Qing Ling] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Pino-Yanes, Maria; Eng, Celeste; Spear, Melissa L.; Hu, Donglei; Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Pino-Yanes, Maria; Eng, Celeste; Spear, Melissa L.; Hu, Donglei; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Pino-Yanes, Maria] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Nugent, Nicole R.] Brown Univ, Sch Med, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Colon-Semidey, Angel; Alvarez, Maria; Acosta-Perez, Edna; Canino, Glorisa] Univ Puerto Rico, Behav Sci Res Inst, San Juan, PR 00936 USA. [Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Martinez, Fernando D.] Univ Arizona, Inst BIO5, Tucson, AZ USA. [Avila, Lydiana; Soto-Quiros, Manuel] Hosp Nacl Ninos Dr Carlos Saenz Herrera, Div Pediat Pulmonol, San Jose, Costa Rica. [Ober, Carole; Nicolae, Dan L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Lemanske, Robert F., Jr.] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA. [Lemanske, Robert F., Jr.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Strunk, Robert C.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Liu, Andrew] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Gilliland, Frank] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Sleiman, Patrick; March, Michael; Hakonarson, Hakon] Childrens Hosp Philadelphia, Res Inst, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Sleiman, Patrick; Hakonarson, Hakon] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Fani, Negar; Stevens, Jennifer S.; Almli, Lynn M.; Ressler, Kerry] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Shin, Jaemin] Georgia Inst Technol, Ctr Adv Brain Imaging, Atlanta, GA 30332 USA. [Shin, Jaemin] Georgia State Univ, Atlanta, GA 30303 USA. RP Celedon, JC (reprint author), UPMC, Div Pediat Pulm Med Allergy & Immunol, Childrens Hosp Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224 USA. EM juan.celedon@chp.edu RI Pino-Yanes, Maria/C-8498-2017; OI Pino-Yanes, Maria/0000-0003-0332-437X; acosta, edna/0000-0001-7101-3157; Rosas-Salazar, Christian/0000-0001-6644-5780; London, Stephanie/0000-0003-4911-5290 FU U.S. National Institutes of Health (NIH) [HL079966, HL073373, HL117191]; NIH [HL066289, HL04370, U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, U01 HL 072438, R01-ES015794, R01-HL088133, R01-HL078885, T32-GM007546, R01-HL004464, R01-HL104608, HL117004, HD052892]; National Institute on Minority Health and Health Disparities [P60MD006902]; Sandler Foundation; American Asthma Foundation; NHLBI [U01 HL51510, U01 HL51834, U01 HL51831, U01 HL51845, U01 HL51843, M01 RR00079, M01 RR03186, T32 HL007427]; Intramural Research Program of the NIH, NIEHS; Mary Beryl Patch Turnbull Scholar Program; Fundacion Ramon Areces FX Supported by grants HL079966, HL073373, and HL117191 from the U.S. National Institutes of Health (NIH). The Genetics of Asthma in Costa Rica Study was supported by grants HL066289 and HL04370 from the NIH. The CAMP Genetics Ancillary Study was supported by grants U01 HL075419, U01 HL65899, P01 HL083069, and R01 HL086601 from the NIH. The RIPRAC study was supported by U01 HL 072438 from the NIH. The SAGE and GALA studies were supported by grants from the NIH (R01-ES015794, R01-HL088133, R01-HL078885, T32-GM007546, R01-HL004464, R01-HL104608, HL117004; and the National Institute on Minority Health and Health Disparities under Award Number P60MD006902), the Sandler Foundation, and the American Asthma Foundation (E.G.B.). The Single-Nucleotide Polymorphism Health Association Asthma Resource Project was funded by NHLBI grants U01 HL51510, U01 HL51834, U01 HL51831, U01 HL51845, U01 HL51843, M01 RR00079, and M01 RR03186, and was performed by researchers from the CAMP and Childhood Asthma Research and Education Network. J.M.B. was supported by grant HD052892 from the NIH. S.J.L. is supported by the Intramural Research Program of the NIH, NIEHS. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. M.P.-Y. was funded by a postdoctoral fellowship from Fundacion Ramon Areces. D.C.C.-C. was supported by grant T32 HL007427 from the NHLBI. NR 64 TC 13 Z9 13 U1 10 U2 17 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2015 VL 192 IS 1 BP 47 EP 56 DI 10.1164/rccm.201501-0037OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CM6YY UT WOS:000357838800011 PM 25918834 ER PT J AU Thomas, SJ Aldstadt, J Jarman, RG Buddhari, D Yoon, IK Richardson, JH Ponlawat, A Iamsirithaworn, S Scott, TW Rothman, AL Gibbons, RV Lambrechts, L Endy, TP AF Thomas, Stephen J. Aldstadt, Jared Jarman, Richard G. Buddhari, Darunee Yoon, In-Kyu Richardson, Jason H. Ponlawat, Alongkot Iamsirithaworn, Sopon Scott, Thomas W. Rothman, Alan L. Gibbons, Robert V. Lambrechts, Louis Endy, Timothy P. TI Improving Dengue Virus Capture Rates in Humans and Vectors in Kamphaeng Phet Province, Thailand, Using an Enhanced Spatiotemporal Surveillance Strategy SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PRIMARY-SCHOOL CHILDREN; AEDES-AEGYPTI; HEMORRHAGIC-FEVER; HUMAN MOVEMENT; TRANSMISSION; INFECTIONS; VILLAGES; EPIDEMIOLOGY; SEVERITY; DISEASE AB Dengue is of public health importance in tropical and sub-tropical regions. Dengue virus (DENV) transmission dynamics was studied in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance of 93 hospitalized subjects with confirmed dengue (initiates) and associated cluster individuals (associates) with entomologic sampling. A total of 438 associates were enrolled from 208 houses with household members with a history of fever, located within a 200-m radius of an initiate case. Of 409 associates, 86(21%) had laboratory-confirmed DENV infection. A total of 63 (1.8%) of the 3,565 mosquitoes collected were dengue polymerase chain reaction positive (PCR+). There was a significant relationship between spatial proximity to the initiate case and likelihood of detecting DENV from associate cases and Aedes mosquitoes. The viral detection rate from human hosts and mosquito vectors in this study was higher than previously observed by the study team in the same geographic area using different methodologies. We propose that the sampling strategy used in this study could support surveillance of DENV transmission and vector interactions. C1 [Thomas, Stephen J.; Jarman, Richard G.] Walter Reed Army Inst Res, Viral Dis Branch, Silver Spring, MD 20910 USA. [Buddhari, Darunee] Armed Forces Res Inst Med Sci, US Army Med Component, Dept Virol, Bangkok 10400, Thailand. [Aldstadt, Jared] SUNY Buffalo, Dept Geog, Buffalo, NY 14260 USA. Armed Forces Res Inst Med Sci, Dept Entomol, Bangkok 10400, Thailand. [Iamsirithaworn, Sopon] Minist Publ Hlth, Dept Dis Control Sci, Bur Epidemiol, Nonthaburi, Thailand. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Rothman, Alan L.] Univ Rhode Isl, Inst Immunol & Informat, Providence, RI 02908 USA. [Lambrechts, Louis] CNRS, Inst Pasteur, Insect Virus Interact Grp, Dept Genomes & Genet, Paris, France. [Endy, Timothy P.] SUNY Syracuse, Dept Infect Dis, Syracuse, NY USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Yoon, In-Kyu; Gibbons, Robert V.] Armed Forces Res Inst Med Sci, Dept Virol, Bangkok 10400, Thailand. [Richardson, Jason H.] Armed Forces Pest Management Board, Silver Spring, MD USA. [Richardson, Jason H.] Walter Reed Army Inst Res, Entomol Branch, Silver Spring, MD 20910 USA. [Ponlawat, Alongkot] Armed Forces Res Inst Med Sci, Entomol Branch, Bangkok 10400, Thailand. RP Thomas, SJ (reprint author), Walter Reed Army Inst Res, Viral Dis Branch, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM stephen.j.thomas3.mil@mail.mil; geojared@buffalo.edu; richard.g.jarman.mil@mail.mil; DaruneeT@afrims.org; In-Kyu.Yoon@afrims.org; jason.h.richardson.mil@mail.mil; AlongkotP@afrims.org; iamsiri@yahoo.com; twscott@ucdavis.edu; alan_rothman@mail.uri.edu; robert.v.gibbons2.mil@mail.mil; lambrechts.louis@gmail.com; endyt@upstate.edu RI Aldstadt, Jared/A-8508-2009; Lambrechts, Louis/A-2057-2010 OI Aldstadt, Jared/0000-0001-9162-7439; Lambrechts, Louis/0000-0001-5958-2138 FU NIAID NIH HHS [P01 AI034533] NR 32 TC 2 Z9 2 U1 1 U2 6 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2015 VL 93 IS 1 BP 24 EP 32 DI 10.4269/ajtmh.14-0242 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CM5YG UT WOS:000357764300007 PM 25986580 ER PT J AU Faust, C Zelner, J Brasseur, P Vaillant, M Badiane, M Cisse, M Grenfell, B Olliaro, P AF Faust, Christina Zelner, Jonathan Brasseur, Philippe Vaillant, Michel Badiane, Malick Cisse, Moustafa Grenfell, Bryan Olliaro, Piero TI Assessing Drivers of Full Adoption of Test and Treat policy for Malaria in Senegal SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID RAPID DIAGNOSTIC-TESTS; PRESUMPTIVE TREATMENT; SOUTHERN SENEGAL; RANDOMIZED-TRIAL; FEBRILE ILLNESS; CASE-MANAGEMENT; TANZANIA; MICROSCOPY; SAFETY; TRANSMISSION AB Malaria treatment policy has changed from presumptive treatment to targeted "test and treat" (T&T) with malaria rapid diagnostic tests (RDTs) and artemisinin combination therapy (ACT). This transition involves changing behavior among health providers, meaning delays between introduction and full implementation are recorded in almost every instance. We investigated factors affecting successful transition, and suggest approaches for accelerating uptake of T&T. Records from 2000 to 2011 from health clinics in Senegal where malaria is mesoendemic were examined (96,166 cases). The study period encompassed the implementation of national T&T policy in 2006. Analysis showed that adherence to test results is the first indicator of T&T adoption and is dependent on accumulation of experience with positive RDTs (odds ratio [OR]: 0.55 [P <= 0.0011, 95% confidence interval [CI]: 0.53-0.58). Reliance on tests for malaria diagnosis (rather than presumptive diagnosis) followed after test adherence is achieved, and was also associated with increased experience with positive RDTs (OR: 0.60 [P <= 0.0011, 95% CI: 0.58-0.62). Logistic models suggest that full adoption of T&T clinical practices can occur within 2 years, that monitoring these behavioral responses rather than RDT or ACT consumption will improve evaluation of T&T uptake, and that accelerating T&T uptake by focusing training on adherence to test results will reduce overdiagnosis and associated health and economic costs in mesoendemic regions. C1 [Faust, Christina] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08542 USA. [Zelner, Jonathan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Brasseur, Philippe] IRD, UMR 198, Dakar, Senegal. [Vaillant, Michel] Ctr Rech Publ CRP Sante, Methodol & Stat Unit CCMS, Strassen, Luxembourg. [Badiane, Malick] Dist Med Oussouye, Oussouye, Senegal. [Cisse, Moustafa] Minist Sante & Prevent, PNLP, Dakar, Senegal. [Grenfell, Bryan] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. [Olliaro, Piero] UNICEF UNDP WB WHO Special Programme Res & Traini, Geneva, Switzerland. [Olliaro, Piero] Univ Oxford, Ctr Trop Med, Oxford, England. RP Faust, C (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, 106A Guyot Hall, Princeton, NJ 08542 USA. EM cfaust@princeton.edu; jzelner@princeton.edu; philippe.brasseur@ird.fr; michel.vaillant@free.fr; serignemalick@yahoo.fr; mcdoussouye@yahoo.fr; grenfell@princeton.edu; olliarop@who.int OI Faust, Christina L./0000-0002-8824-7424 FU National Defense Science and Engineering Graduate (NDSEG) Fellowship; Center for Health and Wellbeing at Princeton University; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the National Institutes of Health; Science and Technology Directorate of the Department of Homeland Security; Bill and Melinda Gates Foundation FX Christina Faust was funded by National Defense Science and Engineering Graduate (NDSEG) Fellowship and Center for Health and Wellbeing at Princeton University. Jonathan Zelner and Bryan Grenfell were funded by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the National Institutes of Health and the Science and Technology Directorate of the Department of Homeland Security. Bryan Grenfell was also funded by the Bill and Melinda Gates Foundation. NR 36 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2015 VL 93 IS 1 BP 159 EP 167 DI 10.4269/ajtmh.14-0595 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CM5YG UT WOS:000357764300028 PM 25962776 ER PT J AU Aranow, C Kamen, DL Dall'Era, M Massarotti, EM Mackay, MC Koumpouras, F Coca, A Chatham, WW Clowse, MEB Criscione-Schreiber, LG Callahan, S Goldmuntz, EA Keyes-Elstein, L Oswald, M Gregersen, PK Diamond, B AF Aranow, Cynthia Kamen, Diane L. Dall'Era, Maria Massarotti, Elena M. Mackay, Meggan C. Koumpouras, Fotios Coca, Andreea Chatham, W. Winn Clowse, Megan E. B. Criscione-Schreiber, Lisa G. Callahan, Sherri Goldmuntz, Ellen A. Keyes-Elstein, Lynette Oswald, Michaela Gregersen, Peter K. Diamond, Betty TI Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D-3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID INDUCIBLE GENE-EXPRESSION; DISEASE-ACTIVITY; CELL-DIFFERENTIATION; D SUPPLEMENTATION; REVISED CRITERIA; D DEFICIENCY; ALPHA; ASSOCIATION; CLASSIFICATION; ACTIVATION AB ObjectiveVitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. MethodsSLE patients (n=57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level 20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D-3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed. ResultsBaseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D-3, or high-dose vitamin D-3) were similar. Repletion of 25(OH)D (i.e., levels 30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D-3. The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n=40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D-3 was well tolerated, and there were no safety concerns. ConclusionVitamin D-3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes. C1 [Aranow, Cynthia; Mackay, Meggan C.; Oswald, Michaela; Gregersen, Peter K.; Diamond, Betty] Feinstein Inst Med Res, Manhasset, NY 11030 USA. [Kamen, Diane L.] Med Univ S Carolina, Charleston, SC USA. [Dall'Era, Maria] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massarotti, Elena M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Massarotti, Elena M.] Harvard Univ, Sch Med, Boston, MA USA. [Koumpouras, Fotios] West Penn Hosp, Pittsburgh, PA USA. [Coca, Andreea] Univ Rochester, Rochester, NY USA. [Chatham, W. Winn] Univ Alabama Birmingham, Birmingham, AL USA. [Criscione-Schreiber, Lisa G.] Duke Univ, Med Ctr, Durham, NC USA. [Callahan, Sherri; Goldmuntz, Ellen A.] NIAID, NIH, Bethesda, MD 20892 USA. [Keyes-Elstein, Lynette] Rho Fed Syst, Chapel Hill, NC USA. RP Aranow, C (reprint author), Feinstein Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA. EM caranow@nshs.edu FU Autoimmunity Centers of Excellence, a consortium - National Institute of Allergy and Infectious Diseases, NIH [U19-AI-056363, U19-AI-0563626]; NIH (National Center for Advancing Translational Sciences) [UL1-TR-00165]; NIH (National Center for Research Resources) [UL1-RR-029882]; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [K23-AR-052364] FX Supported by the Autoimmunity Centers of Excellence (grants U19-AI-056363 and U19-AI-0563626), a consortium funded by the National Institute of Allergy and Infectious Diseases, NIH. Additional support was provided by the NIH (National Center for Advancing Translational Sciences award UL1-TR-00165 to the University of Alabama at Birmingham, National Center for Research Resources award UL1-RR-029882 to the Medical University of South Carolina, and National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K23-AR-052364 to the Medical University of South Carolina). NR 29 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUL PY 2015 VL 67 IS 7 BP 1848 EP 1857 DI 10.1002/art.39108 PG 10 WC Rheumatology SC Rheumatology GA CL5QA UT WOS:000357013500020 PM 25777546 ER PT J AU Grayson, PC Carmona-Rivera, C Xu, LJ Lim, N Gao, Z Asare, AL Specks, U Stone, JH Seo, P Spiera, RF Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Tchao, NK Ytterberg, SR Phippard, DJ Merkel, PA Kaplan, MJ Monach, PA AF Grayson, Peter C. Carmona-Rivera, Carmelo Xu, Lijing Lim, Noha Gao, Zhong Asare, Adam L. Specks, Ulrich Stone, John H. Seo, Philip Spiera, Robert F. Langford, Carol A. Hoffman, Gary S. Kallenberg, Cees G. M. St Clair, E. William Tchao, Nadia K. Ytterberg, Steven R. Phippard, Deborah J. Merkel, Peter A. Kaplan, Mariana J. Monach, Paul A. CA Rituximab ANCA-Associated TI Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID SMALL-VESSEL VASCULITIS; ANCA-ASSOCIATED VASCULITIS; WEGENERS-GRANULOMATOSIS; TREATMENT RESISTANCE; NETTING NEUTROPHILS; EXTRACELLULAR TRAPS; RELAPSE; TRANSCRIPTION; PROTEINASE-3; PREDICTORS AB ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV. MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions. ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (P<0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders (P<0.01) and during active disease than during remission (P<0.01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response (P<0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO. ConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV. C1 [Grayson, Peter C.; Carmona-Rivera, Carmelo; Kaplan, Mariana J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Xu, Lijing; Lim, Noha; Gao, Zhong; Asare, Adam L.; Tchao, Nadia K.; Phippard, Deborah J.] Immune Tolerance Network, Bethesda, MD USA. [Specks, Ulrich; Ytterberg, Steven R.] Mayo Clin Fdn, Rochester, MN USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, Robert F.] Hosp Special Surg, New York, NY 10021 USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Monach, Paul A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Grayson, PC (reprint author), NIAMSD, NIH, 10 Ctr Dr,Bldg 10,Room 216G, Bethesda, MD 20892 USA. EM peter.grayson@nih.gov FU Immune Tolerance Network (NIH), an international clinical research consortium headquartered at the University of California San Francisco [N01-AI-15416]; NIH through National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program; National Center for Advancing Translational Sciences (Boston University-Clinical and Translational Science Institute) [KL2-TR-000158]; Rheumatology Scientist Development Award from Rheumatology Research Foundation; Genentech; ChemoCentryx; GlaxoSmithKline; Eli Lilly; MedImmune FX The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was performed with the support of the Immune Tolerance Network (NIH contract N01-AI-15416, protocol number ITN-21AI), an international clinical research consortium headquartered at the University of California San Francisco. Additional support was provided by the NIH through the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program and the National Center for Advancing Translational Sciences (Boston University-Clinical and Translational Science Institute grant KL2-TR-000158). Dr. Grayson's work was supported by a Rheumatology Scientist Development Award from the Rheumatology Research Foundation.; Drs. Specks and Stone have received consulting fees, speaking fees, and/or honoraria from Genentech (less than $10,000). Dr. Kallenberg has received consulting fees from ChemoCentryx, GlaxoSmithKline, Eli Lilly, and MedImmune (less than $10,000 each). NR 38 TC 19 Z9 20 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUL PY 2015 VL 67 IS 7 BP 1922 EP 1932 DI 10.1002/art.39153 PG 11 WC Rheumatology SC Rheumatology GA CL5QA UT WOS:000357013500028 PM 25891759 ER PT J AU Karamzadeh, N Ardeshirpour, Y Kellman, M Chowdhry, F Anderson, A Chorlian, D Wegman, E Gandjbakhche, A AF Karamzadeh, Nader Ardeshirpour, Yasaman Kellman, Matthew Chowdhry, Fatima Anderson, Afrouz Chorlian, David Wegman, Edward Gandjbakhche, Amir TI Relative brain signature: a population-based feature extraction procedure to identify functional biomarkers in the brain of alcoholics SO BRAIN AND BEHAVIOR LA English DT Article DE Alcoholism; classification; electroencephalography's; functional biomarker ID WORKING-MEMORY; EEG; FMRI; CONNECTIVITY; SPECTROSCOPY; DYSFUNCTION; POTENTIALS; COMPLEXITY; PATTERNS; TASKS AB BackgroundA novel feature extraction technique, Relative-Brain-Signature (RBS), which characterizes subjects' relationship to populations with distinctive neuronal activity, is presented. The proposed method transforms a set of Electroencephalography's (EEG) time series in high dimensional space to a space of fewer dimensions by projecting time series onto orthogonal subspaces. MethodsWe apply our technique to an EEG data set of 77 abstinent alcoholics and 43 control subjects. To characterize subjects' relationship to the alcoholic and control populations, one RBS vector with respect to the alcoholic and one with respect to the control population is constructed. We used the extracted RBS vectors to identify functional biomarkers over the brain of alcoholics. To achieve this goal, the classification algorithm was used to categorize subjects into alcoholics and controls, which resulted in 78% accuracy. Results and ConclusionsUsing the results of the classification, regions with distinctive functionality in alcoholic subjects are detected. These affected regions, with respect to their spatial extent, are frontal, anterior frontal, centro-parietal, parieto-occiptal, and occipital lobes. The distribution of these regions over the scalp indicates that the impact of the alcohol in the cerebral cortex of the alcoholics is spatially diffuse. Our finding suggests that these regions engage more of the right hemisphere relative to the left hemisphere of the alcoholics' brain. C1 [Karamzadeh, Nader; Wegman, Edward] George Mason Univ, Sch Phys Astron & Computat Sci, Fairfax, VA 22030 USA. [Karamzadeh, Nader; Ardeshirpour, Yasaman; Kellman, Matthew; Chowdhry, Fatima; Anderson, Afrouz; Gandjbakhche, Amir] NICHHD, NIH, Bethesda, MD 20814 USA. [Chorlian, David] Suny Downstate Med Ctr, Henri Begleiter Neurodynam Lab, Dept Psychiat, Brooklyn, NY 11203 USA. RP Gandjbakhche, A (reprint author), NICHHD, NIH, BG 9 RM 1E116,9 Mem DR, Bethesda, MD 20814 USA. EM amir@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We acknowledge the funding of the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We would like to thank B. Porjesz, director of the Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Medical Center, for her assistance with the data set. NR 41 TC 1 Z9 1 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD JUL PY 2015 VL 5 IS 7 AR e00335 DI 10.1002/brb3.335 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CM2OK UT WOS:000357520700003 PM 26221569 ER PT J AU Massey, PR Prasad, V Figg, WD Fojo, T AF Massey, Paul R. Prasad, Vinay Figg, William D. Fojo, Tito TI Multiplying therapies and reducing toxicity in metastatic melanoma SO CANCER BIOLOGY & THERAPY LA English DT Article DE Melanoma; MAPK pathway; BRAF; MEK; PD-1; ERK-signaling; vemurafenib; dabrafenib; trametinib; cobimetenib ID SQUAMOUS-CELL CARCINOMAS; BRAF-MUTATED MELANOMA; IMPROVED SURVIVAL; MEK INHIBITION; RAF INHIBITORS; OPEN-LABEL; VEMURAFENIB; TRIAL; MULTICENTER; DABRAFENIB AB Prior to 2011, only 2 systemic treatments were approved for the treatment of melanoma and these had limited efficacy. In the past 4years, 6 novel agents have received FDA approval. Herein, we will focus on 4 recently published NEJM papers reporting the results of clinical trials, comprising 4 agents targeting the MAPK pathway: the BRAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitors trametinib and cobimetenib. These have been developed in parallel with a class of immunologic mediators often referred to as immune checkpoint inhibitors.These recent studies represent a marked acceleration of progress in the treatment of metastatic melanoma. While it was hoped that combining BRAF and MEK inhibitors would significantly mitigate drug resistance, such combinations have yielded only modestly better results than monotherapy. However, these combinations were successful in reducing the development of cutaneous squamous cell carcinomas and keratocanthomas. Therefore, combination therapies are clearly warranted. Thus far there are only limited data addressing the value of combinations of immunotherapeutic agents: a phase 1 trial of concurrent nivolumab plus ipilimumab suggested enhanced activity that may not depend on BRAF mutation status.Despite the attention and publicity given to the progress achieved in the therapy of melanoma, the majority of patients with metastatic disease still have a poor prognosis. Even novel combination regiments of BRAF and MEK inhibitors achieve complete response in only 13% of patients and a median PFS of 11.4months in all patients. Better therapies remain desperately needed, especially for the 30-40% of patients with wild-type BRAF, for whom BRAF/MAPK inhibition offers no benefit. In the latter benefit is expected from emerging immunotherapies either singly or in combinations. The extent to which immunotherapies will add to regimens targeting BRAF remains to be determined. C1 [Massey, Paul R.] Univ Texas Austin, Dell Med Sch, Austin, TX 78712 USA. [Prasad, Vinay; Figg, William D.; Fojo, Tito] NCI, Med Oncol Serv, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Oncol Serv, Ctr Canc Res, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Prasad, Vinay/0000-0002-6110-8221 NR 33 TC 3 Z9 3 U1 1 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2015 VL 16 IS 7 BP 1014 EP 1018 DI 10.1080/15384047.2015.1046650 PG 5 WC Oncology SC Oncology GA CM5AW UT WOS:000357699300003 PM 26016850 ER PT J AU Thrift, AP Gong, J Peters, U Chang-Claude, J Rudolph, A Slattery, ML Chan, AT Locke, A Kahali, B Justice, AE Pers, TH Gallinger, S Hayes, RB Baron, JA Caan, BJ Ogino, S Berndt, SI Chanock, SJ Casey, G Haile, RW Du, MM Harrison, TA Thornquist, M Duggan, DJ Le Marchand, L Lindor, NM Seminara, D Song, MY Wu, K Thibodeau, SN Cotterchio, M Win, AK Jenkins, MA Hopper, J Ulrich, CM Potter, JD Newcomb, PA Hoffmeister, M Brenner, H White, E Hsu, L Campbell, PT AF Thrift, Aaron P. Gong, Jian Peters, Ulrike Chang-Claude, Jenny Rudolph, Anja Slattery, Martha L. Chan, Andrew T. Locke, Adame. Kahali, Bratati Justice, Anne E. Pers, Tune H. Gallinger, Steven Hayes, Richard B. Baron, John A. Caan, Bette J. Ogino, Shuji Berndt, Sonja I. Chanock, Stephen J. Casey, Graham Haile, Robert W. Du, Mengmeng Harrison, Tabitha A. Thornquist, Mark Duggan, David J. Le Marchand, Loic Lindor, Noralane M. Seminara, Daniela Song, Mingyang Wu, Kana Thibodeau, Stephen N. Cotterchio, Michelle Win, Aung Ko Jenkins, Mark A. Hopper, Johnl. Ulrich, Cornelia M. Potter, John D. Newcomb, Polly A. Hoffmeister, Michael Brenner, Hermann White, Emily Hsu, Li Campbell, Peter T. TI Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; INSTRUMENTAL VARIABLES; MICROSATELLITE INSTABILITY; SUSCEPTIBILITY LOCI; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; COLON-CANCER; OBESITY; DESIGN; HEALTH AB Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: Weused data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study-identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk[ per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10-1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m(2), 1.50; 95% CI, 1.13-2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m(2), 1.82; 95% CI, 1.26-2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m(2), 1.18; 95% CI, 0.73-1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. (C) 2015 AACR. C1 [Thrift, Aaron P.; Gong, Jian; Peters, Ulrike; Du, Mengmeng; Harrison, Tabitha A.; Thornquist, Mark; Potter, John D.; Newcomb, Polly A.; White, Emily; Hsu, Li] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA. [Thrift, Aaron P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Thrift, Aaron P.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Peters, Ulrike; Du, Mengmeng; Potter, John D.; Newcomb, Polly A.; White, Emily] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chan, Andrew T.; Du, Mengmeng] Harvard Univ, Sch Med, Boston, MA USA. [Locke, Adame.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kahali, Bratati] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Kahali, Bratati] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Justice, Anne E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Pers, Tune H.] Boston Childrens Hosp, Div Endocrinol & Genet, Boston, MA USA. [Pers, Tune H.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA. [Pers, Tune H.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Pers, Tune H.] Harvard Univ, Cambridge, MA 02138 USA. [Pers, Tune H.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Gallinger, Steven] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Baron, John A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Caan, Bette J.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Song, Mingyang] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Casey, Graham] Univ So Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Haile, Robert W.] Stanford Univ, Div Oncol, Dept Med, Stanford, CA 94305 USA. [Duggan, David J.] Translat Genom Res Inst, Phoenix, AZ USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Song, Mingyang; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Genet, Rochester, MN USA. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Win, Aung Ko; Jenkins, Mark A.; Hopper, Johnl.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Ulrich, Cornelia M.] Populat Sci Huntsman Canc Inst, Salt Lake City, UT USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Hoffmeister, Michael; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Hsu, Li] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. RP Thrift, AP (reprint author), Baylor Coll Med, Dan L Duncan Canc Ctr, 1 Baylor Plaza, Houston, TX 77030 USA. EM aaron.thrift@bcm.edu RI Hoffmeister, Michael/B-5745-2012; Song, Mingyang/M-6701-2013; Jenkins, Mark/P-7803-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Song, Mingyang/0000-0002-1324-0316; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Potter, John/0000-0001-5439-1500; Locke, Adam/0000-0001-6227-198X; Hayes, Richard/0000-0002-0918-661X; Win, Aung Ko/0000-0002-2794-5261 FU Mayo Clinic Cooperative Family Registry for Colon Cancer Studies [U01/U24 CA074800]; University of Hawaii Colorectal Cancer Family Registry [U01/U24 CA074806]; Familial Colorectal Neoplasia Collaborative Group [U01 CA074799]; NIH [R01 CA151993, R01 CA137178, P01 CA53996, R01 AG14358, 1U54CA155626-01, R25 CA094880, R01 DK062370, UM1 CA167551, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA 151993, P50 CA 127003, U01 CA074783, U01 HG004446, R01 CA076366, K05 CA154337]; National Cancer Institute, NIH, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045]; National Cancer Institute, NIH [U01 CA122839, R01 CA143237]; NIH: Australasian Colorectal Cancer Family Registry [U01 CA074778, U01/U24 CA097735]; Ontario Registry for Studies of Familial Colorectal Cancer [U01/U24 CA074783]; Seattle Colorectal Cancer Family Registry [U01/U24 CA074794]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NHS by the NIH [R01 CA151993, R01 CA137178, P50 CA 127003, P01 CA 087969]; PHS by the NIH [R01 CA042182]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH GEI [U01 HG 004438]; National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX N.M. Lindor was supported through the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800). L. Le Marchand was supported through the University of Hawaii Colorectal Cancer Family Registry (U01/U24 CA074806). J.A. Baron was supported through the Familial Colorectal Neoplasia Collaborative Group (U01 CA074799). This work was supported by grants from the NIH (R01 CA151993 to S. Ogino; R01 CA137178 to A.T. Chan; P01 CA53996 and R01 AG14358 to L. Hsu). M. Song was supported by a grant from the NIH (1U54CA155626-01). M. Du was supported by a grant from the NIH (R25 CA094880). A.E. Locke was supported by a grant from the NIH (R01 DK062370).; GECCO is supported by National Cancer Institute, NIH, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045).; CCFR is supported by NIH (UM1 CA167551) and through cooperative agreements with members of the Colon Cancer Family Registry and PIs. This genome-wide scan was supported by the National Cancer Institute, NIH by U01 CA122839 and R01 CA143237 to Graham Casey. The content of this article does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the CCFR. The following CCFR centers contributed data to this article and were supported by NIH: Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (U01/U24 CA074794).; DACHS is supported by German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814).; DALS is supported by NIH (R01 CA48998 to M.L. Slattery).; HPFS is supported by the NIH (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA 151993, and P50 CA 127003), NHS by the NIH (R01 CA137178, P01 CA 087969, R01 CA151993, and P50 CA 127003), and PHS by the NIH (R01 CA042182).; OFCCR is supported by NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation.; PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M. and colleagues. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007 May;39(5):64-59), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L. and colleagues. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep;41(9):986-90, and Petersen, G.M. and colleagues. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar;42(3):224-8), and the Lung Cancer and Smoking study (Landi M.T., and colleagues. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009 Nov;85(5):679-91). The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207. v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping.; PMH is supported by NIH (R01 CA076366 to P.A. Newcomb).; VITAL is supported by NIH (K05 CA154337).; The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 33 TC 13 Z9 14 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2015 VL 24 IS 7 BP 1024 EP 1031 DI 10.1158/1055-9965.EPI-14-1309 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM1FF UT WOS:000357425700003 PM 25976416 ER PT J AU Loftfield, E Shiels, MS Graubard, BI Katki, HA Chaturvedi, AK Trabert, B Pinto, LA Kemp, TJ Shebl, FM Mayne, ST Wentzensen, N Purdue, MP Hildesheim, A Sinha, R Freedman, ND AF Loftfield, Erikka Shiels, Meredith S. Graubard, Barry I. Katki, Hormuzd A. Chaturvedi, Anil K. Trabert, Britton Pinto, Ligia A. Kemp, Troy J. Shebl, Fatma M. Mayne, Susan T. Wentzensen, Nicolas Purdue, Mark P. Hildesheim, Allan Sinha, Rashmi Freedman, Neal D. TI Associations of Coffee Drinking with Systemic Immune and Inflammatory Markers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DOSE-RESPONSE METAANALYSIS; FOOD FREQUENCY QUESTIONNAIRE; TYPE-2 DIABETES-MELLITUS; NF-KAPPA-B; CARDIOVASCULAR-DISEASE; DECAFFEINATED COFFEE; PROSPECTIVE COHORT; INSULIN-RESISTANCE; ENDOTHELIAL-CELLS; SCREENING TRIAL AB Background: Coffee drinking has been inversely associated with mortality as well as cancers of the endometrium, colon, skin, prostate, and liver. Improved insulin sensitivity and reduced inflammation are among the hypothesized mechanisms by which coffee drinking may affect cancer risk; however, associations between coffee drinking and systemic levels of immune and inflammatory markers have not been well characterized. Methods: We used Luminex bead-based assays to measure serum levels of 77 immune and inflammatory markers in 1,728 older non-Hispanic Whites. Usual coffee intake was self-reported using a food frequency questionnaire. We used weighted multivariable logistic regression models to examine associations between coffee and dichotomized marker levels. We conducted statistical trend tests by modeling the median value of each coffee category and applied a 20% false discovery rate criterion to P values. Results: Ten of the 77 markers were nominally associated (P trend < 0.05) with coffee drinking. Five markers withstood correction for multiple comparisons and included aspects of the host response namely chemotaxis of monocytes/macrophages (IFN gamma, CX3CL1/fractalkine, CCL4/MIP-1 beta), proinflammatory cytokines (sTNFRII), and regulators of cell growth (FGF-2). Heavy coffee drinkers had lower circulating levels of IFNg [odds ratios (OR), 0.35; 95% confidence intervals (CI), 0.16-0.75], CX3CL1/fractalkine (OR, 0.25; 95% CI, 0.10-0.64), CCL4/MIP-1 beta (OR, 0.48; 95% CI, 0.24-0.99), FGF-2 (OR, 0.62; 95% CI, 0.28-1.38), and sTNFRII (OR, 0.34; 95% CI, 0.15-0.79) than non-coffee drinkers. Conclusions: Lower circulating levels of inflammatory markers among coffee drinkers may partially mediate previously observed associations of coffee with cancer and other chronic diseases. Impact: Validation studies, ideally controlled feeding trials, are needed to confirm these associations. (C) 2015 AACR. C1 [Loftfield, Erikka; Shiels, Meredith S.; Graubard, Barry I.; Katki, Hormuzd A.; Chaturvedi, Anil K.; Trabert, Britton; Wentzensen, Nicolas; Hildesheim, Allan; Sinha, Rashmi; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Loftfield, Erikka; Shebl, Fatma M.; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Pinto, Ligia A.; Kemp, Troy J.] Leidos Biomed Res Inc, HPV Immunol Lab, SAIC Frederick, NCI Frederick, Frederick, MD USA. [Shebl, Fatma M.; Mayne, Susan T.] Yale Univ, Ctr Canc, New Haven, CT USA. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. RP Loftfield, E (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr 6E332, Bethesda, MD 20892 USA. EM erikka.loftfield@nih.gov RI Freedman, Neal/B-9741-2015; Purdue, Mark/C-9228-2016; Trabert, Britton/F-8051-2015; Chaturvedi, Anil/J-2024-2015 OI Freedman, Neal/0000-0003-0074-1098; Purdue, Mark/0000-0003-1177-3108; Chaturvedi, Anil/0000-0003-2696-8899 FU Yale-NCI [T32 CA105666]; NIH, National Cancer Institute FX This work was supported in part by the Yale-NCI pre-doctoral training grant T32 CA105666 to S.T. Mayne, and by the Intramural Research Program of the NIH, National Cancer Institute (to E. Loftfield, M.S. Shiels, B.I. Graubard, H.A. Katki, A.K. Chaturvedi, B. Trabert, L.A. Pinto, T.J. Kemp, N. Wentzensen, A. Hildesheim, R. Sinha, and N.D. Freedman). NR 54 TC 4 Z9 6 U1 3 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2015 VL 24 IS 7 BP 1052 EP 1060 DI 10.1158/1055-9965.EPI-15-0038-T PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM1FF UT WOS:000357425700007 PM 25999212 ER PT J AU Kane, E Skibola, CF Bracci, PM Cerhan, JR Costas, L Smedby, KE Holly, EA Maynadie, M Novak, AJ Lightfoot, TJ Ansell, SM Smith, AG Liebow, M Melbye, M Morton, L de Sanjose, S Slager, SL Wang, SS Zhang, YW Zheng, TZ Roman, E AF Kane, Eleanor Skibola, Christine F. Bracci, Paige M. Cerhan, James R. Costas, Laura Smedby, Karin Ekstrom Holly, Elizabeth A. Maynadie, Marc Novak, Anne J. Lightfoot, Tracy J. Ansell, Stephen M. Smith, Alex G. Liebow, Mark Melbye, Mads Morton, Lindsay de Sanjose, Silvia Slager, Susan L. Wang, Sophia S. Zhang, Yawei Zheng, Tongzhang Roman, Eve TI Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID B-CELL LYMPHOMA; PHYSICAL-ACTIVITY; UNITED-STATES; ANTHROPOMETRIC CHARACTERISTICS; ALCOHOL-CONSUMPTION; MALIGNANT-LYMPHOMA; MULTIETHNIC COHORT; GENETIC-VARIATION; RISK-FACTORS; TNF-ALPHA AB Background: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported. Method: Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988-2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI). Results: Obesity (BMI >= 30 kg/m(2)) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02-1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07-1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27-2.94), with a RERI of 0.41 (95% CI, -0.05-0.84; P-interaction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected. Conclusions: Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk. Impact: Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma. (C) 2015 AACR. C1 [Kane, Eleanor; Lightfoot, Tracy J.; Smith, Alex G.; Roman, Eve] Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, York YO10 5DD, N Yorkshire, England. [Skibola, Christine F.] Univ Alabama Birmingham, Ctr Comprehens Canc, Dept Epidemiol, Birmingham, AL 35294 USA. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Cerhan, James R.; Novak, Anne J.; Ansell, Stephen M.; Liebow, Mark; Slager, Susan L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Costas, Laura; de Sanjose, Silvia] IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc, Barcelona, Spain. [Costas, Laura; de Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Smedby, Karin Ekstrom] Karolinska Inst, Dept Med Solna, Stockholm, Sweden. [Maynadie, Marc] Univ Hosp Dijon, CRB Ferdinand Cabanne, Biol Hematol Unit, Dijon, France. [Maynadie, Marc] Univ Burgundy, Dijon, France. [Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Morton, Lindsay] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Etiol, Duarte, CA USA. [Zhang, Yawei; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA. RP Kane, E (reprint author), Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, Seebohm Rowntree Bldg, York YO10 5DD, N Yorkshire, England. EM eleanor.kane@ecsg.york.ac.uk RI de Sanjose Llongueras, Silvia/H-6339-2014; OI Costas, Laura/0000-0003-2755-302X FU NCI [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105, CA62006]; NCI, NIH; Public Health Service (NCI-SEER study); NIH [R01 CA92153, P50 CA97274, R01 CA45614, R03 CA89745, R01 CA87014, NCI 263-MQ-701711, U01 CA66529, R01 CA104682, CA154643, 5R01 CA69669-02]; NCI; NCI's SEER Program [HHSN261201000140C]; CDC's National Program of Cancer Registries [U58DP003862-01]; Leukaemia & Lymphoma Research, United Kingdom; Lundbeck Foundation [R19-A2364]; Danish Cancer Society [DP 08-155]; Danish Cancer Research Foundation; Plan Denmark; Swedish Cancer Society [2009/659, 02 6661]; Stockholm County Council [20110209]; Strategic Research Program in Epidemiology at Karolinska Institute; European Commission [QLK4-CT-2000-00422, FOOD-CT-2006-023103]; CIBERESP, Spanish Ministry of Health [PI11/01810, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095]; Marato de TV3 Foundation [051210]; Agencia de Gestio d'Ajuts Universitaris i de Recerca-Generalitat de Catalunya [2009SGR1465]; NIH; Compagnia di San Paolo-Programma Oncologia; Federal Office for Radiation Protection; Jose Carreras Leukemia Foundation [DJCLS-R04/08]; [2014SGR756-F]; [PI14/01219]; [CM13/00232]; [NO1-CO-12400]; [StSch4261]; [StSch4420] FX Studies that contributed data to this pooled analysis were supported by: NCI contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105 and the Intramural Research Program of the NCI, NIH, and Public Health Service (NCI-SEER study); grants R01 CA92153 and P50 CA97274, NIH (Mayo Clinic; to J.R. Cerhan); grants R01 CA45614, R03 CA89745, R01 CA87014, NCI 263-MQ-701711, U01 CA66529, R01 CA104682, and CA154643, NIH and NCI, and collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program; the NCI's SEER Program under contract HHSN261201000140C awarded to CPIC; and the CDC's National Program of Cancer Registries, under agreement # U58DP003862-01 awarded to the California Department of Public Health (E.A. Holly, UCSF); CA62006, NCI (T. Zheng, Connecticut); Leukaemia & Lymphoma Research, United Kingdom (E. Roman, ELCCS); R19-A2364, Lundbeck Foundation Grant, DP 08-155 Danish Cancer Society Grant, 5R01 CA69669-02 NIH, Danish Cancer Research Foundation Grant and Plan Denmark (M. Melbye, SCALE-Denmark); 2009/659, the Swedish Cancer Society, 20110209, Stockholm County Council, 02 6661, Swedish Cancer Society grant and the Strategic Research Program in Epidemiology at Karolinska Institute (K.E. Smedby, SCALE-Sweden); QLK4-CT-2000-00422 and FOOD-CT-2006-023103 European Commission; CIBERESP, PI11/01810, RCESP C03/09, RTICESP C03/10, and RTIC RD06/0020/0095, the Spanish Ministry of Health (grant references), 051210 the Marato de TV3 Foundation, 2009SGR1465 the Agencia de Gestio d'Ajuts Universitaris i de Recerca-Generalitat de Catalunya (who had no role in the data collection, analysis, or interpretation of the results); 2014SGR756-F, PI11/01810, PI14/01219 and CM13/00232; NO1-CO-12400, the NIH, the Compagnia di San Paolo-Programma Oncologia, StSch4261 and StSch4420 grants, the Federal Office for Radiation Protection, DJCLS-R04/08 the Jose Carreras Leukemia Foundation grant (S. de Sanjose, M. Maynadie, EpiLymph studies). NR 51 TC 0 Z9 0 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2015 VL 24 IS 7 BP 1061 EP 1070 DI 10.1158/1055-9965.EPI-14-1355 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM1FF UT WOS:000357425700008 PM 25962811 ER PT J AU Al Olama, AA Benlloch, S Antoniou, AC Giles, GG Severi, G Neal, DE Hamdy, FC Donovan, JL Muir, K Schleutker, J Henderson, BE Haiman, CA Schumacher, FR Pashayan, N Pharoah, PDP Ostrander, EA Stanford, JL Batra, J Clements, JA Chambers, SK Weischer, M Nordestgaard, BG Ingles, SA Sorensen, KD Orntoft, TF Park, JY Cybulski, C Maier, C Doerk, T Dickinson, JL Cannon-Albright, L Brenner, H Rebbeck, TR Zeigler-Johnson, C Habuchi, T Thibodeau, SN Cooney, KA Chappuis, PO Hutter, P Kaneva, RP Foulkes, WD Zeegers, MP Lu, YJ Zhang, HW Stephenson, R Cox, A Southey, MC Spurdle, AB FitzGerald, L Leongamornlert, D Saunders, E Tymrakiewicz, M Guy, M Dadaev, T Little, SJ Govindasami, K Sawyer, E Wilkinson, R Herkommer, K Hopper, JL Lophatonanon, A Rinckleb, AE Kote-Jarai, Z Eeles, RA Easton, DF AF Al Olama, Ali Amin Benlloch, Sara Antoniou, Antonis C. Giles, Graham G. Severi, Gianluca Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Muir, Kenneth Schleutker, Johanna Henderson, Brian E. Haiman, Christopher A. Schumacher, Fredrick R. Pashayan, Nora Pharoah, Paul D. P. Ostrander, Elaine A. Stanford, Janet L. Batra, Jyotsna Clements, Judith A. Chambers, Suzanne K. Weischer, Maren Nordestgaard, Borge G. Ingles, Sue A. Sorensen, Karina D. Orntoft, Torben F. Park, Jong Y. Cybulski, Cezary Maier, Christiane Doerk, Thilo Dickinson, Joanne L. Cannon-Albright, Lisa Brenner, Hermann Rebbeck, Timothy R. Zeigler-Johnson, Charnita Habuchi, Tomonori Thibodeau, Stephen N. Cooney, Kathleen A. Chappuis, Pierre O. Hutter, Pierre Kaneva, Radka P. Foulkes, William D. Zeegers, Maurice P. Lu, Yong-Jie Zhang, Hong-Wei Stephenson, Robert Cox, Angela Southey, Melissa C. Spurdle, Amanda B. FitzGerald, Liesel Leongamornlert, Daniel Saunders, Edward Tymrakiewicz, Malgorzata Guy, Michelle Dadaev, Tokhir Little, Sarah J. Govindasami, Koveela Sawyer, Emma Wilkinson, Rosemary Herkommer, Kathleen Hopper, John L. Lophatonanon, Aritaya Rinckleb, Antje E. Kote-Jarai, Zsofia Eeles, Rosalind A. Easton, Douglas F. CA British Assoc Urological Surgeons UK ProtecT Study Collaborators PRACTICAL Consortium TI Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; MULTIPLE LOCI; PREDICTION; VARIANTS; IDENTIFICATION; BRCA2 AB Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. (C) 2015 AACR. C1 [Al Olama, Ali Amin; Benlloch, Sara; Antoniou, Antonis C.; Pashayan, Nora; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Ctr Canc Genet Epidemiol, Cambridge, England. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Giles, Graham G.; Hopper, John L.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge CB2 2QQ, England. [Neal, David E.] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX3 9DU, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Muir, Kenneth] Univ Manchester, Ctr Epidemiol, Inst Populat Hlth, Manchester, Lancs, England. [Muir, Kenneth; Lophatonanon, Aritaya] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Schleutker, Johanna; Lophatonanon, Aritaya] Univ Tampere, Inst Biomed Technol, BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna] FimLab Labs, Tampere, Finland. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Henderson, Brian E.; Haiman, Christopher A.; Schumacher, Fredrick R.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Pashayan, Nora] UCL, Dept Appl Hlth Res, London, England. [Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Qld, Brisbane, Qld 4001, Australia. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4001, Australia. [Chambers, Suzanne K.] Griffith Univ, Griffith Hlth Inst, Gold Coast, Qld, Australia. [Chambers, Suzanne K.] Canc Council Queensland, Brisbane, Qld, Australia. [Chambers, Suzanne K.] Prostate Canc Fdn Australia, Sydney, NSW, Australia. [Weischer, Maren; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Sorensen, Karina D.; Orntoft, Torben F.] Aarhus Univ Hosp, Dept Mol Med MOMA, Aarhus N, Denmark. [Park, Jong Y.] Univ S Florida, H Lee Moffitt Canc Ctr, Div Canc Prevent & Control, Tampa, FL 33682 USA. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Maier, Christiane; Rinckleb, Antje E.] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Doerk, Thilo] Hannover Biomed Res Sch, Hannover, Germany. [Dickinson, Joanne L.] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cannon-Albright, Lisa] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Ageing Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Rebbeck, Timothy R.] Univ Penn, Philadelphia, PA 19104 USA. [Zeigler-Johnson, Charnita] Thomas Jefferson Univ, Dept Med Oncol, Div Populat Sci, Philadelphia, PA 19107 USA. [Habuchi, Tomonori] Akita Univ, Sch Med, Dept Urol, Akita 010, Japan. [Thibodeau, Stephen N.] Mayo Clin, Rochester, MN USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Div Hematol Oncol, Ann Arbor, MI USA. [Chappuis, Pierre O.] Univ Hosp Geneva, Div Oncol Med, Geneva, Switzerland. [Chappuis, Pierre O.] Univ Hosp Geneva, Dept Med Genet, Geneva, Switzerland. [Hutter, Pierre] Univ Geneva, Hop Cantonal, CH-1211 Geneva, Switzerland. [Kaneva, Radka P.] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Foulkes, William D.] McGill Univ, Montreal, PQ, Canada. [Zeegers, Maurice P.] Maastricht Univ, Med Ctr, NUTRIM Sch Nutr Toxicol & Metab, Dept Complex Genet,Cluster Genet & Cell Biol, NL-6200 MD Maastricht, Netherlands. [Lu, Yong-Jie] Queen Mary Univ London, John Vane Sci Ctr, Barts Canc Inst, London, England. [Zhang, Hong-Wei] Second Mil Med Univ, Shanghai, Peoples R China. [Stephenson, Robert] Univ Utah, Sch Med, Dept Surg, Div Urol, Salt Lake City, UT USA. [Cox, Angela] Univ Sheffield, CR UK YCR Sheffield Canc Res Ctr, Sheffield, S Yorkshire, England. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Spurdle, Amanda B.] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4006, Australia. [FitzGerald, Liesel] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Leongamornlert, Daniel; Saunders, Edward; Tymrakiewicz, Malgorzata; Guy, Michelle; Dadaev, Tokhir; Little, Sarah J.; Govindasami, Koveela; Sawyer, Emma; Wilkinson, Rosemary; Kote-Jarai, Zsofia; Eeles, Rosalind A.] Inst Canc Res, London SW3 6JB, England. [Herkommer, Kathleen] Tech Univ Munich, Dept Urol, D-80290 Munich, Germany. [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, Surrey, England. RP Al Olama, AA (reprint author), Ctr Canc Genet Epidemiol, Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England. EM aa461@medschl.cam.ac.uk; dfe20@medschl.cam.ac.uk RI Chambers, Suzanne/H-5957-2012; Batra, Jyotsna/B-4130-2011; Dork, Thilo/J-8620-2012; Brenner, Hermann/B-4627-2017; OI Samaratunga, Hemamali/0000-0001-5796-1791; Giles, Graham/0000-0003-4946-9099; Sorensen, Karina Dalsgaard/0000-0002-4902-5490; Clements, Judith/0000-0001-6026-1964; Ostrander, Elaine/0000-0001-6075-9738; albright, lisa/0000-0003-2602-3668; Cox, Angela/0000-0002-5138-1099; Risbridger, Gail/0000-0003-3089-4028; Brenner, Hermann/0000-0002-6129-1572; Beltcheva, Olga/0000-0001-6748-9726; Eeles, Rosalind/0000-0002-3698-6241; Lose, Felicity/0000-0001-8337-3547; Foote, Simon/0000-0002-9142-2107; catto, james/0000-0003-2787-8828 FU CR-UK [C1287/A10118, C5047/A10692]; NIH [1U19CA148537-01] FX D.F. Easton was recipient of the CR-UK grant C1287/A10118. R.A. Eeles was recipient of the CR-UK grant C5047/A10692 and B.E. Henderson was recipient of the NIH grant 1U19CA148537-01. NR 22 TC 13 Z9 13 U1 5 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2015 VL 24 IS 7 BP 1121 EP 1129 DI 10.1158/1055-9965.EPI-14-0317 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM1FF UT WOS:000357425700015 ER PT J AU MacDonald, MR She, LL Doenst, T Binkley, PF Rouleau, JL Tan, RS Lee, KL Miller, AB Sopko, G Szalewska, D Waclawiw, MA Dabrowski, R Castelvecchio, S Adlbrecht, C Michler, RE Oh, JK Velazquez, EJ Petrie, MC AF MacDonald, Michael R. She, Lilin Doenst, Torsten Binkley, Philip F. Rouleau, Jean L. Tan, Ru-San Lee, Kerry L. Miller, Alan B. Sopko, George Szalewska, Dominika Waclawiw, Myron A. Dabrowski, Rafal Castelvecchio, Serenella Adlbrecht, Christopher Michler, Robert E. Oh, Jae K. Velazquez, Eric J. Petrie, Mark C. TI Clinical characteristics and outcomes of patients with and without diabetes in the Surgical Treatment for Ischemic Heart Failure (STICH) trial SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Diabetes; Heart failure; Ischaemic heart disease; Coronary artery bypass graft ID VENTRICULAR RECONSTRUCTION; CARDIOVASCULAR-DISEASE; DIASTOLIC DYSFUNCTION; BYPASS SURGERY; CARDIOMYOPATHY; CORONARY; REVASCULARIZATION; DIAGNOSIS AB AimsHypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of 35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. Methods and resultsThe characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73-1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63-1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. ConclusionsPatients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM. C1 [MacDonald, Michael R.] Changi Gen Hosp, Dept Cardiol, Singapore 529889, Singapore. [She, Lilin] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Doenst, Torsten] Univ Jena, Jena Univ Hosp, Dept Cardiothorac Surg, Jena, Germany. [Binkley, Philip F.] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. [Rouleau, Jean L.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Tan, Ru-San] Natl Heart Ctr, Singapore, Singapore. [Lee, Kerry L.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Miller, Alan B.] Univ Florida, Dept Cardiol, Jacksonville, FL USA. [Sopko, George; Waclawiw, Myron A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Szalewska, Dominika] Med Univ Gdansk, Dept Rehabil, Gdansk, Poland. [Dabrowski, Rafal] Inst Cardiol, Warsaw, Poland. [Castelvecchio, Serenella] IRCCS Policlin San Donato, Milan, Italy. [Adlbrecht, Christopher] Med Univ Vienna, Dept Med 2, Div Cardiol, Vienna, Austria. [Michler, Robert E.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Surg, New York, NY USA. [Oh, Jae K.] Mayo Clin, Dept Med, Rochester, MN USA. [Velazquez, Eric J.] Duke Univ, Sch Med, Dept Med Cardiol, Durham, NC USA. [Petrie, Mark C.] Scottish Natl Adv Heart Failure Serv, Golden Jubilee Natl Hosp, Glasgow, Lanark, Scotland. [Petrie, Mark C.] Univ Glasgow, Glasgow, Lanark, Scotland. RP MacDonald, MR (reprint author), Changi Gen Hosp, Dept Cardiol, 2 Simei St 3, Singapore 529889, Singapore. EM michaelrossmacdonald@yahoo.com OI castelvecchio, serenella/0000-0001-5365-7063 FU NHLBI NIH HHS [U01 HL069013, U01 HL069015, U01HL69013, U01HL69015] NR 19 TC 3 Z9 3 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JUL PY 2015 VL 17 IS 7 BP 725 EP 734 DI 10.1002/ejhf.288 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM2OC UT WOS:000357519700013 PM 26011509 ER PT J AU Tassi, I Claudio, E Wang, HS Tang, WH Ha, HL Saret, S Sher, A Jankovic, D Siebenlist, U AF Tassi, Ilaria Claudio, Estefania Wang, Hongshan Tang, Wanhu Ha, Hye-lin Saret, Sun Sher, Alan Jankovic, Dragana Siebenlist, Ulrich TI Adaptive immune-mediated host resistance to Toxoplasma gondii is governed by the NF-kappa B regulator Bcl-3 in dendritic cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Adaptive immunity; Bcl-3; Dendritic cells; IFN-gamma; T-cells; T. gondii ID INTERFERON-GAMMA; ACUTE INFECTION; INTERLEUKIN-12; DIFFERENTIATION; ONCOPROTEIN; PARASITE; ANTIGEN AB The atypical I kappa B family member Bcl-3 associates with p50/NF-kappa B1 or p52/NF-kappa B2 homodimers in nuclei, thereby either positively or negatively modulating transcription in a context-dependent manner. Previously we reported that Bcl-3 was critical for host resistance to Toxoplasma gondii. Bcl-3-deficient mice succumbed within 3-5 weeks after infection, correlating with an apparently impaired Th1-type adaptive immune response. However in which cell type(s) Bcl-3 functioned to assure resistance remained unknown. We now show that Bcl-3 expression in dendritic cells is required to generate a protective Th1-type immune response and confer resistance to T. gondii. Surprisingly, mice lacking Bcl-3 in dendritic cells were as susceptible as mice globally deficient for Bcl-3. Furthermore, early innate defenses were not compromised by the absence of Bcl-3, as initial production of IL-12 by dendritic cells and IFN-gamma by NK cells were preserved. However, subsequent production of IFN-gamma by CD4(+) and CD8(+) T-cells was compromised when dendritic cells lacked Bcl-3, and these mice succumbed at a time when T-cell-mediated IFN-gamma production was essential for host resistance. These findings demonstrate that Bcl-3 is required in dendritic cells to prime protective T-cell-mediated immunity to T. gondii. C1 [Tassi, Ilaria; Claudio, Estefania; Wang, Hongshan; Tang, Wanhu; Ha, Hye-lin; Saret, Sun; Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Sher, Alan; Jankovic, Dragana] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIH Bldg 10,Rm 11B15A, Bethesda, MD 20892 USA. EM usiebenlist@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. NR 31 TC 1 Z9 1 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2015 VL 45 IS 7 BP 1972 EP 1979 DI 10.1002/eji.201445045 PG 8 WC Immunology SC Immunology GA CM4WY UT WOS:000357687700011 PM 25884683 ER PT J AU Augusto, DG O'Connor, GM Lobo-Alves, SC Bass, S Martin, MP Carrington, M McVicar, DW Petzl-Erler, ML AF Augusto, Danillo G. O'Connor, Geraldine M. Lobo-Alves, Sara C. Bass, Sara Martin, Maureen P. Carrington, Mary McVicar, Daniel W. Petzl-Erler, Maria Luiza TI Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE KIR; Autoimmunity; Allele polymorphism; HLA; Pemphigus foliaceus; NK cells ID FOLIACEUS FOGO SELVAGEM; KIR GENE-CLUSTER; FREE H CHAINS; GENOMIC ORGANIZATION; CHROMOSOME 19Q13.4; NK CELLS; T-CELLS; RECEPTORS; DIVERSITY; POLYMORPHISM AB Although HLA-A3 and A11 have been reported to be ligands for KIR3DL2, evidence for any in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, previously associated (lower risk) with activating KIR genes. KIR3DL2*001 was increased in patients (odds ratio (OR) = 2.04; p = 0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA-A3 or A11 (OR = 3.76, p = 0.013), providing the first evidence that HLA-A3 and A11 may interact with KIR3DL2 in vivo. The nonsynonymous single nucleotide polymorphism 1190T (rs3745902) was associated with protection (OR = 0.52, p = 0.018). This SNP results in a threonine-to-methionine substitution. Individuals who have methionine in this position exhibit a lower percentage of KIR3DL2-positive natural killer (NK) cells and also lower intensity of KIR3DL2 on expressing natural killer cells; additionally, we show that the expression of KIR3DL2 is independent of other killer cell immunoglobulin-like receptors. Pemphigus foliaceus is a very unique complex disease strongly associated with immune-related genes. It is the only autoimmune disease known to be endemic, showing a strong correlation with environmental factors. Our data demonstrate that this relatively unknown autoimmune disease may facilitate understanding of the molecular mechanisms of KIR3DL2 ligand recognition. C1 [Augusto, Danillo G.; Lobo-Alves, Sara C.; Petzl-Erler, Maria Luiza] Univ Fed Parana, Dept Genet, BR-81531980 Curitiba, Parana, Brazil. [Augusto, Danillo G.; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Augusto, Danillo G.; Bass, Sara; Martin, Maureen P.; Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [O'Connor, Geraldine M.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Petzl-Erler, ML (reprint author), Univ Fed Parana, Dept Genet, Caixa Postal 19071, BR-81531980 Curitiba, Parana, Brazil. EM mcvicard@mail.nih.gov; perler@ufpr.br RI Augusto, Danillo/F-3147-2013; Petzl-Erler, Maria-Luiza/H-8221-2012 OI Petzl-Erler, Maria-Luiza/0000-0002-0345-5276 FU CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico); CNPq; PRONEX; Institutos do Milenio; Fundacao Araucaria; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX To CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) for a research fellowship. We thank all staff of Hospital Adventista do Penfigo for allowing us to work in this institution and all patients and controls who voluntarily agreed to participate of this work. This project was funded by CNPq, PRONEX, Institutos do Milenio, Fundacao Araucaria, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) and federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 45 TC 4 Z9 4 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2015 VL 45 IS 7 BP 2052 EP 2060 DI 10.1002/eji.201445324 PG 9 WC Immunology SC Immunology GA CM4WY UT WOS:000357687700019 PM 25867094 ER PT J AU Liu, BY Chen, W Natarajan, K Li, ZH Margulies, DH Zhu, C AF Liu, Baoyu Chen, Wei Natarajan, Kannan Li, Zhenhai Margulies, David H. Zhu, Cheng TI The cellular environment regulates in situ kinetics of T-cell receptor interaction with peptide major histocompatibility complex SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Adhesion; Cellular immunology; Molecular immunology; TCRs; T cells ID LIGAND BINDING-KINETICS; SELECTIN GLYCOPROTEIN LIGAND-1; MHC CLASS-II; CATCH BONDS; SIGNAL-TRANSDUCTION; TCR-BINDING; P-SELECTIN; MOLECULES; AFFINITY; IMPACT AB T cells recognize antigens at the two-dimensional (2D) interface with antigen-presenting cells (APCs), which trigger T-cell effector functions. T-cell functional outcomes correlate with 2D kinetics of membrane-embedded T-cell receptors (TCRs) binding to surface-tethered peptide-major histocompatibility complex molecules (pMHCs). However, most studies have measured TCR-pMHC kinetics for recombinant TCRs in 3D by surface plasmon resonance, which differs drastically from 2D measurements. Here, we compared pMHC dissociation from native TCR on the T-cell surface to recombinant TCR immobilized on glass surface or in solution. Force on TCR-pMHC bonds regulated their lifetimes differently for native than recombinant TCRs. Perturbing the cellular environment suppressed 2D on-rates but had no effect on 2D off-rate regardless of whether force was applied. In contrast, for the TCR interacting with its monoclonal antibody, the 2D on-rate was insensitive to cellular perturbations and the force-dependent off-rates were indistinguishable for native and recombinant TCRs. These data present novel features of TCR-pMHC kinetics that are regulated by the cellular environment, underscoring the limitations of 3D kinetics in predicting T-cell functions and calling for further elucidation of the underlying molecular and cellular mechanisms that regulate 2D kinetics in physiological settings. C1 [Liu, Baoyu; Chen, Wei; Li, Zhenhai; Zhu, Cheng] Georgia Inst Technol, Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Zhu, Cheng] Georgia Inst Technol, Woodruff Sch Mech Engn, Atlanta, GA 30332 USA. [Zhu, Cheng] Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA. [Natarajan, Kannan; Margulies, David H.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, C (reprint author), Georgia Inst Technol, Dept Biomed Engn, 315 Ferst Dr,IBB BLDG ROOM 3210, Atlanta, GA 30332 USA. EM cheng.zhu@bme.gatech.edu OI Margulies, David/0000-0001-8530-7375 FU NIH [AI38282, GM096187]; Intramural Research Program of the NIAID, NIH FX We thank the NIH Tetramer Core Facility at Emory University for providing the H2-Kb monomers, Brian D. Evavold for providing the OT1 and 2C transgenic mice and the RAM-S cell line, K. Christopher Garcia for providing the H2-Ld monomers and the recombinant 2C and 42F3 TCRs, David Kranz for providing the 42F3 hybridoma cells, John Altman for providing the H2-Kbalpha 3A2 construct, Rodger P. McEver for providing L-selectin and 2GSP6, and Larissa Doudy for purifying T cells. This work was supported by NIH grants AI38282 and GM096187 (to C.Z.). K.N. and D.H.M are supported by the Intramural Research Program of the NIAID, NIH. NR 62 TC 3 Z9 3 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2015 VL 45 IS 7 BP 2099 EP 2110 DI 10.1002/eji.201445358 PG 12 WC Immunology SC Immunology GA CM4WY UT WOS:000357687700023 PM 25944482 ER PT J AU Ohanjanian, L Remy, KE Li, Y Cui, X Eichacker, PQ AF Ohanjanian, Lernik Remy, Kenneth E. Li, Yan Cui, Xizhong Eichacker, Peter Q. TI An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE anthrax; Bacillus anthracis; lethal and edema toxins; toxin-directed agents; treatment ID ADENYLYL-CYCLASE TOXIN; SMALL-MOLECULE INHIBITORS; HUMAN MONOCLONAL-ANTIBODY; LETHAL FACTOR INHIBITORS; BETA-CYCLODEXTRIN DERIVATIVES; PROTECTIVE ANTIGEN-ANTIBODY; DOMINANT-NEGATIVE MUTANTS; ZEALAND WHITE-RABBITS; IN-VIVO EFFICACY; EDEMA FACTOR AB Introduction: Sepsis with Bacillus anthracis infection has a very high mortality rate despite appropriate antibiotic and supportive therapies. Over the past 15 years, recent outbreaks in the US and in Europe, coupled with anthrax's bioterrorism weapon potential, have stimulated efforts to develop adjunctive therapies to improve clinical outcomes. Since lethal toxin and edema toxin (LT and ET) make central contributions to the pathogenesis of B. anthracis, these have been major targets in this effort. Areas covered: Here, the authors review different investigative biopharmaceuticals that have been recently identified for their therapeutic potential as inhibitors of LT or ET. Among these inhibitors are two antibody preparations that have been included in the Strategic National Stockpile (SNS) and several more that have reached Phase I testing. Presently, however, many of these candidate agents have only been studied in vitro and very few tested in bacteria-challenged models. Expert opinion: Although a large number of drugs have been identified as potential therapeutic inhibitors of LT and ET, in most cases their testing has been limited. The use of the two SNS antibody therapies during a large-scale exposure to B. anthracis will be difficult. Further testing and development of agents with oral bioavailability and relatively long shelf lives should be a focus for future research. C1 [Ohanjanian, Lernik; Remy, Kenneth E.; Li, Yan; Cui, Xizhong; Eichacker, Peter Q.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU NIH, via the Clinical Center, Critical Care Medicine Department FX The authors are employees of the National Institutes of Health and are supported by the Intramural Program of the NIH, via the Clinical Center, Critical Care Medicine Department. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 148 TC 1 Z9 1 U1 4 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1354-3784 EI 1744-7658 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUL PY 2015 VL 24 IS 7 BP 851 EP 865 DI 10.1517/13543784.2015.1041587 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CM5XO UT WOS:000357762500002 PM 25920540 ER PT J AU Burman, B Zhang, ZZZ Pegoraro, G Lieb, JD Misteli, T AF Burman, Bharat Zhang, Zhuzhu Z. Pegoraro, Gianluca Lieb, Jason D. Misteli, Tom TI Histone modifications predispose genome regions to breakage and translocation SO GENES & DEVELOPMENT LA English DT Article DE chromosome translocations; histone modifications; chromatin structure ID DOUBLE-STRAND BREAKS; CLASS-SWITCH RECOMBINATION; DNA-DAMAGE RESPONSE; LARGE-CELL LYMPHOMA; CHROMOSOME TRANSLOCATIONS; CHROMATIN-STRUCTURE; SEQUENCING REVEALS; GENE FUSIONS; STEM-CELLS; REARRANGEMENTS AB Chromosome translocations are well-established hallmarks of cancer cells and often occur at nonrandom sites in the genome. The molecular features that define recurrent chromosome breakpoints are largely unknown. Using a combination of bioinformatics, biochemical analysis, and cell-based assays, we indentify here specific histone modifications as facilitators of chromosome breakage and translocations. We show enrichment of several histone modifications over clinically relevant translocation-prone genome regions. Experimental modulation of histone marks sensitizes genome regions to breakage by endonuclease challenge or irradiation and promotes formation of chromosome translocations of endogenous gene loci. Our results demonstrate that histone modifications predispose genome regions to chromosome breakage and translocations. C1 [Burman, Bharat; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Burman, Bharat] Tufts Univ, Sackler Sch Biomed Sci, Program Cell Mol & Dev Biol, Boston, MA 02111 USA. [Zhang, Zhuzhu Z.; Lieb, Jason D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Zhang, Zhuzhu Z.] Salk Inst Biol Studies, Genom Anal Lab, La Jolla, CA 92037 USA. [Pegoraro, Gianluca] NCI, High Throughput Imaging Facil, NIH, Bethesda, MD 20892 USA. [Lieb, Jason D.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Howard Hughes Medical Institute-National Institutes of Health fellowship FX We thank Katherine McKinnon (National Cancer Institute) for help with FACS experiments, Tatiana Karpova (National Cancer Insitute Fluorescence Imaging Microscopy Facility) for help with microscopy, and Stephan Mathas (Charite-Berlin) for technical assistance. We also thank Grace Gill (Tufts University), Terry Furey (University of North Carolina), and members of the Misteli laboratory for helpful feedback. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and a Howard Hughes Medical Institute-National Institutes of Health fellowship to B.B. B.B. and T.M. designed the study. B.B. performed the majority of experiments and data analysis, Z.Z.Z. and J.D.L. performed bioinformatics analysis, and B.B. and G.P. performed the hiFISH data analysis. B.B. and T.M. wrote the manuscript, the other authors read and approved the manuscript. NR 39 TC 10 Z9 10 U1 3 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 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2015 VL 29 IS 13 BP 1393 EP 1402 DI 10.1101/gad.262170.115 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CM5LI UT WOS:000357729000005 PM 26104467 ER PT J AU Pagnamenta, AT Howard, MF Wisniewski, E Popitsch, N Knight, SJ Keays, DA Quaghebeur, G Cox, H Cox, P Balla, T Taylor, JC Kini, U AF Pagnamenta, Alistair T. Howard, Malcolm F. Wisniewski, Eva Popitsch, Niko Knight, Samantha J. L. Keays, David A. Quaghebeur, Gerardine Cox, Helen Cox, Phillip Balla, Tamas Taylor, Jenny C. Kini, Usha TI Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis SO HUMAN MOLECULAR GENETICS LA English DT Article ID PHOSPHATIDYLINOSITOL 4-KINASE; SACCHAROMYCES-CEREVISIAE; MENDELIAN DISORDERS; DELETION SYNDROME; PLASMA-MEMBRANE; PROTEIN; LOCALIZATION; DIAGNOSIS; PATHWAY; GENE AB Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved. In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome. In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance. The paternally transmitted variant predicted a premature stop mutation (c.2386C > T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G > A; p.D1854N) at a conserved residue within the catalytic domain. Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity. Our results emphasize the importance of phosphoinositide signalling in early brain development. C1 [Pagnamenta, Alistair T.; Howard, Malcolm F.; Popitsch, Niko; Knight, Samantha J. L.; Taylor, Jenny C.] Univ Oxford, Wellcome Trust Ctr Human Genet, Biomed Res Ctr, Natl Inst Hlth Res, Oxford OX3 7BN, England. [Wisniewski, Eva; Balla, Tamas] Eunice Kennedy Shriver NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Keays, David A.] Inst Mol Pathol, A-1030 Vienna, Austria. [Quaghebeur, Gerardine] Univ Oxford, Hosp NHS Trust, Dept Neuroradiol, Oxford OX3 9DU, England. [Kini, Usha] Univ Oxford, Hosp NHS Trust, Dept Clin Genet, Oxford OX3 9DU, England. [Cox, Helen] Birmingham Womens Hosp NHS Fdn Trust, West Midlands Reg Clin Genet Serv, Clin Genet Unit, Birmingham B15 2TG, W Midlands, England. [Cox, Phillip] Birmingham Womens Hosp NHS Fdn Trust, Dept Histopathol, Birmingham B15 2TG, W Midlands, England. RP Kini, U (reprint author), Univ Oxford, Hosp NHS Trust, Dept Clin Genet, Oxford OX3 9DU, England. EM usha.kini@ouh.nhs.uk RI Wisniewski, Eva/O-9233-2015; OI Wisniewski, Eva/0000-0001-8698-6867; Balla, Tamas/0000-0002-9077-3335 FU National Institute for Health Research (NIHR) Biomedical Research Centre Oxford; Department of Health's NIHR Biomedical Research Centre's funding scheme; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; Wellcome Trust [090532/Z/09/Z]; Medical Research Council Hub [G0900747 91070] FX This was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre Oxford with funding from the Department of Health's NIHR Biomedical Research Centre's funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The research of T.B. and E.W. was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Funding for the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics is from Wellcome Trust grant reference 090532/Z/09/Z and Medical Research Council Hub grant G0900747 91070). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 57 TC 5 Z9 7 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2015 VL 24 IS 13 BP 3732 EP 3741 DI 10.1093/hmg/ddv117 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CM2PO UT WOS:000357523900012 PM 25855803 ER PT J AU Rachel, RA Yamamoto, EA Dewanjee, MK May-Simera, HL Sergeev, YV Hackett, AN Pohida, K Munasinghe, J Gotoh, N Wickstead, B Fariss, RN Dong, LJ Li, TS Swaroop, A AF Rachel, Rivka A. Yamamoto, Erin A. Dewanjee, Mrinal K. May-Simera, Helen L. Sergeev, Yuri V. Hackett, Alice N. Pohida, Katherine Munasinghe, Jeeva Gotoh, Norimoto Wickstead, Bill Fariss, Robert N. Dong, Lijin Li, Tiansen Swaroop, Anand TI CEP290 alleles in mice disrupt tissue-specific cilia biogenesis and recapitulate features of syndromic ciliopathies SO HUMAN MOLECULAR GENETICS LA English DT Article ID BARDET-BIEDL-SYNDROME; LEBER CONGENITAL AMAUROSIS; SYNDROME-RELATED DISORDERS; POLYCYSTIC KIDNEY-DISEASE; PLANAR CELL POLARITY; EMBRYONIC STEM-CELLS; JOUBERT-SYNDROME; RETINAL DEGENERATION; TRANSITION ZONE; CENTROSOMAL PROTEIN AB Distinct mutations in the centrosomal-cilia protein CEP290 lead to diverse clinical findings in syndromic ciliopathies. We show that CEP290 localizes to the transition zone in ciliated cells, precisely to the region of Y-linkers between central microtubules and plasma membrane. To create models of CEP290-associated ciliopathy syndromes, we generated Cep290(ko/ko) and Cep290(gt/gt) mice that produce no or a truncated CEP290 protein, respectively. Cep290(ko/ko) mice exhibit early vision loss and die from hydrocephalus. Retinal photoreceptors in Cep290(ko/ko) mice lack connecting cilia, and ciliated ventricular ependyma fails to mature. The minority of Cep290(ko/ko) mice that escape hydrocephalus demonstrate progressive kidney pathology. Cep290(gt/gt) mice die at mid-gestation, and the occasional Cep290(gt/gt) mouse that survives shows hydrocephalus and severely cystic kidneys. Partial loss of CEP290-interacting ciliopathy protein MKKS mitigates lethality and renal pathology in Cep290(gt/gt) mice. Our studies demonstrate domain-specific functions of CEP290 and provide novel therapeutic paradigms for ciliopathies. C1 [Rachel, Rivka A.; Yamamoto, Erin A.; Dewanjee, Mrinal K.; May-Simera, Helen L.; Sergeev, Yuri V.; Hackett, Alice N.; Pohida, Katherine; Gotoh, Norimoto; Fariss, Robert N.; Dong, Lijin; Li, Tiansen; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] NINDS, NIH, Bethesda, MD 20892 USA. [Wickstead, Bill] Univ Nottingham, Sch Life Sci, Nottingham NG7 2RD, England. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, MSC0610,6 Ctr Dr, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Wickstead, Bill/0000-0002-4620-9091; Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute FX This research was supported by Intramural Research Program of the National Eye Institute. NR 97 TC 5 Z9 5 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2015 VL 24 IS 13 BP 3775 EP 3791 DI 10.1093/hmg/ddv123 PG 17 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CM2PO UT WOS:000357523900016 PM 25859007 ER PT J AU Pomes, A Chruszcz, M Gustchina, A Minor, W Mueller, GA Pedersen, LC Wlodawer, A Chapman, MD AF Pomes, Anna Chruszcz, Maksymilian Gustchina, Alla Minor, Wladek Mueller, Geoffrey A. Pedersen, Lars C. Wlodawer, Alexander Chapman, Martin D. TI 100 Years later: Celebrating the contributions of x-ray crystallography to allergy and clinical immunology SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergens; allergy; function; structure; cross-reactivity; x-ray crystallography ID HOUSE-DUST MITE; MAJOR PEANUT ALLERGEN; ARA H 2; BET V 1; 3-DIMENSIONAL FOURIER SYNTHESIS; HUMAN-IMMUNOGLOBULIN E; BIRCH POLLEN ALLERGY; FC-EPSILON-RI; CRYSTAL-STRUCTURE; CROSS-REACTIVITY AB Current knowledge of molecules involved in immunology and allergic disease results from the significant contributions of x-ray crystallography, a discipline that just celebrated its 100th anniversary. The histories of allergens and x-ray crystallography are intimately intertwined. The first enzyme structure to be determined was lysozyme, also known as the chicken food allergen Gal d 4. Crystallography determines the exact 3-dimensional positions of atoms in molecules. Structures of molecular complexes in the disciplines of immunology and allergy have revealed the atoms involved in molecular interactions and mechanisms of disease. These complexes include peptides presented by MHC class II molecules, cytokines bound to their receptors, allergenantibody complexes, and innate immune receptors with their ligands. The information derived from crystallographic studies provides insights into the function of molecules. Allergen function is one of the determinants of environmental exposure, which is essential for IgE sensitization. Proteolytic activity of allergens or their capacity to bind LPSs can also contribute to allergenicity. The atomic positions define the molecular surface that is accessible to antibodies. In turn, this surface determines antibody specificity and cross-reactivity, which are important factors for the selection of allergen panels used for molecular diagnosis and the interpretation of clinical symptoms. This review celebrates the contributions of x-ray crystallography to clinical immunology and allergy, focusing on new molecular perspectives that influence the diagnosis and treatment of allergic diseases. C1 [Pomes, Anna; Chapman, Martin D.] INDOOR Biotechnol, Basic Res, Charlottesville, VA 22903 USA. [Chruszcz, Maksymilian] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. [Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Minor, Wladek] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA USA. [Mueller, Geoffrey A.; Pedersen, Lars C.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Pomes, A (reprint author), INDOOR Biotechnol, 1216 Harris St, Charlottesville, VA 22903 USA. EM apomes@inbio.com OI Chruszcz, Maksymilian/0000-0001-7521-5485; Pomes, Anna/0000-0002-8729-1829; Minor, Wladek/0000-0001-7075-7090 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) [R01AI077653]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Research [Z01-ES050147, ZIA ES102645] FX Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH; award no. R01AI077653; A.P. contact PI), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Research (project no. Z01-ES050147 to G.A.M. and ZIA ES102645 to L.C.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 119 TC 1 Z9 1 U1 1 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2015 VL 136 IS 1 BP 29 EP U87 DI 10.1016/j.jaci.2015.05.016 PG 19 WC Allergy; Immunology SC Allergy; Immunology GA CM2WE UT WOS:000357542200004 PM 26145985 ER PT J AU Yang, IV Pedersen, BS Liu, A O'Connor, GT Teach, SJ Kattan, M Misiak, RT Gruchalla, R Steinbach, SF Szefler, SJ Gill, MA Calatroni, A David, G Hennessy, CE Davidson, EJ Zhang, WM Gergen, P Togias, A Busse, WW Schwartz, DA AF Yang, Ivana V. Pedersen, Brent S. Liu, Andrew O'Connor, George T. Teach, Stephen J. Kattan, Meyer Misiak, Rana Tawil Gruchalla, Rebecca Steinbach, Suzanne F. Szefler, Stanley J. Gill, Michelle A. Calatroni, Agustin David, Gloria Hennessy, Corinne E. Davidson, Elizabeth J. Zhang, Weiming Gergen, Peter Togias, Alkis Busse, William W. Schwartz, David A. TI DNA methylation and childhood asthma in the inner city SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE DNA methylation; atopic asthma; epigenetics; T(H)2 immunity; inner city ID GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; CELL DIFFERENTIATION; EPIGENETIC CHANGES; ALLERGIC-ASTHMA; VIRUS-INFECTION; LUNG-FUNCTION; NITRIC-OXIDE; T-CELLS; DISEASE AB Background: Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important to define epigenetic alterations in asthmatic populations. Objective: We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma. Methods: We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients. Results: Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1. Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively (P < 6 x 10(-12) for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL4 and ST2). Methylation marks involved in T-cell maturation (RUNX3), T(H)2 immunity (IL4), and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city. Conclusions: Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma. C1 [Yang, Ivana V.; Pedersen, Brent S.; Hennessy, Corinne E.; Davidson, Elizabeth J.; Schwartz, David A.] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Yang, Ivana V.; Liu, Andrew; Schwartz, David A.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Yang, Ivana V.; Liu, Andrew; Schwartz, David A.] Natl Jewish Hlth, Dept Med, Denver, CO USA. [O'Connor, George T.; Steinbach, Suzanne F.] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Teach, Stephen J.] Childrens Natl Hlth Syst, Washington, DC USA. [Kattan, Meyer] Columbia Univ, Med Ctr, New York, NY USA. [Misiak, Rana Tawil] Henry Ford Hosp, Dept Med, Detroit, MI 48202 USA. [Gruchalla, Rebecca; Gill, Michelle A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Szefler, Stanley J.] Childrens Hosp Colorado, Dept Pediat, Colorado Springs, CO USA. [Szefler, Stanley J.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Calatroni, Agustin; David, Gloria] Rho Fed Syst Div, Chapel Hill, NC USA. [Zhang, Weiming] Univ Colorado, Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO 80045 USA. [Schwartz, David A.] Univ Colorado, Dept Immunol, Aurora, CO 80045 USA. [Gergen, Peter; Togias, Alkis] NIAID, Bethesda, MD 20892 USA. [Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI USA. RP Schwartz, DA (reprint author), Univ Colorado, 12631 East 17th Ave,B178, Aurora, CO 80045 USA. EM david.schwartz@ucdenver.edu FU National Institute of Allergy and Infectious Diseases [N01-AI90052]; National Heart, Lung, and Blood Institute [R01-HL101251]; National Institute of Environmental Health Sciences [P01-ES18181]; National Center for Advancing Translational Sciences [UL1TR000075] FX Supported by the National Institute of Allergy and Infectious Diseases (N01-AI90052); the National Heart, Lung, and Blood Institute (R01-HL101251); the National Institute of Environmental Health Sciences (P01-ES18181); and the National Center for Advancing Translational Sciences (UL1TR000075). NR 78 TC 19 Z9 20 U1 5 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2015 VL 136 IS 1 BP 69 EP 80 DI 10.1016/j.jaci.2015.01.025 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA CM2WE UT WOS:000357542200008 PM 25769910 ER PT J AU Sundstrom, JB AF Sundstrom, J. Bruce TI Significance of extravascular reservoirs of latent infection for HIV persistence during antiretroviral therapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID CELLS C1 NIAID, Div Extramural Act, NIH, Bethesda, MD 20892 USA. RP Sundstrom, JB (reprint author), NIAID, Div Extramural Act, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sundstromj@niaid.nih.gov NR 7 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 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2015 VL 136 IS 1 BP 213 EP 213 DI 10.1016/j.jaci.2015.03.045 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CM2WE UT WOS:000357542200032 PM 25979519 ER PT J AU Akdis, C Akdis, M Chatila, TA Deniz, G Geha, RS Lenardo, MJ Oettgen, HC AF Akdis, Cezmi Akdis, Muebeccel Chatila, Talal A. Deniz, Guennur Geha, Raif S. Lenardo, Michael J. Oettgen, Hans C. TI In lasting tribute: Professor Dr Isil Berat Barlan (1958-2015) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Biographical-Item C1 [Akdis, Cezmi; Akdis, Muebeccel] Swiss Inst Allergy & Asthma Res, CH-7270 Davos, Switzerland. [Chatila, Talal A.; Geha, Raif S.; Oettgen, Hans C.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Chatila, Talal A.; Geha, Raif S.; Oettgen, Hans C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Deniz, Guennur] Istanbul Univ, Inst Expt Med, Istanbul, Turkey. [Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Bethesda, MD 20892 USA. RP Chatila, TA (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Karp Family Bldg,Room RB 10214,1 Blackfan St, Boston, MA 02115 USA. EM talal.chatila@childrens.harvard.edu 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 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2015 VL 136 IS 1 BP 215 EP 215 DI 10.1016/j.jaci.2015.05.013 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CM2WE UT WOS:000357542200034 ER PT J AU Gunti, S Notkins, AL AF Gunti, Sreenivasulu Notkins, Abner Louis TI Polyreactive Antibodies: Function and Quantification SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE polyreactive antibody; natural antibody; apoptotic cells; phagocytosis; bacteria ID MONOCLONAL AUTOANTIBODIES; INDUCED FIT; PHAGOCYTOSIS; RECOGNITION; REPERTOIRE; ENHANCE; ORGANS; CELLS; REACT; IGM AB Polyreactive antibodies, a major component of the natural antibody repertoire, bind with low affinity to a variety of structurally unrelated antigens. Many of these antibodies are germline or near germline in sequence. Little is known, however, about the function of these antibodies. In the present mini-review we show: (1) that the broad antibacterial activity of the natural antibody repertoire is largely due to polyreactive antibodies, which in the presence of complement lyse bacteria and enhance phagocytosis; (2) that polyreactive antibodies bind to UV-or human immunodeficiency virus-induced apoptotic cells and with complement enhance the phagocytosis of these cells by macrophages; and (3) that dinitrophenol can be used as a surrogate for quantitating the level of polyreactive antibodies in serum. We conclude that polyreactive antibodies protect the host against both foreign invaders and its own damaged/apoptotic cells. C1 [Gunti, Sreenivasulu; Notkins, Abner Louis] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, LSB, NIH, Bldg 30,Room 106,Convent Dr,MSC4322, Bethesda, MD 20892 USA. EM anotkins@mail.nih.gov FU Intramural Research Program of the US National Institutes of Health FX This work was supported by the Intramural Research Program of the US National Institutes of Health. NR 15 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2015 VL 212 SU 1 BP S42 EP S46 DI 10.1093/infdis/jiu512 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CM6SI UT WOS:000357819700010 PM 26116731 ER PT J AU Steplewski, Z Thurin, M Kieber-Emmons, T AF Steplewski, Zenon Thurin, Magdalena Kieber-Emmons, Thomas TI Antibodies: At The Nexus of Antigens and Cancer Vaccines SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Monoclonal antibodies; cancer therapeutics; cancer vaccines; anti-idiotypes; mimicry; carbohydrate mimetic peptides; biotechnology; team science ID TUMOR-ASSOCIATED ANTIGENS; SOMATIC-CELL HYBRIDS; LEWIS-Y ANTIGEN; MONOCLONAL-ANTIBODY; HUMAN-MELANOMA; COLORECTAL-CARCINOMA; PEPTIDE MIMOTOPES; BLOOD-GROUP; MEDIATED CYTOTOXICITY; GD2 GANGLIOSIDE AB This review describes the development of monoclonal antibodies and the inception of their use in cancer therapy, their impact on defining cancer biomarkers, and their structural utility in new cancer vaccine development. C1 [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Rockville, MD USA. [Kieber-Emmons, Thomas] Univ Arkansas Med Sci, Winthrop P Rockefeller Canc Inst, Little Rock, AR 72202 USA. RP Kieber-Emmons, T (reprint author), Univ Arkansas Med Sci, Winthrop P Rockefeller Canc Inst, Little Rock, AR 72202 USA. EM tke@uams.edu FU Department of Defense Breast Cancer Program [W81XWH-06-1-0542] FX This work was supported by the Department of Defense Breast Cancer Program (clinical translational award W81XWH-06-1-0542 to T. K.-E.) NR 50 TC 1 Z9 1 U1 5 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2015 VL 212 SU 1 BP S59 EP S66 DI 10.1093/infdis/jiu638 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CM6SI UT WOS:000357819700013 PM 26116735 ER PT J AU Trinchieri, G AF Trinchieri, Giorgio TI Cancer Immunity: Lessons From Infectious Diseases SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE immunity; infection; cancer; microbiota; cancer therapy ID DENDRITIC CELLS; INTESTINAL MICROBIOTA; BACTERIAL-INFECTION; GUT MICROBIOTA; INFLAMMATION; BLOCKADE; THERAPY; CARCINOGENESIS; IMMUNOTHERAPY; MACROPHAGES AB Innate and adaptive immunity are activated by both infections and tumors. The immune cells infiltrating infected tissues are similar to those infiltrating neoplastic tissues, but their function in the first setting is quite different from that in the latter. Infected tissues are usually characterized by an acute inflammatory environment that favors the generation of protective immunity, whereas tumors are characterized by chronic inflammation that suppresses antitumor immune responses and promotes tumor growth and escape from the immune system. During resolution of the immune response to infection or in chronic infections, immunosuppressive mechanisms that are typical of the tumor microenvironment are observed in infected tissues. Conversely, immunotherapy and chemotherapy may redirect the tumor microenvironment and allow the activation of effective anticancer immune responses. The transformation of neoplastic cells is determined by intrinsic genetic alteration but tumor progression is controlled by the tumor microenvironment and by the inflammatory and immune response to the tumors. Commensal microorganisms live in great numbers in all our barrier epithelia and control inflammation and immunity both locally and systemically. The commensal microbiota is essential for optimal immune response to pathogens and for the establishment of autoimmunity. It also modulates inflammation and immune responses that affect tumor growth and it is required for the effectiveness of anticancer immunotherapy and chemotherapy. C1 NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bldg 37,Rm 4146A, Bethesda, MD 20892 USA. EM trinchig@mail.nih.gov NR 55 TC 5 Z9 5 U1 4 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2015 VL 212 SU 1 BP S67 EP S73 DI 10.1093/infdis/jiv070 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CM6SI UT WOS:000357819700014 PM 26116736 ER PT J AU Mohr, DC Schueller, SM Riley, WT Brown, CH Cuijpers, P Duan, N Kwasny, MJ Stiles-Shields, C Cheung, K AF Mohr, David C. Schueller, Stephen M. Riley, William T. Brown, C. Hendricks Cuijpers, Pim Duan, Naihua Kwasny, Mary J. Stiles-Shields, Colleen Cheung, Ken TI Trials of Intervention Principles: Evaluation Methods for Evolving Behavioral Intervention Technologies SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE mHealth; eHealth; clinical trials; methodology ID RANDOMIZED CONTROLLED-TRIAL; EHEALTH INTERVENTIONS; HEALTH; IMPLEMENTATION; FRAMEWORK; MODEL; RECOMMENDATIONS; ASSIGNMENT; STRATEGY; PROGRAMS AB In recent years, there has been increasing discussion of the limitations of traditional randomized controlled trial (RCT) methodologies for the evaluation of eHealth and mHealth interventions, and in particular, the requirement that these interventions be locked down during evaluation. Locking down these interventions locks in defects and eliminates the opportunities for quality improvement and adaptation to the changing technological environment, often leading to validation of tools that are outdated by the time that trial results are published. Furthermore, because behavioral intervention technologies change frequently during real-world deployment, even if a tested intervention were deployed in the real world, its shelf life would be limited. We argue that RCTs will have greater scientific and public health value if they focus on the evaluation of intervention principles (rather than a specific locked-down version of the intervention), allowing for ongoing quality improvement modifications to the behavioral intervention technology based on the core intervention principles, while continuously improving the functionality and maintaining technological currency. This paper is an initial proposal of a framework and methodology for the conduct of trials of intervention principles (TIPs) aimed at minimizing the risks of in-trial changes to intervention technologies and maximizing the potential for knowledge acquisition. The focus on evaluation of intervention principles using clinical and usage outcomes has the potential to provide more generalizable and durable information than trials focused on a single intervention technology. C1 [Mohr, David C.; Schueller, Stephen M.; Stiles-Shields, Colleen] Northwestern Univ, Ctr Behav Intervent Technol CBITs, Chicago, IL 60611 USA. [Riley, William T.] NIH, Off Behav & Social Sci Res, Washington Dc, DC USA. [Brown, C. Hendricks] Northwestern Univ, Dept Psychiat, Chicago, IL 60611 USA. [Cuijpers, Pim] Vrije Univ Amsterdam, Dept Psychol & Pedag, Amsterdam, Netherlands. [Duan, Naihua] Columbia Univ, Dept Psychiat, New York, NY USA. [Kwasny, Mary J.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Cheung, Ken] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Mohr, DC (reprint author), Northwestern Univ, Ctr Behav Intervent Technol CBITs, 750 N Lakeshore Dr,10th Floor, Chicago, IL 60611 USA. EM d-mohr@northwestern.edu OI Stiles-Shields, Colleen/0000-0002-6759-8380; Mohr, David/0000-0002-5443-7596; Brown, C Hendricks/0000-0002-0294-2419 FU United States National Institutes of Health [P20 MH090318, R01 MH095753, R01 MH100482, R34 MH095907, P30DA027828, R01MH040859, R01 NS072127, K08 MH102336, F31 MH106321] FX We are grateful for support from the United States National Institutes of Health, including P20 MH090318, R01 MH095753, R01 MH100482, and R34 MH095907 (PI Mohr); P30DA027828 and R01MH040859 (PI Brown); R01 NS072127 (PI Cheung); K08 MH102336 (PI Schueller); F31 MH106321 (PI Stiles-Shields). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 45 TC 20 Z9 20 U1 8 U2 19 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUL PY 2015 VL 17 IS 7 AR e166 DI 10.2196/jmir.4391 PG 13 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA CM3PE UT WOS:000357594000001 PM 26155878 ER PT J AU Sojkova, J Goh, J Bilgel, M Landman, B Yang, X Zhou, Y An, Y Beason-Held, LL Kraut, MA Wong, DF Resnick, SM AF Sojkova, Jitka Goh, Joshua Bilgel, Murat Landman, Bennett Yang, Xue Zhou, Yun An, Yang Beason-Held, Lori L. Kraut, Michael A. Wong, Dean F. Resnick, Susan M. TI Voxelwise Relationships Between Distribution Volume Ratio and Cerebral Blood Flow: Implications for Analysis of beta-Amyloid Images SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE amyloid; cerebral blood flow; PiB; aging; DVR ID PITTSBURGH COMPOUND-B; REFERENCE TISSUE MODEL; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; SPATIAL CONSTRAINT; DEPOSITION; PET; DECLINE; HYPOMETABOLISM; BIOMARKERS AB Quantification of beta-amyloid (A beta) in vivo is often accomplished using the distribution volume ratio (DVR), based on a simplified reference tissue model. We investigated the local relationships between DVR and cerebral blood flow (CBF), as well as relative CBF (R-1), in nondemented older adults. Methods: Fifty-five nondemented participants (mean age, 78.5 y) in the Baltimore Longitudinal Study of Aging underwent O-15-H2O PET CBF and dynamic C-11-PiB PET. O-15-H2O PET images were normalized and smoothed using SPM. A simplified reference tissue model with linear regression and spatial constraints was used to generate parametric DVR images. The DVR images were regressed on CBF images on a voxel-by-voxel basis using robust biologic parametric mapping, adjusting for age and sex (false discovery rate, P = 0.05; spatial extent, 50 voxels). DVR images were also regressed on R1 images, a measure of the transport rate constant from vascular space to tissue. All analyses were performed on the entire sample, and on high and low tertiles of mean cortical DVR. Results: Voxel-based analyses showed that increased DVR is associated with increased CBF in the frontal, parietal, temporal, and occipital cortices. However, this association appears to spare regions that typically show early A beta,deposition. A more robust relationship between DVR and CBF was observed in the lower tertile of DVR, that is, negligible cortical A beta load, compared with the upper tertile of cortical DVR and A beta load. The spatial distributions of the DVR-CBF and DVR-R-1 correlations showed similar patterns. No reliable negative voxelwise relationships between DVR and CBF or R-1 were observed. Conclusion: Robust associations between DVR and CBF at negligible A beta levels, together with similar spatial distributions of DVR-CBF and DVR-R-1 correlations, suggest that regional distribution of DVR reflects blood flow and tracer influx rather than pattern of A beta deposition in those with minimal A beta load. DVR-CBF associations in individuals with a higher DVR are more likely to reflect true associations between patterns of A beta deposition and CBF or neural activity. These findings have important implications for analysis and interpretation of voxelwise correlations with external variables in individuals with varying amounts of A beta load. C1 [Sojkova, Jitka; Goh, Joshua; Bilgel, Murat; An, Yang; Beason-Held, Lori L.; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Goh, Joshua] Natl Taiwan Univ, Taipei 10764, Taiwan. [Bilgel, Murat] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Landman, Bennett; Yang, Xue] Vanderbilt Univ, Dept Elect Engn, Nashville, TN 37235 USA. [Zhou, Yun; Kraut, Michael A.; Wong, Dean F.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Wong, Dean F.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Wong, Dean F.] Johns Hopkins Univ, Solomon Snyder Dept Neurosci, Baltimore, MD USA. [Wong, Dean F.] Johns Hopkins Univ, Environm Hlth Sci, Baltimore, MD USA. RP Resnick, SM (reprint author), NIA, Lab Behav Neurosci, Biomed Res Ctr, IRP, 251 Bayview Blvd,Room 4B335, Baltimore, MD 21224 USA. EM resnicks@mail.nih.gov FU NIH; National Institute on Aging [HHSN260200400012C, K24 DA000412] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This research was supported by the Intramural Research Program of the NIH and by National Institute on Aging research and development contracts HHSN260200400012C and K24 DA000412. No other potential conflict of interest relevant to this article was reported. NR 35 TC 1 Z9 1 U1 1 U2 4 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 JUL PY 2015 VL 56 IS 7 BP 1042 EP 1047 DI 10.2967/jnumed.114.151480 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CM5UN UT WOS:000357754600035 PM 25977462 ER PT J AU Fahey, F Zukotynski, K Jadvar, H Capala, J AF Fahey, Frederic Zukotynski, Katherine Jadvar, Hossein Capala, Jacek CA NCI-SNMMI Workshop Targeted Radion TI Proceedings of the Second NCI-SNMMI Workshop on Targeted Radionuclide Therapy SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article ID NON-HODGKIN-LYMPHOMA; PANCREATIC NEUROENDOCRINE TUMORS; PROSTATE-CANCER; LUNG-CANCER; SCINTIGRAPHY; THERANOSTICS; TRIAL C1 [Fahey, Frederic] Boston Childrens Hosp, Boston, MA 02115 USA. [Fahey, Frederic] Harvard Univ, Sch Med, Boston, MA USA. [Zukotynski, Katherine] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Zukotynski, Katherine] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Jadvar, Hossein] Univ Calif Los Angeles, Los Angeles, CA USA. [Capala, Jacek] NCI, NIH, Bethesda, MD 20892 USA. RP Fahey, F (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM frederic.fahey@childrens.harvard.edu NR 30 TC 3 Z9 3 U1 0 U2 4 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 JUL PY 2015 VL 56 IS 7 BP 1119 EP 1129 DI 10.2967/jnumed.115.159038 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CM5UN UT WOS:000357754600047 PM 25999432 ER PT J AU Carter, TC Pangilinan, F Molloy, AM Fan, RZ Wang, YF Shane, B Gibney, ER Midttun, O Ueland, PM Cropp, CD Kim, Y Wilson, AF Bailey-Wilson, JE Brody, LC Mills, JL AF Carter, Tonia C. Pangilinan, Faith Molloy, Anne M. Fan, Ruzong Wang, Yifan Shane, Barry Gibney, Eileen R. Midttun, Oivind Ueland, Per M. Cropp, Cheryl D. Kim, Yoonhee Wilson, Alexander F. Bailey-Wilson, Joan E. Brody, Lawrence C. Mills, James L. TI Common Variants at Putative Regulatory Sites of the Tissue Nonspecific Alkaline Phosphatase Gene Influence Circulating Pyridoxal 5 '-Phosphate Concentration in Healthy Adults SO JOURNAL OF NUTRITION LA English DT Article DE vitamin B-6; pyridoxal phosphate; pyridoxal; pyridoxic acid; alkaline phosphatase; dietary supplements ID GENOME-WIDE ASSOCIATION; VITAMIN-B6 METABOLISM; DEPENDENT ENZYMES; LIVER-ENZYMES; PLASMA; HYPOPHOSPHATASIA; POPULATION; LOCI; PYRIDOXAL-5'-PHOSPHATE; VISUALIZATION AB Background: Vitamin B-6 interconversion enzymes are important for supplying pyridoxal 5'-phosphate (PLP), the co-enzyme form, to tissues. Variants in the genes for these enzymes [tissue nonspecific alkaline phosphatase (ALPL), pyridoxamine 5'-phosphate oxidase, pyridoxal kinase, and pyridoxal phosphatase) could affect enzyme function and vitamin B-6 status. Objectives: We tested whether single-nucleotide polymorphisms (SNPs) in these genes influence vitamin B-6 status markers [plasma PLP, pyridoxal (PL), and 4-pyridoxic acid (PM, and explored potential functional effects of the SNPs. Methods: Study subjects were young, healthy adults from Ireland In = 2345). We measured plasma PLP, PL, and PA with liquid chromatography-tandem mass spectrometry and genotyped 66 tag SNPs in the 4 genes. We tested for associations with single SNPs in candidate genes and also performed genome-wide association study (GWAS) and gene-based analyses. Results: Seventeen SNPs in ALPL were associated with altered plasma PLP in candidate gene analyses (P < 1.89 x 10(-4)). In the GWAS, 5 additional ALPL SNPs were associated with altered plasma PLP (P< 5.0 10(-8)). Gene-based analyses that used the functional linear model beta-spline (P = 4.04 x 10(-15)) and Fourier spline (P = 5.87 x 10(-15)) methods also showed associations between ALPL and altered plasma PLP. No SNPs in other genes were associated with plasma PLP. The association of the minor CC genotype of 1 ALPL SNP, rs1256341, with reduced ALPL expression in the HapMap Northern European ancestry population is consistent with the positive association between the CC genotype and plasma PLP in our study (P = 0.008). No SNP was associated with altered plasma PL or PA. Conclusions: In healthy adults, common variants in ALPL influence plasma PLP concentration, the most frequently used biomarker for vitamin B-6 status. Whether these associations are indicative of functional changes in vitamin B-6 status requires more investigation. C1 [Carter, Tonia C.] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI USA. [Pangilinan, Faith; Cropp, Cheryl D.; Kim, Yoonhee; Wilson, Alexander F.; Bailey-Wilson, Joan E.; Brody, Lawrence C.] Nat Human Genome Res Inst, Bethesda, MD USA. [Fan, Ruzong; Wang, Yifan; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Molloy, Anne M.] Trinity Coll Dublin, Sch Med, Inst Mol Med, Dublin, Ireland. [Shane, Barry] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Gibney, Eileen R.] Univ Coll Dublin, UCD Inst Food & Hlth, Dublin 2, Ireland. [Midttun, Oivind] Bevital AS, Bergen, Norway. [Ueland, Per M.] Univ Bergen, Dept Clin Sci, Bergen, Norway. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM jamesmills@nih.gov RI Ueland, Per/C-7340-2013; OI Bailey-Wilson, Joan/0000-0002-9153-2920; Molloy, Anne/0000-0002-1688-9049 FU Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01HD33348] FX Supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development contract N01HD33348. NR 48 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2015 VL 145 IS 7 BP 1386 EP 1393 DI 10.3945/jn.114.208769 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM1FE UT WOS:000357425600003 PM 25972531 ER PT J AU Kirkpatrick, SI Dodd, KW Parsons, R Ng, C Garriguet, D Tarasuk, V AF Kirkpatrick, Sharon I. Dodd, Kevin W. Parsons, Ruth Ng, Carmina Garriguet, Didier Tarasuk, Valerie TI Household Food Insecurity Is a Stronger Marker of Adequacy of Nutrient Intakes among Canadian Compared to American Youth and Adults SO JOURNAL OF NUTRITION LA English DT Article DE household food insecurity; usual dietary intake; National Cancer Institute method; nutrient inadequacies; 24-hour recalls; Dietary Reference Intakes; Estimated Average Requirement; between-country comparison; Canadian Community Health Survey; National Health and Nutrition Examination Survey ID NUTRITION EXAMINATION SURVEY; US ADULTS; RECOVERY BIOMARKERS; NATIONAL-HEALTH; UNITED-STATES; 5 VALIDATION; INCOME; CHILDREN; SECURITY; FAMILIES AB Background: The most recent statistics indicate that the prevalence of food insecurity in the United States is double that in Canada, but the extent to which the nutrition implications of this problem differ between the countries is not known. Objective: This study was undertaken to compare adequacy of nutrient intakes in relation to household food insecurity among youth and adults in Canada and the United States. Methods: Data from comparable nationally representative surveys, the 2004 Canadian Community Health Survey and the 2003-2006 NHANES, were used to estimate prevalences of inadequate intakes of vitamins A and C, folate, calcium, magnesium, and zinc among youth and adults in food-secure and food-insecure households. Potential differences in the composition of the populations between the 2 countries were addressed by using standardization, and analyses also accounted for participation in food and nutrition assistance programs in the United States. Results: Larger gaps in the prevalences of inadequate intakes between those in food-secure and food-insecure households were observed in Canada than in the United States for calcium and magnesium. For calcium, the prevalences of inadequate intakes among those in food-secure and food-insecure households in Canada were 50% and 66%, respectively, compared with 50% and 51%, respectively, in the United States. For magnesium, the prevalences of inadequate intakes in Canada were 39% and 60% among those in food-secure and food-insecure households, respectively, compared with 60% and 61%, respectively, in the United States. These findings were largely unchanged after we accounted for participation in food and nutrition assistance programs in the United States. Conclusions: This study suggests that household food insecurity is a stronger marker of nutritional vulnerability in Canada than in the United States. The results highlight the need for research to elucidate the effects of domestic policies affecting factors such as food prices' and fortification on the nutritional manifestations of food insecurity. C1 [Kirkpatrick, Sharon I.] Univ Waterloo, Sch Publ Hlth & Hlth Syst, Waterloo, ON N2L 3G1, Canada. [Dodd, Kevin W.] Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. [Parsons, Ruth] Informat Management Serv Inc, Rockville, MD USA. [Ng, Carmina] Stat Canada Res Data Ctr, Toronto, ON, Canada. [Garriguet, Didier] STAT Canada, Hlth Stat Div, Ottawa, ON, Canada. [Tarasuk, Valerie] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. RP Kirkpatrick, SI (reprint author), Univ Waterloo, Sch Publ Hlth & Hlth Syst, Waterloo, ON N2L 3G1, Canada. EM sharon.kirkpatrick@uwaterloo.ca OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU DCCPS; Division of Cancer Prevention, National Cancer Institute; Programmatic Grant in Health and Health Equity, Canadian Institutes of Health Research [FRN 115208] FX At the time that the initial analyses were conducted, Sharon Kirkpatrick was a nutritionist with the Division of Cancer Control and Population Sciences (DCCPS) at the National Cancer Institute. Analyses of NHANES were supported by DCCPS, as well as the Division of Cancer Prevention, National Cancer Institute. Analyses of data from Canadian Community Health Survey cycle 2.2 were supported by funds from a Programmatic Grant in Health and Health Equity, Canadian Institutes of Health Research (FRN 115208), held by VT. NR 83 TC 5 Z9 5 U1 0 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2015 VL 145 IS 7 BP 1596 EP 1603 DI 10.3945/jn.114.208579 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM1FE UT WOS:000357425600030 PM 25995277 ER PT J AU Taylor, CL Bailey, RL Carriquiry, AL AF Taylor, Christine L. Bailey, Regan L. Carriquiry, Alicia L. TI Use of Folate-Based and Other Fortification Scenarios Illustrates Different Shifts for Tails of the Distribution of Serum 25-Hydroxyvitamin D Concentrations SO JOURNAL OF NUTRITION LA English DT Article DE fortification; vitamin D; serum 25-hydroxoyvitamin D; folate; modeling scenarios ID FOLIC-ACID INTERVENTION; FOOD FORTIFICATION; VITAMIN-D; POPULATION; BIOMARKERS; LEVEL AB Background: The purpose of food fortification is to affect those at the lower end of the distribution curve for nutrient status while avoiding unintended consequences for those at the high end of the distribution. Vitamin D presents challenges in this regard. Objectives: We used scenarios to model changes in concentrations of serum 25-hydroxyvitamin D [(25(OH)D] based on increases made because of assumptions about fortification. We then examined the outcomes for balance between improving serum (25(OH)D status for those at risk of inadequacy while avoiding high concentrations for those not at risk. Methods: Data from NHANES 2001-2006 served as baseline serum (25(OH)D concentrations and were used to model shifts in serum (25(OH)D distribution after application of 3 fortification scenarios, including conceptual scenarios and an experiential predictive scenario we developed with the use of statistical modeling of changes in NHANES serum folate concentrations between prefortification and postfortification time periods. Results: All scenarios suggested the possibility of increasing serum (25(OH)D above 125 nmol/L among the proportion of the population at the high end of baseline serum (25(OH)D distribution. The scenario based on serum folate change struck a middle ground between the 2 conceptual scenarios. It predicted a prevalence of 11%, <40 nmol/L serum 25(OH)D compared with 17% currently (study baseline), and 8% prevalence of serum (25(OH)D >125 nmol/L compared with <1% currently (study baseline). It also confirmed that fortification affects those at the low end of the status distribution curve differently from those at the high end. Conclusions: Nutrient inadequacy of the type demonstrated by vitamin D-in which the risk is not universal-requires a thorough exploration of the unintended consequences of the overall shift in the distribution of serum (25(OH)D if efforts are made to use fortification to increase the status of persons at risk of deficiency. Fortification is at best a blunt instrument that must be implemented with caution. Moreover, fortification must be preceded by more research to elucidate the dose-response relation between intake and changes in serum 25(OH)D. C1 [Taylor, Christine L.; Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA USA. RP Taylor, CL (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM TaylorCL3@od.nih.gov NR 24 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2015 VL 145 IS 7 BP 1623 EP 1629 DI 10.3945/jn.115.211185 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM1FE UT WOS:000357425600033 PM 25972526 ER PT J AU Nicastro, HL Bailey, RL Dodd, KW AF Nicastro, Holly L. Bailey, Regan L. Dodd, Kevin W. TI Using 2 Assessment Methods May Better Describe Dietary Supplement Intakes in the United States SO JOURNAL OF NUTRITION LA English DT Article DE dietary supplement; NHANES; multivitamin multimineral; measurement error; dietary assessment ID NUTRITION EXAMINATION SURVEY; US ADULTS; NATIONAL-HEALTH; NUTRIENT INTAKE; ENERGY; BIAS; PREFERENCE; HEIGHT AB Background: One-half of US adults report using a dietary supplement. NHANES has traditionally assessed dietary supplement use via a 30-d questionnaire but in 2007 added a supplement module to the 24-h dietary recall (24HR). Objective: We compared these 2 dietary assessment methods, examined potential biases in the methods, and determined the effect that instrument choice had on estimates of prevalence of multivitamin/multimineral dietary supplement (MVMM) use. Methods: We described prevalence of dietary supplement use by age, sex, and assessment instrument in 12,285 adults in the United States (>19 y of age) from NHANES 2007-2010. Results: When using data from the questionnaire alone, 29.3% +/- 1.0% of men and 35.5% +/- 1.0% of women were users of MVMMs, whereas data from the 24HR only produced prevalence estimates of 26.3% +/- 1.1% for men and 33.2% +/- 1.0% for women. When using data from both instruments combined, 32.3% +/- 1.2% of men and 39.5% +/- 1.1% of women were classified as MVMM users. Prevalence estimates were significantly higher by 2-9% in all age-sex groups when using information from both instruments combined than when using data from either instrument individually. A digit preference bias and flattened slope phenomenon were observed in responses to the dietary supplement questionnaire. A majority (67%) of MVMMs were captured on both instruments, whereas 19% additional MVMMs were captured on the questionnaire and 14% additional on the 24HR. Of those captured only on the 24HR, 26% had missing label information, whereas only 12% and 9% of those captured on the questionnaire or both, respectively, had missing information. Conclusions: Use of both the dietary supplement questionnaire and the 24HR can provide advantages to researchers over the use of a single instrument and potentially capture a larger fraction of dietary supplement users. C1 [Nicastro, Holly L.] Natl Canc Inst, NIH, Div Cardiovasc Sci, Natl Heart Lung & Blood Inst, Bethesda, MD 20892 USA. [Bailey, Regan L.] Natl Canc Inst, NIH, Off Dietary Supplements, Off Director, Bethesda, MD USA. [Dodd, Kevin W.] Natl Canc Inst, NIH, Div Canc Prevent, Bethesda, MD USA. RP Nicastro, HL (reprint author), Natl Canc Inst, NIH, Div Cardiovasc Sci, Natl Heart Lung & Blood Inst, Bethesda, MD 20892 USA. EM holly.nicastro@nih.gov NR 18 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2015 VL 145 IS 7 BP 1630 EP 1634 DI 10.3945/jn.115.211466 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM1FE UT WOS:000357425600034 PM 26019244 ER PT J AU Bailey, LB Stover, PJ McNulty, H Fenech, MF Gregory, JF Mills, JL Pfeiffer, CM Fazili, Z Zhang, M Ueland, PM Molloy, AM Caudill, MA Shane, B Berry, RJ Bailey, RL Hausman, DB Raghavan, R Raiten, DJ AF Bailey, Lynn B. Stover, Patrick J. McNulty, Helene Fenech, Michael F. Gregory, Jesse F., III Mills, James L. Pfeiffer, Christine M. Fazili, Zia Zhang, Mindy Ueland, Per M. Molloy, Anne M. Caudill, Marie A. Shane, Barry Berry, Robert J. Bailey, Regan L. Hausman, Dorothy B. Raghavan, Ramkripa Raiten, Daniel J. TI Biomarkers of Nutrition for Development-Folate Review SO JOURNAL OF NUTRITION LA English DT Review DE BOND; folate biomarkers; serum folate; RBC folate; homocysteine ID NEURAL-TUBE DEFECTS; ONE-CARBON METABOLISM; TANDEM MASS-SPECTROMETRY; FOLIC-ACID SUPPLEMENTATION; PLASMA TOTAL HOMOCYSTEINE; METHYLENETETRAHYDROFOLATE-REDUCTASE GENE; PERFORMANCE LIQUID-CHROMATOGRAPHY; PERIPHERAL-BLOOD LYMPHOCYTES; GLOBAL DNA HYPOMETHYLATION; B-VITAMIN STATUS AB The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. C1 [Bailey, Lynn B.; Hausman, Dorothy B.] Univ Georgia, Dept Foods & Nutr, Athens, GA 30602 USA. [Stover, Patrick J.; Caudill, Marie A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [McNulty, Helene] Univ Ulster, Northern Ireland Ctr Food & Hlth, Biomed Sci Res Inst, Londonderry, NH USA. [Fenech, Michael F.] CSIRO, Genome Hlth Nutrigen Lab, Food Nutr & Bioprod Flagship, Adelaide, SA, Australia. [Gregory, Jesse F., III] Univ Florida, Food Sci & Human Nutr Dept, Gainesville, FL USA. [Mills, James L.; Raghavan, Ramkripa; Raiten, Daniel J.] Eunice Kennedy Shriner Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Pfeiffer, Christine M.; Fazili, Zia; Zhang, Mindy] CDC, Nat Ctr Environm Hlth, Atlanta, GA 30333 USA. [Ueland, Per M.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Molloy, Anne M.] Trinity Coll Dublin, Inst Mol Med, Dublin, Ireland. [Shane, Barry] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Berry, Robert J.] CDC, Nat Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Bailey, LB (reprint author), Univ Georgia, Dept Foods & Nutr, Athens, GA 30602 USA. EM folate@uga.edu; raitend@mail.nih.gov RI Ueland, Per/C-7340-2013; OI Molloy, Anne/0000-0002-1688-9049; Berry, Robert/0000-0002-7162-5046 FU Bill & Melinda Gates Foundation; PepsiCo; Division of Nutrition Research Coordination (DNRC, NIH); Office of Dietary Supplements (ODS, NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH) FX Published in a supplement to The Journal of Nutrition. The Biomarkers of Nutrition for Development (BOND) project was developed by the nutrition program staff of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the NIH within the US Department of Health and Human Services (DHHS). The initial 6 nutrients selected, iodine, vitamin A, iron, zinc, folate, and vitamin B-12, were chosen for their high public health importance. Expert panels on each nutrient were constituted and charged with developing comprehensive reviews for publication in the BOND series. The BOND program received its core funding from the Bill & Melinda Gates Foundation, PepsiCo, the Division of Nutrition Research Coordination (DNRC, NIH), the Office of Dietary Supplements (ODS, NIH), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH). The Supplement Coordinators for this supplement were Daniel J Raiten (NICHD, NIH) and Lynn B Bailey (University of Georgia). Supplement Coordinators disclosures: no conflicts of interest. This supplement is the responsibility of the Guest Editor to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The Guest Editor for this supplement was Kevin L Schalinske. Guest Editor disclosure: no conflicts of interest. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition. NR 445 TC 20 Z9 21 U1 9 U2 31 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2015 VL 145 IS 7 BP 1636 EP 1680 DI 10.3945/jn.114.206599 PG 45 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM1FE UT WOS:000357425600035 PM 26451605 ER PT J AU Fekrazad, R Mirmoezzi, A Kalhori, KAM Arany, P AF Fekrazad, Reza Mirmoezzi, Amir Kalhori, Katayoun A. M. Arany, Praveen TI The effect of red, green and blue lasers on healing of oral wounds in diabetic rats SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Article ID IRRADIATION; THERAPY AB Background and objective: Many studies have demonstrated that low-level laser therapy (LLLT) can improve wound healing in non-diabetic and diabetic animals. We compared the effects of red, green, and blue lasers in terms of accelerating oral wound healing in diabetic rats. Material and methods: Diabetes was successfully induced in 32 male Wistar rats using intraperitoneal injection of Streptozotocin (150 mg/kg). After intraperitoneal injection of the anesthetic agent, a full-thickness oral wound (10 mm x 2 mm) was created aseptically with a scalpel on hard palate of the diabetic rats. The study was performed using red (630 nm), green (532 nm), and blue (425 nm) lasers and a control group. We used an energy density of 2 J/cm2 and a treatment schedule of 3 times/week for 10 days. The area of wounds was measured and recorded on a chart for all rats. On the 10th day, the samples were then sacrificed and a full-thickness sample of wound area was prepared for pathological study. Results: We observed a significant difference (p < 0.001) in the mean slope values of wound healing between treatment and control groups. Moreover, the mean slope of wound healing differed significantly between red laser and two other lasers - blue and green (p < 0.001). The mean slopes of wound healing were not significantly different between blue laser and green laser (p = 0.777). Conclusion: The results of the present study provide evidence that wound healing is slower in control rats compared to the treatment groups. Moreover, the findings suggest that wound healing occurs faster with red laser compared to blue and green lasers. (C) 2015 Elsevier B.V. All rights reserved. C1 [Fekrazad, Reza] AJA Univ Med Sci, Laser Res Ctr Med Sci, Tehran, Iran. [Kalhori, Katayoun A. M.] Iranian Med Laser Assoc, Tehran, Iran. [Arany, Praveen] NICDR, NIH, Bethesda, MD USA. RP Kalhori, KAM (reprint author), Flat 12,Moj Bldg,27,First Behestan,Pasdaran St, Tehran, Iran. EM dr_kalhori@yahoo.com NR 20 TC 3 Z9 3 U1 2 U2 5 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD JUL PY 2015 VL 148 BP 242 EP 245 DI 10.1016/j.jphotobiol.2015.04.018 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CM0DN UT WOS:000357348700030 PM 25981185 ER PT J AU Freedman, DM Kitahara, CM Linet, MS Alexander, BH Neta, G Little, MP Cahoon, EK AF Freedman, D. Michal Kitahara, Can M. Linet, Martha S. Alexander, Bruce H. Neta, Gila Little, Mark P. Cahoon, Elizabeth K. TI Ambient temperature and risk of first primary basal cell carcinoma: A nationwide United States cohort study SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Article ID SKIN-CANCER; RADIOLOGIC TECHNOLOGISTS; CLIMATE-CHANGE; CARCINOGENESIS; RADIATION AB The Earth's surface is warming and animal studies have shown higher temperatures promote ultraviolet radiation (UVR) skin carcinogenesis. There are, however, no population studies of long-term temperature exposure and basal cell carcinoma (BCC) risk. We linked average lifetime summer ambient temperatures (based on weather station data) and satellite-based UVR estimates to self-reported lifetime residences in the U.S. Radiologic Technologists' cohort. We assessed the relationship between time-dependent average lifetime summer ambient temperature (20-year lag) in quintiles and BCC in whites, using Cox proportional hazards regression. Risks were adjusted for time-dependent lagged average lifetime UVR and time outdoors, body mass index, eye color, and sex (baseline hazard stratified on birth cohort). During a median 19.4 years follow-up, we identified 3556 BCC cases. There was no significant trend in risk between temperature and BCC. However, BCC risk was highest in the fourth quintile of temperature (Q4 vs. Q1; hazards ratio (HR) = 1.18; 95% confidence interval (CI) = 1.06-1.31, p-trend = 0.09). BCC risk was strongly related to average lifetime ambient UVR exposure (Q5 vs. Q1; HR = 1.54 (95% CI = 1.35-1.75, p-trend = <0.001)). Future studies of temperature and BCC risk should include a broad range of UVR and temperature values, along with improved indicators of exposure to temperatures and UVR. Published by Elsevier B.V. C1 [Freedman, D. Michal; Kitahara, Can M.; Linet, Martha S.; Neta, Gila; Little, Mark P.; Cahoon, Elizabeth K.] NCI, Div Canc Control & Populat Sci, NIH, DHHS, Rockville, MD USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Freedman, DM (reprint author), 9609 Med Ctr Dr,7E358, Rockville, MD 20850 USA. EM freedmam@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Little, Mark/0000-0003-0980-7567 NR 23 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD JUL PY 2015 VL 148 BP 284 EP 289 DI 10.1016/j.jphotobiol.2015.04.025 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CM0DN UT WOS:000357348700036 ER PT J AU Lee, E Barsalou, J Mohan, S Levy, D Kaplan, M Silverman, E AF Lee, Erika Barsalou, Julie Mohan, Smriti Levy, Deborah Kaplan, Mariana Silverman, Earl TI The Association of Type I Interferon and Disease Activity in Childhood-Onset Systemic Lupus Erythematosus (cSLE) SO JOURNAL OF RHEUMATOLOGY LA English DT Meeting Abstract CT 70th Annual Meeting of the Canadian-Rheumatology-Association (CRA) CY FEB 04-07, 2015 CL Quebec, CANADA SP Canadian Rheumatol Assoc C1 [Lee, Erika; Levy, Deborah; Silverman, Earl] Hosp Sick Children, Ottawa, ON, Canada. [Barsalou, Julie] Ctr Hosp Univ St Justine, Montreal, PQ, Canada. [Mohan, Smriti] Univ Michigan, Ann Arbor, MI 48109 USA. [Kaplan, Mariana] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 2015 VL 42 IS 7 MA 5 BP 1265 EP 1265 PG 1 WC Rheumatology SC Rheumatology GA CL9FF UT WOS:000357280700038 ER PT J AU Potapov, A Yau, WM Ghirlando, R Thurber, KR Tycko, R AF Potapov, Alexey Yau, Wai-Ming Ghirlando, Rodolfo Thurber, Kent R. Tycko, Robert TI Successive Stages of Amyloid-beta Self-Assembly Characterized by Solid-State Nuclear Magnetic Resonance with Dynamic Nuclear Polarization SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ATOMIC-FORCE MICROSCOPY; NMR CHEMICAL-SHIFTS; ALZHEIMERS-DISEASE; STRUCTURAL BASIS; MOLECULAR-STRUCTURE; CASCADE HYPOTHESIS; SHEET STRUCTURES; IN-REGISTER; C-13 NMR; FIBRILS AB Self-assembly of amyloid-beta (A beta) peptides in human brain tissue leads to neurodegeneration in Alzheimers disease (AD). Amyloid fibrils, whose structures have been extensively characterized by solid state nuclear magnetic resonance (ssNMR) and other methods, are the thermodynamic end point of A beta self-assembly. Oligomeric and protofibrillar assemblies, whose structures are less well-understood, are also observed as intermediates in the assembly process in vitro and have been implicated as important neurotoxic species in AD. We report experiments in which the structural evolution of 40-residue A beta (A beta 40) is monitored by ssNMR measurements on frozen solutions prepared at four successive stages of the self-assembly process. Measurements on transient intermediates are enabled by ssNMR signal enhancements from dynamic nuclear polarization (DNP) at temperatures below 30 K. DNP-enhanced ssNMR data reveal a monotonic increase in conformational order from an initial state comprised primarily of monomers and small oligomers in solution at high pH, to larger oligomers near neutral pH, to metastable protofibrils, and finally to fibrils. Surprisingly, the predominant molecular conformation, indicated by C-13 NMR chemical shifts and by side chain contacts between F19 and L34 residues, is qualitatively similar at all stages. However, the in-register parallel beta-sheet supramolecular structure, indicated by intermolecular C-13 spin polarization transfers, does not develop before the fibril stage. This work represents the first application of DNP-enhanced ssNMR to the characterization of peptide or protein self-assembly intermediates. C1 [Potapov, Alexey; Yau, Wai-Ming; Thurber, Kent R.; Tycko, Robert] Natl Inst Diabet & Digest & Kidney Dis, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] Natl Inst Diabet & Digest & Kidney Dis, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov OI Potapov, Alexey/0000-0002-9518-4679 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Human Frontier Science Program FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. A.P. was supported by a postdoctoral research fellowship from the Human Frontier Science Program. NR 102 TC 22 Z9 22 U1 11 U2 85 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 1 PY 2015 VL 137 IS 25 BP 8294 EP 8307 DI 10.1021/jacs.5b04843 PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA CM1JD UT WOS:000357436300052 PM 26068174 ER PT J AU Tsai, WY Durbin, A Tsai, JJ Hsieh, SC Whitehead, S Wang, WK AF Tsai, Wen-Yang Durbin, Anna Tsai, Jih-Jin Hsieh, Szu-Chia Whitehead, Stephen Wang, Wei-Kung TI Complexity of Neutralizing Antibodies against Multiple Dengue Virus Serotypes after Heterotypic Immunization and Secondary Infection Revealed by In-Depth Analysis of Cross-Reactive Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; ORIGINAL ANTIGENIC SIN; ENVELOPE PROTEIN; FUSION LOOP; DOMAIN-III; HEMORRHAGIC-FEVER; IMMUNE-RESPONSE; VACCINE; EPITOPES; HUMANS AB The four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primaryDENVinfection. The nature of neutralizing antibodies after secondaryDENVinfection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and secondDENVserotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we foundGRand CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion ofGRantibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted ofGRand CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies forDENVvaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection. IMPORTANCE The four serotypes of dengue virus (DENV) are the leading cause of arboviral diseases in humans. Despite the presence of neutralizing antibodies, a moderate efficacy was recently reported in phase 2b and 3 trials of a dengue vaccine; a better understanding of neutralizing antibodies in polyclonal human sera is urgently needed. Westudied vaccinees who received heterotypic immunization of live-attenuated vaccines, as they were known to have received the first and secondDENVserotype exposures. Wefound anti-envelope antibodies consist of group-reactive (GR), complex-reactive (CR), and type-specific (TS) antibodies, and that bothGRand CR antibodies contribute significantly to multitypic neutralizing activities after secondaryDENVimmunization. These findings have implications for alternative strategies forDENVvaccination. Certain TS antibodies were recently discovered to contribute to the monotypic neutralizing activity and protection after primaryDENVinfection; our findings of the complexity of neutralizing activities after secondary immunization/ infection provide new insights for neutralizing antibodies as surrogates of protection. C1 [Tsai, Wen-Yang; Hsieh, Szu-Chia; Wang, Wei-Kung] Univ Hawaii Manoa, Dept Trop Med Med Microbiol & Pharmacol, John A Burns Sch Med, Honolulu, HI 96822 USA. [Durbin, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Dept Int Hlth, Baltimore, MD USA. [Tsai, Jih-Jin] Kaohsiung Med Univ, Div Infect Dis, Dept Internal Med, Kaohsiung, Taiwan. [Tsai, Jih-Jin] Kaohsiung Med Univ, Trop Med Ctr, Kaohsiung, Taiwan. [Tsai, Jih-Jin] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Kaohsiung, Taiwan. [Tsai, Jih-Jin] Kaohsiung Med Univ, Dept Internal Med, Sch Med, Kaohsiung, Taiwan. [Tsai, Jih-Jin] Kaohsiung Med Univ, Ctr Dengue Fever Control & Res, Kaohsiung, Taiwan. [Whitehead, Stephen] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wang, WK (reprint author), Univ Hawaii Manoa, Dept Trop Med Med Microbiol & Pharmacol, John A Burns Sch Med, Honolulu, HI 96822 USA. EM wangwk@hawaii.edu FU National Institute of General Medical Sciences, NIH [P20GM103516]; National Institute of Allergy and Infectious Diseases, NIH [R01AI110769-01]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by grants P20GM103516 from the National Institute of General Medical Sciences, NIH, R01AI110769-01 from the National Institute of Allergy and Infectious Diseases, NIH, and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 69 TC 8 Z9 8 U1 3 U2 5 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 JUL PY 2015 VL 89 IS 14 BP 7348 EP 7362 DI 10.1128/JVI.00273-15 PG 15 WC Virology SC Virology GA CM3XU UT WOS:000357619500033 PM 25972550 ER PT J AU O'Connor, GM Vivian, JP Gostick, E Pymm, P Lafont, BAP Price, DA Rossjohn, J Brooks, AG McVicar, DW AF O'Connor, Geraldine M. Vivian, Julian P. Gostick, Emma Pymm, Phillip Lafont, Bernard A. P. Price, David A. Rossjohn, Jamie Brooks, Andrew G. McVicar, Daniel W. TI Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1 (vol 89, pg 5213, 2015) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [O'Connor, Geraldine M.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Vivian, Julian P.; Pymm, Phillip; Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic, Australia. [Vivian, Julian P.; Pymm, Phillip; Rossjohn, Jamie] Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic, Australia. [Gostick, Emma; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Lafont, Bernard A. P.] NIAID, Nonhuman Primate Immunogenet & Cellular Immunol U, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Brooks, Andrew G.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. RP O'Connor, GM (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 1 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2015 VL 89 IS 14 BP 7442 EP 7442 DI 10.1128/JVI.01159-15 PG 1 WC Virology SC Virology GA CM3XU UT WOS:000357619500047 PM 26089339 ER PT J AU Kreimer, AR Struyf, F Del Rosario-Raymundo, MR Hildeshim, A Skinner, SR Wacholder, S Garland, SM Herrero, R David, MP Mfeeler, CM AF Kreimer, Aimee R. Struyf, Frank Del Rosario-Raymundo, Mora Rowena Hildeshim, Allan Skinner, S. Rachel Wacholder, Sholom Garland, Suzanne M. Herrero, Rolando David, Marfe-Pierre Mfeeler, Cosette M. CA Costa Rica Vaccine Trfal PATRICIA TI Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA trials SO LANCET ONCOLOGY LA English DT Article ID OF-STUDY ANALYSIS; RANDOMIZED CLINICAL-TRIAL; HUMAN-PAPILLOMAVIRUS; DOUBLE-BLIND; HPV VACCINE; INTRAEPITHELIAL NEOPLASIA; PARTICLE VACCINE; BROAD-SPECTRUM; YOUNG-WOMEN; IMMUNOGENICITY AB Background There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. Methods Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and similar to the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. Findings We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77.0% (95% CI 74.7-79.1), two doses was 76.0% (62.0-85.3), and one dose was 85.7% (70.7-93.7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59.7% (56.0-63.0), two doses was 37.7% (12.4-55.9), and one dose was 36.6% (-5.4 to 62.2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75.3% (54.2-87.5) and 82.6% (42.3-96.1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68.1%, 27.0-87.0; CVT data only), but not those receiving it at one month (10.1%, -42.0 to 43.3), was similar to the three-dose group. Interpretation 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. C1 [Kreimer, Aimee R.; Hildeshim, Allan; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Struyf, Frank; David, Marfe-Pierre] GSK Vaccines, Wavre, Belgium. [Del Rosario-Raymundo, Mora Rowena] San Pablo Coll Med Ctr, Dept Obstet & Gynecol, San Pablo City, Philippines. [Skinner, S. Rachel] Telethon Inst Child Hlth Res, Vaccine Trials Grp, Perth, WA, Australia. [Skinner, S. Rachel] Univ Sydney, Childrens Hosp Westmead, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Garland, Suzanne M.] Royal Womens Hosp, Microbiol & Infect Dis Dept, Melbourne, Vic, Australia. [Garland, Suzanne M.] Univ Melbourne, Murdoch Childrens Res Inst, Dept Obstet & Gynaecol, Melbourne, Vic, Australia. [Herrero, Rolando] Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Herrero, Rolando] Int Agcy Res Canc, Sect Early Detect & Prevent, F-69372 Lyon, France. [Mfeeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. [Mfeeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. RP Mfeeler, CM (reprint author), US Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM cwheeler@salud.unm.edu RI Castellsague Pique, Xavier/N-5795-2014; OI Castellsague Pique, Xavier/0000-0002-0802-3595; Apter, Dan/0000-0002-5175-8845 FU US National Cancer Institute; National Institutes of Health Office of Research on Women's Health; Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA) FX US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA). NR 26 TC 60 Z9 64 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2015 VL 16 IS 7 BP 775 EP 786 DI 10.1016/S1470-2045(15)00047-9 PG 12 WC Oncology SC Oncology GA CL9CU UT WOS:000357273600051 PM 26071347 ER PT J AU Rajaraman, P Anderson, BO Basu, P Belinson, JL D'Cruz, A Dhillon, PK Gupta, P Jawahar, TS Joshi, N Kailash, U Kapambwe, S Katoch, VM Krishnan, S Panda, D Sankaranarayanan, R Selvam, JM Shah, KV Shastri, S Shridhar, K Siddiqi, M Sivaram, S Seth, T Srivastava, A Trimble, E Mehrotra, R AF Rajaraman, Preetha Anderson, Benjamin O. Basu, Partha Belinson, Jerome L. D'Cruz, Anil Dhillon, Preet K. Gupta, Prakash Jawahar, Tenkasi S. Joshi, Niranjan Kailash, Uma Kapambwe, Sharon Katoch, Vishwa Mohan Krishnan, Suneeta Panda, Dharitri Sankaranarayanan, R. Selvam, Jerard M. Shah, Keerti V. Shastri, Surendra Shridhar, Krithiga Siddiqi, Maasood Sivaram, Sudha Seth, Tulika Srivastava, Anurag Trimble, Edward Mehrotra, Ravi TI Recommendations for screening and early detection of common cancers in India SO LANCET ONCOLOGY LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; COMPUTER-ASSISTED ANALYSIS; MIDDLE-INCOME COUNTRIES; ORAL BRUSH BIOPSY; CERVICAL-CANCER; BREAST-CANCER; HUMAN-PAPILLOMAVIRUS; COST-EFFECTIVENESS; PRIMARY PREVENTION; ALCOHOL-DRINKING AB Cancers of the breast, uterine cervix, and lip or oral cavity are three of the most common malignancies in India. Together, they account for about 34% of more than 1 million individuals diagnosed with cancer in India each year. At each of these cancer sites, tumours are detectable at early stages when they are most likely to be cured with standard treatment protocols. Recognising the key role that effective early detection and screening programmes could have in reducing the cancer burden, the Indian Institute for Cytology and Preventive Oncology, in collaboration with the US National Cancer Institute Center for Global Health, held a workshop to summarise feasible options and relevant evidence for screening and early detection of common cancers in India. The evidence-based recommendations provided in this Review are intended to act as a guide for policy makers, clinicians, and public health practitioners who are developing and implementing strategies in cancer control for the three most common cancers in India. C1 [Rajaraman, Preetha; Sivaram, Sudha; Trimble, Edward] NCI, Ctr Global Hlth, US Dept Hlth & Human Serv, Rockville, MD 20892 USA. [Anderson, Benjamin O.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Anderson, Benjamin O.] Univ Washington, Dept Global Hlth Med, Seattle, WA 98195 USA. [Basu, Partha] Chittaranjan Natl Canc Inst, Dept Gynecol Oncol, Kolkata, India. [Belinson, Jerome L.] Cleveland Clin, Lerner Sch Med, Womens Hlth Inst, Prevent Oncol Int, Cleveland, OH 44106 USA. [Belinson, Jerome L.] Cleveland Clin, Lerner Sch Med, Womens Hlth Inst, Dept Surg, Cleveland, OH 44106 USA. [D'Cruz, Anil] Tata Mem Hosp, Dept Head & Neck Serv, Mumbai 400012, Maharashtra, India. [Dhillon, Preet K.; Shridhar, Krithiga] Publ Hlth Fdn India, Ctr Control Chron Condit, Gurgaon, India. [Gupta, Prakash] Healis Sekhsaria Inst Publ Hlth, Navi Mumbai, India. [Jawahar, Tenkasi S.; Katoch, Vishwa Mohan] Indian Council Med Res, New Delhi, India. [Joshi, Niranjan] IIT Madras Res Pk, Healthcare Technol Innovat Ctr, Madras, Tamil Nadu, India. [Kailash, Uma; Panda, Dharitri; Mehrotra, Ravi] Inst Cytol & Prevent Oncol, Noida, India. [Kapambwe, Sharon] Africa Ctr Excellence Womens Canc Control, Ctr Infect Dis Res, Lusaka, Zambia. [Krishnan, Suneeta] Res Triangle Inst Int, Womens Global Hlth Imperat, San Francisco, CA USA. [Sankaranarayanan, R.] Int Agcy Res Canc, Early Detect Prevent Sect & Screening Grp, Lyon, France. [Selvam, Jerard M.] Tamil Nadu Hlth Syst Project, Madras, Tamil Nadu, India. [Shah, Keerti V.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Shastri, Surendra] Tata Mem Hosp, Dept Prevent Oncol, Bombay, Maharashtra, India. [Siddiqi, Maasood] Canc Fdn India, Kolkata, India. [Seth, Tulika; Srivastava, Anurag] All India Inst Med Sci, New Delhi, India. RP Rajaraman, P (reprint author), NCI, Ctr Global Hlth, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM rajarama@mail.nih.gov FU Susan G Komen for the Cure; BD India FX BOA received salary support from Susan G Komen for the Cure. NJ reports grants from BD India, outside the submitted work. All other authors declare no competing interests. NR 92 TC 9 Z9 9 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2015 VL 16 IS 7 BP E352 EP E361 PG 10 WC Oncology SC Oncology GA CL9CU UT WOS:000357273600029 PM 26149887 ER PT J AU Lunsford, RD Melillo, AA Somerman, MJ AF Lunsford, Robert D. Melillo, Amanda A. Somerman, Martha J. TI Guest editorial for special oral microbes edition SO MICROBES AND INFECTION LA English DT Editorial Material C1 [Lunsford, Robert D.; Melillo, Amanda A.; Somerman, Martha J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Lunsford, RD (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM lunsfordr@nidcr.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD JUL PY 2015 VL 17 IS 7 SI SI BP 471 EP 472 DI 10.1016/j.micinf.2015.03.005 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CM5TQ UT WOS:000357752100002 PM 25797397 ER PT J AU Chowdhury, SM Zhu, XW Aloor, JJ Azzam, KM Gabor, KA Ge, W Addo, KA Tomer, KB Parks, JS Fessler, MB AF Chowdhury, Saiful M. Zhu, Xuewei Aloor, Jim J. Azzam, Kathleen M. Gabor, Kristin A. Ge, William Addo, Kezia A. Tomer, Kenneth B. Parks, John S. Fessler, Michael B. TI Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID T-CELL-ACTIVATION; OXIDATIVE-PHOSPHORYLATION SYSTEM; RESISTANT LIPID RAFTS; ATP SYNTHASE COMPLEX; ABCA1-DEFICIENT MACROPHAGES; HUMAN NEUTROPHIL; HUMAN MONOCYTES; CHOLESTEROL; MEMBRANE; LIPOPOLYSACCHARIDE AB Lipid raft membrane microdomains organize signaling by many prototypical receptors, including the Toll-like receptors (TLRs) of the innate immune system. Raft-localization of proteins is widely thought to be regulated by raft cholesterol levels, but this is largely on the basis of studies that have manipulated cell cholesterol using crude and poorly specific chemical tools, such as beta-cyclodextrins. To date, there has been no proteome-scale investigation of whether endogenous regulators of intracellular cholesterol trafficking, such as the ATP binding cassette (ABC) A1 lipid efflux transporter, regulate targeting of proteins to rafts. Abca1(-/-) macrophages have cholesterolladen rafts that have been reported to contain increased levels of select proteins, including TLR4, the lipopolysaccharide receptor. Here, using quantitative proteomic profiling, we identified 383 proteins in raft isolates from Abca1(-/-) and Abca1(-/-) macrophages. ABCA1 deletion induced wide-ranging changes to the raft proteome. Remarkably, many of these changes were similar to those seen in Abca1(-/-) macrophages after lipopolysaccharide exposure. Stomatin-like protein (SLP)-2, a member of the stomatin-prohibitin-flotillin-HflK/C family of membrane scaffolding proteins, was robustly and specifically increased in Abca1(-/-) rafts. Pursuing SLP-2 function, we found that rafts of SLP-2-silenced macrophages had markedly abnormal composition. SLP-2 silencing did not compromise ABCA1-dependent cholesterol efflux but reduced macrophage responsiveness to multiple TLR ligands. This was associated with reduced raft levels of the TLR co-receptor, CD14, and defective lipopolysaccharide-induced recruitment of the common TLR adaptor, MyD88, to rafts. Taken together, we show that the lipid transporter ABCA1 regulates the protein repertoire of rafts and identify SLP-2 as an ABCA1-dependent regulator of raft composition and of the innate immune response. C1 [Chowdhury, Saiful M.; Aloor, Jim J.; Azzam, Kathleen M.; Gabor, Kristin A.; Ge, William; Addo, Kezia A.; Fessler, Michael B.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Zhu, Xuewei; Parks, John S.] Wake Forest Sch Med, Sect Mol Med, Dept Internal Med, Winston Salem, NC 27157 USA. RP Fessler, MB (reprint author), NIEHS, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005]; American Heart Association [09POST2250225]; [HL094525]; [HL119962] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES102005), by American Heart Association Fellowship 09POST2250225 (to X.Z.), and by HL094525 and HL119962 (to J.P.). NR 57 TC 3 Z9 3 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUL PY 2015 VL 14 IS 7 BP 1859 EP 1870 DI 10.1074/mcp.M114.045179 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CM1IL UT WOS:000357434400010 PM 25910759 ER PT J AU Bernstein, HD AF Bernstein, Harris D. TI Looks can be deceiving: recent insights into the mechanism of protein secretion by the autotransporter pathway SO MOLECULAR MICROBIOLOGY LA English DT Review ID BACTERIAL OUTER MEMBRANES; GRAM-NEGATIVE BACTERIA; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; TRIMERIC AUTOTRANSPORTER; 2-PARTNER SECRETION; VIRULENCE PROTEINS; PASSENGER DOMAIN; TRANSMEMBRANE DOMAIN; TRANSLOCATOR DOMAIN AB Autotransporters are a large superfamily of cell surface proteins produced by Gram-negative bacteria that consist of an N-terminal extracellular domain (passenger domain') and a C-terminal -barrel domain that resides in the outer membrane (OM). Although it was originally proposed that the passenger domain is translocated across the OM through a channel formed exclusively by the covalently linked -barrel domain, this idea has been strongly challenged by a variety of observations. Recent experimental results have suggested a new model in which both the translocation of the passenger domain and the membrane integration of the -barrel domain are facilitated by the Bam complex, a highly conserved heteroligomer that plays a general role in OM protein assembly. Other factors, including periplasmic chaperones and inner membrane proteins, have also recently been implicated in the biogenesis of at least some members of the autotransporter superfamily. New results have raised intriguing questions about the energetics of the secretion reaction and the relationship between the assembly of autotransporters and the assembly of other classes of OM proteins. Concomitantly, new mechanistic and structural insights have expanded the utility of the autotransporter pathway for the surface display of heterologous peptides and proteins of interest. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX I would like to thank Travis Barnard for helping to construct Fig. 1, and Raffa Ieva for providing helpful comments on the manuscript. Work conducted in the author's laboratory was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 95 TC 8 Z9 8 U1 5 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2015 VL 97 IS 2 BP 205 EP 215 DI 10.1111/mmi.13031 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CM6FC UT WOS:000357782500004 PM 25881492 ER PT J AU Smith, CE Follis, JL Nettleton, JA Foy, M Wu, JHY Ma, YY Tanaka, T Manichakul, AW Wu, HY Chu, AY Steffen, LM Fornage, M Mozaffarian, D Kabagambe, EK Ferruci, L Chen, YDI Rich, SS Djousse, L Ridker, PM Tang, WH McKnight, B Tsai, MY Bandinelli, S Rotter, JI Hu, FB Chasman, DI Psaty, BM Arnett, DK King, IB Sun, Q Wang, L Lumley, T Chiuve, SE Siscovick, DS Ordovas, JM Lemaitre, RN AF Smith, Caren E. Follis, Jack L. Nettleton, Jennifer A. Foy, Millennia Wu, Jason H. Y. Ma, Yiyi Tanaka, Toshiko Manichakul, Ani W. Wu, Hongyu Chu, Audrey Y. Steffen, Lyn M. Fornage, Myriam Mozaffarian, Dariush Kabagambe, Edmond K. Ferruci, Luigi Chen, Yii-Der Ida Rich, Stephen S. Djousse, Luc Ridker, Paul M. Tang, Weihong McKnight, Barbara Tsai, Michael Y. Bandinelli, Stefania Rotter, Jerome I. Hu, Frank B. Chasman, Daniel I. Psaty, Bruce M. Arnett, Donna K. King, Irena B. Sun, Qi Wang, Lu Lumley, Thomas Chiuve, Stephanie E. Siscovick, David S. Ordovas, Jose M. Lemaitre, Rozenn N. TI Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE FADS1; Gene-diet interactions; Meta-analysis; Omega-3 fatty acids ID ALPHA-LINOLENIC ACID; LONG-CHAIN OMEGA-3-FATTY-ACIDS; HEART-FAILURE; OLDER-ADULTS; COHORT; PHOSPHOLIPIDS; METABOLISM; HUMANS; HEALTH; RATIO AB ScopeTissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid. Methods and resultsWe conducted meta-analyses (N = 11668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid. ConclusionOur findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes. C1 [Smith, Caren E.; Ma, Yiyi; Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA 02111 USA. [Follis, Jack L.] Univ St Thomas, Dept Math Comp Sci & Cooperat Engn, Houston, TX 77006 USA. [Nettleton, Jennifer A.; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Foy, Millennia; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Wu, Jason H. Y.] Univ Sydney, George Inst Global Hlth, Sydney, NSW 2006, Australia. [Tanaka, Toshiko; Ferruci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Manichakul, Ani W.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Manichakul, Ani W.; Rich, Stephen S.] Univ Virginia, Dept Biostat & Epidemiol, Charlottesville, VA USA. [Wu, Hongyu; Hu, Frank B.; Sun, Qi; Chiuve, Stephanie E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chu, Audrey Y.; Ridker, Paul M.; Chasman, Daniel I.; Wang, Lu] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Steffen, Lyn M.; Tang, Weihong] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Sch Med, Dept Epidemiol, Boston, MA 02115 USA. [Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Sch Med, Dept Nutr, Boston, MA 02115 USA. [Mozaffarian, Dariush] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Kabagambe, Edmond K.] Vanderbilt Univ, Dept Med, Div Epidemiol, Nashville, TN USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst Harbor, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Djousse, Luc] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Djousse, Luc; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [McKnight, Barbara] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.; Sun, Qi] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hu, Frank B.; Sun, Qi] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Psaty, Bruce M.; Lemaitre, Rozenn N.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA USA. [Psaty, Bruce M.; Siscovick, David S.] Grp Hlth Res Inst, Grp Hlth Cooperat, Dept Epidemiol, Seattle, WA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Dept Hlth Serv, Seattle, WA USA. [Arnett, Donna K.] Univ Alabama Birmingham, Sect Stat Genet, Dept Epidemiol, Birmingham, AL USA. [King, Irena B.] Univ New Mexico, Dept Internal Med, Div Endocrinol, Albuquerque, NM 87131 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Ordovas, Jose M.] CNIC, Dept Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] Inst Madrilenos Estudios Avanzados Alimentac, Madrid, Spain. RP Smith, CE (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr & Genom Lab, 711 Washington St, Boston, MA 02111 USA. EM caren.smith@tufts.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [HL105756, R00HL098459, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, RR-024156]; NHLBI [HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN268201100 008C, HHSN268201100009C, HHSN268201100010C, HHS N268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute (NHGRI) [U01HG004402]; NIH [HSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging; National Human Genome Research Institute [U01-HG-004729, U01-HG-004446, U01-HG-004424]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant [DK063491]; National Heart, Lung, and Blood Institute (NHLBI) [U01HL072524, HL043851, HL080467]; U.S. Department of Agriculture, Agriculture Research Service [53-K06-5-10, 58-1950-9-001]; National Institutes of Health [P01 CA87969, R01 HL034594, UM1 CA167552, R01 HL35464, HL60712, CA055075]; American Diabetes Association [1-12-JF-13]; American Heart Association [11SDG7380016]; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; National Cancer Institute (NCI) [CA047988]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; NCI [CA047988]; The NHLBI [HL105756, HL043851, HL080467, R01-HL-084099, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL085710, R01 HL091357, HL54776, HL078885, N02HL64278, R00-HL095649, HL099355]; [K08 HL112845] FX C.S. is supported by K08 HL112845. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant HL105756. Funding for the individual cohorts is identified below.; ARIC: This study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN268201100 008C, HHSN268201100009C, HHSN268201100010C, HHS N268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute (NHGRI) contract U01HG004402; and NIH contract HSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH Roadmap for Medical Research. CARDIA: This study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. Genotyping of the CARDIA participants was supported by grants U01-HG-004729, U01-HG-004446, and U01-HG-004424 from the National Human Genome Research Institute. Statistical analyses and fatty acid measures were funded by R01-HL-084099 from the NHLBI to Dr. Fornage. CHS: This research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The fatty acid measurements were supported by grant HL085710 from NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. GOLDN: This study was supported by National Heart, Lung, and Blood Institute (NHLBI) grant no. U01HL072524 (Genetic and Environmental Determinants of Triglycerides), NHLBI R01 HL091357 (Genome-wide Association Study of Lipid Response to Fenofibrate and Dietary Fat), NHLBI grant number HL54776 and HL078885; and by contracts 53-K06-5-10 and 58-1950-9-001 from the U.S. Department of Agriculture, Agriculture Research Service. Dr. C.E.S. is supported by K08 HL112845. HPFS and NHS: The research grant P01 CA87969, R01 HL034594, UM1 CA167552, R01 HL35464, HL60712, and CA055075 from National Institutes of Health, a career development award R00HL098459 from the National Heart, Lung, and Blood Institute, and research grant 1-12-JF-13 from American Diabetes Association, and 11SDG7380016 from American Heart Association. InCHIANTI: This study investigators thank the Intramural Research Program of the NIH, National Institute on Aging who are responsible for the InCHIANTI samples. Investigators also thank the InCHIANTI participants. The InCHIANTI study baseline (1998--2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336).; MESA: The MESA and MESA SHARe were supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung, and Blood Institute. Funding for MESA SHARe genotyping was provided by NHLBI contract N02HL64278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The authors thank the other investigators, staff, and participants of the MESA study for their valuable contributions. Afull list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.; WGHS: The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute (NHLBI) and CA047988 from the National Cancer Institute (NCI), the Donald W. Reynolds Foundation, and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The WHS is supported by HL043851, HL080467, and HL099355 from the NHLBI and CA047988 from NCI. The measurement of erythrocyte fatty acid is supported by 0735390N from the American Heart Association (AHA). Dr. Wang is supported by R00-HL095649 from the NHLBI. NR 26 TC 13 Z9 13 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD JUL PY 2015 VL 59 IS 7 BP 1373 EP 1383 DI 10.1002/mnfr.201400734 PG 11 WC Food Science & Technology SC Food Science & Technology GA CM1FX UT WOS:000357427700011 PM 25626431 ER PT J AU Case, LB Baird, MA Shtengel, G Campbell, SL Hess, HF Davidson, MW Waterman, CM AF Case, Lindsay B. Baird, Michelle A. Shtengel, Gleb Campbell, Sharon L. Hess, Harald F. Davidson, Michael W. Waterman, Clare M. TI Molecular mechanism of vinculin activation and nanoscale spatial organization in focal adhesions SO NATURE CELL BIOLOGY LA English DT Article ID CELL-MATRIX ADHESIONS; INTRAMOLECULAR ASSOCIATION; PAXILLIN PHOSPHORYLATION; INTEGRIN ACTIVATION; NASCENT ADHESIONS; ACTIN INTERACTION; BINDING PROTEIN; TALIN BINDING; ALPHA-ACTININ; TAIL DOMAINS AB Focal adhesions (FAs) link the extracellular matrix to the actin cytoskeleton to mediate cell adhesion, migration, mechanosensing and signalling. FAs have conserved nanoscale protein organization, suggesting that the position of proteins within FAs regulates their activity and function. Vinculin binds different FA proteins to mediate distinct cellular functions, but how vinculin's interactions are spatiotemporally organized within FAs is unknown. Using interferometric photoactivation localization super-resolution microscopy to assay vinculin nanoscale localization and a FRET biosensor to assay vinculin conformation, we found that upward repositioning within the FA during FA maturation facilitates vinculin activation and mechanical reinforcement of FAs. Inactive vinculin localizes to the lower integrin signalling layer in FAs by binding to phospho-paxillin. Talin binding activates vinculin and targets active vinculin higher in FAs where vinculin can engage retrograde actin flow. Thus, specific protein interactions are spatially segregated within FAs at the nanoscale to regulate vinculin activation and function. C1 [Case, Lindsay B.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32310 USA. [Shtengel, Gleb; Hess, Harald F.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Campbell, Sharon L.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU Division of Intramural Research, NHLBI; Howard Hughes Medical Institute; [GM081764]; [GM080568] FX Division of Intramural Research, NHLBI (L.B.C. and C.M.W.); Howard Hughes Medical Institute (G.S. and H.F.H.); GM081764 (S.L.C.), GM080568 (S.L.C.). NR 50 TC 34 Z9 34 U1 4 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2015 VL 17 IS 7 BP 880 EP 892 DI 10.1038/ncb3180 PG 13 WC Cell Biology SC Cell Biology GA CM0FI UT WOS:000357353400009 PM 26053221 ER PT J AU Hu, GW McQuiston, T Bernard, A Park, YD Qiu, J Vural, A Zhang, NN Waterman, SR Blewett, NH Myers, TG Maraia, RJ Kehrl, JH Uzel, G Klionsky, DJ Williamson, PR AF Hu, Guowu McQuiston, Travis Bernard, Amelie Park, Yoon-Dong Qiu, Jin Vural, Ali Zhang, Nannan Waterman, Scott R. Blewett, Nathan H. Myers, Timothy G. Maraia, Richard J. Kehrl, John H. Uzel, Gulbu Klionsky, Daniel J. Williamson, Peter R. TI A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy SO NATURE CELL BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CRYPTOCOCCUS-NEOFORMANS; PHOSPHOPROTEOME REVEALS; TRANSCRIPTION FACTOR; PULMONARY INFECTION; PROTEIN; TRANSLATION; INDUCTION; COMPLEX; INFLAMMASOMES AB Autophagy is an essential eukaryotic pathway requiring tight regulation to maintain homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved mechanism of autophagy regulation by RNA helicase RCK family members in association with the decapping enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TOR-dependent phosphorylation and associates with RCK members to form a complex with autophagy-related (ATG) mRNA transcripts, leading to decapping, degradation and autophagy suppression. Simultaneous with the induction of ATG mRNA synthesis, starvation reverses the process, facilitating ATG mRNA accumulation and autophagy induction. This conserved post-transcriptional mechanism modulates fungal virulence and the mammalian inflammasome, the latter providing mechanistic insight into autoimmunity reported in a patient with a PIK3CD/p110 delta gain-of-function mutation. We propose a dynamic model wherein RCK family members, in conjunction with Dcp2, function in controlling ATG mRNA stability to govern autophagy, which in turn modulates vital cellular processes affecting inflammation and microbial pathogenesis. C1 [Hu, Guowu; McQuiston, Travis; Park, Yoon-Dong; Qiu, Jin; Zhang, Nannan; Waterman, Scott R.; Uzel, Gulbu; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bernard, Amelie; Klionsky, Daniel J.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Vural, Ali; Kehrl, John H.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Blewett, Nathan H.; Maraia, Richard J.] NICHHD, Intramural Res Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU University of Michigan, National Institutes of Health [GM088565]; Intramural Research Program of the NIH, NIAID, NICHD; National Institutes of Health [GM053396] FX The authors thank J. Kim (University of Michigan, National Institutes of Health grant GM088565) for providing the RBP knockout library and V. Nagarajan (Genomic Technologies Section, Research Technologies Branch, NIAID, NIH) for genomic analysis. This work was financially supported, in part, by the Intramural Research Program of the NIH, NIAID, NICHD and by National Institutes of Health grant GM053396 (to D.J.K.). NR 44 TC 14 Z9 20 U1 3 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2015 VL 17 IS 7 BP 930 EP 942 DI 10.1038/ncb3189 PG 13 WC Cell Biology SC Cell Biology GA CM0FI UT WOS:000357353400013 PM 26098573 ER PT J AU Xue, RD Lynes, MD Dreyfuss, JM Shamsi, F Schulz, TJ Zhang, HB Huang, TL Townsend, KL Li, YM Takahashi, H Weiner, LS White, AP Lynes, MS Rubin, LL Goodyear, LJ Cypess, AM Tseng, YH AF Xue, Ruidan Lynes, Matthew D. Dreyfuss, Jonathan M. Shamsi, Farnaz Schulz, Tim J. Zhang, Hongbin Huang, Tian Lian Townsend, Kristy L. Li, Yiming Takahashi, Hirokazu Weiner, Lauren S. White, Andrew P. Lynes, Maureen S. Rubin, Lee L. Goodyear, Laurie J. Cypess, Aaron M. Tseng, Yu-Hua TI Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes SO NATURE MEDICINE LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; ADIPOSE-TISSUE; ADULT HUMANS; FUNCTIONAL-CHARACTERIZATION; ENERGY-EXPENDITURE; COLD-EXPOSURE; IN-VIVO; FAT; ADIPOCYTES; IDENTIFICATION AB Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter-and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes. C1 [Xue, Ruidan; Lynes, Matthew D.; Shamsi, Farnaz; Schulz, Tim J.; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L.; Takahashi, Hirokazu; Weiner, Lauren S.; Goodyear, Laurie J.; Cypess, Aaron M.; Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02115 USA. [Xue, Ruidan; Li, Yiming] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Div Endocrinol & Metab, Shanghai 200433, Peoples R China. [Dreyfuss, Jonathan M.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Bioinformat Core, Boston, MA 02115 USA. [Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [White, Andrew P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Orthoped Surg, Boston, MA 02215 USA. [Lynes, Maureen S.; Rubin, Lee L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lynes, Maureen S.; Rubin, Lee L.; Tseng, Yu-Hua] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. RP Tseng, YH (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02115 USA. EM yu-hua.tseng@joslin.harvard.edu OI Schulz, Tim/0000-0002-8413-3972 FU US National Institutes of Health (NIH) [R01DK077097, R01DK099511, K23DK081604, P30DK036836]; National Institute of Diabetes and Digestive and Kidney Diseases; Chugai Pharmaceutical Co.; American Diabetes Association [ADA 7-12-BS-191]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Harvard Stem Cell Institute; NIH [T32DK007260, F32DK102320] FX This work was supported in part by US National Institutes of Health (NIH) grants R01DK077097 (to Y.-H.T.), R01DK099511 (to L.J.G.), K23DK081604 (to A.M.C.) and P30DK036836 (to Joslin Diabetes Center's Diabetes Research Center, DRC) from the National Institute of Diabetes and Digestive and Kidney Diseases, a sponsored research grant from Chugai Pharmaceutical Co. (to Y.-H.T. and A.M.C.), a research grant from the American Diabetes Association (ADA 7-12-BS-191, to Y.-H.T.), the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and by funding from the Harvard Stem Cell Institute (to Y.-H.T.). M.D.L. was supported by NIH fellowships (T32DK007260 and F32DK102320). We thank M.-E. Patti and K. Hughes of the Advanced Genomics and Genetics Core of Joslin's DRC for advice and expert technical assistance. The authors thank Stryker Regenerative Medicine (Hopkinton, Massachusetts) for the generous gift of recombinant BMP7. NR 51 TC 33 Z9 33 U1 3 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2015 VL 21 IS 7 BP 760 EP + DI 10.1038/nm.3881 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CM3SO UT WOS:000357604600017 PM 26076036 ER PT J AU Do Kwon, Y Pancera, M Acharya, P Georgiev, IS Crooks, ET Gorman, J Joyce, MG Guttman, M Ma, XC Narpala, S Soto, C Terry, DS Yang, YP Zhou, TQ Ahlsen, G Bailer, RT Chambers, M Chuang, GY Doria-Rose, NA Druz, A Hallen, MA Harned, A Kirys, T Louder, MK O'Dell, S Ofek, G Osawa, K Prabhakaran, M Sastry, M Stewart-Jones, GBE Stuckey, J Thomas, PV Tittley, T Williams, C Zhang, B Zhao, H Zhou, Z Donald, BR Lee, LK Zolla-Pazner, S Baxa, U Schon, A Freire, E Shapiro, L Lee, KK Arthos, J Munro, JB Blanchard, SC Mothes, W Binley, JM McDermott, AB Mascola, JR Kwong, PD AF Do Kwon, Young Pancera, Marie Acharya, Priyamvada Georgiev, Ivelin S. Crooks, Emma T. Gorman, Jason Joyce, M. Gordon Guttman, Miklos Ma, Xiaochu Narpala, Sandeep Soto, Cinque Terry, Daniel S. Yang, Yongping Zhou, Tongqing Ahlsen, Goran Bailer, Robert T. Chambers, Michael Chuang, Gwo-Yu Doria-Rose, Nicole A. Druz, Aliaksandr Hallen, Mark A. Harned, Adam Kirys, Tatsiana Louder, Mark K. O'Dell, Sijy Ofek, Gilad Osawa, Keiko Prabhakaran, Madhu Sastry, Mallika Stewart-Jones, Guillaume B. E. Stuckey, Jonathan Thomas, Paul V. Tittley, Tishina Williams, Constance Zhang, Baoshan Zhao, Hong Zhou, Zhou Donald, Bruce R. Lee, Lawrence K. Zolla-Pazner, Susan Baxa, Ulrich Schoen, Arne Freire, Ernesto Shapiro, Lawrence Lee, Kelly K. Arthos, James Munro, James B. Blanchard, Scott C. Mothes, Walther Binley, James M. McDermott, Adrian B. Mascola, John R. Kwong, Peter D. TI Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; RESPIRATORY SYNCYTIAL VIRUS; ENVELOPE GLYCOPROTEIN COMPLEX; NEUTRALIZING ANTIBODY; FUSION GLYCOPROTEIN; BINDING-SITE; BROAD NEUTRALIZATION; SOLUBLE CD4; GP120 CORE AB As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens. C1 [Do Kwon, Young; Pancera, Marie; Acharya, Priyamvada; Georgiev, Ivelin S.; Gorman, Jason; Joyce, M. Gordon; Narpala, Sandeep; Soto, Cinque; Yang, Yongping; Zhou, Tongqing; Bailer, Robert T.; Chambers, Michael; Chuang, Gwo-Yu; Doria-Rose, Nicole A.; Druz, Aliaksandr; Hallen, Mark A.; Kirys, Tatsiana; Louder, Mark K.; O'Dell, Sijy; Ofek, Gilad; Prabhakaran, Madhu; Sastry, Mallika; Stewart-Jones, Guillaume B. E.; Stuckey, Jonathan; Thomas, Paul V.; Tittley, Tishina; Zhang, Baoshan; Shapiro, Lawrence; McDermott, Adrian B.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Crooks, Emma T.; Osawa, Keiko; Binley, James M.] San Diego Biomed Res Inst, San Diego, CA USA. [Guttman, Miklos; Lee, Kelly K.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [Ma, Xiaochu; Munro, James B.; Mothes, Walther] Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT USA. [Terry, Daniel S.; Zhao, Hong; Zhou, Zhou; Blanchard, Scott C.] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Ahlsen, Goran; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Ahlsen, Goran] Columbia Univ, Dept Syst Biol, New York, NY USA. [Hallen, Mark A.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Harned, Adam; Donald, Bruce R.; Baxa, Ulrich] Frederick Natl Lab Canc Res, Leidos Biomed Res, Canc Res Technol Program, Electron Microscopy Lab, Frederick, MD USA. [Williams, Constance; Zolla-Pazner, Susan] NYU, Sch Med, New York, NY USA. [Donald, Bruce R.] Duke Univ, Dept Chem, Durham, NC 27706 USA. [Donald, Bruce R.] Duke Univ, Dept Comp Sci, Durham, NC 27706 USA. [Lee, Kelly K.] Victor Chang Cardiac Res Inst, Struct & Computat Biol Div, Darlinghurst, NSW, Australia. [Zolla-Pazner, Susan] New York Vet Affairs Harbor Healthcare Syst, New York, NY USA. [Schoen, Arne; Freire, Ernesto] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Arthos, James] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Munro, James B.] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010; Kwon, Young Do/A-6957-2010; Blanchard, Scott/A-5804-2009 OI Zhou, Tongqing/0000-0002-3935-4637; FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH); Division of AIDS, NIAID, NIH [P01-AI100151, P01-AI104722, R01-AI93278, R21-AI100696, R21-AI112389, R33-AI84714]; US National Institutes of General Medical Sciences [P01-GM56550, R01-GM78031, R01-GM98859]; US National Institute of Heart, Lung and Blood [PO1-HL59725]; US National Science Foundation [MCB-1157506]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery [OPP1033102]; Australian Research Council [DP130102219]; Irvington Fellows Program of the Cancer Research Program; Department of Veterans Affairs; China Scholarship Council-Yale World Scholars; Federal funds from the Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank Y. Dai (The Scripps Research Institute) for ERV MuLV Gag plasmid, M. Murphy for SPR discussions, B. Whalen (Altravax) for the Rev plasmid, members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center for discussions and comments on the manuscript and the Weill Cornell Medical College, the Academic Medical Center of the University of Amsterdam and The Scripps Research Institute HIV Vaccine Research and Design Program for their contributions to the design and validation of near-native mimicry for soluble BG505 SOSIP.664 trimers. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson and L. Zhang for contributing the HIV-1-Env plasmids used in our neutralization panel. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH) (to J. A., A. B. M., J. R. M. and P.D.K.); the Division of AIDS, NIAID, NIH (P01-AI100151 to S.Z.-P., P01-AI104722 to L. S., R01-AI93278 to J. M. B., R21-AI100696 to W.M. and S. C. B., R21-AI112389 to K. K. L. and R33-AI84714 to J. M. B.); the US National Institutes of General Medical Sciences (P01-GM56550 to E. F., S. C. B. and W.M., R01-GM78031 to B. R. D. and R01-GM98859 to S. C. B.); the US National Institute of Heart, Lung and Blood (PO1-HL59725 to S.Z.-P.); the US National Science Foundation (MCB-1157506 to E. F.); the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (OPP1033102 to K. K. L.); the Australian Research Council (DP130102219 to L. K. L.); the Irvington Fellows Program of the Cancer Research Program (to J. B. M.); the Department of Veterans Affairs (to S.Z.-P.); and the China Scholarship Council-Yale World Scholars (fellowship to X.M.). This project was funded in part with Federal funds to U.B. from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. NR 87 TC 59 Z9 59 U1 4 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUL PY 2015 VL 22 IS 7 BP 522 EP + DI 10.1038/nsmb.3051 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CM3WC UT WOS:000357614900003 PM 26098315 ER PT J AU Hashizume, A Katsuno, M Suzuki, K Banno, H Suga, N Mano, T Araki, A Hijikata, Y Grunseich, C Kokkinis, A Hirakawa, A Watanabe, H Yamamoto, M Fischbeck, KH Sobue, G AF Hashizume, Atsushi Katsuno, Masahisa Suzuki, Keisuke Banno, Haruhiko Suga, Noriaki Mano, Tomoo Araki, Amane Hijikata, Yasuhiro Grunseich, Christopher Kokkinis, Angela Hirakawa, Akihiro Watanabe, Hirohisa Yamamoto, Masahiko Fischbeck, Kenneth H. Sobue, Gen TI A functional scale for spinal and bulbar muscular atrophy: Cross-sectional and longitudinal study SO NEUROMUSCULAR DISORDERS LA English DT Article DE Spinal and bulbar muscular atrophy; Validation; Functional rating scale; Motor neuron disease ID QUALITY-OF-LIFE; AMYOTROPHIC-LATERAL-SCLEROSIS; OUTCOME MEASURES; RATING-SCALE; BULBOSPINAL NEURONOPATHY; HUNTINGTONS-DISEASE; RESPONSIVENESS; VALIDATION; DISABILITY; QUESTIONNAIRE AB We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [TCCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects. (C) 2015 Elsevier B.V. All rights reserved. C1 [Hashizume, Atsushi; Katsuno, Masahisa; Suzuki, Keisuke; Banno, Haruhiko; Suga, Noriaki; Mano, Tomoo; Araki, Amane; Hijikata, Yasuhiro; Watanabe, Hirohisa; Sobue, Gen] Nagoya Univ, Dept Neurol, Grad Sch Med, Nagoya, Aichi 4668550, Japan. [Banno, Haruhiko] Nagoya Univ, Inst Adv Res, Nagoya, Aichi 4648601, Japan. [Grunseich, Christopher; Kokkinis, Angela; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Hirakawa, Akihiro] Nagoya Univ, Grad Sch Med, Biostat Sect, Ctr Adv Med & Clin Res, Nagoya, Aichi 4668550, Japan. [Yamamoto, Masahiko] Aichi Gakuin Univ, Sch Hlth Sci, Dept Speech Pathol & Audiol, Nisshin 4700195, Japan. RP Sobue, G (reprint author), Nagoya Univ, Dept Neurol, Grad Sch Med, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM sobueg@med.nagoya-u.ac.jp RI Banno, Haruhiko/Q-1029-2015; Katsuno, Masahisa/I-7502-2014 OI Banno, Haruhiko/0000-0002-0404-3839; FU MEXT, Japan [22110005]; KAKENHI grants from MEXT/JSPS, Japan [22110005, 26293206, 26670440, 26670439, 21229011]; Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST); Daiichi Sankyo Foundation of Life Science; Ministry of Health, Labour and Welfare, Japan FX Dr. Katsuno is supported by a Grant-in-Aid for Scientific Research on Innovated Areas "Foundation of Synapse and Neurocircuit Pathology" from MEXT, Japan, (22110005); KAKENHI grants from MEXT/JSPS, Japan, (No. 22110005, 26293206, 26670440, and 26670439); and Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST); and a grant from the Daiichi Sankyo Foundation of Life Science.; Dr. Sobue is supported by KAKENHI grants from MEXT/JSPS, Japan (No. 21229011); grants from the Ministry of Health, Labour and Welfare, Japan; and Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST). NR 37 TC 6 Z9 6 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD JUL PY 2015 VL 25 IS 7 BP 554 EP 562 DI 10.1016/j.nmd.2015.03.008 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CM5TZ UT WOS:000357753100004 PM 25913211 ER PT J AU Liu, G Yu, FX Kim, YC Meng, Z Naipauer, J Looney, DJ Liu, X Gutkind, JS Mesri, EA Guan, KL AF Liu, G. Yu, F-X Kim, Y. C. Meng, Z. Naipauer, J. Looney, D. J. Liu, X. Gutkind, J. S. Mesri, E. A. Guan, K-L TI Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway SO ONCOGENE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; ORGAN SIZE CONTROL; PRIMARY EFFUSION LYMPHOMA; YES-ASSOCIATED PROTEIN; SCF-BETA-TRCP; GENE-EXPRESSION; CELL-PROLIFERATION; YAP PATHWAY; TEAD/TEF FAMILY; GROWTH-CONTROL AB Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention. C1 [Liu, G.; Yu, F-X; Kim, Y. C.; Meng, Z.; Guan, K-L] Shandong Univ, Sch Life Sci, Jinan 250100, Peoples R China. [Liu, G.; Yu, F-X; Kim, Y. C.; Meng, Z.; Guan, K-L] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Liu, G.; Yu, F-X; Kim, Y. C.; Meng, Z.; Guan, K-L] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Naipauer, J.; Mesri, E. A.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Naipauer, J.; Mesri, E. A.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Viral Oncol Program,Miami Ctr AIDS Res, Miami, FL 33136 USA. [Looney, D. J.] Univ Calif San Diego, VA San Diego Healthcare Syst, Dept Med, La Jolla, CA 92093 USA. [Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Guan, KL (reprint author), Univ Calif San Diego, Dept Pharmacol, RM4010,2880 Torrey Pines Scenic Dr, La Jolla, CA 92093 USA. EM kuguan@ucsd.edu RI Liu, Xiangguo/G-1091-2010; Liu, Guangbo/O-7636-2016 OI Liu, Guangbo/0000-0001-5623-8227 FU NIH/NCI [P30 CA23100]; NIAID [P30 AI36214, R01CA132809, R01GM51586]; Chinese Scholarship Council; NIH [CA136387]; Miami CFAR Grant [P30AI073961] FX We thank AIDS and Cancer Specimen Resource at the University of California, San Francisco (particularly Ronald Honrada, Andrew Ma and Michael McGrath) for providing the tissue microarrays and carrying out the HHV-8 staining. We also thank Jenna Jewell, Steve Plouffe and Fabian Flores for critical reading of this manuscript, and Drs Dirk Dittmer, Carsten Gram Hansen and Toshiro Moroishi for insightful discussions. EAM and JN would like to thank Santas Rosario and Darlah Lopez Rodriguez for their help with the infection systems. This study was supported by grants from NIH/NCI P30 CA23100, NIAID P30 AI36214, R01CA132809, R01GM51586 (to KLG) and the Chinese Scholarship Council (to GL). EAM and JN were supported by NIH Grants CA136387 and Miami CFAR Grant P30AI073961. NR 67 TC 12 Z9 13 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUL PY 2015 VL 34 IS 27 BP 3536 EP 3546 DI 10.1038/onc.2014.281 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CM1IQ UT WOS:000357434900006 PM 25195862 ER PT J AU Zolkowska, D Andres-Mach, M Prisinzano, TE Baumann, MH Luszczki, JJ AF Zolkowska, Dorota Andres-Mach, Marta Prisinzano, Thomas E. Baumann, Michael H. Luszczki, Jarogniew J. TI Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model SO PSYCHOPHARMACOLOGY LA English DT Article DE Antiepileptic drugs; Maximal electroshock-induced seizures; Pharmacokinetic/pharmacodynamic interaction; Modafinil; GBR 12909 ID P-ISOPROPOXYPHENYLSUCCINIMIDE; ISOBOLOGRAPHIC ANALYSIS; DOPAMINE TRANSPORTERS; AGENT MODAFINIL; CONSCIOUS RAT; MICE; VALPROATE; PHENYTOIN; THRESHOLD; TIAGABINE AB Seizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies. The aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)-carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA). Anticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Intraperitoneal injection of 75 mg kg(-1) of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg(-1) of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg(-1) dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg(-1)) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT. Enhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients. C1 [Zolkowska, Dorota] Univ Calif Davis, Sch Med, Dept Neurol, Sacramento, CA 95817 USA. [Andres-Mach, Marta; Luszczki, Jarogniew J.] Inst Rural Hlth, Isobolog Anal Lab, Lublin, Poland. [Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. [Baumann, Michael H.] NIDA, Med Chem Sect, IRP, NIH, Baltimore, MD USA. [Luszczki, Jarogniew J.] Med Univ Lublin, Dept Pathophysiol, PL-20150 Lublin, Poland. RP Luszczki, JJ (reprint author), Med Univ Lublin, Dept Pathophysiol, Ceramiczna 1, PL-20150 Lublin, Poland. EM jluszczki@yahoo.com RI Prisinzano, Thomas/B-7877-2010 FU Medical University of Lublin; Institute of Rural Health (Lublin, Poland) [11230/2011-2013]; Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse] FX This study was supported by grants from the Medical University of Lublin and Institute of Rural Health (Lublin, Poland) [Grant 11230/2011-2013] (J.J.L.). This research was supported [in part] by the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse] (D.Z., M.H.B.). Professor J.J. Luszczki is a Member of the Academy of Young Scholars of the Polish Academy of Sciences in Warsaw, Poland. The authors are grateful for the generous gifts of carbamazepine from Polpharma S.A. (Starogard Gdanski, Poland) and valproate from ICN-Polfa S.A. (Rzeszow, Poland). NR 48 TC 3 Z9 3 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2015 VL 232 IS 14 BP 2463 EP 2479 DI 10.1007/s00213-015-3884-3 PG 17 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CL2YL UT WOS:000356814000004 PM 25697861 ER PT J AU Gooch, B Goodman, J Gracia, JN Griffin, SO Grummer-Strawn, L Hirschman, J Hyman, F Iafolla, T Kohn, W Lester, AM Makrides, NS Manski, R Osorio, AM Silverman, B Sinks, T AF Gooch, Barbara Goodman, Jesse Gracia, J. Nadine Griffin, Susan O. Grummer-Strawn, Laurence Hirschman, Jay Hyman, Frederick Iafolla, Timothy Kohn, William Lester, Arlene M. Makrides, Nicholas S. Manski, Richard Osorio, Ana Maria Silverman, Benson Sinks, Thomas CA US Dept Hlth Human Serv Federal Pa TI US Public Health Service Recommendation for Fluoride Concentration in Drinking Water for the Prevention of Dental Caries SO PUBLIC HEALTH REPORTS LA English DT Article ID UNITED-STATES; ENAMEL FLUOROSIS; INFANT FORMULA; CHILDRENS INTELLIGENCE; RISK-FACTORS; ORAL-HEALTH; OSTEOSARCOMA; COMMUNITY; IMPACT; NEEDS C1 [Gooch, Barbara; Griffin, Susan O.; Kohn, William] US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Oral Hlth, Washington, DC USA. [Goodman, Jesse] US Dept HHS, Sci & Publ Hlth, US FDA, Washington, DC USA. [Gracia, J. Nadine] US Dept HHS, Off Assistant Secretary Hlth, Washington, DC USA. [Grummer-Strawn, Laurence] US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr Phys Act & Obes,Maternal & Child Nutr Br, Washington, DC USA. [Hirschman, Jay] Food & Nutr Serv, USDA, Off Res & Anal, Washington, DC USA. [Hyman, Frederick] US Dept HHS, US FDA, Ctr Drug Evaluat & Res, Div Dermatol & Dent Prod, Washington, DC USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, US Dept HHS, NIH, Off Sci & Policy Anal, Washington, DC USA. [Lester, Arlene M.; Makrides, Nicholas S.] US PHS, Washington, DC USA. [Lester, Arlene M.] US Dept HHS, Off Secretary, Washington, DC USA. [Makrides, Nicholas S.] US Dept Justice, Fed Bur Prisons, Washington, DC USA. [Manski, Richard] US Dept HHS, Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Washington, DC USA. [Osorio, Ana Maria] US PHS, US Dept HHS, Off Assistant Secretary Hlth, Washington, DC USA. [Silverman, Benson] US Dept HHS, US FDA, Ctr Food Safety & Appl Nutr, Washington, DC USA. [Sinks, Thomas] US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Agcy Tox Subst & Dis Registry, Washington, DC USA. RP Gooch, B (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Oral Hlth, 4770 Buford Hwy NE,MS F-80, Atlanta, GA 30341 USA. EM bgooch@cdc.gov NR 90 TC 0 Z9 0 U1 5 U2 17 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1900 M ST NW, STE 710, WASHINGTON, DC 20036 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JUL-AUG PY 2015 VL 130 IS 4 BP 318 EP 331 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM5DN UT WOS:000357707100008 ER PT J AU Mull, HJ Brennan, CW Folkes, T Hermos, J Chan, J Rosen, AK Simon, SR AF Mull, Hillary J. Brennan, Caitlin W. Folkes, Tiffany Hermos, John Chan, Jeffrey Rosen, Amy K. Simon, Steven R. TI Identifying Previously Undetected Harm: Piloting the Institute for Healthcare Improvement's Global Trigger Tool in the Veterans Health Administration SO QUALITY MANAGEMENT IN HEALTH CARE LA English DT Article ID ADVERSE EVENTS; PATIENT SAFETY; HOSPITALIZED-PATIENTS; PERFORMANCE; QUALITY; PROGRAM; RATES AB Background: Adverse event (AE) surveillance may be enhanced by the Institute for Healthcare Improvement's Global Trigger Tool (GTT). A pilot study of the GTT was conducted in one Veterans Health Administration (VA) facility to assess the rates, types, and harm of AEs detected and to examine the overlap in AE detection between the GTT and existing surveillance mechanisms. Methods: GTT guidelines were followed and medical records were reviewed for 17 weeks of acute care hospitalizations. Investigators met monthly, first to adjudicate discordant reviewer categorizations of harm and later to categorize the AEs detected using standardized definitions. GTT-detected AEs were compared with incident reports, Patient Safety Indicators, and the VA Surgical Quality Improvement Program. Results: Medical records were reviewed for 273 of 1980 eligible cases. Using the GTT, a total of 109 AEs were identified. More than 1 of 5 hospitalizations (21%) were associated with an AE. The majority of AEs detected (60%) were minor harms; there were no deaths attributable to medical care. Ninety-six of the 109 AEs (88%) were not detected by other measures. Conclusions: The GTT identified previously undetected AEs at one VA. The GTT has the potential to track AEs and guide quality improvement efforts in conjunction with existing AE surveillance mechanisms. C1 [Mull, Hillary J.; Brennan, Caitlin W.; Chan, Jeffrey; Rosen, Amy K.; Simon, Steven R.] VA Boston Healthcare Syst, Patient Safety Ctr Inquiry, Measurement Assess Patient Safety, Boston, MA 02130 USA. [Mull, Hillary J.; Chan, Jeffrey; Rosen, Amy K.; Simon, Steven R.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. [Folkes, Tiffany] VA Boston Healthcare Syst, Dept Nursing, Boston, MA 02130 USA. [Hermos, John; Simon, Steven R.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA 02130 USA. [Mull, Hillary J.; Rosen, Amy K.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Brennan, Caitlin W.] NIH, Ctr Clin, Dept Nursing, Res & Practice Dev Sect, Bethesda, MD 20892 USA. [Simon, Steven R.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. RP Mull, HJ (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave 152M, Boston, MA 02130 USA. EM Hillary.mull@va.gov FU VA National Center for Patient Safety (NCPS) through the Patient Safety Center of Inquiry at VA Boston Healthcare System [VA NCPS XVA 68-023] FX This work was supported by the VA National Center for Patient Safety (NCPS) through the Patient Safety Center of Inquiry at VA Boston Healthcare System (VA NCPS XVA 68-023, Director: Amy Rosen, PhD). The authors acknowledge the contributions of Frank Federico, RPh, from the Institute for Healthcare Improvement, for guidance and support throughout our study. William O'Brien provided programming support to complete the analyses of our data. NR 28 TC 2 Z9 2 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1063-8628 EI 1550-5154 J9 QUAL MANAG HEALTH CA JI Qual. Manag. Health Care PD JUL-SEP PY 2015 VL 24 IS 3 BP 140 EP 146 DI 10.1097/QMH.0000000000000060 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CM8HY UT WOS:000357941400006 PM 26115062 ER PT J AU Hansen, JG Gao, W Dupuis, J O'Connor, GT Tang, W Kowgier, M Sood, A Gharib, SA Palmer, LJ Fornage, M Heckbert, SR Psaty, BM Booth, SL Cassano, PA AF Hansen, J. G. Gao, W. Dupuis, J. O'Connor, G. T. Tang, W. Kowgier, M. Sood, A. Gharib, S. A. Palmer, L. J. Fornage, M. Heckbert, S. R. Psaty, B. M. Booth, S. L. Cassano, Patricia A. CA SUNLIGHT Consortium TI Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study SO RESPIRATORY RESEARCH LA English DT Article DE Vitamin D; 25-hydroxyvitamin D; FEV1; CYP2R1; Lung function; Framingham Heart Study ID GENOME-WIDE ASSOCIATION; NUTRITION EXAMINATION SURVEY; OBSTRUCTIVE PULMONARY-DISEASE; RESPIRATORY-TRACT INFECTIONS; 3RD NATIONAL-HEALTH; D-BINDING PROTEIN; LUNG-FUNCTION; D DEFICIENCY; CONTROLLED-TRIAL; COPD AB Background: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults. Methods: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts. Results: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09). Conclusions: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies. C1 [Hansen, J. G.; Tang, W.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Gao, W.; Dupuis, J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, J.; O'Connor, G. T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Connor, G. T.] Boston Univ, Sch Med, Dept Med, Pulmon Ctr, Boston, MA 02118 USA. [Kowgier, M.] Ontario Inst Canc Res, Toronto, ON, Canada. [Kowgier, M.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Sood, A.] Univ New Mexico, Albuquerque, NM 87131 USA. [Gharib, S. A.] Univ Washington, Computat Med Core, Ctr Lung Biol, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Palmer, L. J.] Univ Adelaide, Sch Publ Hlth, Adelaide, SA, Australia. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Heckbert, S. R.; Psaty, B. M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, S. R.; Psaty, B. M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, S. R.; Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Psaty, B. M.] Univ Washington, Dept Med, Seattle, WA USA. [Booth, S. L.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Div Biostat & Epidemiol, Dept Healthcare Policy & Res, New York, NY USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, 209 Savage Hall, Ithaca, NY 14853 USA. EM pac6@cornell.edu RI Palmer, Lyle/K-3196-2014 OI Palmer, Lyle/0000-0002-1628-3055 FU NRSA Institutional Research Training Grant [T32-DK-7158-36]; NHLBI [N01-HC-25195, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-45204, HHSN268201200036C, N01 HHSN268200800007C]; Affymetrix [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; NIH-NIA [AG14759]; Healthways, Western Australia; The Great Wine Estates of the Margaret River region of Western Australia; The Ark at University of Western Australia; NHGRI [U01-HG-004729, U01-HG-004446, U01-HG-004424]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Advancing Translational Sciences [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; NIA [N01AG62101, N01AG2103, N01AG62106, R01-AG028050, 1R01AG032098-01A1]; NINR [R01-NR012459]; Intramural Research Program of the NIA, NIH; National Institutes of Health [HHSN268200782096C]; The NHLBI [N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]; [R01-HL-084099]; [RC1AG035835] FX This research was supported by NRSA Institutional Research Training Grant T32-DK-7158-36 (JGH).; This research used data from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. Framingham Heart Study (FHS) research was conducted in part using data and resources of the NHLBI and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by NHLBI (contract no. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract no. 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. Measurement of vitamin D in the Offspring participants was funded by NIH-NIA AG14759.; The 1994 Busselton follow-up Health Study was supported by Healthways, Western Australia. The Busselton Health Study is supported by The Great Wine Estates of the Margaret River region of Western Australia. The study gratefully acknowledges the assistance of the Western Australian DNA Bank (NHMRC Enabling Facility) with DNA samples and the support provided by The Ark at University of Western Australia for this study.; The Coronary Artery Risk Development in Young Adults (CARDIA) study was funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from NHLBI to the CARDIA investigators. Genotyping of the CARDIA participants was supported by grants U01-HG-004729, U01-HG-004446, and U01-HG-004424 from the NHGRI. Statistical analyses were supported by grants U01-HG-004729 and R01-HL-084099 to MF.; The Cardiovascular Health Study was supported by NHLBI contracts HHSN268201200036C, N01 HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at https://chs-nhlbi.org/pi. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.; The Health, Aging, and Body Composition Study was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, NIA grant R01-AG028050, NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIA, NIH. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was further supported by RC1AG035835. NR 40 TC 2 Z9 2 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X EI 1465-9921 J9 RESP RES JI Respir. Res. PD JUL 1 PY 2015 VL 16 AR 81 DI 10.1186/s12931-015-0238-y PG 8 WC Respiratory System SC Respiratory System GA CL9OP UT WOS:000357308300001 PM 26122139 ER PT J AU Agyemang, AF Harrison, SR Siegel, RM McDermott, MF AF Agyemang, Amma F. Harrison, Stephanie R. Siegel, Richard M. McDermott, Michael F. TI Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review ID ENDOPLASMIC-RETICULUM STRESS; NF-KAPPA-B; PERIODIC SYNDROME TRAPS; FACTOR RECEPTOR-I; CHAPERONE-MEDIATED AUTOPHAGY; PIGMENT EPITHELIAL-CELLS; MUCKLE-WELLS-SYNDROME; NECROSIS-FACTOR-ALPHA; PARKINSONS-DISEASE; MACULAR DEGENERATION AB Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of "self-eating" where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis. C1 [Agyemang, Amma F.; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Harrison, Stephanie R.; McDermott, Michael F.] St James Univ, NIHR, LMBRU, Leeds LS9 7TF, W Yorkshire, England. [Harrison, Stephanie R.; McDermott, Michael F.] St James Univ, LIRMM, Leeds LS9 7TF, W Yorkshire, England. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov; M.McDermott@leeds.ac.uk FU Leeds Teaching Hospitals Special Trustees [9/R01/2002]; Arthritis Research UK [19269]; NIHR-Leeds Musculoskeletal Biomedical Research Unit; Wolfson Foundation; NIAMS intramural research program; NIH UGSP scholar FX The authors would like to thank the Leeds Teaching Hospitals Special Trustees (9/R01/2002), Arthritis Research UK (grant 19269) and the NIHR-Leeds Musculoskeletal Biomedical Research Unit who funded McD and the Wolfson Foundation who funded an intercalated degree research scholarship for SH. RMS and AA are supported by the NIAMS intramural research program, and AA is an NIH UGSP scholar. NR 158 TC 2 Z9 2 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD JUL PY 2015 VL 37 IS 4 BP 335 EP 347 DI 10.1007/s00281-015-0496-2 PG 13 WC Immunology; Pathology SC Immunology; Pathology GA CM1YB UT WOS:000357475400004 PM 25994946 ER PT J AU Canna, SW Goldbach-Mansky, R AF Canna, Scott W. Goldbach-Mansky, Raphaela TI New monogenic autoinflammatory diseases-a clinical overview SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review ID MACROPHAGE ACTIVATION SYNDROME; FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; CONGENITAL SIDEROBLASTIC ANEMIA; JUVENILE IDIOPATHIC ARTHRITIS; PITYRIASIS-RUBRA-PILARIS; DEVELOPMENTAL DELAY SIFD; X-LINKED INHIBITOR; XIAP DEFICIENCY; PROTEASOME SUBUNIT; INNATE IMMUNITY AB Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN's as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases. C1 [Canna, Scott W.] NIAMSD, Autoinflammatory Pathogenesis Unit, NIH, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. RP Canna, SW (reprint author), NIAMSD, Autoinflammatory Pathogenesis Unit, NIH, Bldg 10,Room 13c103,10 Ctr Dr, Bethesda, MD 20892 USA. EM scott.canna@nih.gov; goldbacr@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the NIH FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the NIH NR 50 TC 7 Z9 7 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD JUL PY 2015 VL 37 IS 4 BP 387 EP 394 DI 10.1007/s00281-015-0493-5 PG 8 WC Immunology; Pathology SC Immunology; Pathology GA CM1YB UT WOS:000357475400010 PM 25963521 ER PT J AU Aksentijevich, I AF Aksentijevich, Ivona TI Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Autoinflammation; Next generation sequencing (NGS); Deficiency of ADA2 (DADA2); STING-associated vasculopathy with onset in infancy (SAVI); NLRC4-associated inflammatory diseases; TRNT1 deficiency/SIFD; LACC1-associated monogenic disease ID ADENOSINE-DEAMINASE 2; CONGENITAL SIDEROBLASTIC ANEMIA; JUVENILE IDIOPATHIC ARTHRITIS; DEVELOPMENTAL DELAY SIFD; GENOMEWIDE ASSOCIATION; GROWTH-FACTOR; NLRC4 CAUSES; MUTATION; VASCULOPATHY; LEPROSY AB Autoinflammatory diseases are a genetically heterogeneous group of rheumatologic diseases that are driven by abnormal activation of the innate immune system. Patients present with recurrent episodes of systemic inflammation and a spectrum of organ-specific comorbidities. These diseases are mediated by the overproduction of various inflammatory cytokines, such as IL-1, IL-18, IL-6, TNF alpha, and type I interferon. Treatments with biologic agents that inhibit these cytokines have been very efficient in most patients. During the past 2 years, remarkable progress has been made in the identification of disease-associated genes owing mostly to new technologies. Next generation sequencing technologies (NGS) have become instrumental in finding single-gene defects in undiagnosed patients with early onset symptoms. NGS has advanced the field of autoinflammation by identifying disease-causing genes that point to pathways not known to regulate cytokine signaling or inflammation. They include a protein that has a role in differentiation of myeloid cells, a ubiquitously expressed enzyme that catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors, and an enzyme that catalyzes the oxidation of a broad range of substrates. Lastly, newly described mutations have informed a whole new dimension on genotype-phenotype relationships. Mutations in the same gene can give rise to a range of phenotypes with a common inflammatory component. This suggests greater than anticipated contributions by modifying alleles and environmental factors to disease expressivity. C1 NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. RP Aksentijevich, I (reprint author), NHGRI, Inflammatory Dis Sect, Bldg 10-Rm B2-5235,10 Ctr Dr MSC 1849, Bethesda, MD 20892 USA. EM aksentii@mail.nih.gov NR 49 TC 7 Z9 7 U1 3 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD JUL PY 2015 VL 37 IS 4 BP 395 EP 401 DI 10.1007/s00281-015-0478-4 PG 7 WC Immunology; Pathology SC Immunology; Pathology GA CM1YB UT WOS:000357475400011 PM 25860799 ER PT J AU Ombrello, MJ AF Ombrello, Michael J. TI Advances in the genetically complex autoinflammatory diseases SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Autoinflammation; Polygenic; Chronic recurrent multifocal osteomyelitis (CRMO); Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA); Behcet's disease; Systemic juvenile idiopathic arthritis (sJIA) ID GENOME-WIDE ASSOCIATION; RECURRENT MULTIFOCAL OSTEOMYELITIS; CERVICAL ADENITIS SYNDROME; JUVENILE IDIOPATHIC ARTHRITIS; MHC CLASS-I; BEHCETS-DISEASE; APHTHOUS STOMATITIS; PERIODIC FEVER; SUSCEPTIBILITY LOCI; GENE AB Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Beh double dagger et's disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases-namely, the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically complex autoinflammatory phenotypes. C1 NIAMSD, Translat Genet & Genom Unit, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Ombrello, MJ (reprint author), NIAMSD, Translat Genet & Genom Unit, Off Clin Director, NIH, 10 Ctr Dr,MSC 1560 Bldg 10,Room 10C101C, Bethesda, MD 20892 USA. EM Michael.Ombrello@nih.gov FU Intramural Research Program of the National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, USA FX This study was supported by the Intramural Research Program of the National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, USA. NR 36 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD JUL PY 2015 VL 37 IS 4 BP 403 EP 406 DI 10.1007/s00281-015-0498-0 PG 4 WC Immunology; Pathology SC Immunology; Pathology GA CM1YB UT WOS:000357475400012 PM 26077134 ER PT J AU Lyerly, MJ Albright, KC Boehme, AK Shahripour, RB Donnelly, JP Houston, JT Rawal, PV Kapoor, N Alvi, M Sisson, A Alexandrov, AW Alexandrov, AV AF Lyerly, Michael J. Albright, Karen C. Boehme, Amelia K. Shahripour, Reza Bavarsad Donnelly, John P. Houston, James T. Rawal, Pawan V. Kapoor, Niren Alvi, Muhammad Sisson, April Alexandrov, Anne W. Alexandrov, Andrei V. TI Patient Selection for Drip and Ship Thrombolysis in Acute Ischemic Stroke SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE ischemic stroke; thrombolysis; race ID TISSUE-PLASMINOGEN ACTIVATOR; UNITED-STATES; SECULAR TRENDS; DISPARITIES; CARE; US AB Objectives The drip and ship model is a method used to deliver thrombolysis to acute stroke patients in facilities lacking onsite neurology coverage. We sought to determine whether our drip and ship population differs from patients treated directly at our stroke center (direct presenters). Methods We retrospectively reviewed consecutive patients who received thrombolysis at an outside facility with subsequent transfer to our center between 2009 and 2011. Patients received thrombolysis after telephone consultation with a stroke specialist. We examined demographics, vascular risk factors, laboratory values, and stroke severity in drip and ship patients compared with direct presenters. Results Ninety-six patients were identified who received thrombolysis by drip and ship compared with 212 direct presenters. The two groups did not differ with respect to sex, ethnicity, vascular risk factors, or admission glucose. The odds ratio (OR) of arriving at our hospital as a drip and ship for someone 80 years or older was 0.31 (95% confidence interval [CI] 0.15-0.61, P < 0.001). Only 21% of drip and ship patients were black versus 38% of direct presenters (OR 0.434, 95% CI 0.25-0.76, P = 0.004). Even after stratifying by age (<80 vs 80), a smaller proportion of drip and ship patients were black (OR 0.44, 95% CI 0.24-0.81, P = 0.008). Furthermore, we found that fewer black patients with severe strokes arrived by drip and ship (OR 0.33, 95% CI 0.11-0.98, P = 0.0028). Conclusions Our study showed that a smaller proportion of blacks and older adults arrived at our center by the drip and ship model. This may reflect differences in how patients are selected for thrombolysis and transfer to a higher level of care. C1 Univ Alabama Birmingham, Dept Neurol, Sch Med, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Epidemiol, Sch Publ Hlth, Birmingham, AL 35294 USA. Vanderbilt Univ, Sch Med, Dept Neurol, Nashville, TN 37212 USA. Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Bethesda, MD USA. Univ Tennessee, Dept Neurol, Sch Med, Memphis, TN USA. RP Lyerly, MJ (reprint author), Univ Alabama Birmingham, Dept Neurol, Stroke Program, 1813 6th Ave S,RWUH M226, Birmingham, AL 35294 USA. EM mjlyerly@uab.edu OI Donnelly, John/0000-0002-0646-9470; Lyerly, Michael/0000-0003-4236-1018 FU American Heart Association; American Heart Association [13PRE13830003]; AHRQ; Direct One FX K.C.A. has grants/grants pending with the American Heart Association; A.K.B. has a past grant paid to her institution from the American Heart Association, had graduate stipend support though award numbers 13PRE13830003 from the American Heart Association (the content is solely the responsibility of the authors and does not necessarily represent the official views of the association); J.P.D. works under AHRQ T32 Predoctoral Fellowship in Health Services Research; P.V.R. has received payment for manuscript preparation from Direct One (neurology report for American Epilepsy Society meeting, honorarium for preparing report for AES session and case study); A.W.A. employed by and receives board member compensation from Health Outcomes Institute; A.V.A. has stock/stock options in and receives royalties from Cerevast Therapeutics. The remaining authors have no financial relationships to disclose and no conflicts of interest to report. NR 28 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD JUL PY 2015 VL 108 IS 7 BP 393 EP 398 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CL9ID UT WOS:000357290500004 PM 26192934 ER PT J AU Keenan, CM Baker, J Bradley, A Goodman, DG Harada, T Herbert, R Kaufmann, W Kellner, R Mahler, B Meseck, E Nolte, T Rittinghausen, S Vahle, J Yoshizawa, K AF Keenan, C. M. Baker, J. Bradley, A. Goodman, D. G. Harada, T. Herbert, R. Kaufmann, W. Kellner, R. Mahler, B. Meseck, E. Nolte, T. Rittinghausen, S. Vahle, J. Yoshizawa, K. TI International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Progress to Date and Future Plans SO TOXICOLOGIC PATHOLOGY LA English DT Article DE preclinical research and development; rodent pathology; toxicologic pathology AB The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice proposal (INHAND) has been operational since 2005. A Global Editorial Steering Committee manages the overall objectives of the project, and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups, drawing upon experts from North America, Europe, and Japan. Great progress has been made with 9 systems published to daterespiratory, hepatobiliary, urinary, central/peripheral nervous systems, male reproductive and mammary, zymbals, clitoral, and preputial glands in Toxicologic Pathology and the integument and soft tissue and female reproductive in the Journal of Toxicologic Pathology as supplements and on a Web sitewww.goReni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photomicrographs of morphologic changes, information regarding pathogenesis, and key references. The purpose of this brief communication is to provide an update on the progress of INHAND. C1 [Keenan, C. M.] CM Keenan ToxPath Consulting, Doylestown, PA 18901 USA. [Baker, J.] Charles River Pathol Associates, Frederick, MD USA. [Bradley, A.] Charles River Labs, Tranent, Scotland. [Harada, T.] Inst Environm Toxicol, Joso, Ibaraki, Japan. [Herbert, R.; Mahler, B.] NIEHS, Res Triangle Pk, NC 27709 USA. [Kaufmann, W.] Merck KGaA, Darmstadt, Germany. [Kellner, R.; Rittinghausen, S.] Fraunhofer ITEM, Hannover, Germany. [Meseck, E.] Novartis Inst Biomed Res, E Hanover, NJ USA. [Nolte, T.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Vahle, J.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Yoshizawa, K.] Kansai Med Univ, Hirakata, Osaka, Japan. RP Keenan, CM (reprint author), CM Keenan ToxPath Consulting, 874 Limekiln Rd, Doylestown, PA 18901 USA. EM charlotte.keenan@msn.com NR 2 TC 2 Z9 2 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2015 VL 43 IS 5 BP 730 EP 732 DI 10.1177/0192623314560031 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA CM2UI UT WOS:000357537400013 PM 25530274 ER PT J AU Williams, AS Kang, L Wasserman, DH AF Williams, Ashley S. Kang, Li Wasserman, David H. TI The extracellular matrix and insulin resistance SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review DE extracellular matrix; integrins; glucose homeostasis; insulin resistance; liver; muscle ID FOCAL-ADHESION-KINASE; INTEGRIN-LINKED KINASE; HIGH-FAT DIET; HEPATIC STELLATE CELLS; SKELETAL-MUSCLE CELLS; ADIPOSE-TISSUE; LIVER-DISEASE; DIABETIC-NEPHROPATHY; METABOLIC SYNDROME; MICE AB The extracellular matrix (ECM) is a highly-dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggests that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. In addition, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review addresses what is currently known about the ECM, integrins, and insulin action in the muscle, liver, and adipose tissue. Understanding how ECM remodeling and integrin signaling regulate insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes (T2D). C1 [Williams, Ashley S.; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Kang, Li] Univ Dundee, Ninewells Hosp & Med Sch, Div Cardiovasc & Diabet Med, Dundee DD1 9SY, Scotland. [Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37235 USA. RP Wasserman, DH (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. EM david.wasserman@vanderbilt.edu FU National Institutes of Health grants [DK54902, DK050277, DK059637] FX This work was supported by National Institutes of Health grants DK54902, DK050277, and DK059637 to D.H.W. NR 100 TC 13 Z9 13 U1 1 U2 11 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 JUL PY 2015 VL 26 IS 7 BP 357 EP 366 DI 10.1016/j.tem.2015.05.006 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CM5UT UT WOS:000357755200007 PM 26059707 ER PT J AU Fernandez-Romero, JA Deal, C Herold, BC Schiller, J Patton, D Zydowsky, T Romano, J Petro, CD Narasimhan, M AF Fernandez-Romero, Josa A. Deal, Carolyn Herold, Betsy C. Schiller, John Patton, Dorothy Zydowsky, Thomas Romano, Joe Petro, Christopher D. Narasimhan, Manjulaa TI Multipurpose prevention technologies: the future of HIV and STI protection SO TRENDS IN MICROBIOLOGY LA English DT Review DE multipurpose prevention technologies; STI; HIV; HSV-2; HPV; Trichomonas vaginalis ID SIMPLEX-VIRUS TYPE-2; HUMAN-IMMUNODEFICIENCY-VIRUS; TRICHOMONAS-VAGINALIS INFECTION; SEXUALLY-TRANSMITTED INFECTIONS; HUMAN-PAPILLOMAVIRUS INFECTION; TENOFOVIR DISOPROXIL FUMARATE; PREEXPOSURE PROPHYLAXIS; GENITAL HERPES; IN-VIVO; POSITIVE WOMEN AB Every day, more than 1 million people are newly infected with sexually transmitted infections (STIs) that can lead to morbidity, mortality, and an increased risk of human immunodeficiency virus (HIV) acquisition. Existing prevention and management strategies, including behavior change, condom promotion, and therapy have not reduced the global incidence and prevalence, pointing to the need for novel innovative strategies. This review summarizes important issues raised during a satellite session at the first HIV Research for Prevention (R4P) conference, held in Cape Town, on October 31,2014. We explore key M.'s that are challenging public health today, new biomedical prevention approaches including multipurpose prevention technologies (MPTs), and the scientific and regulatory hurdles that must be overcome to make combination prevention tools a reality. C1 [Fernandez-Romero, Josa A.; Zydowsky, Thomas] Populat Council, Ctr Biomed Res, New York, NY 10021 USA. [Deal, Carolyn] NIAID, Bethesda, MD 20892 USA. [Herold, Betsy C.; Petro, Christopher D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Schiller, John] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Patton, Dorothy] Univ Washington, Obstet & Gynecol, Seattle, WA 98195 USA. [Romano, Joe] NWJ Grp, Wayne, PA USA. [Narasimhan, Manjulaa] WHO, Dept Reprod Hlth & Res, CH-1211 Geneva, Switzerland. RP Fernandez-Romero, JA (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM jromero@popcouncil.org FU US Agency for International Development (USAID) [AID-OAA-A-14-00009]; National Institutes of Health (NIH) [U19-AI103461] FX We would like to thank Jennifer Brunet and Susanna Grecky at Population Council for their valuable input. This work was made possible by the generous support of the American people through the US Agency for International Development (USAID; grant AID-OAA-A-14-00009. This work was also supported by the National Institutes of Health (NIH; grant U19-AI103461). The contents of this paper are the sole responsibility of the authors and do not necessarily reflect the views of the funding agencies. NR 59 TC 16 Z9 16 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD JUL PY 2015 VL 23 IS 7 BP 429 EP 436 DI 10.1016/j.tim.2015.02.006 PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CM5UO UT WOS:000357754700008 PM 25759332 ER PT J AU Passos-Bueno, MR Kobayashi, G Alvizi, L Brito, LA AF Passos-Bueno, Maria Rita Kobayashi, Gerson Alvizi, Lucas Brito, Luciano A. TI Transcriptome, Epigenome and Exome analyses to explore the missing heritability in nonsyndromic cleft lip and palate (NSCLP) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 18, 2014 CL Sanford Consortium Regenerat Med, LaJolla, CA SP Soc Craniofacial Genet & Dev Biol HO Sanford Consortium Regenerat Med C1 NHGRI, NIH, Bethesda, MD USA. [Passos-Bueno, Maria Rita; Kobayashi, Gerson; Alvizi, Lucas; Brito, Luciano A.] Univ Sao Paulo, Dept Genet & Biol Evolut, Inst Biociencias, BR-05508 Sao Paulo, Brazil. EM passos@ib.usp.br RI Passos-Bueno, Maria Rita/I-6796-2016; Brito, Luciano/L-5505-2016; Fapesp-Cepid, CEGH-CEL/J-3613-2015; Kobayashi, Gerson/H-4017-2013 OI Passos-Bueno, Maria Rita/0000-0002-9248-3008; Kobayashi, Gerson/0000-0002-6520-5774 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2015 VL 167 IS 7 BP 1457 EP 1458 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CL1BB UT WOS:000356676200008 ER PT J AU Butali, A Mossey, PA Adeyemo, WL Mekonen, E Gaines, LA Busch, T Braimoh, RO Aregbesola, SB Rigdon, J Emeka, CI James, OO Ogunlewe, MO Ladeinde, AL Abate, F Hailu, T Mohammed, I Gravem, PE Adeyemo, AA Marazita, M Murray, JC AF Butali, Azeez Mossey, P. A. Adeyemo, W. L. Mekonen, E. Gaines, L. A. Busch, Tamara Braimoh, R. O. Aregbesola, S. B. Rigdon, J. Emeka, C., I James, O. O. Ogunlewe, M. O. Ladeinde, A. L. Abate, Fikre Hailu, Taye Mohammed, Ibrahim Gravem, Paul Egl Adeyemo, A. A. Marazita, Mary Murray, J. C. TI Genome-wide Association Identified Candidate Genes Analysis for Non-syndromic Clefts in Two African Populations SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 18, 2014 CL Sanford Consortium Regenerat Med, LaJolla, CA SP Soc Craniofacial Genet & Dev Biol HO Sanford Consortium Regenerat Med C1 [Butali, Azeez; Gaines, L. A.; Busch, Tamara; Rigdon, J.; Murray, J. C.] Univ Iowa, Iowa City, IA USA. [Mossey, P. A.] Univ Dundee, Dundee DD1 4HN, Scotland. [Adeyemo, W. L.; Emeka, C., I; James, O. O.; Ogunlewe, M. O.; Ladeinde, A. L.] Univ Lagos, Lagos, Nigeria. [Mekonen, E.; Abate, Fikre; Hailu, Taye; Mohammed, Ibrahim; Gravem, Paul Egl] Univ Addis Ababa, Addis Ababa, Ethiopia. [Braimoh, R. O.; Aregbesola, S. B.] Obafemi Awolowo Univ, Lagos, Nigeria. [Adeyemo, A. A.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2015 VL 167 IS 7 BP 1463 EP 1464 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CL1BB UT WOS:000356676200027 ER PT J AU Nedvetsky, PI Emmerson, E Finley, JK Ettinger, A Cruz-Pacheco, N Prochazka, J Haddox, CL Northrup, E Hodges, C Mostov, KE Hoffman, MP Knox, SM AF Nedvetsky, Pavel I. Emmerson, Elaine Finley, Jennifer K. Ettinger, Andreas Cruz-Pacheco, Noel Prochazka, Jan Haddox, Candace L. Northrup, Emily Hodges, Craig Mostov, Keith E. Hoffman, Matthew P. Knox, Sarah M. TI Parasympathetic innervation regulates tubulogenesis in the developing salivary gland SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 18, 2014 CL Sanford Consortium Regenerat Med, LaJolla, CA SP Soc Craniofacial Genet & Dev Biol HO Sanford Consortium Regenerat Med C1 [Emmerson, Elaine; Finley, Jennifer K.; Ettinger, Andreas; Cruz-Pacheco, Noel; Northrup, Emily; Knox, Sarah M.] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. [Nedvetsky, Pavel I.; Mostov, Keith E.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Prochazka, Jan] Univ Calif San Francisco, Dept Orofacial Sci, San Francisco, CA 94143 USA. [Haddox, Candace L.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Hodges, Craig] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2015 VL 167 IS 7 BP 1467 EP 1467 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CL1BB UT WOS:000356676200037 ER PT J AU Leiding, JW Sriaroon, P Ly, JMB Petrovic, A Howard, DL Shamblott, M Kuehn, HS Fleisher, TA AF Leiding, Jennifer W. Sriaroon, Panida Ly, Jean M. B. Petrovic, Aleksandra Howard, Deborah L. Shamblott, Michael Kuehn, Hye-Sun Fleisher, Thomas A. TI Hypomorphic interleukin-7 receptor alpha-chain mutations and T-cell deficiency: a delay in diagnosis SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Editorial Material ID SEVERE COMBINED IMMUNODEFICIENCY; DISEASE C1 [Leiding, Jennifer W.; Sriaroon, Panida; Ly, Jean M. B.; Howard, Deborah L.] Univ S Florida, Div Allergy Immunol & Rheumatol, Dept Pediat, St Petersburg, FL 33701 USA. [Petrovic, Aleksandra] Univ S Florida, All Childrens Hosp, Blood & Bone Marrow Transplant Program, St Petersburg, FL 33701 USA. [Shamblott, Michael] Univ S Florida, Childrens Res Inst, St Petersburg, FL 33701 USA. [Kuehn, Hye-Sun; Fleisher, Thomas A.] NCI, Ctr Clin, NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Leiding, JW (reprint author), Univ S Florida, Div Allergy Immunol & Rheumatol, Dept Pediat, Childrens Res Inst, 140 7th Ave South,4th Floor,CRI 4008, St Petersburg, FL 33701 USA. EM jleiding@health.usf.edu FU Intramural NIH HHS NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD JUL PY 2015 VL 115 IS 1 BP 1 EP 3 DI 10.1016/j.anai.2015.04.024 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA CL4YL UT WOS:000356964000002 PM 26123418 ER PT J AU Ghosh, S Vivar, J Nelson, CP Willenborg, C Segre, AV Maekinen, VP Nikpay, M Erdmann, J Blankenberg, S O'Donnell, C Maerz, W Laaksonen, R Stewart, AFR Epstein, SE Shah, SH Granger, CB Hazen, SL Kathiresan, S Reilly, MP Yang, X Quertermous, T Samani, NJ Schunkert, H Assimes, TL McPherson, R AF Ghosh, Sujoy Vivar, Juan Nelson, Christopher P. Willenborg, Christina Segre, Ayellet V. Maekinen, Ville-Petteri Nikpay, Majid Erdmann, Jeannette Blankenberg, Stefan O'Donnell, Christopher Maerz, Winfried Laaksonen, Reijo Stewart, Alexandre F. R. Epstein, Stephen E. Shah, Svati H. Granger, Christopher B. Hazen, Stanley L. Kathiresan, Sekar Reilly, Muredach P. Yang, Xia Quertermous, Thomas Samani, Nilesh J. Schunkert, Heribert Assimes, Themistocles L. McPherson, Ruth CA CARDIoGRAM Consortium TI Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary artery disease; pathway analysis ID SET ENRICHMENT ANALYSIS; GUIDANCE CUE NETRIN-1; EXPRESSION; IDENTIFICATION; PATHWAY; LOCI; ATHEROSCLEROSIS; SUSCEPTIBILITY; MACROPHAGES; INFERENCE AB Objective Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15502 cases/55730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. C1 [Ghosh, Sujoy] Duke NUS Grad Med Sch, Program Cardiovasc & Metab Disorders, Singapore, Singapore. [Ghosh, Sujoy] Duke NUS Grad Med Sch, Ctr Computat Biol, Singapore, Singapore. [Ghosh, Sujoy; Vivar, Juan] N Carolina Cent Univ, Biomed Biotechnol Res Inst, Dept Cardiovasc & Metab Res, Durham, NC USA. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Willenborg, Christina; Erdmann, Jeannette] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Willenborg, Christina; Erdmann, Jeannette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Segre, Ayellet V.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Cambridge, MA USA. [Maekinen, Ville-Petteri; Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Atherogen Lab, Ottawa, ON K1Y 4W7, Canada. [Stewart, Alexandre F. R.; McPherson, Ruth] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Res, Ottawa, ON K1Y 4W7, Canada. [McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON K1Y 4W7, Canada. [Blankenberg, Stefan] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Framingham, MA USA. [O'Donnell, Christopher] NHLBI, Framingham Heart Study, Boston, MA USA. [Maerz, Winfried] Heidelberg Univ, Mannheim Inst Publ Hlth Social & Prevent Med, D-69115 Heidelberg, Germany. [Maerz, Winfried] Synlab Acad, Mannheim, Germany. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Epstein, Stephen E.] Duke Univ, Washington Hosp Ctr, Med Ctr, Cardiovasc Res Inst, Durham, NC USA. [Shah, Svati H.; Granger, Christopher B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Hazen, Stanley L.] Cleveland Clin, Cleveland, OH USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Div Cardiol, Massachusetts Gen Hosp,Ctr Human Genet Res, Boston, MA USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Boston, MA USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Samani, Nilesh J.] Glenfield Hosp, Natl Inst Hlth Res NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Nelson, Christopher P.; Schunkert, Heribert] Partner Site Munich Heart Alliance, DZHK German Res Ctr Cardiovasc Res, Munich, Germany. RP McPherson, R (reprint author), Univ Ottawa, Inst Heart, Div Cardiol, 40 Ruskin St H4203, Ottawa, ON K1Y 4W7, Canada. EM sujoy.ghosh@duke-nus.edu.sg; rmcpherson@ottawaheart.ca RI Erdmann, Jeanette/P-7513-2014; OI Makinen, Ville-Petteri/0000-0002-7262-2656; Stewart, Alexandre/0000-0003-2673-9164; Erdmann, Jeanette/0000-0002-4486-6231; GHOSH, SUJOY/0000-0002-7601-165X; Assimes, Themistocles/0000-0003-2349-0009 FU American Heart Association [AHA10SDG4230068, 13POST17240095, 13SDG17290032]; National Institutes of Health [1R21DK088319, 2P20MD000175-11, P01HL098055, P01HL076491, P20HL113452, R01-HL095987, K23DK088942]; Wellcome Trust [076113, 085475]; British Heart Foundation; European Union [201668]; Deutsche Forschungsgemeinschaft; German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2); German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-plus); EU [LSHM-CT-2006-037593, 201413]; BMBF/ANR [01KU0908A]; Canadian Institutes of Health Research [MOP-2380941, MOP82810, MOP77682]; Canada Foundation for Innovation [11966]; Heart and Stroke Foundation of Canada [NA6001, NA6650] FX This work was supported by grants from the American Heart Association (AHA10SDG4230068 to S. Ghosh; 13POST17240095 to V.-P. Makinen; 13SDG17290032 to X. Yang); National Institutes of Health (1R21DK088319, 2P20MD000175-11 to S. Ghosh); (P01HL098055, P01HL076491, P20HL113452 to S.L. Hazen); (R01-HL095987 to S.H. Shah); (K23DK088942 to T.L. Assimes); Wellcome Trust (No. 076113 and No. 085475) British Heart Foundation (to N.J. Samani); European Union (No. 201668 to R. Laaksonen). Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus), the FP6 and FP7 EU funded integrated projects Cardiogenics (No. LSHM-CT-2006-037593) and ENGAGE (No. 201413), and the binational BMBF/ANR funded project CARDomics (No. 01KU0908A); Canadian Institutes of Health Research (No. MOP-2380941 to R. McPherson), (No. MOP82810, MOP77682 to A.F.R. Stewart and R. McPherson); Canada Foundation for Innovation (No. 11966 to A.F.R. Stewart and R. McPherson; Heart and Stroke Foundation of Canada (No. NA6001, No. NA6650 to R. McPherson). NR 46 TC 15 Z9 15 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2015 VL 35 IS 7 BP 1712 EP 1722 DI 10.1161/ATVBAHA.115.305513 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CL3RE UT WOS:000356867300021 PM 25977570 ER PT J AU Nash, SH Schenk, JM Kristal, AR Goodman, PJ Lucia, MS Parnes, HL Thompson, IM Lippman, SM Song, XL Gurel, B De Marzo, A Platz, EA AF Nash, Sarah H. Schenk, Jeannette M. Kristal, Alan R. Goodman, Phillis J. Lucia, M. Scott Parnes, Howard L. Thompson, Ian M. Lippman, Scott M. Song, Xiaoling Gurel, Bora De Marzo, Angelo Platz, Elizabeth A. TI Association between Serum Phospholipid Fatty Acids and Intraprostatic Inflammation in the Placebo Arm of the Prostate Cancer Prevention Trial SO CANCER PREVENTION RESEARCH LA English DT Article ID RISK; DIET; DESIGN; TISSUE; MICE AB Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are antiinflammatory, whereas n-6 and trans fatty acids are proinflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid [OR of all cores with inflammation versus none (95% CI), 0.35 (0.14-0.89)] and docosahexaenoic acid [OR (95% CI), 0.42 (0.17-1.02)] were inversely associated with, whereas linoleic acid [OR (95% CI), 3.85 (1.41-10.55)] was positively associated with intraprostatic inflammation. Serum trans fatty acids were not associated with intraprostatic inflammation. No significant associations were observed in cases; however, we could not rule out a positive association with linoleic acid and an inverse association with arachidonic acid. Thus, in the PCPT, we found that serum n-3 fatty acids were inversely, n-6 fatty acids were positively, and trans fatty acids were not associated with intraprostatic inflammation in controls. Although, in theory, inflammation could mediate associations of serum fatty acids with prostate cancer risk, our findings cannot explain the epidemiologic associations observed with n-3 and n-6 fatty acids. (C) 2015 AACR. C1 [Nash, Sarah H.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Schenk, Jeannette M.; Kristal, Alan R.; Song, Xiaoling] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Goodman, Phillis J.] Southwest Oncol Grp Stat Ctr, Seattle, WA USA. [Lucia, M. Scott] Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. [Parnes, Howard L.] NCI, Prostate & Urol Canc Res Grp, Canc Prevent Div, Bethesda, MD USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Urol, San Antonio, TX 78229 USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, Off Director, San Diego, CA 92103 USA. [Gurel, Bora] Kocaeli Univ, Dept Pathol, Sch Med, Kocaeli, Turkey. [De Marzo, Angelo] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [De Marzo, Angelo; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [De Marzo, Angelo; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA. [De Marzo, Angelo; Platz, Elizabeth A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM eplatz1@jhu.edu RI Gurel, Bora/A-5458-2016 OI Gurel, Bora/0000-0002-5018-8078 FU NCI; NIH [P01 CA108964, 5UM1CA182883-01, U10CA37429, P50 CA58236]; Cancer Prevention Fellowship Program of the NCI FX This work was funded by the NCI, NIH P01 CA108964 (I.M. Thompson, Project 4 E.A. Platz), 5UM1CA182883-01 (I.M. Thompson), U10CA37429, P50 CA58236. Dr. Nash is supported by the Cancer Prevention Fellowship Program of the NCI. NR 28 TC 1 Z9 1 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2015 VL 8 IS 7 BP 590 EP 596 DI 10.1158/1940-6207.CAPR-14-0398 PG 7 WC Oncology SC Oncology GA CM1FY UT WOS:000357427800004 PM 25926387 ER PT J AU Namiki, T Yaguchi, T Nakamura, K Valencia, JC Coelho, SG Yin, LL Kawaguchi, M Vieira, WD Kaneko, Y Tanemura, A Katayama, I Yokozeki, H Kawakami, Y Hearing, VJ AF Namiki, Takeshi Yaguchi, Tomonori Nakamura, Kenta Valencia, Julio C. Coelho, Sergio G. Yin, Lanlan Kawaguchi, Masakazu Vieira, Wilfred D. Kaneko, Yasuhiko Tanemura, Atsushi Katayama, Ichiro Yokozeki, Hiroo Kawakami, Yutaka Hearing, Vincent J. TI NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation SO CANCER RESEARCH LA English DT Article ID MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; ACRAL MELANOMA; MUTATIONS; GROWTH; MITF; PROLIFERATION; INHIBITION; ONCOGENE; SURVIVAL AB The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulated p21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted. (C) 2015 AACR. C1 [Namiki, Takeshi; Valencia, Julio C.; Coelho, Sergio G.; Yin, Lanlan; Kawaguchi, Masakazu; Vieira, Wilfred D.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Namiki, Takeshi; Yaguchi, Tomonori; Nakamura, Kenta; Kawakami, Yutaka] Keio Univ, Sch Med, Inst Adv Med Res, Div Cellular Signaling, Tokyo 1608582, Japan. [Namiki, Takeshi; Yokozeki, Hiroo] Tokyo Med & Dent Univ, Grad Sch, Dept Dermatol, Bunkyo Ku, Tokyo, Japan. [Namiki, Takeshi; Yokozeki, Hiroo] Tokyo Med & Dent Univ, Fac Med, Dept Dermatol, Bunkyo Ku, Tokyo 113, Japan. [Nakamura, Kenta] Shinshu Univ, Sch Med, Dept Dermatol, Matsumoto, Nagano 390, Japan. [Kaneko, Yasuhiko] Saitama Canc Ctr, Res Inst Clin Oncol, Kita Adachi, Saitama, Japan. [Tanemura, Atsushi; Katayama, Ichiro] Osaka Univ, Grad Sch Med, Dept Dermatol, Suita, Osaka, Japan. RP Kawakami, Y (reprint author), Keio Univ, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. EM yutakawa@z5.keio.jp FU National Cancer Institute at NIH [ZIA BC 010785]; Japan Society for Promotion of Science [26221005] FX This work was supported in part by the Intramural Research Program (ZIA BC 010785) of the National Cancer Institute at NIH and Grants-in-Aid for Scientific Research (26221005) from the Japan Society for Promotion of Science. NR 27 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 IS 13 BP 2708 EP 2715 DI 10.1158/0008-5472.CAN-13-3209 PG 8 WC Oncology SC Oncology GA CL9YJ UT WOS:000357334700013 PM 25832654 ER PT J AU Pattyn, T Van Den Eede, F Lamers, F Veltman, D Sabbe, BG Penninx, BW AF Pattyn, Thomas Van Den Eede, Filip Lamers, Femke Veltman, Dick Sabbe, Bernard G. Penninx, Brenda W. TI IDENTIFYING PANIC DISORDER SUBTYPES USING FACTOR MIXTURE MODELING SO DEPRESSION AND ANXIETY LA English DT Article DE anxiety disorder; classification; factor analysis; latent class analysis; panic; factor mixture modeling; subtype; Beck anxiety inventory; NESDA; nosology ID BECK ANXIETY INVENTORY; PSYCHOMETRIC PROPERTIES; HETEROGENEITY; RELIABILITY; VALIDITY AB BackgroundThe clinical presentation of panic disorder (PD) is known to be highly heterogeneous, complicating research on its etiology, neurobiological pathways, and treatment. None of the attempts to identify PD subtypes have been independently reproduced, rendering the current literature inconclusive. MethodsUsing a data-driven, case-centered approach (factor mixture modeling) on a broad range of anxiety symptoms assessed with the Beck anxiety inventory, the present study identifies PD disorder subtypes in a large (n = 658), well-documented mixed-population sample from the Netherlands Study of Depression and Anxiety (NESDA), with subtypes being validated and detailed using a variety of clinical characteristics. ResultsA three-class, one-factor model proved superior to all other possible models (Bayesian information criterion = 13,200; Lo-Mendel-Rubin = 0.0295; bootstrapped likelihood ratio test 0.0001), with the first class, a cognitive-autonomic subtype, accounting for 29.8%, the second class, the autonomic subtype, for 29.9%, and a third class, the aspecific subtype, for 40.3% of the population. The cognitive-autonomic and autonomic subtypes showed significant differences compared to the aspecific subtype (e.g., comorbidity and suicide attempts) but on severity differed between themselves only. ConclusionThree qualitatively different PD subtypes were identified: a severe cognitive-autonomic subtype, a moderate autonomic subtype, and a mild aspecific subtype. Qualitative and quantitative differences were related to severity and clinical properties such as comorbidity, suicide attempts, sleep, and sense of mastery. (C) 2015 Wiley Periodicals, Inc. C1 [Pattyn, Thomas; Van Den Eede, Filip; Sabbe, Bernard G.] Univ Antwerp, Collaborat Antwerp Psychiat Res Inst CAPRI, B-2610 Antwerp, Belgium. [Pattyn, Thomas; Van Den Eede, Filip] Campus Antwerp Univ Hosp, Dept Psychiat, Antwerp, Belgium. [Lamers, Femke] NIMH, Bethesda, MD 20892 USA. [Lamers, Femke; Veltman, Dick; Penninx, Brenda W.] Vrije Univ Amsterdam Med Ctr, Neurosci Campus Amsterdam, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands. [Sabbe, Bernard G.] Campus Psychiat Hosp Duffel, Dept Psychiat, Duffel, Belgium. RP Pattyn, T (reprint author), Univ Antwerp, Collaborat Antwerp Psychiat Res Inst CAPRI, Univ Pl 1 R3-22, B-2610 Antwerp, Belgium. EM thomas.pattyn@uantwerpen.be FU Geestkracht programme of the Netherlands Organization for Health Research and Development (Zon-Mw) [10-000-1002]; VU University Medical Center; GGZ inGeest; Arkin; Leiden University Medical Center; GGZ Rivierduinen; University Medical Center Groningen; Lentis; GGZ Friesland; GGZ Drenthe; Scientific Institute for Quality of Healthcare (IQ healthcare); Netherlands Institute for Health Services Research (NIVEL); Netherlands Institute of Mental Health and Addiction (Trimbos); Cassiers for panic research on panic disorder (CAPRI) grant [5739] FX The infrastructure for the NESDA (www.nesda.nl) is funded through by the Geestkracht programme of the Netherlands Organization for Health Research and Development (Zon-Mw, grant no. 10-000-1002) and is supported by the following participating universities and mental health care organizations: VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), the Netherlands Institute for Health Services Research (NIVEL) and the Netherlands Institute of Mental Health and Addiction (Trimbos). We are very much grateful for the bequest Cassiers for panic research on panic disorder (CAPRI) grant no. 5739. NR 41 TC 2 Z9 2 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2015 VL 32 IS 7 BP 509 EP 517 DI 10.1002/da.22379 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CL9WZ UT WOS:000357330700006 PM 26014910 ER PT J AU Bazick, J Donithan, M Neuschwander-Tetri, BA Kleiner, D Brunt, EM Wilson, L Doo, E Lavine, J Tonascia, J Loomba, R AF Bazick, Jessica Donithan, Michele Neuschwander-Tetri, Brent A. Kleiner, David Brunt, Elizabeth M. Wilson, Laura Doo, Ed Lavine, Joel Tonascia, James Loomba, Rohit TI Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD SO DIABETES CARE LA English DT Article ID NONALCOHOLIC FATTY LIVER; NATURAL-HISTORY; UNITED-STATES; RISK-FACTORS; HEPATIC STEATOSIS; FOLLOW-UP; VITAMIN-E; DISEASE; STEATOHEPATITIS; PREVALENCE AB OBJECTIVEApproximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment.RESEARCH DESIGN AND METHODSThis study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI.RESULTSThe mean SD age and BMI of patients with diabetes and NAFLD was 52.5 +/- 10.3 years and 35.8 +/- 6.8 kg/m(2), respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA(1c), HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75-0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76-0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis.CONCLUSIONSRoutinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. C1 [Bazick, Jessica; Loomba, Rohit] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Donithan, Michele; Wilson, Laura; Tonascia, James] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. [Kleiner, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Brunt, Elizabeth M.] Washington Univ St Louis Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Doo, Ed] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. [Lavine, Joel] Columbia Univ, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, New York, NY 10027 USA. [Loomba, Rohit] Univ Calif San Diego, Div Gastroenterol, La Jolla, CA 92093 USA. [Loomba, Rohit] Univ Calif San Diego, Div Epidemiol, La Jolla, CA 92093 USA. RP Loomba, R (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. EM roloomba@ucsd.edu FU American Gastroenterological Association (AGA) Foundation-Sucampo-Association of Specialty Professors (ASP) Designated Research Award in Geriatric Gastroenterology; T. Franklin Williams Scholarship Award; Atlantic Philanthropies; John A. Hartford Foundation; ASP; AGA; NIDDK, National Institutes of Health [K23-DK-090303]; University of California, San Diego; Digestive Diseases Research Development Center; Public Health Service [DK-080506]; NIDDK [U01-DK-061718, U01-DK-061728, U01-DK-061731, U01-DK-061732, U01-DK-061734, U01-DK-061737, U01-DK-061738, U01-DK-061730, U01-DK-061713]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health FX This work was supported in part by the American Gastroenterological Association (AGA) Foundation-Sucampo-Association of Specialty Professors (ASP) Designated Research Award in Geriatric Gastroenterology and by a T. Franklin Williams Scholarship Award. Funding was also provided by The Atlantic Philanthropies, the John A. Hartford Foundation, the ASP, the AGA (to R.L.), and the NIDDK, National Institutes of Health (grant K23-DK-090303). This research was funded in part with the support of the University of California, San Diego, Digestive Diseases Research Development Center, Public Health Service grant DK-080506. NASH CRN is supported by the NIDDK (grants U01-DK-061718, U01-DK-061728, U01-DK-061731, U01-DK-061732, U01-DK-061734, U01-DK-061737, U01-DK-061738, U01-DK-061730, and U01-DK-061713), by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by the National Institutes of Health. NR 51 TC 20 Z9 20 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2015 VL 38 IS 7 BP 1347 EP 1355 DI 10.2337/dc14-1239 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CL4OW UT WOS:000356933600031 PM 25887357 ER PT J AU An, YL Zhang, P Wang, JP Gong, QH Gregg, EW Yang, WY Li, H Zhang, B Shuai, Y Chen, YY Engelgau, MM Cheng, YL Hu, YH Bennett, PH Li, GW AF An, Yali Zhang, Ping Wang, Jinping Gong, Qiuhong Gregg, Edward W. Yang, Wenying Li, Hui Zhang, Bo Shuai, Ying Chen, Yanyan Engelgau, Michael M. Cheng, Yiling Hu, Yinghua Bennett, Peter H. Li, Guangwei TI Cardiovascular and All-Cause Mortality Over a 23-Year Period Among Chinese With Newly Diagnosed Diabetes in the Da Qing IGT and Diabetes Study SO DIABETES CARE LA English DT Article ID CORONARY-HEART-DISEASE; IMPAIRED GLUCOSE-TOLERANCE; 20-YEAR FOLLOW-UP; DEATH; RISK; PREVALENCE; MELLITUS; HYPERGLYCEMIA; METAANALYSIS; POPULATION AB OBJECTIVEDespite its growing prevalence in China, the extent to which diabetes leads to excess cardiovascular disease (CVD) mortality and all-cause mortality is unclear.RESEARCH DESIGN AND METHODSWe compared death rates and causes of death among 630 people with newly diagnosed diabetes (NDD) and 519 with normal glucose tolerance (NGT) who, in 1986, were identified as a result of screening 110,660 adults aged 25-74 years for diabetes in Da Qing, China.RESULTSDuring 23 years of follow-up, 338 (56.5%) participants with NDD and 100 (20.3%) with NGT died. CVD was the predominant cause of death in those with diabetes (47.5% in men and 49.7% in women), almost half of which was due to stroke (52.3% in men and 42.3% in women). The age-standardized incidence of all-cause death was three times as high in those with NDD as in those with NGT with incidences (per 1,000 person-years) of 36.9 (95% CI 31.5-42.3) vs. 13.3 (10.2-16.5) in men (P < 0.0001) and 27.1 (22.9-31.4) vs. 9.2 (7.8-10.6) in women (P < 0.0001). The incidence of CVD deaths in men and women with NDD (17.5 [13.8-21.2] vs. 13.5 [10.5-16.5]) did not differ significantly. Significantly higher death rates attributable to renal disease and infection were also found in the NDD group.CONCLUSIONSDiabetes is associated with a substantially increased risk of death in Chinese adults, especially from CVD, almost half of which is due to stroke. C1 [An, Yali; Gong, Qiuhong; Shuai, Ying; Chen, Yanyan; Li, Guangwei] Chinese Acad Med Sci, Dept Endocrinol, Fu Wai Hosp, Beijing 100730, Peoples R China. [Zhang, Ping; Gregg, Edward W.; Cheng, Yiling] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Wang, Jinping; Li, Hui; Hu, Yinghua] Da Qing First Hosp, Dept Cardiol, Da Qing, Peoples R China. [Yang, Wenying; Zhang, Bo; Li, Guangwei] China Japan Friendship Hosp, Dept Endocrinol, Beijing, Peoples R China. [Engelgau, Michael M.] NHLBI, Ctr Translat Res & Implementat Sci, Bethesda, MD 20892 USA. [Bennett, Peter H.] NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Li, GW (reprint author), Chinese Acad Med Sci, Dept Endocrinol, Fu Wai Hosp, Beijing 100730, Peoples R China. EM pzhang@cdc.gov; guangwei_li@medmail.com.cn FU Centers for Disease Control and Prevention/WHO Cooperative Agreement [U58/CCU424123-01-02]; China-Japan Friendship Hospital FX This work was supported by the Centers for Disease Control and Prevention/WHO Cooperative Agreement U58/CCU424123-01-02 and the China-Japan Friendship Hospital. NR 27 TC 8 Z9 11 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2015 VL 38 IS 7 BP 1365 EP 1371 DI 10.2337/dc14-2498 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CL4OW UT WOS:000356933600033 PM 25887356 ER PT J AU Acar, O Esen, T Colakoglu, B Vural, M Onay, A Saglican, Y Turkbey, B Rozanes, I AF Acar, Omer Esen, Tarik Colakoglu, Bulent Vural, Metin Onay, Aslihan Saglican, Yesim Tuerkbey, Baris Rozanes, Izzet TI Multiparametric MRI guidance in first-time prostate biopsies: what is the real benefit? SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Article ID ULTRASOUND FUSION; CANCER DETECTION; RESONANCE; ANTIGEN; MEN; ERA AB PURPOSE With the increased recognition of the capabilities of prostate multiparametric (mp) magnetic resonance imaging (MRI), attempts are being made to incorporate MRI into routine prostate biopsies. In this study, we aimed to analyze the diagnostic yield via cognitive fusion, transrectal ultrasound (TRUS)-guided, and in-bore MRI-guided biopsies in biopsy-naive patients with positive findings for prostate cancer screening. METHODS Charts of 140 patients, who underwent transrectal prostate biopsy after the adaptation of mp-MRI into our routine clinical practice, were reviewed retrospectively. Patients with previous negative biopsies (n=24) and digital rectal examination findings suspicious for >= cT3 prostate cancer (n=16) were excluded. T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging were included in mp-MRI. Cognitive fusion biopsies were performed after a review of mp-MRI data, whereas TRUS-guided biopsies were performed blinded to MRI information. In-bore biopsies were conducted by means of real-time targeting under MRI guidance. RESULTS Between January 2012 and February 2014, a total of 100 patients fulfilling the inclusion criteria underwent TRUS-guided (n=37), cognitive fusion (n=49), and in-bore (n=14) biopsies. Mean age, serum prostate specific antigen level, and prostate size did not differ significantly among the study groups. In TRUS-guided biopsy group, 51.3% were diagnosed with prostate cancer, while the same ratio was 55.1% and 71.4% in cognitive fusion and in-bore biopsy groups, respectively (P = 0.429). Clinically significant prostate cancer detection rate was 69.1%, 70.3%, and 90% in TRUS-guided, cognitive fusion, and in-bore biopsy groups, respectively (P = 0.31). According to histopathologic variables in the prostatectomy specimen, significant prostate cancer was detected in 85.7%, 93.3%, and 100% of patients in TRUS-guided, cognitive fusion, and in-bore biopsy groups, respectively. CONCLUSION In the first set of transrectal prostate biopsies, mp-MRI guidance did not increase the diagnostic yield significantly. C1 [Acar, Omer; Esen, Tarik] Koc Univ, Sch Med, Dept Urol, Istanbul, Turkey. [Onay, Aslihan; Rozanes, Izzet] Koc Univ, Sch Med, Dept Radiol, Istanbul, Turkey. [Colakoglu, Bulent; Vural, Metin] VKF Amer Hosp, Dept Radiol, Istanbul, Turkey. [Saglican, Yesim] Acibadem Univ, Sch Med, Dept Pathol, Istanbul, Turkey. [Tuerkbey, Baris] Natl Canc Inst, Mol Imaging Program, NIH, Bethesda, MD USA. RP Acar, O (reprint author), Koc Univ, Sch Med, Dept Urol, Istanbul, Turkey. EM omer_acar_@hotmail.com NR 19 TC 3 Z9 3 U1 0 U2 2 PU TURKISH SOC RADIOLOGY PI ANKARA PA HOSDERE CAD, GUZELKENT SOK, CANKAYA EVLERI, F-2, ANKARA, 06540, TURKEY SN 1305-3825 EI 1305-3612 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD JUL-AUG PY 2015 VL 21 IS 4 BP 271 EP 276 DI 10.5152/dir.2015.46014 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL9XL UT WOS:000357332300002 PM 26027768 ER PT J AU Strong, DR Messer, K Hartman, SJ Conway, KP Hoffman, AC Pharris-Ciurej, N White, M Green, VR Compton, WM Pierce, J AF Strong, David R. Messer, Karen Hartman, Sheri J. Conway, Kevin P. Hoffman, Allison C. Pharris-Ciurej, Nikolas White, Martha Green, Victoria R. Compton, Wilson M. Pierce, John TI Measurement of multiple nicotine dependence domains among cigarette, non-cigarette and poly-tobacco users: Insights from item response theory SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Nicotine dependence; Poly-tobacco use; Item response theory; Tobacco ID SYNDROME SCALE; SMOKERS; CONTINUUM; SYMPTOMS AB Background: Nicotine dependence (ND) is a key construct that organizes physiological and behavioral symptoms associated with persistent nicotine intake. Measurement of ND has focused primarily on cigarette smokers. Thus, validation of brief instruments that apply to a broad spectrum of tobacco product users is needed. Methods: We examined multiple domains of ND in a longitudinal national study of the United States population, the United States National Epidemiological Survey of Alcohol and Related Conditions (NESARC). We used methods based in item response theory to identify and validate increasingly brief measures of ND that included symptoms to assess ND similarly among cigarette, cigar, smokeless, and poly tobacco users. Results: Confirmatory factor analytic models supported a single, primary dimension underlying symptoms of ND across tobacco use groups. Differential Item Functioning (DIF) analysis generated little support for systematic differences in response to symptoms of ND across tobacco use groups. We established significant concurrent and predictive validity of brief 3- and 5-symptom indices for measuring ND. Conclusions: Measuring ND across tobacco use groups with a common set of symptoms facilitates evaluation of tobacco use in an evolving marketplace of tobacco and nicotine products. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Strong, David R.; Messer, Karen; Hartman, Sheri J.; White, Martha; Pierce, John] Moores UC San Diego Canc Ctr, Canc Prevent & Control Program, La Jolla, CA 92093 USA. [Strong, David R.; Messer, Karen; Hartman, Sheri J.; White, Martha; Pierce, John] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Hoffman, Allison C.; Pharris-Ciurej, Nikolas] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Conway, Kevin P.; Green, Victoria R.; Compton, Wilson M.] NIDA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Green, Victoria R.] Kelly Govt Solut, Bethesda, MD USA. RP Strong, DR (reprint author), Univ Calif San Diego, Canc Prevent & Control Program, Moores UC San Diego Canc Ctr, La Jolla, CA 92093 USA. EM dstrong@ucsd.edu OI Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; National Cancer Institute [1R01CA172058-1]; UC Tobacco-Related Disease Research Program [21XT-0076, 21RT-0135] FX This project has been funded with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under Contract No. HHSN271201100027C. In addition, Drs. Strong, Pierce, Messer, Hartman, and Ms. White were partially supported on National Cancer Institute (1R01CA172058-1) and UC Tobacco-Related Disease Research Program grants (21XT-0076; 21RT-0135). The role of Drs. Hoffman, Pharris-Ciurej, Conway, Compton, and Ms. Green on this paper were through their involvement on contract no. HHSN271201100027C. They had no involvement in the cited grants. NR 34 TC 1 Z9 1 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2015 VL 152 BP 185 EP 193 DI 10.1016/j.drugalcdep.2015.03.040 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CL1XN UT WOS:000356738300025 PM 26005043 ER PT J AU Hasin, DS Shmulewitz, D Stohl, M Greenstein, E Aivadyan, C Morita, K Saha, T Aharonovich, E Jung, J Zhang, HT Nunes, EV Grant, BF AF Hasin, Deborah S. Shmulewitz, Dvora Stohl, Malka Greenstein, Eliana Aivadyan, Christina Morita, Kara Saha, Tulshi Aharonovich, Efrat Jung, Jeesun Zhang, Haitao Nunes, Edward V. Grant, Bridget F. TI Procedural validity of the AUDADIS-5 depression, anxiety and post-traumatic stress disorder modules: Substance abusers and others in the general population SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol use disorder; Substance use disorder; Reliability; Validity; Alcohol Use Disorder and Associated; Disabilities Interview Schedule-5; Psychiatric Research Interview for Substance and Mental Disorders-5 ID ALCOHOL-USE DISORDER; PSYCHIATRIC RESEARCH INTERVIEW; DSM-IV ALCOHOL; FACE-TO-FACE; MENTAL-DISORDERS; UNITED-STATES; RELIABILITY; CONCORDANCE; DIAGNOSES; SCHEDULE AB Background: Little is known about the procedural validity of lay-administered, fully-structured assessments of depressive, anxiety and post-traumatic stress (PTSD) disorders in the general population as determined by comparison with clinical re-appraisal, and whether this differs between current regular substance abusers and others. We evaluated the procedural validity of the Alcohol Use Disorder and Associated Disabilities Interview Schedule, DSM-5 Version (AUDADIS-5) assessment of these disorders through clinician re-interviews. Methods: Test-retest design among respondents from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III): (264 current regular substance abusers, 447 others). Clinicians blinded to AUDADIS-5 results administered the semi-structured Psychiatric Research Interview for Substance and Mental Disorders, DSM-5 version (PRISM-5). AUDADIS-5/PRISM-5 concordance was indicated by kappa (k) for diagnoses and intraclass correlation coefficients (ICC) for dimensional measures (DSM-5 symptom or criterion counts). Results were compared between current regular substance abusers and others. Results: AUDADIS-5 and PRISM-5 concordance for DSM-5 depressive disorders, anxiety disorders and PTSD was generally fair to moderate (k = 0.24-0.59), with concordance on dimensional scales much better (ICC = 0.53-0.81). Concordance differed little between regular substance abusers and others. Conclusions: AUDADIS-5/PRISM-5 concordance indicated procedural validity for the AUDADIS-5 among substance abusers and others, suggesting that AUDADIS-5 diagnoses of DSM-5 depressive, anxiety and PTSD diagnoses are informative measures in both groups in epidemiological studies. The stronger concordance on dimensional measures supports the current movement toward dimensional psychopathology measures, suggesting that such measures provide important information for research in the NESARC-III and other datasets, and possibly for clinical purposes as well. (C) 2015 Published by Elsevier Ireland Ltd. C1 [Hasin, Deborah S.; Shmulewitz, Dvora; Aharonovich, Efrat; Nunes, Edward V.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Hasin, Deborah S.; Shmulewitz, Dvora; Stohl, Malka; Greenstein, Eliana; Aivadyan, Christina; Morita, Kara; Aharonovich, Efrat; Nunes, Edward V.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Saha, Tulshi; Jung, Jeesun; Zhang, Haitao; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD 20892 USA. RP Hasin, DS (reprint author), Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. EM deborah.hasin@gmail.com FU National Institutes of Health [HHSN275200900007C, K05AA014223, K24DA022412]; New York State Psychiatric Institute; National Institute on Alcohol Abuse and Alcoholism; NIAAA, National Institutes of Health FX Support is acknowledged from the National Institutes of Health, Contract HHSN275200900007C, K05AA014223 (Hasin), K24DA022412 (Nunes) and the New York State Psychiatric Institute (Hasin, Nunes). The National Epidemiologic Survey on Alcohol and Related Conditions-III was sponsored by the National Institute on Alcohol Abuse and Alcoholism and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health. No authors have any relevant financial interests. NR 46 TC 14 Z9 14 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2015 VL 152 BP 246 EP 256 DI 10.1016/j.drugalcdep.2015.03.027 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CL1XN UT WOS:000356738300033 PM 25939727 ER PT J AU Guidry, VT Longnecker, MP Aase, H Eggesbo, M Zeiner, P Reichborn-Kjennerud, T Knudsen, GP Bertelsen, RJ Ye, XY Calafat, AM Engel, SM AF Guidry, Virginia T. Longnecker, Matthew P. Aase, Heidi Eggesbo, Merete Zeiner, Pal Reichborn-Kjennerud, Ted Knudsen, Gun P. Bertelsen, Randi J. Ye, Xiaoyun Calafat, Antonia M. Engel, Stephanie M. TI Measurement of Total and Free Urinary Phenol and Paraben Concentrations over the Course of Pregnancy: Assessing Reliability and Contamination of Specimens in the Norwegian Mother and Child Cohort Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BISPHENOL-A CONCENTRATIONS; TANDEM MASS-SPECTROMETRY; HPLC-MS/MS METHOD; ENVIRONMENTAL PHENOLS; PRENATAL EXPOSURE; BIRTH OUTCOMES; VARIABILITY; WOMEN; PREDICTORS; BEHAVIOR AB BACKGROUND: Exposures to environmental phenols and parabens may be harmful, especially in utero. Prior studies have demonstrated high within-person variability of urinary concentrations across pregnancy. OBJECTIVES: We sought to measure phenol and paraben biomarker concentrations for the Norwegian Mother and Child Cohort (MoBa) study, assess within-person variability, and investigate any possible external phenol or paraben contamination of specimens. METHODS: We collected three spot urine samples at approximately 17, 23, and 29 weeks gestation in a hospital setting and added a preservative containing ethyl paraben. We measured urinary concentrations and within-person variability for phenols and parabens in a MoBa sample (n = 45), including a subgroup of 15 participants previously randomly selected for a bisphenol A (BPA) exposure study who had unusually high total BPA concentrations. Additionally, we compared reliability results for total, conjugated, and free concentrations of phenolic compounds. RESULTS: We detected total and free BPA, butyl paraben, propyl paraben, and methyl paraben in 100% of samples, total benzophenone-3 in 95% of samples, and infrequently detected free benzo-phenone-3 and total and free 2,4-dichlorophenol and 2,5-dichlorophenol. Intraclass correlation coefficients (ICCs) for total, conjugated, and free concentrations ranged from relatively low for BPA to moderate for propyl paraben. ICCs were generally similar overall and by subgroup. CONCLUSIONS: Using conjugated concentrations improved reliability estimates only for BPA. Measuring total and free concentrations, an approach that may be useful for future studies, allowed us to identify likely BPA and butyl paraben contamination of archived MoBa urine specimens. C1 [Guidry, Virginia T.; Engel, Stephanie M.] UNC Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Aase, Heidi] Norwegian Inst Publ Hlth, Dept Child Dev & Mental Hlth, Oslo, Norway. [Eggesbo, Merete] Norwegian Inst Publ Hlth, Dept Genes & Environm, Oslo, Norway. [Zeiner, Pal] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Reichborn-Kjennerud, Ted; Knudsen, Gun P.] Norwegian Inst Publ Hlth, Dept Genet Environm & Mental Hlth, Oslo, Norway. [Bertelsen, Randi J.] Haukeland Hosp, Dept Occupat Med, N-5021 Bergen, Norway. [Ye, Xiaoyun; Calafat, Antonia M.] Ctr Dis Control & Prevent, Div Sci Lab, Atlanta, GA USA. RP Guidry, VT (reprint author), UNC Gillings Sch Global Publ Hlth, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. EM virginia.guidry@unc.edu OI Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU National Institute of Environmental Health Sciences (NIEHS), National Institute of Health (NIH) [P30ES010126, R01ES021777]; Intramural Research Program of the NIEHS/NIH; NIEHS [ES07018]; Norwegian Ministry of Health; Ministry of Education and Research, NIEHS/NIH [NO1-ES-75558]; National Institute of Neurological Disorders and Stroke, NIH [UO1 NS 047537-01, UO1 NS047537-06A1]; Norwegian Research Council/Bioinformatics and Functional Genomics (FUGE) [151918/S10] FX This study was supported by grants from the National Institute of Environmental Health Sciences (NIEHS), National Institute of Health (NIH) (P30ES010126, R01ES021777) and the Intramural Research Program of the NIEHS/NIH. V.T.G. was supported by NIEHS grant ES07018. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIEHS/NIH (contract NO1-ES-75558), National Institute of Neurological Disorders and Stroke, NIH (grants UO1 NS 047537-01 and UO1 NS047537-06A1), and the Norwegian Research Council/Bioinformatics and Functional Genomics (FUGE) (grant 151918/S10). NR 46 TC 9 Z9 9 U1 3 U2 29 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2015 VL 123 IS 7 BP 705 EP 711 DI 10.1289/ehp.1408325 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CL9KQ UT WOS:000357297500021 PM 25782115 ER PT J AU Calafat, AM Longnecker, MP Koch, HM Swan, SH Hauser, R Goldman, LR Lanphear, BP Rudel, RA Engel, SM Teitelbaum, SL Whyatt, RM Wolff, MS AF Calafat, Antonia M. Longnecker, Matthew P. Koch, Holger M. Swan, Shanna H. Hauser, Russ Goldman, Lynn R. Lanphear, Bruce P. Rudel, Ruthann A. Engel, Stephanie M. Teitelbaum, Susan L. Whyatt, Robin M. Wolff, Mary S. TI Optimal Exposure Biomarkers for Nonpersistent Chemicals in Environmental Epidemiology SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BISPHENOL-A CONCENTRATIONS; PHTHALATE METABOLITE CONCENTRATIONS; CHROMATOGRAPHY-MASS-SPECTROMETRY; 24-H URINE SAMPLES; TEMPORAL VARIABILITY; PREGNANT-WOMEN; BLANK PROBLEMS; PUERTO-RICO; HUMAN BLOOD; PREDICTORS AB We discuss considerations that are essential when evaluating exposure to nonpersistent, semivolatile environmental chemicals such as phthalates and phenols (e.g., bisphenol A). A biomarker should be chosen to best represent usual personal exposures and not recent, adventitious, or extraneous exposures. Biomarkers should be selected to minimize contamination arising from collection, sampling, or analysis procedures. Pharmacokinetics should be considered; for example, nonpersistent, semivolatile chemicals are metabolized quickly, and urine is the compartment with the highest concentrations of metabolites. Because these chemicals are nonpersistent, knowledge of intraindividual reliability over the biologic window of interest is also required. In recent years researchers have increasingly used blood as a matrix for characterizing exposure to nonpersistent chemicals. However, the biologic and technical factors noted above strongly support urine as the optimal matrix for measuring nonpersistent, semivolatile, hydrophilic environmental agents. C1 [Calafat, Antonia M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Longnecker, Matthew P.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Koch, Holger M.] Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, Bochum, Germany. [Swan, Shanna H.; Teitelbaum, Susan L.; Wolff, Mary S.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Goldman, Lynn R.] George Washington Univ, Milken Inst, Sch Publ Hlth, Washington, DC USA. [Lanphear, Bruce P.] British Columbia Childrens Hosp, Vancouver, BC, Canada. [Rudel, Ruthann A.] Silent Spring Inst, Boston, MA USA. [Engel, Stephanie M.] Univ N Carolina, Chapel Hill, NC USA. [Whyatt, Robin M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Wolff, MS (reprint author), Mt Sinai Med Ctr, Prevent Med, One Gustave L Levy Pl, Box 1057, New York, NY 10029 USA. EM mary.wolff@mssm.edu RI Koch, Holger/B-3277-2011; OI Koch, Holger/0000-0002-8328-2837; Longnecker, Matthew/0000-0001-6073-5322 FU Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services FX The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services. We thank Sandra Chambers at the NIEHS for help in identifying articles listed in Figure 1. NR 48 TC 12 Z9 12 U1 4 U2 20 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2015 VL 123 IS 7 BP A166 EP A168 DI 10.1289/ehp.1510041 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CL9KQ UT WOS:000357297500001 PM 26132373 ER PT J AU Hofmann, JN Corley, DA Colt, JS Shuch, B Chow, WH Purdue, MP AF Hofmann, Jonathan N. Corley, Douglas A. Colt, Joanne S. Shuch, Brian Chow, Wong-Ho Purdue, Mark P. TI Differences in 25-Hydroxyvitamin D Concentrations May Explain the Black-White Differences in Chronic Kidney Disease and Risk of Renal Cell Carcinoma Response SO EPIDEMIOLOGY LA English DT Letter C1 [Hofmann, Jonathan N.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Corley, Douglas A.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Colt, Joanne S.; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shuch, Brian] Yale Univ, Sch Med, Dept Urol, New Haven, CT USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. RP Hofmann, JN (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS [ZIA CP010123-15] NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2015 VL 26 IS 4 BP E49 EP E49 DI 10.1097/EDE.0000000000000305 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL7YT UT WOS:000357189600008 PM 25899997 ER PT J AU Zhen, DB Rabe, KG Gallinger, S Syngal, S Schwartz, AG Goggins, MG Hruban, RH Cote, ML McWilliams, RR Roberts, NJ Cannon-Albright, LA Li, DH Moyes, K Wenstrup, RJ Hartman, AR Seminara, D Klein, AP Petersen, GM AF Zhen, David B. Rabe, Kari G. Gallinger, Steven Syngal, Sapna Schwartz, Ann G. Goggins, Michael G. Hruban, Ralph H. Cote, Michele L. McWilliams, Robert R. Roberts, Nicholas J. Cannon-Albright, Lisa A. Li, Donghui Moyes, Kelsey Wenstrup, Richard J. Hartman, Anne-Renee Seminara, Daniela Klein, Alison P. Petersen, Gloria M. TI BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study SO GENETICS IN MEDICINE LA English DT Article DE BRCA1; BRCA2; PALB2; CDKN2A; familial pancreatic cancer ID GERMLINE MUTATIONS; HIGH-RISK; ADENOCARCINOMA; PREVALENCE; SUSCEPTIBILITY; CONSORTIUM; VARIANTS; CARRIERS; KINDREDS; PARTNER AB Purpose: Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing. Methods: Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). We also examined the impact of family history on breast and ovarian cancers and melanoma. Results: Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: 1.06-5.44; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer. Conclusion: Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer. C1 [Zhen, David B.] Mayo Clin, Dept Internal Med, Rochester, MN USA. [Rabe, Kari G.; Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Gallinger, Steven] Univ Toronto, Div Gen Surg, Toronto, ON, Canada. [Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Schwartz, Ann G.; Cote, Michele L.] Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. [Schwartz, Ann G.; Cote, Michele L.] Wayne State Univ, Detroit, MI USA. [Goggins, Michael G.; Hruban, Ralph H.; Klein, Alison P.] Johns Hopkins Univ, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [McWilliams, Robert R.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Roberts, Nicholas J.] Johns Hopkins Univ, Ludwig Ctr Canc Genet, Baltimore, MD USA. [Cannon-Albright, Lisa A.] Univ Utah, Sch Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Moyes, Kelsey; Wenstrup, Richard J.; Hartman, Anne-Renee] Myriad Genet Labs Inc, Salt Lake City, UT USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Petersen, GM (reprint author), Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. EM petersen.gloria@mayo.edu RI Gallinger, Steven/E-4575-2013; OI Zhen, David/0000-0003-3375-5912; albright, lisa/0000-0003-2602-3668 FU National Cancer Institute (NCI) [R01 CA97075]; National Institutes of Health NCI SPORE [P50 CA102701, P50 CA62924, K24113433]; Sol Goldman Pancreatic Cancer Research Center [N01-PC35145, P30 CA22453]; Karp Family H.H. & M. Metals, Inc. Fund; Sheikh Ahmed Center for Pancreatic Cancer Research; American Association for Cancer Research Innovation [11-60-25-CANN] FX The authors thank the probands and their families. They also thank study assistants Ryan Wuertz, Bridget Eversman, Sarah Amundson, Megan Reichmann, Denesia Parris, Chinedu Ukaegbu, Chelsea Michael, and Diane Echavarria, for their contributions to the study. The Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium is funded by National Cancer Institute (NCI) grant R01 CA97075. Other funding support for this study includes National Institutes of Health NCI SPORE grants P50 CA102701 and P50 CA62924, Susan Wojcicki, Dennis Troper, grant K24113433, the Sol Goldman Pancreatic Cancer Research Center (grants N01-PC35145 and P30 CA22453), the Karp Family H.H. & M. Metals, Inc. Fund, the Sheikh Ahmed Center for Pancreatic Cancer Research, and the American Association for Cancer Research Innovation (grant 11-60-25-CANN, awarded to L.A.C.-A.). This work was presented at the American Society of Human Genetics annual meeting, Boston, MA, 24 October 2013. NR 40 TC 23 Z9 23 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUL PY 2015 VL 17 IS 7 BP 569 EP 577 DI 10.1038/gim.2014.153 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CM0ID UT WOS:000357360700007 PM 25356972 ER PT J AU Varshney, GK Pei, WH LaFave, MC Idol, J Xu, LS Gallardo, V Carrington, B Bishop, K Jones, M Li, MY Harper, U Huang, SC Prakash, A Chen, WB Sood, R Ledin, J Burgess, SM AF Varshney, Gaurav K. Pei, Wuhong LaFave, Matthew C. Idol, Jennifer Xu, Lisha Gallardo, Viviana Carrington, Blake Bishop, Kevin Jones, MaryPat Li, Mingyu Harper, Ursula Huang, Sunny C. Prakash, Anupam Chen, Wenbiao Sood, Raman Ledin, Johan Burgess, Shawn M. TI High-throughput gene targeting and phenotyping in zebrafish using CRISPR/Cas9 SO GENOME RESEARCH LA English DT Article ID HUMAN GENOME; CHROMOSOMAL DELETIONS; CAS9 NUCLEASE; DNA CLEAVAGE; RNA; SEQUENCE; CELLS; EXPRESSION; SYSTEM; SPECIFICITY AB The use of CRISPR/Cas9 as a genome-editing tool in various model organisms has radically changed targeted mutagenesis. Here, we present a high-throughput targeted mutagenesis pipeline using CRISPR/Cas9 technology in zebrafish that will make possible both saturation mutagenesis of the genome and large-scale phenotyping efforts. We describe a cloning-free single-guide RNA (sgRNA) synthesis, coupled with streamlined mutant identification methods utilizing fluorescent PCR and multiplexed, high-throughput sequencing. We report germline transmission data from 162 loci targeting 83 genes in the zebrafish genome, in which we obtained a 99% success rate for generating mutations and an average germline transmission rate of 28%. We verified 678 unique alleles from 58 genes by high-throughput sequencing. We demonstrate that our method can be used for efficient multiplexed gene targeting. We also demonstrate that phenotyping can be done in the F-1 generation by inbreeding two injected founder fish, significantly reducing animal husbandry and time. This study compares germline transmission data from CRISPR/Cas9 with those of TALENs and ZFNs and shows that efficiency of CRISPR/Cas9 is sixfold more efficient than other techniques. We show that the majority of published "rules" for efficient sgRNA design do not effectively predict germline transmission rates in zebrafish, with the exception of a GG or GA dinucleotide genomic match at the 5' end of the sgRNA. Finally, we show that predicted off-target mutagenesis is of low concern for in vivo genetic studies. C1 [Varshney, Gaurav K.; Pei, Wuhong; LaFave, Matthew C.; Idol, Jennifer; Xu, Lisha; Gallardo, Viviana; Carrington, Blake; Bishop, Kevin; Huang, Sunny C.; Prakash, Anupam; Sood, Raman; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Jones, MaryPat; Harper, Ursula] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Li, Mingyu; Chen, Wenbiao] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Ledin, Johan] Uppsala Univ, Dept Organismal Biol, Sci Life Lab, SE-75236 Uppsala, Sweden. RP Burgess, SM (reprint author), NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Burgess, Shawn/0000-0003-1147-0596; Ledin, Johan/0000-0002-7319-7735; LaFave, Matthew/0000-0001-9165-041X; Varshney, Gaurav K./0000-0002-0429-1904 FU National Human Genome Research Institute (NHGRI), National Institutes of Health [R01DK088686]; Science for Life Laboratory, Sweden FX We thank Colin Huck, Dustin Prebilic, and other staff of the National Institutes of Health zebrafish facility for excellent animal care, Julia Fekecs for illustrations and graphics work, and Robert Blakesley, Alice Young, Baishali Maskeri, and the National Intramural Sequencing Center (NISC) for providing sequence data. This research was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI), National Institutes of Health (S.M.B. and R.S.), R01DK088686 (W.C.), and Science for Life Laboratory, Sweden (J.L.). NR 54 TC 49 Z9 51 U1 7 U2 53 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUL PY 2015 VL 25 IS 7 BP 1030 EP 1042 DI 10.1101/gr.186379.114 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA CM0GR UT WOS:000357356900010 PM 26048245 ER PT J AU Huang, BX Lee, R Akbar, M Kim, HY AF Huang, Bill X. Lee, Rachel Akbar, Mohammed Kim, Hee-Yong TI Threonine 34 phosphorylation by phosphoinositide-dependent protein kinase 1 facilitates dissociation of Akt from the plasma membrane SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Protein kinase B; Threonine 34; Membrane translocation; Akt activation; PDK1 ID PLECKSTRIN HOMOLOGY DOMAIN; CHEMICAL CROSS-LINKING; CONFORMATIONAL-CHANGES; MASS-SPECTROMETRY; ACTIVATION; MECHANISM; SURVIVAL; STABILITY; MODULATOR; 3-KINASE AB Akt is a key mediator of cell proliferation, survival and metabolism. After translocation to the membrane and phosphorylation at T308 and S473, the activated Akt dissociates from the plasma membrane to cytoplasm, which is an important step to phosphorylate its downstream targets. In addition to its central role in regulating the kinase activity, phosphorylation of T308 in the kinase loop has been reported to be necessary for this dissociation process. However, it is not clear whether the membrane detachment requires further mechanisms. In the present report, we demonstrate that membrane dissociation of Akt requires phosphoinositide-dependent protein kinase 1 (PDK1) which directly phosphorylates not only T308 but also T34 in the pleckstrin homology (PH) domain. Like T308, T34 was phosphorylated in a phosphatidylinositol 3,4,5-trisphosphate- and phosphatidylserine-dependent manner. Phosphorylation of T34 also occurred in cells following growth factor stimulation, concurrently with T308 phosphorylation. Moreover, when T34 was mutated to aspartic acid (T34D) to mimic its phosphorylation, Akt-membrane association assessed by surface plasmon resonance spectroscopy was significantly reduced. In cells, this mutation impaired the IGF-induced Akt membrane translocation and subsequent phosphorylation at T308 and S473. Taken together, our results demonstrate that 134 phosphorylation by PDK1 promotes the membrane dissociation of activated Akt for its downstream action through attenuating membrane binding affinity. This membrane dissociation mechanism offers a new insight for Akt activation process and provides a potential new target for controlling the Akt-dependent cellular processes. Published by Elsevier Ltd. C1 [Huang, Bill X.; Lee, Rachel; Akbar, Mohammed; Kim, Hee-Yong] NIAAA, NIH, Lab Mol Signaling, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, NIH, Lab Mol Signaling, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Intramural NIH HHS [Z01 AA000284-18] NR 32 TC 0 Z9 0 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUL PY 2015 VL 64 BP 195 EP 201 DI 10.1016/j.biocel.2015.04.007 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CM0EM UT WOS:000357351200022 PM 25912234 ER PT J AU Hur, W Lee, JH Kim, SW Kim, JH Bae, SH Kim, M Hwang, D Kim, YS Park, T Um, SJ Song, BJ Yoon, SK AF Hur, Wonhee Lee, Joon Ho Kim, Sung Woo Kim, Jung-Hee Bae, Si Hyun Kim, Minhyung Hwang, Daehee Kim, Young Seok Park, Taesun Um, Soo-Jong Song, Byoung-Joon Yoon, Seung Kew TI Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Non-alcoholic fatty liver; Non-alcoholic steatohepatitis; MicroRNAs; MicroRNA-451; Cab39/MO25; Inflammation ID LIVER-DISEASE; LKB1-STRAD-MO25 COMPLEX; KINASE ACTIVATION; TNF-ALPHA; P38 MAPK; MIR-451; REVEALS; INTERLEUKIN-8; ANGIOGENESIS; PATHOGENESIS AB Mechanisms associated with the progression of non-alcoholic fatty liver disease (NAFLD) remain unclear. We attempted to identify the pattern of altered gene expression at different time points in a high fat diet (HFD)-induced NAFLD mouse model. The early up-regulated genes are mainly involved in the innate immune responses, while the late up-regulated genes represent the inflammation processes. Although recent studies have shown that microRNAs play important roles in hepatic metabolic functions, the pivotal role of microRNAs in the progression of NAFLD is not fully understood. We investigated the functions of miR-451, which was identified as a target gene in the inflammatory process in NAFLD. miR-451 expression was significantly decreased in the palmitate (PA)-exposed HepG2 cells and in liver tissues of HFD-induced non-alcoholic steatohepatitis (NASH) mice. Its decreased expressions were also observed in liver specimens of NASH patients. In vitro analysis of the effect of miR-451 on proinflammatory cytokine provided evidence for negative regulation of PA-induced interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-alpha) production. Furthermore, miR-451 over-expression inhibited translocation of the PA-induced NF-kappa B p65 subunit into the nucleus. Our result showed that Cab39 is a direct target of miRNA-451 in steatotic cells. Further study showed that AMPK activated through Cab39 inhibits NF-kappa B transactivation induced in steatotic HepG2 cells. miR-451 over-expression in steatotic cells significantly suppressed PA-induced inflammatory cytokine. These results provide new insights into the negative regulation of miR-451 in fatty acid-induced inflammation via the AMPK/AKT pathway and demonstrate potential therapeutic applications for miR-451 in preventing the progression from simple steatosis to severely advanced liver disease. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [Hur, Wonhee; Lee, Joon Ho; Kim, Sung Woo; Kim, Jung-Hee; Bae, Si Hyun; Yoon, Seung Kew] Catholic Univ Korea, Coll Med, Catholic Univ Liver Res Ctr, Seoul, South Korea. [Hur, Wonhee; Lee, Joon Ho; Kim, Sung Woo; Kim, Jung-Hee; Bae, Si Hyun; Yoon, Seung Kew] Catholic Univ Korea, Coll Med, WHO Collaborating Ctr Viral Hepatitis, Seoul, South Korea. [Bae, Si Hyun; Yoon, Seung Kew] Catholic Univ Korea, Coll Med, Seoul St Marys Hosp, Dept Internal Med, Seoul, South Korea. [Kim, Minhyung; Hwang, Daehee] POSTECH, Sch Interdisciplinary Biosci & Bioengn, Pohang, South Korea. [Hwang, Daehee] DGIST, Inst Basic Sci, Dept New Biol, Daegu, South Korea. [Hwang, Daehee] DGIST, Inst Basic Sci, Ctr Plant Aging Res, Daegu, South Korea. [Kim, Young Seok] Soon Chun Hyang Univ, Coll Med, Hosp Bucheon, Dept Internal Med, Bucheon, South Korea. [Park, Taesun] Yonsei Univ, Dept Food & Nutr, Seoul 120749, South Korea. [Um, Soo-Jong] Sejong Univ, Inst Biosci, Dept Biosci & Biotechnol, Seoul, South Korea. [Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. RP Yoon, SK (reprint author), Catholic Univ Korea, Coll Med, Seoul St Marys Hosp, Dept Internal Med, Banpo Daero 222, Seoul, South Korea. EM wendyhur@catholic.ac.kr; JoonHo@catholic.ac.kr; never-i@nate.com; kim.jh@catholic.ac.kr; baesh@catholic.ac.kr; hyung926@postech.ac.kr; dhwang@dgist.ac.kr; liverkys@schmc.ac.kr; tspark@yonsei.ac.kr; umsj@sejong.ac.kr; bj.song@nih.gov; yoonsk@catholic.ac.kr FU Basic Science Research Program from the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0014620, 2012-001941]; Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [2011-08-0168-A0094] FX This research was partially supported by grants of Basic Science Research Program from the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014620 and 2012-001941) and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (no. 2011-08-0168-A0094). NR 44 TC 22 Z9 22 U1 4 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUL PY 2015 VL 64 BP 265 EP 276 DI 10.1016/j.biocel.2015.04.016 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CM0EM UT WOS:000357351200029 PM 25957914 ER PT J AU Mitchell, JE King, WC Pories, W Wolfe, B Flum, DR Spaniolas, K Bessler, M Devlin, M Marcus, MD Kalarchian, M Engel, S Khandelwal, S Yanovski, S AF Mitchell, James E. King, Wendy C. Pories, Walter Wolfe, Bruce Flum, David R. Spaniolas, Konstatinos Bessler, Mark Devlin, Michael Marcus, Marsha D. Kalarchian, Melissa Engel, Scott Khandelwal, Saurobh Yanovski, Susan TI Binge Eating Disorder and Medical Comorbidities in Bariatric Surgery Candidates SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE binge eating disorder; metabolic syndrome; medical comorbidities ID LONGITUDINAL ASSESSMENT; METABOLIC SYNDROME; DEPRESSION; PREVALENCE; WEIGHT AB Objective: To determine whether binge eating disorder (BED) status is associated with medical comorbidities in obese adults scheduled for bariatric surgery. Method: The study utilized Longitudinal Assessment of Bariatric Surgery-2 data obtained from six clinical centers around the United States. This is a well-phenotyped cohort of individuals who were evaluated within 30 days before their scheduled surgery using standardized protocols. In the cohort, 350 participants were classified as having BED and 1,875 as not having BED (non-BED). Multi variable logistic regression was used to determine whether BED status was independently related to medical comorbidities. As an exploratory analysis, significance was based on nominal p-values (p<. 05). Holm's-adjusted p-values were also reported. Results: After adjusting for age, sex, education, and body mass index, BED status was found to be independently associated with four of the 15 comorbidities (i.e., impaired glucose levels (odds ratio [OR] = 1.45 (95% confidence interval [CI]: 1.12-1.87)), high triglycerides (OR = 1.28 (95% CI: 1.002-1.63)), and urinary incontinence (OR = 1.30 (95% CI: 1.02-1.66)), all being more common among the BED sample, and severe walking limitations being less common in the BED sample (OR = 0.53 (95% CI: 0.29-0.96)). With further adjustment for psychiatric/emotional health indicators, BED status was independently associated with three comorbidities (impaired glucose levels (OR = 1.36 (95% CI: 1.04-1.79)), cardiovascular disease (OR = 0.50 (95% CI: 0.30-0.86)), and severe walking limitations (OR = 0.38 (95% CI: 0.19-0.77)). However, Holm's-adjusted p-values for all variables were greater than .05. Discussion: The results suggest the possibility of a contribution of BED to risk of specific medical comorbidities in severely obese adults. (C) 2015 Wiley Periodicals, Inc. C1 [Mitchell, James E.; Engel, Scott] Neuropsychiat Res Inst, Fargo, ND 58103 USA. [King, Wendy C.] Univ Pittsburgh, Grad Sch Publ Hlth, Data Coordinating Ctr, Pittsburgh, PA USA. [Pories, Walter; Spaniolas, Konstatinos] East Carolina Med Ctr, Dept Surg, Greenville, NC USA. [Wolfe, Bruce] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Flum, David R.; Khandelwal, Saurobh] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Bessler, Mark; Devlin, Michael] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY USA. [Marcus, Marsha D.] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Kalarchian, Melissa] Dusquesne Univ, Coll Nursing, Pittsburgh, PA USA. [Yanovski, Susan] NIDDKD, Bethesda, MD USA. RP Mitchell, JE (reprint author), Neuropsychiat Res Inst, Fargo, ND 58103 USA. EM jmitchell@nrifargo.com OI King, Wendy/0000-0002-0740-0029 FU NIDDK NIH HHS [U01 DK066471] NR 23 TC 7 Z9 8 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD JUL PY 2015 VL 48 IS 5 BP 471 EP 476 DI 10.1002/eat.22389 PG 6 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA CL1ED UT WOS:000356684500004 PM 25778499 ER PT J AU Zareian, M Ciuffo, L Habibi, M Opdahl, A Chamera, EH Wu, CO Bluemke, DA Lima, JAC Venkatesh, BA AF Zareian, Mytra Ciuffo, Luisa Habibi, Mohammadali Opdahl, Anders Chamera, Elzbieta H. Wu, Colin O. Bluemke, David A. Lima, Joao A. C. Venkatesh, Bharath Ambale TI Left atrial structure and functional quantitation using cardiovascular magnetic resonance and multimodality tissue tracking: validation and reproducibility assessment SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Left atrial function; Tissue tracking; Left atrial strain; Reproducibility; Cardiovascular magnetic resonance ID BIPLANE AREA-LENGTH; HEART-FAILURE; CARDIAC MRI; STRAIN; VOLUME; SIZE; ECHOCARDIOGRAPHY; QUANTIFICATION; ASSOCIATION; RELIABILITY AB Background: Left atrium (LA) strain, volume and function are important markers of cardiovascular disease and myocardial impairment. We aimed to assess the accuracy of LA biplane volume and function measured by Multimodality Tissue Tracking (MTT). Also we assessed the inter-study reproducibility for cardiovascular magnetic resonance (CMR) derived LA volume and function parameters. Methods: Thirty subjects (mean age: 71.3 +/- 8.7, 87 % male) including twenty subjects with cardiovascular events and ten healthy subjects, with CMR were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA). LA volumes were computed by the modified biplane method from 2- and 4-chamber projections and the Simpson's method from short-axis slices using both methods - manual and semi-automated delineation using MTT. LA total, active and passive ejection fractions were calculated. Pearson's correlation and Bland-Altman analysis were used to compare the measurements. In a second sample of 25 subjects (age: 65.7 +/- 7.1, 72 % males) inter study, intra and inter reader reliability analysis was performed. The intra-class correlation coefficient (ICC) was evaluated. Results: Left atrial MTT structural and functional parameters were not different from manual delineation, yet image analysis was only half as time consuming on average with MTT. Maximal volume MTT was not different between the Simpson's and Biplane methods, functional parameters, however were different. MTT allowed us to measure multiple LA parameters with good-excellent (ICC; 0.88-0.98, p < 0.001) intra-and inter reader reproducibility and fair-good (ICC; 0.44-0.82, p < 0.05-0.001) inter study reproducibility. Conclusions: MTT derived LA biplane volume and function is accurate and reproducible and is suited for use in longitudinal studies. C1 [Zareian, Mytra; Ciuffo, Luisa; Habibi, Mohammadali; Chamera, Elzbieta H.; Lima, Joao A. C.; Venkatesh, Bharath Ambale] Johns Hopkins Univ, Radiol, Baltimore, MD 21287 USA. [Opdahl, Anders] Oslo Univ Hosp, N-0450 Oslo, Norway. [Opdahl, Anders] Univ Oslo, Oslo, Norway. [Wu, Colin O.; Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Venkatesh, BA (reprint author), Johns Hopkins Univ, Radiol, MR 110, Baltimore, MD 21287 USA. EM bambale1@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-TR-000040, UL1-TR-001079] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at HTTP://WWW.MESA-NHLBI.ORG. NR 28 TC 6 Z9 6 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUL 1 PY 2015 VL 17 AR 52 DI 10.1186/s12968-015-0152-y PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CL9QT UT WOS:000357313900001 PM 26126732 ER PT J AU Solon-Biet, SM Mitchell, SJ de Cabo, R Raubenheimer, D Le Couteur, DG Simpson, SJ AF Solon-Biet, Samantha M. Mitchell, Sarah J. de Cabo, Rafael Raubenheimer, David Le Couteur, David G. Simpson, Stephen J. TI Macronutrients and caloric intake in health and longevity SO JOURNAL OF ENDOCRINOLOGY LA English DT Review DE calories; macronutrients; health; lifespan; longevity ID LIFE-SPAN EXTENSION; GENETICALLY HETEROGENEOUS MICE; NUTRIENT-SENSING MECHANISMS; REGULATES ENERGY-METABOLISM; SMALL-MOLECULE ACTIVATORS; CHAIN AMINO-ACIDS; GROWTH-FACTOR 21; DIETARY RESTRICTION; RHESUS-MONKEYS; METHIONINE RESTRICTION AB Both lifespan and healthspan are influenced by nutrition, with nutritional interventions proving to be robust across a wide range of species. However, the relationship between nutrition, health and aging is still not fully understood. Caloric restriction is the most studied dietary intervention known to extend life in many organisms, but recently the balance of macronutrients has been shown to play a critical role. In this review, we discuss the current understanding regarding the impact of calories and macronutrient balance in mammalian health and longevity, and highlight the key nutrient-sensing pathways that mediate the effects of nutrition on health and ageing. C1 [Solon-Biet, Samantha M.; Raubenheimer, David; Le Couteur, David G.; Simpson, Stephen J.] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Solon-Biet, Samantha M.; Le Couteur, David G.] Univ Sydney, Concord Hosp, Ctr Educ & Res Ageing, ANZAC Res Inst & Ageing, Sydney, NSW 2006, Australia. [Solon-Biet, Samantha M.; Le Couteur, David G.] Univ Sydney, Concord Hosp, Ctr Educ & Res Ageing, Alzheimers Inst, Sydney, NSW 2006, Australia. [Solon-Biet, Samantha M.; Raubenheimer, David; Simpson, Stephen J.] Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Raubenheimer, David] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. RP Solon-Biet, SM (reprint author), Univ Sydney, Charles Perkins Ctr, Bldg D17, Sydney, NSW 2006, Australia. EM samantha.solon-biet@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Simpson, Stephen J./0000-0003-0256-7687; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This review was, in part, supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 131 TC 21 Z9 23 U1 35 U2 72 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD JUL PY 2015 VL 226 IS 1 BP R17 EP R28 DI 10.1530/JOE-15-0173 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CM3IE UT WOS:000357574600002 PM 26021555 ER PT J AU Gbadegesin, RA Adeyemo, A Webb, NJA Greenbaum, LA Abeyagunawardena, A Thalgahagoda, S Kale, A Gipson, D Srivastava, T Lin, JJ Chand, D Hunley, TE Brophy, PD Bagga, A Sinha, A Rheault, MN Ghali, J Nicholls, K Abraham, E Janjua, HS Omoloja, A Barletta, GM Cai, Y Milford, DD O'Brien, C Awan, A Belostotsky, V Smoyer, WE Homstad, A Hall, G Wu, GH Nagaraj, S Wigfall, D Foreman, J Winn, MP AF Gbadegesin, Rasheed A. Adeyemo, Adebowale Webb, Nicholas J. A. Greenbaum, Larry A. Abeyagunawardena, Asiri Thalgahagoda, Shenal Kale, Arundhati Gipson, Debbie Srivastava, Tarak Lin, Jen-Jar Chand, Deepa Hunley, Tracy E. Brophy, Patrick D. Bagga, Arvind Sinha, Aditi Rheault, Michelle N. Ghali, Joanna Nicholls, Kathy Abraham, Elizabeth Janjua, Halima S. Omoloja, Abiodun Barletta, Gina-Marie Cai, Yi Milford, David D. O'Brien, Catherine Awan, Atif Belostotsky, Vladimir Smoyer, William E. Homstad, Alison Hall, Gentzon Wu, Guanghong Nagaraj, Shashi Wigfall, Delbert Foreman, John Winn, Michelle P. CA Mid-West Pediat Nephrology Consort TI HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article DE children; nephrotic syndrome; genetic renal disease; glomerular disease ID GENOME-WIDE ASSOCIATION; AFRICAN-AMERICANS; DISEASE; CHILDREN; RARE; VARIANTS; COMMON; IMMUNODEFICIENCY; AUTOIMMUNITY; METAANALYSIS AB Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68x10(-6) (Fisher exact test). Two of these SNPsthe missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42x10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825x10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS. C1 [Gbadegesin, Rasheed A.; Homstad, Alison; Nagaraj, Shashi; Wigfall, Delbert; Foreman, John] Duke Univ Med Ctr, Div Nephrol & Ctr Human Genet, Dept Pediat, Durham, NC USA. [Gbadegesin, Rasheed A.; Homstad, Alison; Nagaraj, Shashi; Wigfall, Delbert; Foreman, John] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Srivastava, Tarak] Univ Manchester, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, Dept Pediat Nephrol, Manchester, Lancs, England. [Srivastava, Tarak] Univ Manchester, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, NIHR Wellcome Trust Childrens Clin Res Facil, Manchester, Lancs, England. [Greenbaum, Larry A.] Emory Univ, Sch Med, Div Pediat Nephrol, Atlanta, GA 30322 USA. [Greenbaum, Larry A.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Abeyagunawardena, Asiri; Thalgahagoda, Shenal] Univ Peradeniya, Dept Pediat, Peradeniya, Sri Lanka. [Kale, Arundhati] Baylor Coll Med, Div Nephrol, Houston, TX 77030 USA. [Kale, Arundhati] Texas Childrens Hosp, Houston, TX 77030 USA. [Gipson, Debbie] Univ Michigan, Dept Pediat, Div Nephrol, Ann Arbor, MI 48109 USA. [Webb, Nicholas J. A.] Childrens Mercy Hosp, Div Nephrol, Kansas City, MO 64108 USA. [Lin, Jen-Jar] Wake Forest Univ, Baptist Med Ctr, Div Nephrol, Dept Pediat, Winston Salem, NC 27109 USA. [Chand, Deepa] Rush Univ, Dept Pediat, Div Nephrol, Chicago, IL 60612 USA. [Hunley, Tracy E.; Janjua, Halima S.] Vanderbilt Univ, Dept Pediat, Div Nephrol, Nashville, TN USA. [Brophy, Patrick D.] Univ Iowa, Dept Pediat, Div Nephrol, Iowa City, IA 52242 USA. [Bagga, Arvind; Sinha, Aditi] All India Inst Med Sci, Dept Pediat, Div Nephrol, New Delhi, India. [Rheault, Michelle N.] Univ Minnesota, Dept Pediat, Div Nephrol, Amplatz Childrens Hosp, Minneapolis, MN 55455 USA. [Ghali, Joanna; Nicholls, Kathy] Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic 3050, Australia. [Abraham, Elizabeth] St Louis Univ, Div Nephrol, Dept Pediat, St Louis, MO 63103 USA. [Janjua, Halima S.] Cleveland Clin, Ctr Pediat Nephrol, Inst Pediat, Cleveland, OH 44106 USA. [Omoloja, Abiodun] Dayton Childrens Hosp, Div Nephrol, Dayton, OH USA. [Barletta, Gina-Marie] Phoenix Childrens Hosp, Div Nephrol, Phoenix, AZ USA. [Cai, Yi] Helen Devos Childrens Hosp, Div Nephrol, Grand Rapids, MI USA. [Milford, David D.; O'Brien, Catherine] Birmingham Childrens Hosp, Birmingham, W Midlands, England. [Awan, Atif] Childrens Univ Hosp, Div Nephrol, Dublin, Ireland. [Belostotsky, Vladimir] Leeds Teaching Hosp, Div Nephrol, Dept Pediat, Leeds, W Yorkshire, England. [Smoyer, William E.] Nationwide Childrens Hosp, Ctr Clin & Translat Res, Res Inst, Columbus, OH USA. [Hall, Gentzon; Wu, Guanghong; Winn, Michelle P.] Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA. [Hall, Gentzon; Wu, Guanghong; Winn, Michelle P.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA. RP Gbadegesin, RA (reprint author), Duke Univ, Med Ctr, Div Nephrol, Dept Pediat, T Level RM0909 CHC,Box 3959, Durham, NC 27710 USA. EM rasheed.gbadegesin@duke.edu; adeyemoa@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU Doris Duke Charitable Foundation; Doris Duke Clinical Scientist Development Award; National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) [K08-DK082495-05]; P&F grant from Duke O'Brien Center for Kidney research - NIH NIDDK [P30-DK096493]; Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH); Office of the Director, NIDDK; National Human Genome Research Institute at the NIH [Z01-HG200362] FX This work was supported by the Doris Duke Charitable Foundation. R.G. is the recipient of a Doris Duke Clinical Scientist Development Award and National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) K08-DK082495-05 award. R.G. is also the recipient of a P&F grant from Duke O'Brien Center for Kidney research supported by NIH NIDDK P30-DK096493 award. A.A. is supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by funds from the Office of the Director, NIDDK and National Human Genome Research Institute at the NIH (Z01-HG200362). The funding sources have no role in the writing of the manuscript or the decision to submit it for publication. NR 35 TC 14 Z9 14 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2015 VL 26 IS 7 BP 1701 EP 1710 DI 10.1681/ASN.2014030247 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CM0UE UT WOS:000357393300024 PM 25349203 ER PT J AU Muller, L Kailas, A Jackson, SN Roux, A Barbacci, DC Schultz, JA Balaban, CD Woods, AS AF Muller, Ludovic Kailas, Ajay Jackson, Shelley N. Roux, Aurelie Barbacci, Damon C. Schultz, J. Albert Balaban, Carey D. Woods, Amina S. TI Lipid imaging within the normal rat kidney using silver nanoparticles by matrix-assisted laser desorption/ionization mass spectrometry SO KIDNEY INTERNATIONAL LA English DT Article DE ceramides; kidney lipids; MALDI mass spectrometric imaging (MALDI-MSI); mass spectrometry; silver nanoparticle matrix; tissue implantation ID BRAIN-TISSUE; DESORPTION IONIZATION; MALDI-MS; REVEALS; SECTIONS; PROTEINS; DISEASE; TOFMS AB The well-characterized cellular and structural components of the kidney show distinct regional compositions and distribution of lipids. In order to more fully analyze the renal lipidome we developed a matrix-assisted laser desorption/ionization mass spectrometry approach for imaging that may be used to pinpoint sites of changes from normal in pathological conditions. This was accomplished by implanting sagittal cryostat rat kidney sections with a stable, quantifiable and reproducible uniform layer of silver using a magnetron sputtering source to form silver nanoparticles. Thirty-eight lipid species including seven ceramides, eight diacylglycerols, 22 triacylglycerols, and cholesterol were detected and imaged in positive ion mode. Thirty-six lipid species consisting of seven sphingomyelins, 10 phosphatidylethanolamines, one phosphatidylglycerol, seven phosphatidylinositols, and 11 sulfatides were imaged in negative ion mode for a total of seventy-four high-resolution lipidome maps of the normal kidney. Thus, our approach is a powerful tool not only for studying structural changes in animal models of disease, but also for diagnosing and tracking stages of disease in human kidney tissue biopsies. C1 [Muller, Ludovic; Kailas, Ajay; Jackson, Shelley N.; Roux, Aurelie; Barbacci, Damon C.; Woods, Amina S.] NIDA, Struct Biol Unit, IRP, NIH, Baltimore, MD 21224 USA. [Muller, Ludovic; Balaban, Carey D.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Muller, Ludovic; Balaban, Carey D.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [Muller, Ludovic; Balaban, Carey D.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Barbacci, Damon C.; Schultz, J. Albert] Ionwerks, Houston, TX USA. RP Woods, AS (reprint author), NIDA, Struct Biol Unit, IRP, NIH, 333 Cassell Dr,Room 1120, Baltimore, MD 21224 USA. EM awoods@mail.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, NIH; ARRA through NIDA phase II SBIR grant [1RC3DA031431-01] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors acknowledge Mari Prieto and Glen Gregory of the Thermo Fisher for technical and instrumentation advices. Ionwerks and the University of Pittsburgh gratefully acknowledge ARRA support through NIDA phase II SBIR grant 1RC3DA031431-01. NR 30 TC 13 Z9 13 U1 5 U2 38 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2015 VL 88 IS 1 BP 186 EP 192 DI 10.1038/ki.2015.3 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CL7FN UT WOS:000357138000024 PM 25671768 ER PT J AU Matsushita, K Coresh, J Sang, YY Chalmers, J Fox, C Guallar, E Jafar, T Jassal, SK Landman, GWD Muntner, P Roderick, P Sairenchi, T Schottker, B Shankar, A Shlipak, M Tonelli, M Townend, J van Zuilen, A Yamagishi, K Yamashita, K Gansevoort, R Sarnak, M Warnock, DG Woodward, M Arnlov, J AF Matsushita, Kunihiro Coresh, Josef Sang, Yingying Chalmers, John Fox, Caroline Guallar, Eliseo Jafar, Tazeen Jassal, Simerjot K. Landman, Gijs W. D. Muntner, Paul Roderick, Paul Sairenchi, Toshimi Schoettker, Ben Shankar, Anoop Shlipak, Michael Tonelli, Marcello Townend, Jonathan van Zuilen, Arjan Yamagishi, Kazumasa Yamashita, Kentaro Gansevoort, Ron Sarnak, Mark Warnock, David G. Woodward, Mark Arnlov, Johan CA CKD Prognosis Consortium TI Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; ARTERY-DISEASE; CYSTATIN C; RISK; CREATININE; MORTALITY; HEART; CKD; ASSOCIATION; EQUATION AB Background The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. Methods We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4.2-19.0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. Findings The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0.0139 [95% CI 0.0105- 0.0174] for ACR and 0.0065 [0.0042-0.0088] for eGFR) and heart failure (0.0196 [0.0108-0.0284] and 0.0109 [0.0059-0.0159]) than for coronary disease (0.0048 [0.0029-0.0067] and 0.0036 [0.0019-0.0054]) and stroke (0.0105 [0.0058-0.0151]and 0.0036 [0.0004-0.0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0.0227 (0.0158-0.0296) after omission of eGFR and ACR compared with less than 0.007 for any single modifiable traditional predictor. Interpretation Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. C1 [Matsushita, Kunihiro; Coresh, Josef; Sang, Yingying; Guallar, Eliseo; Woodward, Mark] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Chalmers, John; Woodward, Mark] Univ Sydney, George Inst Global Hlth, Sydney, NSW 2006, Australia. [Fox, Caroline] NHLBI, Framingham Heart Study & Ctr Populat Studies, Framingham, MA USA. [Jafar, Tazeen] Duke NUS Grad Med Sch, Singapore, Singapore. [Jassal, Simerjot K.] VA San Diego Healthcare, San Diego, CA USA. [Jassal, Simerjot K.] Univ Calif San Diego, San Diego, CA 92103 USA. [Landman, Gijs W. D.] Isala Hosp, Diabet Ctr Zwolle, Zwolle, Netherlands. [Muntner, Paul; Warnock, David G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Roderick, Paul] Univ Southampton, Fac Med, Primary Care & Populat Sci, Southampton SO9 5NH, Hants, England. [Sairenchi, Toshimi] Dokkyo Med Univ, Sch Med, Dept Publ Hlth, Shimotsuga, Tochigi, Japan. [Schoettker, Ben] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Shlipak, Michael] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Div Gen Internal Med, San Francisco, CA 94143 USA. [Shlipak, Michael] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tonelli, Marcello] Univ Calgary, Dept Med, Calgary, AB, Canada. [Townend, Jonathan] Queen Elizabeth Hosp, Dept Cardiol, Birmingham B15 2TH, W Midlands, England. [van Zuilen, Arjan] Univ Utrecht, Med Ctr, Dept Hypertens & Nephrol, Utrecht, Netherlands. [Yamagishi, Kazumasa] Univ Tsukuba, Fac Med, Dept Publ Hlth Med, Tsukuba, Ibaraki, Japan. [Yamashita, Kentaro] Nagoya Univ, Grad Sch Med, Dept Cardiol, Nagoya, Aichi 4648601, Japan. [Gansevoort, Ron] Univ Groningen, Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands. [Sarnak, Mark] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Woodward, Mark] Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England. [Arnlov, Johan] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden. RP Coresh, J (reprint author), Data Coordinating Ctr, Chron Kidney Dis Prognosis Consortium, Baltimore, MD 21205 USA. EM ckdpc@jhmi.edu RI Stengel, Benedicte/G-5730-2015; Wetzels, Jack/A-1720-2014; Woodward, Mark/D-8492-2015; Brenner, Hermann/B-4627-2017; Moyes, Simon/D-2574-2017; Tonelli, Marcello/B-3028-2009 OI Brenner, Hermann/0000-0002-6129-1572; Moyes, Simon/0000-0001-9580-1545; Emberson, Jonathan/0000-0001-7792-9422; Grams, Morgan/0000-0002-4430-6023; Kenealy, Timothy/0000-0001-6002-4766; yamagishi, kazumasa/0000-0003-3301-5519; FU US National Kidney Foundation; National Institute of Diabetes and Digestive and Kidney Diseases FX US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases. NR 33 TC 56 Z9 57 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUL PY 2015 VL 3 IS 7 BP 514 EP 525 DI 10.1016/S2213-8587(15)00040-6 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CM1DC UT WOS:000357419500027 PM 26028594 ER PT J AU Wong, HKA El Fatimy, R Onodera, C Wei, ZY Yi, M Mohan, A Gowrisankaran, S Karmali, P Marcussont, E Wakimoto, H Stephens, R Uhlmann, EJ Song, JS Tannous, B Krichevsky, AM AF Wong, Hon-Kit Andus El Fatimy, Rachid Onodera, Courtney Wei, Zhiyun Yi, Ming Mohan, Athul Gowrisankaran, Sindhuja Karmali, Priya Marcussont, Eric Wakimoto, Hiroaki Stephens, Robert Uhlmann, Erik J. Song, Jun S. Tannous, Bakhos Krichevsky, Anna M. TI The Cancer Genome Atlas Analysis Predicts MicroRNA for Targeting Cancer Growth and Vascularization in Glioblastoma SO MOLECULAR THERAPY LA English DT Article ID HYPOXIA-INDUCIBLE FACTORS; TUMOR-INITIATING CELLS; STEM-CELLS; ENDOTHELIAL-CELLS; IN-VIVO; GLIOMA; NOTCH; PATHWAY; MAINTENANCE; INHIBITION AB Using in silico analysis of The Cancer Genome Atlas (TCGA), we identified microRNAs associated with glioblastoma (GBM) survival, and predicted their functions in glioma growth and progression. Inhibition of two "risky" miRNAs, miR-148a and miR-31, in orthotopic xenograft GBM mouse models suppressed tumor growth and thereby prolonged animal survival. Intracranial tumors treated with uncomplexed miR-148a and miR-31 antagomirs exhibited reduced proliferation, stem cell depletion, and normalized tumor vasculature. Growth-promoting functions of these two nniRNAs were, in part, mediated by the common target, the factor inhibiting hypoxia-inducible factor 1 (FIH1), and the downstream pathways involving hypoxia-inducible factor HIF1 alpha and Notch signaling. Therefore, miR-31 and miR-148a regulate glioma growth by maintaining tumor stem cells and their niche, and providing the tumor a way to activate angiogenesis even in a normoxic environment. This is the first study that demonstrates intratumoral uptake and growth-inhibiting effects of unconnplexed antagomirs in orthotopic glioma. C1 [Wong, Hon-Kit Andus; El Fatimy, Rachid; Wei, Zhiyun; Mohan, Athul; Gowrisankaran, Sindhuja; Uhlmann, Erik J.; Krichevsky, Anna M.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Wong, Hon-Kit Andus; El Fatimy, Rachid; Wei, Zhiyun; Mohan, Athul; Gowrisankaran, Sindhuja; Uhlmann, Erik J.; Krichevsky, Anna M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Onodera, Courtney; Song, Jun S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yi, Ming; Stephens, Robert] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res & Technol Program, Frederick, MD USA. [Karmali, Priya; Marcussont, Eric] Regulus Therapeut Inc, San Diego, CA USA. [Wakimoto, Hiroaki] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Tannous, Bakhos] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Tannous, Bakhos] Harvard Univ, Sch Med, Charlestown, MA USA. RP Krichevsky, AM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Neurol,Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA. EM akrichevsky@rics.bwh.harvard.edu RI Wei, Zhiyun/E-2008-2016 OI Wei, Zhiyun/0000-0002-3554-4142 FU NIH/NCI [R01CA138734, R01CA163336]; Sontag Foundation Distinguished Scientist Award; National Brain Tumor Society; Brain Science Foundation FX This work was supported by grants from NIH/NCI (R01CA138734), Sontag Foundation Distinguished Scientist Award, National Brain Tumor Society, and Brain Science Foundation to AMK, and NIH/NCI R01CA163336 and Sontag Foundation Distinguished Scientist Award to J.S.S. We thank Regulus Therapeutics, Inc. for providing us with specific antagomirs. There is no potential conflict of interest NR 51 TC 13 Z9 14 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JUL PY 2015 VL 23 IS 7 BP 1234 EP 1247 DI 10.1038/mt.2015.72 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CM0FY UT WOS:000357355000013 PM 25903473 ER PT J AU Burotto, M Edgerly, M Poruchynsky, M Velarde, M Wilkerson, J Kotz, H Bates, S Balasubramaniam, S Fojo, T AF Burotto, Mauricio Edgerly, Maureen Poruchynsky, Marianne Velarde, Margarita Wilkerson, Julia Kotz, Herb Bates, Susan Balasubramaniam, Sanjeeve Fojo, Tito TI Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma SO ONCOLOGIST LA English DT Article ID RENAL-CELL CARCINOMA; EPOTHILONE-B ANALOG; RADIATION RECALL; PACLITAXEL; BMS-247550; CANCER AB Background. Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC. Methods. Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. Results. In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naive, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. Conclusion. Ixabepilone was well tolerated but showed very modest activity in second-or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC. C1 [Burotto, Mauricio; Edgerly, Maureen; Poruchynsky, Marianne; Velarde, Margarita; Wilkerson, Julia; Kotz, Herb; Bates, Susan; Fojo, Tito] NCI, NIH, Bethesda, MD 20892 USA. [Balasubramaniam, Sanjeeve] Food & Drug Adm, Silver Spring, MD USA. RP Burotto, M (reprint author), NCI, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM mburotto@alemana.cl OI Wilkerson, Julia/0000-0002-6965-0867; Balasubramaniam, Sanjeeve/0000-0002-0643-2117 FU Cancer Therapy Evaluation Program (CTEP) FX Cancer Therapy Evaluation Program (CTEP) NR 13 TC 1 Z9 1 U1 0 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD JUL PY 2015 VL 20 IS 7 BP 725 EP 726 DI 10.1634/theoncologist.2015-0104 PG 2 WC Oncology SC Oncology GA CL9DK UT WOS:000357275500008 PM 26040622 ER PT J AU Yeung, EH McLain, AC Anderson, N Lawrence, D Boghossian, NS Druschel, C Bell, E AF Yeung, Edwina H. McLain, Alexander C. Anderson, Nancy Lawrence, David Boghossian, Nansi S. Druschel, Charlotte Bell, Erin TI Newborn Adipokines and Birth Outcomes SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE adiponectin; leptin; newborn dried blood spots; preterm birth; twins; birth weight ID DRIED BLOOD SPOTS; CORD BLOOD; ADIPONECTIN LEVELS; INTRAUTERINE GROWTH; DIABETIC MOTHERS; RESISTIN LEVELS; TERM NEWBORNS; LEPTIN LEVELS; WEIGHT; SERUM AB BackgroundAdipokines can serve as a measure of adipose tissue activity. Although birthweight correlates with neonatal adiposity, findings for cord blood levels of adipokines and birth outcomes have been conflicted. Therefore, we determined the cross-sectional associations between adipokines measured in newborn dried blood spots (DBS) and birth outcomes. MethodsThe Upstate KIDS study enrolled mothers and infants from 2008 to 2010. Among infants whose parents consented to the use of residual DBS from newborn screening, 2397 singletons and 1240 twins had adipokine measurements from the Human Obesity Panel (R&D Systems) by Luminex. Odds ratios were estimated by multivariable logistic regression for risk of birth outcomes of preterm delivery (<37 weeks for singletons, <32 for twins) and small-for-gestational age (SGA <10th for singletons and <3rd for twins age- and sex-specific percentiles) by adipokine quintiles. Generalised estimating equations were applied to account for correlations between twins. ResultsSingletons in the lowest compared with the highest quintile of adiponectin were more likely preterm (adjusted odds ratio 3.26; 95% confidence interval [CI] 1.99, 5.34) and SGA (1.81; [95% CI 1.18, 2.77]). Similar associations were observed among twins. Resistin was associated with preterm birth (Q1 vs. Q5: 2.08; [95% CI 1.20, 3.62]) only among singletons. Adipsin had inconsistent associations after adjustment. ConclusionsThis large population-based study demonstrates that newborn DBS-measured adipokines are associated with birth outcomes, particularly preterm birth and SGA among those with lower adiponectin levels regardless of plurality. C1 [Yeung, Edwina H.; McLain, Alexander C.; Boghossian, Nansi S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [McLain, Alexander C.; Boghossian, Nansi S.] Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC USA. [Anderson, Nancy; Lawrence, David] New York State Dept Hlth, Ctr Med Sci, Wadsworth Ctr, Immunol Lab, Albany, NY USA. [Druschel, Charlotte] New York State Dept Hlth, Bur Environm & Occupat Epidemiol, Ctr Environm Hlth, Albany, NY USA. [Bell, Erin] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY USA. [Bell, Erin] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM yeungedw@mail.nih.gov RI Yeung, Edwina/F-5992-2015 OI Yeung, Edwina/0000-0002-3851-2613 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200005C, HHSN267200700019C] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C). The authors thank all the Upstate KIDS families and staff for their important contributions. NR 35 TC 6 Z9 6 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2015 VL 29 IS 4 BP 317 EP 325 DI 10.1111/ppe.12203 PG 9 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA CL3TZ UT WOS:000356874800007 PM 26111443 ER PT J AU Paltiel, O Tikellis, G Linet, M Golding, J Lemeshow, S Phillips, G Lamb, K Stoltenberg, C Haberg, SE Strom, M Granstrom, C Northstone, K Klebanoff, M Ponsonby, AL Milne, E Pedersen, M Kogevinas, M Ha, E Dwyer, T AF Paltiel, Ora Tikellis, Gabriella Linet, Martha Golding, Jean Lemeshow, Stanley Phillips, Gary Lamb, Karen Stoltenberg, Camilla Haberg, Siri E. Strom, Marin Granstrom, Charlotta Northstone, Kate Klebanoff, Mark Ponsonby, Anne-Louise Milne, Elizabeth Pedersen, Marie Kogevinas, Manolis Ha, Eunhee Dwyer, Terence CA Int Childhood Canc Cohort Consorti TI Birthweight and Childhood Cancer: Preliminary Findings from the International Childhood Cancer Cohort Consortium (I4C) SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Childhood cancer; leukemia; cohort studies; pooled analysis ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BODY-MASS INDEX; FETAL-GROWTH; GESTATIONAL-AGE; RISK-FACTORS; PREGNANCY; CHILDREN; GAIN; ASSOCIATIONS; METAANALYSIS AB BackgroundEvidence relating childhood cancer to high birthweight is derived primarily from registry and case-control studies. We aimed to investigate this association, exploring the potential modifying roles of age at diagnosis and maternal anthropometrics, using prospectively collected data from the International Childhood Cancer Cohort Consortium. MethodsWe pooled data on infant and parental characteristics and cancer incidence from six geographically and temporally diverse member cohorts [the Avon Longitudinal Study of Parents and Children (UK), the Collaborative Perinatal Project (USA), the Danish National Birth Cohort (Denmark), the Jerusalem Perinatal Study (Israel), the Norwegian Mother and Child Cohort Study (Norway), and the Tasmanian Infant Health Survey (Australia)]. Birthweight metrics included a continuous measure, deciles, and categories (4.0 vs. <4.0 kilogram). Childhood cancer (377 cases diagnosed prior to age 15 years) risk was analysed by type (all sites, leukaemia, acute lymphoblastic leukaemia, and non-leukaemia) and age at diagnosis. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models stratified by cohort. ResultsA linear relationship was noted for each kilogram increment in birthweight adjusted for gender and gestational age for all cancers [HR=1.26; 95% CI 1.02, 1.54]. Similar trends were observed for leukaemia. There were no significant interactions with maternal pre-pregnancy overweight or pregnancy weight gain. Birthweight 4.0kg was associated with non-leukaemia cancer among children diagnosed at age 3 years [HR=1.62; 95% CI 1.06, 2.46], but not at younger ages [HR=0.7; 95% CI 0.45, 1.24, P for difference=0.02]. ConclusionChildhood cancer incidence rises with increasing birthweight. In older children, cancers other than leukaemia are particularly related to high birthweight. Maternal adiposity, currently widespread, was not demonstrated to substantially modify these associations. Common factors underlying foetal growth and carcinogenesis need to be further explored. C1 [Paltiel, Ora] Hadassah Hebrew Univ, Dept Hematol, IL-91120 Jerusalem, Israel. [Paltiel, Ora] Hadassah Hebrew Univ, Braun Sch Publ Hlth, IL-91120 Jerusalem, Israel. [Tikellis, Gabriella; Ponsonby, Anne-Louise; Dwyer, Terence] Univ Melbourne, Royal Childrens Hosp, Dept Environm & Genet Epidemiol, Murdoch Childrens Res Inst, Melbourne, Vic 3010, Australia. [Lamb, Karen] Deakin Univ, Ctr Phys Act & Nutr, Burwood, Vic, Australia. [Ponsonby, Anne-Louise; Dwyer, Terence] Univ Tasmania, Menzies Res Inst, Hobart, Tas, Australia. [Milne, Elizabeth] Univ Western Australia, Telethon Kids Inst, Perth, WA 6009, Australia. [Linet, Martha] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lemeshow, Stanley; Klebanoff, Mark] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. [Phillips, Gary] Ohio State Univ, Div Biostat, Ctr Biostat, Columbus, OH 43210 USA. [Klebanoff, Mark] Ohio State Univ, Coll Med, Res Inst, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Golding, Jean] Univ Bristol, Ctr Child & Adolescent Hlth, Sch Social & Community Med, Bristol, Avon, England. [Northstone, Kate] Univ Bristol, Sch Social & Community Med, ALSPAC Children 90s, Bristol, Avon, England. [Stoltenberg, Camilla; Haberg, Siri E.] Norwegian Inst Publ Hlth, Oslo, Norway. [Stoltenberg, Camilla] Univ Bergen, Dept Global Publ Hlth & Community Care, Bergen, Norway. [Strom, Marin; Granstrom, Charlotta] Statenserum Inst, Ctr Fetal Programming, Dept Epidemiol Res, Copenhagen, Denmark. [Pedersen, Marie; Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Pedersen, Marie] Univ Pompeu Fabra, Barcelona, Spain. [Pedersen, Marie; Kogevinas, Manolis] Hosp del Mar, Res Inst, IMIM, Barcelona, Spain. [Pedersen, Marie; Kogevinas, Manolis] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Pedersen, Marie] Natl Inst Hlth & Med Res, INSERM, Team Environm Epidemiol Appl Reprod & Resp Hlth, Albert Bonniot,U823, Grenoble, France. [Dwyer, Terence] Int Agcy Res Canc, F-69372 Lyon, France. [Kogevinas, Manolis] Natl Sch Publ Hlth, Dept Nutr, Athens, Greece. [Ha, Eunhee] Ewha Womans Univ, Dept Prevent Med, Sch Med, Ewha Med Res Ctr, Seoul, South Korea. RP Paltiel, O (reprint author), Hadassah Hebrew Univ, Dept Hematol, POB 12000, IL-91120 Jerusalem, Israel. EM orap@hadassah.org.il RI Milne, Elizabeth/E-5349-2012; Lamb, Karen/P-4988-2016; Kogevinas, Manolis/C-3918-2017; OI Lamb, Karen/0000-0001-9782-8450; Golding, Jean/0000-0003-2826-3307; Pedersen, Marie/0000-0002-9930-0446 FU NIH (NCI, NICHD) USA; National Children's Study - USA; Childrens Cancer Centre Foundation - Australia; Bluey Day Foundation - Australia; Baxter Family Foundation - Australia; Rotary Club of North Brighton - Australia; Tour de Cure - Australia; Private philanthropic donations - Australia; Murdoch Children's Research Institution, Australia [M1300049]; UK Medical Research Council; Wellcome Trust [092731]; University of Bristol FX This work was supported by: NIH (NCI, NICHD) USA; National Children's Study - USA; the Childrens Cancer Centre Foundation - Australia; Bluey Day Foundation - Australia; Baxter Family Foundation - Australia; The Rotary Club of North Brighton - Australia; Tour de Cure - Australia; Private philanthropic donations - Australia; and Murdoch Children's Research Institution (M1300049), Australia. The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. The Maria Ascoli Foundation, Jerusalem, Israel, provided support for data pooling of the JPS. NR 40 TC 5 Z9 5 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2015 VL 29 IS 4 BP 335 EP 345 DI 10.1111/ppe.12193 PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA CL3TZ UT WOS:000356874800009 PM 25989709 ER PT J AU Root, DH Melendez, RI Zaborszky, L Napier, TC AF Root, David H. Melendez, Roberto I. Zaborszky, Laszlo Napier, T. Celeste TI The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Nucleus accumbens; Ventral tegmental area; GABA; Dopamine; Glutamate; Addiction ID COCAINE-SEEKING BEHAVIOR; MEDIAL PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS SHELL; CONTEXT-INDUCED REINSTATEMENT; CENTRAL-NERVOUS-SYSTEM; ROSTROMEDIAL TEGMENTAL NUCLEUS; BASAL FOREBRAIN NEURONS; RAT FRONTAL-CORTEX; CONDITIONED PLACE PREFERENCE; RECEPTOR MESSENGER-RNA AB The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally relevant stimuli and coherent adaptive behaviors. Published by Elsevier Ltd. C1 [Root, David H.] Rutgers State Univ, Dept Psychol, New Brunswick, NJ 08854 USA. [Melendez, Roberto I.] Univ Puerto Rico, Sch Med, Dept Anat & Neurobiol, San Juan, PR 00936 USA. [Zaborszky, Laszlo] Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. [Napier, T. Celeste] Rush Univ, Med Ctr, Ctr Compuls Behav & Addict, Dept Pharmacol, Chicago, IL 60612 USA. [Napier, T. Celeste] Rush Univ, Med Ctr, Ctr Compuls Behav & Addict, Dept Psychiat, Chicago, IL 60612 USA. RP Root, DH (reprint author), NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM david.root@outlook.com; roberto.melendez2@upr.edu; zaborszky@axon.rutgers.edu; celeste_napier@rush.edu OI Root, David/0000-0002-1927-2175 FU USPHSGs [NS23945, DA05255, DA015760]; National Institute on Drug Abuse; NRSAs [F32 DA05651, F30 MH45180, F31 DA019763, DA019783, DA023306, DA021475, DA024923, DA0331231] FX This review and the included research were supported by the USPHSGs NS23945 (LZ), DA05255 (TCN) and DA015760 (TCN), and the Intramural Research Program at the National Institute on Drug Abuse (DHR). Research support was also provided by NRSAs to trainees in TCN's laboratory including: F32 DA05651 to P Johnson, F30 MH45180 to MS Turner, F31 DA019763 to F Shen, DA019783 to AL Mickiewicz, DA023306 to AA Herrold, DA021475 to RM Voigt, DA024923 to SM Graves and DA0331231 to SE Tedford. Gratitude is extended to each of these trainees for their contribution to VP-related research that is overviewed here. The authors thank Dr. Mark O. West for valuable discussions and mentorship to DHR under DA026252 (DHR) and DA006886 (MOW). The funders had no role in the decision to publish or preparation of the manuscript. The authors thank Dr. Marisela Morales for providing material prepared with in situ hybridization and immunohistochemical techniques. NR 543 TC 23 Z9 23 U1 1 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JUL PY 2015 VL 130 BP 29 EP 70 DI 10.1016/j.pneurobio.2015.03.005 PG 42 WC Neurosciences SC Neurosciences & Neurology GA CL8LR UT WOS:000357226700002 PM 25857550 ER PT J AU Hokland, P Ommen, HB Mule, MP Hourigan, CS AF Hokland, Peter Ommen, Hans B. Mule, Matthew P. Hourigan, Christopher S. TI Advancing the Minimal Residual Disease Concept in Acute Myeloid Leukemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; STEM-CELL TRANSPLANTATION; LONG-TERM REMISSION; POLYMERASE-CHAIN-REACTION; TIME QUANTITATIVE PCR; ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERNAL TANDEM DUPLICATION; CLONAL HEMATOPOIESIS; ADULT PATIENTS; MOLECULAR RELAPSE AB The criteria to evaluate response to treatment in acute myeloid leukemia (AML) have changed little in the past 60 years. It is now possible to use higher sensitivity tools to measure residual disease burden in AML. Such minimal or measurable residual disease (MRD) measurements provide a deeper understanding of current patient status and allow stratification for risk of subsequent clinical relapse. Despite these obvious advantages, and after over a decade of laboratory investigation and preclinical validation, MRD measurements are not currently routinely used for clinical decision-making or drug development in non-acute promyelocytic leukemia (non-APL) AML. We review here some potential constraints that may have delayed adoption, including a natural hesitancy of end users, economic impact concerns, misperceptions regarding the meaning of and need for assay sensitivity, the lack of one single MRD solution for all AML patients, and finally the need to involve patients in decision-making based on such correlates. It is our opinion that none of these issues represent insurmountable barriers and our hope is that by providing potential solutions we can help map a path forward to a future where our patients will be offered personalized treatment plans based on the amount of AML they have left remaining to treat. C1 [Hokland, Peter; Ommen, Hans B.] Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark. [Mule, Matthew P.; Hourigan, Christopher S.] NHLBI, Mycloid Malignancies Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Hourigan, CS (reprint author), Room 6C-103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM hourigan@nih.gov RI Hourigan, Christopher/S-2476-2016; OI Hourigan, Christopher/0000-0002-6189-8067; Hokland, Peter/0000-0002-1177-9756; Ommen, Hans Beier/0000-0001-7628-8694 FU Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health. NR 99 TC 13 Z9 13 U1 3 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2015 VL 52 IS 3 BP 184 EP 192 DI 10.1053/j.seminhematol.2015.04.001 PG 9 WC Hematology SC Hematology GA CM1IF UT WOS:000357433800005 PM 26111465 ER PT J AU Sinha, C Cunningham, LC Liu, PP AF Sinha, Chandrima Cunningham, Lea C. Liu, Paul P. TI Core Binding Factor Acute Myeloid Leukemia: New Prognostic Categories and Therapeutic Opportunities SO SEMINARS IN HEMATOLOGY LA English DT Article ID FRENCH AML INTERGROUP; MYOSIN HEAVY-CHAIN; ACUTE MYELOGENOUS LEUKEMIA; FETAL LIVER HEMATOPOIESIS; MINIMAL RESIDUAL DISEASE; C-KIT MUTATIONS; FACTOR-BETA; GENE-MUTATIONS; FUSION GENE; CBF-BETA AB Core binding factor (CBF) is a heterodimeric protein complex involved in the transcriptional regulation of normal hematopoiesis. Mutations in CBF-encoding genes result in leukemogenic proliferative advantages and impaired differentiation of the hematopoietic progenitors. CBF molecular aberrations are responsible for approximately 20% of all adult acute myeloid leukemia (AML). Although CBF-AMLs are considered to have relatively good prognosis compared to other leukemia subtypes, they are a heterogeneous group of disorders and modern therapy frequently leads to relapse and the associated morbidity and mortality. Improvements in risk stratification and development of targeted therapies are needed for better outcomes. In this review we provide a brief overview of the molecular basis, prognostic categories and the advanced treatment strategies for CBF leukemias. Published by Elsevier Inc. C1 [Sinha, Chandrima; Cunningham, Lea C.] St Jude Childrens Res Hosp, Bone Marrow Transplant & Cellular Therapy, Memphis, TN 38105 USA. [Liu, Paul P.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), 49 Convent Dr,Bldg 49,Room 3A26, Bethesda, MD 20892 USA. EM Lea.Cunningham@STJUDE.ORG; pliu@mail.nih.gov FU St. Jude Children's Research Hospital; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; ALSAC FX Supported by St. Jude Children's Research Hospital, ALSAC and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 76 TC 5 Z9 5 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2015 VL 52 IS 3 BP 215 EP 222 DI 10.1053/j.seminhematol.2015.04.002 PG 8 WC Hematology SC Hematology GA CM1IF UT WOS:000357433800009 PM 26111469 ER PT J AU Kanakry, CG de Lima, MJ Luznik, L AF Kanakry, Christopher G. de Lima, Marcos J. Luznik, Leo TI Alternative Donor Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; UMBILICAL-CORD BLOOD; MATCHED UNRELATED DONORS; ACUTE MYELOGENOUS LEUKEMIA; VERSUS-HOST-DISEASE; RISK ACUTE-LEUKEMIA; HLA CLASS-I; IDENTICAL SIBLING TRANSPLANTATION; 1ST COMPLETE REMISSION; REDUCED-INTENSITY AB Allogeneic hematopoietic cell transplantation (alloHCT) provides a potentially curative therapy for patients with high-risk or chemorefractory acute myeloid leukemia (AML). Historically, the applicability of alloHCT has been limited as only 30%-35% of patients have human leukocyte antigen (HLA)matched siblings and outcomes using other donor types have been markedly inferior due to excess toxicity, graft failure, graft-versus-host disease (GVHD), and consequently non-relapse mortality. Advances in HLA typing, GVHD prophylactic approaches, and other transplantation techniques have successfully addressed these historical challenges. Herein, we review recent alloHCT studies using volunteer unrelated donors, umbilical cord blood units, or HLA-haploidentical donors, specifically focusing on studies that compared outcomes between donor sources. Although none are randomized and most are retrospective, these analyses suggest that current outcomes for AML patients using most alternative donor types are comparable to those seen using HLA-matched siblings. Published by Elsevier Inc. C1 [Kanakry, Christopher G.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [de Lima, Marcos J.] Case Western Reserve Univ, Univ Hosp, Case Med Ctr, Sch Med, Cleveland, OH 44106 USA. [Luznik, Leo] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Kanakry, CG (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr,Room 4-3142,MSC 1203, Bethesda, MD 20892 USA. EM christopher.kanakry@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 81 TC 2 Z9 4 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 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2015 VL 52 IS 3 BP 232 EP 242 DI 10.1053/j.seminhematol.2015.03.005 PG 11 WC Hematology SC Hematology GA CM1IF UT WOS:000357433800011 PM 26111471 ER PT J AU Bailit, JL Grobman, WA McGee, P Reddy, UM Wapner, RJ Varner, MW Thorp, JM Leveno, KJ Iams, JD Tita, ATN Saade, G Sorokin, Y Rouse, DJ Blackwell, SC AF Bailit, Jennifer L. Grobman, William A. McGee, Paula Reddy, Uma M. Wapner, Ronald J. Varner, Michael W. Thorp, John M. Leveno, Kenneth J. Iams, Jay D. Tita, Alan T. N. Saade, George Sorokin, Yoram Rouse, Dwight J. Blackwell, Sean C. TI Does the presence of a condition-specific obstetric protocol lead to detectable improvements in pregnancy outcomes? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE obstetrics; protocols; quality of care ID CARE AB OBJECTIVE: We sought to evaluate whether the presence of condition-specific obstetric protocols within a hospital was associated with better maternal and neonatal outcomes. STUDY DESIGN: This was a cohort study of a random sample of deliveries performed at 25 hospitals over 3 years. Condition-specific protocols were collected from all hospitals and categorized independently by 2 authors. Data on maternal and neonatal outcomes, as well as data necessary for risk adjustment were collected. Risk-adjusted outcomes were compared according to whether the patient delivered in a hospital with condition-specific obstetric protocols at the time of delivery. RESULTS: Hemorrhage-specific protocols were not associated with a lower rate of postpartum hemorrhage or with fewer cases of estimated blood loss > 1000 mL. Similarly, in the presence of a shoulder dystocia protocol, there were no differences in the frequency of shoulder dystocia or number of shoulder dystocia maneuvers used. Conversely, preeclampsia-specific protocols were associated with fewer intensive care unit admissions (odds ratio, 0.28; 95% confidence interval, 0.18-0.44) and fewer cases of severe maternal hypertension (odds ratio, 0.86; 95% confidence interval, 0.77-0.96). CONCLUSION: The presence of condition-specific obstetric protocols was not consistently shown to be associated with improved risk-adjusted outcomes. Our study would suggest that the presence or absence of a protocol does not matter and regulations to require protocols are not fruitful. C1 [Bailit, Jennifer L.] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet, Cleveland, OH 44106 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Gynecol, Cleveland, OH 44106 USA. [Iams, Jay D.] Ohio State Univ, Columbus, OH 43210 USA. [Grobman, William A.] Northwestern Univ, Prentice Womens Hosp, Chicago, IL 60611 USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Thorp, John M.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Blackwell, Sean C.] Univ Texas Houston, Hlth Sci Ctr, Childrens Mem Hermann Hosp, Houston, TX USA. [Tita, Alan T. N.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Detroit, MI USA. [Rouse, Dwight J.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [McGee, Paula] George Washington Univ, Ctr Biostat, Washington, DC USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bailit, JL (reprint author), Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet, Cleveland, OH 44106 USA. EM jbailit@metrohealth.org RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources [UL1 RR024989, 5UL1 RR025764] FX This study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118) and the National Center for Research Resources (UL1 RR024989; 5UL1 RR025764). NR 13 TC 5 Z9 5 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2015 VL 213 IS 1 AR 86.e1 DI 10.1016/j.ajog.2015.01.055 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CL3FQ UT WOS:000356836200027 PM 25659468 ER PT J AU Okamoto, K Honda, K Doi, K Ishizu, T Katagiri, D Wada, T Tomita, K Ohtake, T Kaneko, T Kobayashi, S Nangaku, M Tokunaga, K Noiri, E AF Okamoto, Koji Honda, Kenjiro Doi, Kent Ishizu, Tomoko Katagiri, Daisuke Wada, Takehiko Tomita, Kenji Ohtake, Takayasu Kaneko, Toyoji Kobayashi, Shuzo Nangaku, Masaomi Tokunaga, Katsushi Noiri, Eisei TI Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; GLOMERULAR MESANGIAL CELLS; EPITHELIAL-CELLS; EXTRACELLULAR-MATRIX; RAT-KIDNEY; PROLIFERATION; NEPHROPATHY; EXPRESSION; INVITRO; MICE AB Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genome-wide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial. cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy. C1 [Okamoto, Koji; Honda, Kenjiro; Doi, Kent; Ishizu, Tomoko; Katagiri, Daisuke; Wada, Takehiko; Nangaku, Masaomi; Noiri, Eisei] Univ Hosp, Dept Nephrol Endocrinol Hemodialysis & Apheresis, Tokyo, Japan. [Okamoto, Koji; Tokunaga, Katsushi] Univ Tokyo, Dept Human Genet, Grad Sch Med, Tokyo 1138655, Japan. [Kaneko, Toyoji] Univ Tokyo, Adv Technol Ctr, Grad Sch Agr & Life Sci, Tokyo 1138655, Japan. [Okamoto, Koji; Tomita, Kenji] Natl Inst Diabet & Digest & Kidney Dis, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD USA. [Ohtake, Takayasu; Kobayashi, Shuzo] Shonan Kamakura Gen Hosp, Dept Nephrol Immunol & Vasc Med, Kamakura, Kanagawa, Japan. RP Noiri, E (reprint author), Univ Tokyo, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM noiri-tky@umin.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology [221S0002]; Adaptable and Seamless Technology Transfer Program through Target-Driven R&D from Japan Science and Technology Agency grant [AS2617903Q]; Japan Society for the Promotion of Science [15K09245]; Japan Society for the Promotion of Science; intramural research programs of the National Institute for Diabetes, Digestive, and Kidney Diseases [ZO-1 DK043308]; Science and Technology Research Partnership for Sustainable Development, Japan Science and Technology Agency/Japan International Cooperation Agency (Tokyo, Japan) grant [10000284] FX Supported by Grants-in-Aid for Scientific Research on the Priority Areas of Comprehensive Genomics 221S0002 (K.Tok.) and Tailor-made Medical Treatment Program (M.N. and E.N.) from the Ministry of Education, Culture, Sports, Science, and Technology; Adaptable and Seamless Technology Transfer Program through Target-Driven R&D from Japan Science and Technology Agency grant AS2617903Q (E.N.); and Grant-in-Aid for Scientific Research (B) 15K09245, Japan Society for the Promotion of Science (E.N.). K.O. received a 2012 Postdoctoral Fellowship for Research Abroad funded by the Japan Society for the Promotion of Science and is supported intramural research programs of the National Institute for Diabetes, Digestive, and Kidney Diseases (ZO-1 DK043308). E.N. is a leading researcher of the Science and Technology Research Partnership for Sustainable Development, Japan Science and Technology Agency/Japan International Cooperation Agency (Tokyo, Japan) grant 10000284. NR 36 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2015 VL 185 IS 7 BP 1889 EP 1898 DI 10.1016/j.ajpath.2015.03.025 PG 10 WC Pathology SC Pathology GA CL5KA UT WOS:000356997600010 PM 25987249 ER PT J AU Turkbey, B Agarwal, HK Shih, J Bernardo, M McKinney, YL Daar, D Griffiths, GL Sankineni, S Johnson, L Grant, KB Weaver, J Rais-Bahrami, S Harisinghani, M Jacobs, P Dahut, W Merino, MJ Pinto, PA Choyke, PL AF Turkbey, Baris Agarwal, Harsh K. Shih, Joanna Bernardo, Marcelino McKinney, Yolanda L. Daar, Dagane Griffiths, Gary L. Sankineni, Sandeep Johnson, Linda Grant, Kinzya B. Weaver, Juanita Rais-Bahrami, Soroush Harisinghani, Mukesh Jacobs, Paula Dahut, William Merino, Maria J. Pinto, Peter A. Choyke, Peter L. TI A Phase I Dosing Study of Ferumoxytol for MR Lymphography at 3 T in Patients With Prostate Cancer SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE ferumoxytol; lymph node; metastases; prostate cancer; staging; ultrasmall superparamagnetic iron oxide (USPIO) ID ULTRASMALL SUPERPARAMAGNETIC PARTICLES; LYMPH-NODE METASTASES; RADICAL PROSTATECTOMY; BLADDER; NANOPARTICLE; PROGRESSION; EXPERIENCE; CARCINOMA; EFFICACY; OUTCOMES AB OBJECTIVE. The objective of our study was to determine the optimal dose of ferumoxytol for performing MR lymphography (MRL) at 3 T in patients with prostate cancer. SUBJECTS AND METHODS. This phase I trial enrolled patients undergoing radical prostatectomy (RP) with bilateral pelvic lymph node dissection (PLND). Three groups of five patients each (total of 15 patients) received IV ferumoxytol before RP with bilateral PLND at each of the following doses of iron: 4, 6, and 7.5 mg Fe/kg. Patients underwent abdominopelvic MRI at 3 T before and 24 hours after ferumoxytol injection using T2-and T2*-weighted sequences. Normalized signal intensity (SI) and normalized SD changes from baseline to 24 hours after injection within visible lymph nodes were calculated for each dose level. Linear mixed effects models were used to estimate the effects of dose on the percentage SI change and log-transformed SD change within visible lymph nodes to determine the optimal dose of ferumoxytol for achieving uniform low SI in normal nodes. RESULTS. One patient who was excluded from the study group had a mild allergic reaction requiring treatment after approximately 2.5 mg Fe/kg ferumoxytol injection whereupon the injection was interrupted. The 15 study group patients tolerated ferumoxytol at all dose levels. The mean percentage SI change in 13 patients with no evidence of lymph metastasis was -36.4%, -45.4%, and -65.1% for 4, 6, and 7.5 mg Fe/kg doses, respectively (p = 0.041). CONCLUSION. A dose level of 7.5 mg Fe/kg ferumoxytol was safe and effective in deenhancing benign lymph nodes. This dose therefore can be the starting point for future phase II studies regarding the efficacy of ferumoxytol for MRL. C1 [Turkbey, Baris; Agarwal, Harsh K.; Bernardo, Marcelino; McKinney, Yolanda L.; Daar, Dagane; Sankineni, Sandeep; Johnson, Linda; Grant, Kinzya B.; Weaver, Juanita; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Agarwal, Harsh K.] Philips Healthcare Res North Amer, Briarcliff Manor, NY USA. [Shih, Joanna] NCI, Biomet Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Griffiths, Gary L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Frederick, MD USA. [Rais-Bahrami, Soroush; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Harisinghani, Mukesh] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent Radiol,Sch Med, Boston, MA USA. [Jacobs, Paula] NCI, Canc Imaging Program, NIH, Rockville, MD USA. [Dahut, William] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Rm B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 NR 22 TC 9 Z9 9 U1 0 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2015 VL 205 IS 1 BP 64 EP 69 DI 10.2214/AJR.14.13009 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL2NK UT WOS:000356781000028 PM 26102381 ER PT J AU Bi, K Nishihara, K Machleidt, T Hermanson, S Wang, J Sakamuru, S Huang, RL Xia, MH AF Bi, Kun Nishihara, Kana Machleidt, Thomas Hermanson, Spencer Wang, Jun Sakamuru, Srilatha Huang, Ruili Xia, Menghang TI Identification of known drugs targeting the endoplasmic reticulum stress response SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE ATF6; ER stress pathways; NPC library; qHTS; XBP1 ID UNFOLDED PROTEIN RESPONSE; MYELOMA CELLS; ER STRESS; MECHANISMS; INHIBITORS; DISEASE; DEATH AB The endoplasmic reticulum (ER), a multifunctional organelle, plays a central role in cellular signaling, development, and stress response. Dysregulation of ER homeostasis has been associated with human diseases, such as cancer, inflammation, and diabetes. A broad spectrum of stressful stimuli including hypoxia as well as a variety of pharmacological agents can lead to the ER stress response. In this study, we have developed a stable ER stress reporter cell line that stably expresses a beta-lactamase reporter gene under the control of the ER stress response element (ESRE) present in the glucose-regulated protein, 78 kDa (GRP78) gene promoter. This assay has been optimized and miniaturized into a 1536-well plate format. In order to identify clinically used drugs that induce ER stress response, we screened approximately 2800 drugs from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC library) using a quantitative high-throughput screening (qHTS) platform. From this study, we have identified several known ER stress inducers, such as 17-AAG (via HSP90 inhibition), as well as several novel ER stress inducers such as AMI-193 and spiperone. The confirmed drugs were further studied for their effects on the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha), the X-box-binding protein (XBP1) splicing, and GRP78 gene expression. These results suggest that the ER stress inducers identified from the NPC library using the qHTS approach could shed new lights on the potential therapeutic targets of these drugs. C1 [Bi, Kun] Thermo Fisher Sci, Life Sci Solut Grp, Rockford, IL 61105 USA. [Nishihara, Kana; Sakamuru, Srilatha; Huang, Ruili; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Nishihara, Kana] Kyoto Univ, Grad Sch Med, Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. [Machleidt, Thomas; Hermanson, Spencer; Wang, Jun] Promega Corp, Fitchburg, WI 53711 USA. RP Xia, MH (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU National Center for Advancing Translational Sciences, National Institutes of Health FX We thank Sam Michael and Paul Shinn for assistance with automated screening and compound management. These studies were supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. NR 25 TC 2 Z9 2 U1 2 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JUL PY 2015 VL 407 IS 18 BP 5343 EP 5351 DI 10.1007/s00216-015-8694-2 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CL2SW UT WOS:000356796000012 PM 25925857 ER PT J AU Komori, M Blake, A Greenwood, M Lin, YC Kosa, P Ghazali, D Winokur, P Natrajan, M Wuest, SC Romm, E Panackal, AA Williamson, PR Wu, TX Bielekova, B AF Komori, Mika Blake, Andrew Greenwood, Mark Lin, Yen Chih Kosa, Peter Ghazali, Danish Winokur, Paige Natrajan, Muktha Wuest, Simone C. Romm, Elena Panackal, Anil A. Williamson, Peter R. Wu, Tianxia Bielekova, Bibiana TI Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis SO ANNALS OF NEUROLOGY LA English DT Article ID TRANSPLANTATION FAILS; CELL TRANSPLANTATION; DISEASE; LESIONS; CXCL13; MRI; NEURODEGENERATION; HETEROGENEITY; DEMYELINATION; ACTIVATION AB ObjectiveThe management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools. MethodsBecause biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays. ResultsAmong markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group. InterpretationThe cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS. Ann Neurol 2015;78:3-20 C1 [Komori, Mika; Blake, Andrew; Lin, Yen Chih; Kosa, Peter; Ghazali, Danish; Winokur, Paige; Natrajan, Muktha; Wuest, Simone C.; Romm, Elena; Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, NIH, Bethesda, MD 20892 USA. [Greenwood, Mark] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. [Panackal, Anil A.; Williamson, Peter R.] NIAID, Translat Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Dis Unit, NIH, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU NIH National Institute of Neurological Disorders and Stroke; NIH National Institute of Allergy and Infectious Diseases; Japan Society of the Promotion of Science FX This work was supported by the intramural research program of the NIH National Institute of Neurological Disorders and Stroke and by the intramural research program of the NIH National Institute of Allergy and Infectious Diseases. M.K. received postdoctoral fellowship support from the Japan Society of the Promotion of Science. NR 45 TC 16 Z9 16 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2015 VL 78 IS 1 BP 3 EP 20 DI 10.1002/ana.24408 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CL3AQ UT WOS:000356821200002 PM 25808056 ER PT J AU Saenz, C Tisdale, JF AF Saenz, Carla Tisdale, John F. TI Assessing Costs, Benefits, and Risks in Chronic Disease: Taking the Long View SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article ID STEM-CELL TRANSPLANTATION C1 [Saenz, Carla] Pan Amer Hlth Org, Reg Program Bioeth Knowledge Management Bioeth &, Washington, DC USA. [Tisdale, John F.] NHLBI, NIDDK, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU Pan American Health Organization or the National Institutes of Health FX The opinions expressed herein are those of the authors and do not necessarily reflect the views of the Pan American Health Organization or the National Institutes of Health, from which the authors receive their funding and support. NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2015 VL 21 IS 7 BP 1149 EP 1150 DI 10.1016/j.bbmt.2015.03.007 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CL2AY UT WOS:000356747200001 PM 25783634 ER PT J AU Carpenter, PA Kitko, CL Elad, S Flowers, MED Gea-Banacloche, JC Halter, JP Hoodin, F Johnston, L Lawitschka, A McDonald, GB Opipari, AW Savani, BN Schultz, KR Smith, SR Syrjala, KL Treister, N Vogelsang, GB Williams, KM Pavletic, SZ Martin, PJ Lee, SJ Couriel, DR AF Carpenter, Paul A. Kitko, Carrie L. Elad, Sharon Flowers, Mary E. D. Gea-Banacloche, Juan C. Halter, Jorg P. Hoodin, Flora Johnston, Laura Lawitschka, Anita McDonald, George B. Opipari, Anthony W. Savani, Bipin N. Schultz, Kirk R. Smith, Sean R. Syrjala, Karen L. Treister, Nathaniel Vogelsang, Georgia B. Williams, Kirsten M. Pavletic, Steven Z. Martin, Paul J. Lee, Stephanie J. Couriel, Daniel R. TI National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Supportive care; Consensus; Guidelines ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; BRONCHIOLITIS OBLITERANS SYNDROME; SEVERE DRY EYE; RANDOMIZED CONTROLLED-TRIAL; CASE-MATCHED CONTROLS; DOUBLE-BLIND; INTRAVENOUS IMMUNOGLOBULIN; CHRONIC GVHD AB The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Carpenter, Paul A.; Flowers, Mary E. D.; McDonald, George B.; Syrjala, Karen L.; Martin, Paul J.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Kitko, Carrie L.; Couriel, Daniel R.] Univ Michigan, Ctr Comprehens Canc, Blood & Marrow Transplantat Program, Ann Arbor, MI 48109 USA. [Elad, Sharon] Univ Rochester, Med Ctr, Div Oral Med, Eastman Inst Oral Hlth, Rochester, NY 14642 USA. [Elad, Sharon] Univ Rochester, Med Ctr, Wilmot Canc Ctr, Rochester, NY 14642 USA. [Gea-Banacloche, Juan C.; Williams, Kirsten M.; Pavletic, Steven Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Halter, Jorg P.] Univ Basel Hosp, Dept Hematol, CH-4031 Basel, Switzerland. [Hoodin, Flora] Eastern Michigan Univ, Dept Psychol, Ypsilanti, MI 48197 USA. [Johnston, Laura] Stanford Univ, Med Ctr, Dept Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Lawitschka, Anita] Med Univ, St Anna Childrens Hosp, Vienna, Austria. [Opipari, Anthony W.] Univ Michigan Hlth Syst, Dept Obstet & Gynecol, Ann Arbor, MI USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Schultz, Kirk R.] BC Childrens Hosp, Michael Cuccione Childhood Canc Res Program, Vancouver, BC, Canada. [Schultz, Kirk R.] Univ British Columbia, Vancouver, BC, Canada. [Smith, Sean R.] Univ Michigan, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. [Treister, Nathaniel] Dana Farber Brigham & Womens Canc Ctr, Div Oral Med & Dent, Boston, MA USA. [Vogelsang, Georgia B.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Carpenter, PA (reprint author), Fred Hutchinson Canc Res Ctr, D5-290,POB 19024, Seattle, WA 98109 USA. EM pcarpent@fredhutch.org FU National Institutes of Health's (NIH) National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Disease; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources FX This project was supported by the National Institutes of Health's (NIH) National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Disease; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources. The authors want to acknowledge the following individuals and organizations that, by their participation, made this project possible: American Society for Blood and Marrow Transplantation, Center for International Bone and Marrow Transplant Research, US Chronic GVHD Consortium (supported by ORD and NCI), German-Austrian-Swiss GVHD Consortium, National Marrow Donor Program, the Health Resources and Services Administration, Division of Transplantation, US Department of Human Health and Services, Canadian Blood and Marrow Transplant Group, European Group for Blood and Marrow Transplantation, Pediatric Blood and Marrow Transplant Consortium, and the representatives of the Brazilian Chronic GVHD consortium (Drs. Maria Claudia Moreira, Marcia and Vaneuza Funke) and Deutsche Jose Carreras Leukarnie-Stiftung. The organizers are in debt to patients and patient and research advocacy groups, who made this process much more meaningful by their engagement. Acknowledgement goes to the Meredith Cowden GVHD foundation for facilitating the initial planning meeting in Cleveland in November of 2013 in conjunction with the National GVHD Symposium. The project group also recognizes the contributions of numerous colleagues in the field of blood and marrow transplantation in the US and internationally, medical specialists and consultants, the pharmaceutical industry, and the NIH and US Food and Drug Administration professional staff for their intellectual input, dedication, and enthusiasm on the road to completion of these documents. Project participants also recognize Drs. Joseph Antin and Gerard Socie for their independent expert reviews and comments on final documents at the June 2014 meeting. NR 182 TC 19 Z9 21 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2015 VL 21 IS 7 BP 1167 EP 1187 DI 10.1016/j.bbmt.2015.03.024 PG 21 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CL2AY UT WOS:000356747200005 PM 25838185 ER PT J AU Holter-Chakrabarty, JL Pierson, N Zhang, MJ Zhu, XC Akpek, G Aljurf, MD Artz, AS Baron, F Bredeson, CN Dvorak, CC Epstein, RB Lazarus, HM Olsson, RF Selby, GB Williams, KM Cooke, KR Pasquini, MC McCarthy, PL AF Holter-Chakrabarty, Jennifer L. Pierson, Namali Zhang, Mei-Jie Zhu, Xiaochun Akpek, Goerguen Aljurf, Mahmoud D. Artz, Andrew S. Baron, Frederic Bredeson, Christopher N. Dvorak, Christopher C. Epstein, Robert B. Lazarus, Hillard M. Olsson, Richard F. Selby, George B. Williams, Kirsten M. Cooke, Kenneth R. Pasquini, Marcelo C. McCarthy, Philip L. TI The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic transplantation; Total body irradiation; Leukemia ID ALLOGENEIC MARROW TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; HEMATOLOGIC MALIGNANCY; BONE-MARROW; CHEMOTHERAPY; REMISSION; REGIMENS; TOXICITY; THERAPY; TRIAL AB Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk,.89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk,.93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk,.9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk,.96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Holter-Chakrabarty, Jennifer L.; Pierson, Namali; Epstein, Robert B.; Selby, George B.] Univ Oklahoma, Dept Hematol Oncol, Oklahoma City, OK USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie; Zhu, Xiaochun; Pasquini, Marcelo C.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Hematol Oncol Sect, Gilbert, AZ USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr Ea Res, Dept Oncol, Riyadh, Saudi Arabia. [Artz, Andrew S.] Univ Chicago, Sch Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Baron, Frederic] Univ Liege, CHU Sart Tilman, Liege, Belgium. [Bredeson, Christopher N.] Ottawa Hosp, Ottawa, ON, Canada. [Bredeson, Christopher N.] Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bredeson, Christopher N.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Dvorak, Christopher C.] Univ Calif San Francisco, Med Ctr, Dept Pediat, San Francisco, CA 94143 USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Seidman Canc Ctr, Cleveland, OH 44106 USA. [Olsson, Richard F.] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Williams, Kirsten M.] NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Cooke, Kenneth R.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Pediat Blood & Marrow Transplantat Program, Baltimore, MD USA. [McCarthy, Philip L.] Roswell Pk Canc Inst, Blood & Marrow Transplant Program, Dept Med, Buffalo, NY 14263 USA. RP Pasquini, MC (reprint author), 9200 W Wisconsin Ave,CCC5500, Milwaukee, WI 53226 USA. EM mpasquini@mcw.edu FU National Cancer Institute (NCI) [U24-CA076518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; Medical College of Wisconsin; Merck Co., Inc.; Millennium; Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc.; Therakos; University of Minnesota; University of Utah; Well Point; StemCyte, A Global Cord Blood Therapeutics Co. FX The CIBMTR is supported by Public Health Service grant/cooperative agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 Grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium; The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *Terumo BCT; *Teva Neuroscience, Inc.; *Therakos;University of Minnesota; University of Utah; and *Well Point. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration or any other agency of the US Government. NR 20 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2015 VL 21 IS 7 BP 1251 EP 1257 DI 10.1016/j.bbmt.2015.03.017 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CL2AY UT WOS:000356747200014 PM 25840335 ER PT J AU Bates, SE Eisch, R Ling, A Rosing, D Turner, M Pittaluga, S Prince, HM Kirschbaum, MH Allen, SL Zain, J Geskin, LJ Joske, D Popplewell, L Cowen, EW Jaffe, ES Nichols, J Kennedy, S Steinberg, SM Liewehr, DJ Showe, LC Steakley, C Wright, J Fojo, T Litman, T Piekarz, RL AF Bates, Susan E. Eisch, Robin Ling, Alexander Rosing, Douglas Turner, Maria Pittaluga, Stefania Prince, H. Miles Kirschbaum, Mark H. Allen, Steven L. Zain, Jasmine Geskin, Larisa J. Joske, David Popplewell, Leslie Cowen, Edward W. Jaffe, Elaine S. Nichols, Jean Kennedy, Sally Steinberg, Seth M. Liewehr, David J. Showe, Louise C. Steakley, Caryn Wright, John Fojo, Tito Litman, Thomas Piekarz, Richard L. TI Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE epigenetic therapy; histone deacetylase inhibitor; romidepsin; T-cell lymphoma; chromatin ID HISTONE DEACETYLASE INHIBITOR; PHASE-II TRIAL; SUBEROYLANILIDE HYDROXAMIC ACID; THERAPEUTIC ACTIVITIES; DEPSIPEPTIDE FR901228; DEPENDENT APOPTOSIS; MYCOSIS-FUNGOIDES; SEZARY-SYNDROME; SOLID TUMORS; LUNG-CANCER AB Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 35months to 10years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action. C1 [Bates, Susan E.; Eisch, Robin] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Ling, Alexander] NIH, Dept Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Rosing, Douglas] NHLBI, Consultat Cardiol, NIH, Bethesda, MD 20892 USA. [Turner, Maria; Cowen, Edward W.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, CCR, Bethesda, MD 20892 USA. [Prince, H. Miles] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. [Kirschbaum, Mark H.] Penn State Hershey Med Ctr, Hematol Malignancies, Hershey, PA USA. [Allen, Steven L.] Hofstra North Shore LIJ Sch Med & Monter Canc Ctr, New York, NY USA. [Zain, Jasmine] Columbia Univ, New York, NY USA. [Geskin, Larisa J.] Univ Pittsburgh, Med Ctr, Dept Dermatol, Pittsburgh, PA USA. [Joske, David] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Popplewell, Leslie] City Hope Natl Canc Ctr, Duarte, CA USA. [Nichols, Jean] Celgene Corp, Cambridge, MA USA. [Steinberg, Seth M.; Liewehr, David J.] NCI, Biostat & Data Management, Bethesda, MD 20892 USA. [Showe, Louise C.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Steakley, Caryn; Fojo, Tito] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Wright, John; Piekarz, Richard L.] NCI, Canc Therapy Evaluat Program, DCTDC, Bethesda, MD 20892 USA. [Litman, Thomas] LEO Pharma AS, Ballerup, Denmark. RP Bates, SE (reprint author), NCI, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM batess@helix.nih.gov OI Allen, Steven/0000-0002-3482-3182 FU National Institutes of Health, USA; CRADA; Celgene Corporation; Cancer Therapy Evaluation Program (CTEP) FX This work was supported by the intramural programme of the National Institutes of Health, USA, and by a CRADA with Celgene Corporation. The authors would also like to acknowledge individuals in the Cancer Therapy Evaluation Program (CTEP) for their participation in the sponsorship of this trial and the editorial assistance of Rob Robey. NR 67 TC 11 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUL PY 2015 VL 170 IS 1 BP 96 EP 109 DI 10.1111/bjh.13400 PG 14 WC Hematology SC Hematology GA CL1PQ UT WOS:000356716500013 PM 25891346 ER PT J AU Papadakis, GZ Bagci, U Sadowski, SM Patronas, NJ Stratakis, CA AF Papadakis, Georgios Z. Bagci, Ulas Sadowski, Samira M. Patronas, Nicholas J. Stratakis, Constantine A. TI Ectopic ACTH and CRH Co-secreting Tumor Localized by Ga-68-DOTA-TATE PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material ID CORTICOTROPIN-RELEASING HORMONE; CUSHINGS-SYNDROME; NEUROENDOCRINE TUMORS; EXPERIENCE AB Diagnosis of ectopic adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) co-secreting tumors causing Cushing syndrome (CS) is challenging because these tumors are rare and their diagnosis is frequently confused with Cushing disease (CD), caused by the effect of CRH on the pituitary. We report a case of a 21-year-old male patient who was referred to our institution with persistent hypercortisolemia and CS after undergoing unnecessary transsphenoidal surgery (TSS). Ga-68-DOTA-TATE PET/CT revealed increased tracer uptake in the thymus, which was histologically proven to be a neuroendocrine tumor (NET) that stained positive for ACTH and CRH. Imaging with F-18-FDG PET/CT was not diagnostic. C1 [Papadakis, Georgios Z.; Bagci, Ulas; Patronas, Nicholas J.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Bagci, Ulas] Univ Cent Florida, CRCV, Orlando, FL 32816 USA. [Sadowski, Samira M.] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, PDEGEN, NICHD,NIH,CRC, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Bagci, Ulas/0000-0001-7379-6829 FU Intramural NIH HHS [ZIA HD008920-03] NR 15 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD JUL PY 2015 VL 40 IS 7 BP 576 EP 578 DI 10.1097/RLU.0000000000000806 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK6YL UT WOS:000356375000010 PM 26018709 ER PT J AU St Charles, JA Liberti, SE Williams, JS Lujan, SA Kunkel, TA AF St Charles, Jordan A. Liberti, Sascha E. Williams, Jessica S. Lujan, Scott A. Kunkel, Thomas A. TI Quantifying the contributions of base selectivity, proofreading and mismatch repair to nuclear DNA replication in Saccharomyces cerevisiae SO DNA REPAIR LA English DT Article DE Replication fidelity; DNA polymerase; Genome stability; Mutation rate ID POLYMERASE-EPSILON; EXONUCLEASE ACTIVITY; HIGH-FIDELITY; REACTION PH; DELTA; YEAST; GENOME; ALPHA; MUTATIONS; ERRORS AB Mismatches generated during eukaryotic nuclear DNA replication are removed by two evolutionarily conserved error correction mechanisms acting in series, proofreading and mismatch repair (MMR). Defects in both processes are associated with increased susceptibility to cancer. To better understand these processes, we have quantified base selectivity, proofreading and MMR during nuclear DNA replication in Saccharomyces cerevisiae. In the absence of proofreading and MMR, the primary leading and lagging strand replicases, polymerase a and polymerase delta respectively, synthesize DNA in vivo with somewhat different error rates and specificity, and with apparent base selectivity that is more than 100 times higher than measured in vitro. Moreover, leading and lagging strand replication fidelity rely on a different balance between proofreading and MMR. On average, proofreading contributes more to replication fidelity than does MMR, but their relative contributions vary from nearly all proofreading of some mismatches to mostly MMR of other mismatches. Thus accurate replication of the two DNA strands results from a non-uniform and variable balance between error prevention, proofreading and MMR. Published by Elsevier B.V. C1 [St Charles, Jordan A.; Liberti, Sascha E.; Williams, Jessica S.; Lujan, Scott A.; Kunkel, Thomas A.] DHHS, NIH, Genome Integr & Struct Biol Lab, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), DHHS, NIH, Genome Integr & Struct Biol Lab, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070, Z01 ES065089] FX The authors thank Dmitry Gordenin and members of the Genome Integrity and Structural Biology Laboratory at the NIEHS for helpful discussions on experiments, and Kin Chan and Deepa Singh for valuable comments on the manuscript. This work was supported by the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences, by Projects Z01 ES065070 and Z01 ES065089 to TAK. NR 57 TC 7 Z9 7 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUL PY 2015 VL 31 BP 41 EP 51 DI 10.1016/j.dnarep.2015.04.006 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CL7FT UT WOS:000357138600005 PM 25996407 ER PT J AU Gassman, NR Wilson, SH AF Gassman, Natalie R. Wilson, Samuel H. TI Micro-irradiation tools to visualize base excision repair and single-strand break repair SO DNA REPAIR LA English DT Article DE DNA repair; DNA damage; Base excision repair; Single-strand break repair; Micro-irradiation; PARP-1; XRCC1; PARP inhibitors; Reactive oxygen species ID OXIDATIVE DNA-DAMAGE; HISTONE H2AX PHOSPHORYLATION; IN-SITU ANALYSIS; MAMMALIAN-CELLS; VISIBLE-LIGHT; LASER-PULSES; LIGASE-III; SPATIOTEMPORAL DYNAMICS; WAVELENGTH DEPENDENCE; PROTEIN RECRUITMENT AB Microscopy and micro-irradiation imaging techniques have significantly advanced our knowledge of DNA damage tolerance and the assembly of DNA repair proteins at the sites of damage. While these tools have been extensively applied to the study of nucleotide excision repair and double-strand break repair, their application to the repair of oxidatively-induced base lesions and single-strand breaks is just beginning to yield new insights. This review will focus on examining micro-irradiation techniques reported to create base lesions and single-strand breaks; these lesions are considered to be primarily addressed by proteins involved in the base excision repair (BER) pathway. By examining conditions for generating these DNA lesions and reviewing information on the assembly and dissociation of repair complexes at the induced lesion sites, we hope to promote further investigations into BER and to stimulate further development and enhancement of these techniques for the study of BER. Published by Elsevier B.V. C1 [Gassman, Natalie R.; Wilson, Samuel H.] NIEHS, NIH, Genome Integr & Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, NIH, Genome Integr & Struct Biol Lab, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov OI Gassman, Natalie/0000-0002-8488-2332 FU Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (NIH) [Z01-ES050158, Z01-ES050159]; NRG [1K99ED5023813-01] FX The authors are supported by the Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Z01-ES050158 and Z01-ES050159, and NRG is also funded by 1K99ED5023813-01. We thank C. Jeff Tucker at the NIEHS Fluorescence Microscopy and Imaging Center for his expert assistance with the micro-irradiation studies and thoughtful comments on the manuscript. We also thank Bill Beard for helpful discussions. NR 82 TC 2 Z9 2 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUL PY 2015 VL 31 BP 52 EP 63 DI 10.1016/j.dnarep.2015.05.001 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CL7FT UT WOS:000357138600006 PM 25996408 ER PT J AU Hinkle, SN Johns, AM Albert, PS Kim, S Grantz, KL AF Hinkle, Stefanie N. Johns, Alicia M. Albert, Paul S. Kim, Sungduk Grantz, Katherine L. TI Longitudinal changes in gestational weight gain and the association with intrauterine fetal growth SO EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY LA English DT Article DE Fetal growth; Growth restriction; Small-for-gestational-age; Weight gain ID MATERNAL WEIGHT; BIRTH-WEIGHT; PREGNANCY; POPULATION; PATTERNS; WOMEN; AGE AB Objective: Total pregnancy weight gain has been associated with infant birthweight; however, most prior studies lacked repeat ultrasound measurements. Understanding of the longitudinal changes in maternal weight gain and intrauterine changes in fetal anthropometrics is limited. Study design: Prospective data from 1314 Scandinavian singleton pregnancies at high-risk for delivering small-for-gestational-age (SGA) were analyzed. Women had >= 1 (median 12) antenatal weight measurements. Ultrasounds were targeted at17, 25, 33, and 37 weeks of gestation. Analyses involved a multi-step process. First, trajectories were estimated across gestation for maternal weight gain and fetal biometrics [abdominal circumference (AC, mm), biparietal diameter (BPD, mm), femur length (FL, mm), and estimated fetal weight (EFW, g)] using linear mixed models. Second, the association between maternal weight changes (per 5 kg) and corresponding fetal growth from 0 to 17, 17 to 28, and 28 to 37 weeks was estimated for each fetal parameter adjusting for prepregnancy body mass index, height, parity, chronic diseases, age, smoking, fetal sex, and weight gain up to the respective period as applicable. Third, the probability of fetal SGA, EFW <10th percentile, at the 3rd ultrasound was estimated across the spectrum of maternal weight gain rate by SGA status at the 2nd ultrasound. Results: From 0 to 17 weeks, changes in maternal weight were most strongly associated with changes in BPD [beta = 0.51 per 5 kg (95%CI 0.26, 0.76)] and FL [beta = 0.46 per 5 kg (95%CI 0.26, 0.65)]. From 17 to 28 weeks, AC [beta = 2.92 per 5 kg (95%CI 1.62, 4.22)] and EFW [beta = 58.7 per 5 kg (95%CI 29.5, 88.0)] were more strongly associated with changes in maternal weight. Increased maternal weight gain was significantly associated with a reduced probability of intrauterine SGA; for a normal weight woman with SGA at the 2nd ultrasound, the probability of fetal SGA with a weight gain rate of 0.29 kg/w (10th percentile) was 59%, compared to 38% with a rate of 0.67 kg/w (90th percentile). Conclusion: Among women at high-risk for SGA, maternal weight gain was associated with fetal growth throughout pregnancy, but had a differential relationship with specific biometrics across gestation. For women with fetal SGA identified mid-pregnancy, increased antenatal weight gain was associated with a decreased probability of fetal SGA approximately 7 weeks later. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Hinkle, Stefanie N.; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Johns, Alicia M.; Albert, Paul S.; Kim, Sungduk] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Hinkle, SN (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. EM hinklesn@mail.nih.gov RI Hinkle, Stefanie/F-8253-2013; OI Hinkle, Stefanie/0000-0003-4312-708X; Grantz, Katherine/0000-0003-0276-8534 FU intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 22 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-2115 EI 1872-7654 J9 EUR J OBSTET GYN R B JI Eur. J. Obstet. Gynecol. Reprod. Biol. PD JUL PY 2015 VL 190 BP 41 EP 47 DI 10.1016/j.ejogrb.2015.04.006 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CL5IB UT WOS:000356991900008 PM 25978857 ER PT J AU Steinckwich, N Myers, P Janardhan, KS Flagler, ND King, D Petranka, JG Putney, JW AF Steinckwich, Natacha Myers, Page Janardhan, Kyathanahalli S. Flagler, Norris D. King, Debra Petranka, John G. Putney, James W. TI Role of the store-operated calcium entry protein, STIM1, in neutrophil chemotaxis and infiltration into a murine model of psoriasis-inflamed skin SO FASEB JOURNAL LA English DT Article DE calcium signaling; chronic inflammatory disease; leukocyte migration ID CA2+ INFLUX; CELLS; ACTIVATION; INTEGRIN; MICE; POLARIZATION; INFLAMMATION; RECRUITMENT; MECHANISMS; RECEPTORS AB Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor protein that initiates store-operated calcium entry (SOCE). STIM1 is known to be involved in the chemoattractant signaling pathway for FPR1 in cell lines, but its role in in vivo functioning of neutrophils is unclear. Plaque-type psoriasis is a chronic inflammatory skin disorder associated with chemoattractants driving neutrophils into the epidermis. We investigated the involvement of STIM1 in neutrophil chemotaxis in vitro, as well as during chronic psoriatic inflammation. To this end, we used conditional knockout (KO) mice lacking STIM1 in cells of myeloid lineage (STIM1(fl/fl) LysM-cre). We demonstrate that STIM1 is required for chemotaxis because of multiple chemoattractants in mouse neutrophils in vitro. Using an imiquimod-induced psoriasis-like skin model, we show that KO mice had less neutrophil infiltration in the epidermis than controls, whereas neither chemoattractant production in the epidermis nor macrophage migration was decreased. KO mice displayed a more rapid reversal of the outward signs of psoriasis (plaques). Thus, KO of STIM1 impairs neutrophil contribution to psoriatic inflammation. Our data provide new insights to our understanding of how STIM1 orchestrates the cellular behavior underlying chemotaxis and illustrate the important role of SOCE in a disease-related pathologic model. C1 [Steinckwich, Natacha; Petranka, John G.; Putney, James W.] NIEHS, Signal Transduct Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Myers, Page] NIEHS, Comparat Med Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.] NIEHS, Integrated Syst Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.; Flagler, Norris D.; King, Debra] NIEHS, Cellular & Mol Pathol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.; Flagler, Norris D.; King, Debra] NIEHS, Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Flagler, Norris D.; King, Debra] NIEHS, Special Tech Grp, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov FU Intramural Research Program of the NIH National Institute of Environmental Health Sciences FX Drs. Michael Fessler and Xiaoling Li read the manuscript and provided useful comments. The authors thank Gary Bird for fruitful discussion. Mice carrying a floxed STIM1 gene were kindly provided by Dr. Masatsugu Ohora (Tokyo Medical and Dental University, Tokyo, Japan). The YFP-STIM1 construct that was subcloned into a viral vector was provided by Dr. Tobias Meyer (Stanford University, Stanford, CA, USA). The authors also thank Jeff Tucker and Agnes Janoshazi for assistance with the confocal microscopy; Carl Bortner and Maria Sifre for assistance with the flow cytometry; Diane D'Agostin for technical support in mouse colony management and in in situ hybridization experiments; Dr. Shyamal D. Peddada for assistance with statistical analyses; Negin Martin and Charles Romeo for help in producing lentiviral particles; and Julie Foley and the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences histology group members for support in histology. This research was supported by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences. The authors declare no conflicts of interest. NR 35 TC 5 Z9 5 U1 1 U2 12 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2015 VL 29 IS 7 BP 3003 EP 3013 DI 10.1096/fj.14-265215 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CL3OI UT WOS:000356859100028 PM 25837581 ER PT J AU Sanyal, AJ Gao, B Szabo, G AF Sanyal, Arun J. Gao, Bin Szabo, Gyongyi TI Gaps in Knowledge and Research Priorities for Alcoholic Hepatitis SO GASTROENTEROLOGY LA English DT Editorial Material ID LIVER-DISEASE; STEATOHEPATITIS; MORTALITY; MICE C1 [Sanyal, Arun J.; Gao, Bin] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Szabo, Gyongyi] NIAAA, NIH, Bethesda, MD USA. [Szabo, Gyongyi] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Sanyal, AJ (reprint author), Virginia Commonwealth Univ, Richmond, VA 23284 USA. FU NIAAA NIH HHS [U01 AA021891]; NIDDK NIH HHS [R01 DK105961] NR 28 TC 7 Z9 7 U1 2 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2015 VL 149 IS 1 BP 4 EP 9 DI 10.1053/j.gastro.2015.05.015 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CL0DW UT WOS:000356610400007 PM 26008859 ER PT J AU Sei, Y Zhao, XL Forbes, J Szymczak, S Li, Q Trivedi, A Voellinger, M Joy, G Feng, JY Whatley, M Jones, MS Harper, UL Marx, SJ Venkatesan, AM Chandrasekharappa, SC Raffeld, M Quezado, MM Louie, A Chen, CC Lim, RM Agarwala, R Schaffer, AA Hughes, MS Bailey-Wilson, JE Wank, SA AF Sei, Yoshitatsu Zhao, Xilin Forbes, Joanne Szymczak, Silke Li, Qing Trivedi, Apurva Voellinger, Mark Joy, Grishma Feng, Jianying Whatley, Millie Jones, MaryPat Sussex Harper, Ursula L. Marx, Stephen J. Venkatesan, Aradhana M. Chandrasekharappa, Settara C. Raffeld, Mark Quezado, Martha M. Louie, Adeline Chen, Clara C. Lim, Ramona M. Agarwala, Richa Schaeffer, Alejandro A. Hughes, Marybeth S. Bailey-Wilson, Joan E. Wank, Stephen A. TI A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase SO GASTROENTEROLOGY LA English DT Article DE Familial; Screening; Tumor Suppressor Gene; Linkage ID MESSENGER-RNA EXPORT; NEUROENDOCRINE TUMORS; PHOSPHATE MULTIKINASE; FAMILIAL OCCURRENCE; HUMAN HOMOLOG; PATHWAY; KINASE; 1,4,5-TRISPHOSPHATE; TRANSCRIPTION; COACTIVATOR AB BACKGROUND & AIMS: Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. METHODS: We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. RESULTS: Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. CONCLUSIONS: We found that small intestinal carcinoids can occur as an inherited autosomaldominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis. C1 [Sei, Yoshitatsu; Zhao, Xilin; Forbes, Joanne; Trivedi, Apurva; Voellinger, Mark; Joy, Grishma; Feng, Jianying; Lim, Ramona M.; Wank, Stephen A.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Marx, Stephen J.] NIDDK, Metabol Dis Branch, NIH, Bethesda, MD 20892 USA. [Szymczak, Silke; Li, Qing; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Jones, MaryPat Sussex; Harper, Ursula L.] NHGRI, Genom Core Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Whatley, Millie; Chen, Clara C.] NCI, Div Nucl Med, NIH, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.; Louie, Adeline] NCI, Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Raffeld, Mark; Quezado, Martha M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Hughes, Marybeth S.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Agarwala, Richa] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Wank, SA (reprint author), NIDDK, Digest Dis Branch, NIH, 10-9C 101, Bethesda, MD 20892 USA. EM stevew@mail.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural Research Programs of the National Institute of Diabetes Digestive and Kidney Diseases, National Human Genome Research Institute, Clinical Research Center, National Cancer Institute; National Library of Medicine, National Institutes of Health FX Supported by the Intramural Research Programs of the National Institute of Diabetes Digestive and Kidney Diseases, National Human Genome Research Institute, Clinical Research Center, National Cancer Institute, and National Library of Medicine, National Institutes of Health. NR 50 TC 13 Z9 15 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2015 VL 149 IS 1 BP 67 EP 78 DI 10.1053/j.gastro.2015.04.008 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CL0DW UT WOS:000356610400023 PM 25865046 ER PT J AU Serti, E Chepa-Lotrea, X Kim, YJ Keane, M Fryzek, N Liang, TJ Ghany, M Rehermann, B AF Serti, Elisavet Chepa-Lotrea, Xenia Kim, Yun Ju Keane, Meghan Fryzek, Nancy Liang, T. Jake Ghany, Marc Rehermann, Barbara TI Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function SO GASTROENTEROLOGY LA English DT Article DE Immune Regulation; NS5A Inhibitor; NS3 Inhibitor; ISG ID PERSISTENT LCMV INFECTION; NK CELLS; T-CELLS; B-VIRUS; EXPRESSION; BLOCKADE; CYTOTOXICITY; RECEPTORS; FUTURE AB BACKGROUND & AIMS: Chronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer (NK) cells-the most prevalent innate immune cell in the liver. We investigated whether the elimination of hepatitis C virus with direct-acting antiviral normalizes expression of IFN-stimulated genes and NK cell function. METHODS: We used multicolor flow cytometry to analyze NK cells from the liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir and compared with samples from the blood of 13 healthy individuals (controls). Serum levels of chemokine C-X-C motif ligand (CXCL) 10 or CXCL11 were measured by enzyme-linked immunosorbent assay. RESULTS: Before treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFN gamma and tumor necrosis factor alpha compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (end of treatment). CONCLUSIONS: Direct-acting antiviral-mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFN alpha, which is indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function. C1 [Serti, Elisavet; Chepa-Lotrea, Xenia; Keane, Meghan; Rehermann, Barbara] NIDDK, Immunol Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Serti, Elisavet; Chepa-Lotrea, Xenia; Kim, Yun Ju; Keane, Meghan; Fryzek, Nancy; Liang, T. Jake; Ghany, Marc; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,US Dept HHS, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM rehermann@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, intramural research program FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, intramural research program. NR 30 TC 35 Z9 35 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2015 VL 149 IS 1 BP 190 EP + DI 10.1053/j.gastro.2015.03.004 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CL0DW UT WOS:000356610400034 PM 25754160 ER PT J AU Hirte, H Lheureux, S Fleming, GF Sugimoto, A Morgan, R Biagi, J Wang, L McGill, S Ivy, SP Oza, AM AF Hirte, H. Lheureux, S. Fleming, G. F. Sugimoto, A. Morgan, R. Biagi, J. Wang, L. McGill, S. Ivy, S. P. Oza, A. M. TI A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: A trial of the Princess Margaret, Chicago and California Phase II Consortia SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Recurrence; Cediranib; Phase 2 ID TYROSINE KINASE INHIBITOR; TRIPLE ANGIOKINASE INHIBITOR; PLATINUM-RESISTANT; EPITHELIAL OVARIAN; MAINTENANCE THERAPY; DOUBLE-BLIND; INTRAVENOUS AFLIBERCEPT; CLINICAL-TRIALS; SOLID TUMORS; OPEN-LABEL AB Purpose. Cediranib is a potent multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3. The study was initiated to evaluate the activity of cediranib in patients (pts) with recurrent ovarian, peritoneal or fallopian tube cancer (OC). Methods. Eligible pts had persistent/recurrent OC following one prior platinum-based chemotherapy with measurable disease or progression based on Gynecologic Cancer Inter Group CA-125 criteria. Because of toxicities observed in the first 23 pts, the initial starting dose of oral daily (od) cediranib was reduced from 45 mg to 30 mg. The primary endpoint was objective response rate at 16 weeks. This study was stratified into two arms: platinum-sensitive (PL-S) and platinum-resistant (PL-R). Results. 74 pts were enrolled; 39 were PL-S and 35 PL-R, with a median age of 58 years [31-87]. In PL-S group, 10 (26%) partial responses (PR) and 20 (51%) stable disease (SD) were confirmed while in the PL-R arm there were no confirmed PR and 23 pts (66%) had SD. The main grade 3/4 toxicities observed at the 30 mg starting dose were hypertension (27%), fatigue (20%) and diarrhea (14%). The median progression-free survival for all patients was 4.9 months [3.9-7.0], 7.2 months [4.3-9] for PL-S and 3.7 months [2.6-4.5] for PL-R groups. The median overall survival was 18.9 months (95% CI: 13.5-31.5); 27.7 months [17.8-433] for PL-S and 11.9 months [8.1-18.9] for PL-R groups. Conclusion. Cediranib shows significant activity in recurrent platinum sensitive OC. The toxicities were expected and manageable at the dose of 30 mg od. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hirte, H.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Lheureux, S.; Wang, L.; McGill, S.; Oza, A. M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Fleming, G. F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Sugimoto, A.] London Hlth Sci Ctr, London, ON, Canada. [Morgan, R.] City Hope Med Ctr, Duarte, CA USA. [Biagi, J.] Canc Ctr Southeastern Ontario, Kingston, ON, Canada. [Ivy, S. P.] NCI, Bethesda, MD 20892 USA. RP Oza, AM (reprint author), Univ Toronto, Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM anit.oza@uhn.ca FU NCI-US-CTEP [NO1-CM-62203] FX This trial carried out through the Princess Margaret, Chicago and California Phase II Consortia was supported by funding from the NCI-US-CTEP (NO1-CM-62203). NR 37 TC 15 Z9 16 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 55 EP 61 DI 10.1016/j.ygyno.2015.04.009 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100010 PM 25895616 ER PT J AU Frimer, M Sun, C McAndrew, T Smith, B Harari, A Chen, ZG Mirabello, L Wentzensen, N Goldberg, GL Rodriguez, AC Schiffman, M Burk, RD AF Frimer, Marina Sun, Chang McAndrew, Thomas Smith, Benjamin Harari, Ariana Chen, Zigui Mirabello, Lisa Wentzensen, Nicolas Goldberg, Gary L. Rodriguez, Ana C. Schiffman, Mark Burk, Robert D. TI HPV16 CpG methyl-haplotypes are associated with cervix precancer and cancer in the Guanacaste natural history study SO GYNECOLOGIC ONCOLOGY LA English DT Article DE HPV16; DNA methylation; Cervix cancer; Next generation sequencing ID HUMAN-PAPILLOMAVIRUS INFECTION; DNA METHYLATION; INTRAEPITHELIAL NEOPLASIA; COSTA-RICA; WOMEN; DISCOVERY; PRIMERS; L1; L2 AB Objective. To evaluate HPV16 CpG methylation and methyl-haplotypes and their association with cervix precancer and cancer utilizing massively parallel single molecule next-generation sequencing (NGS). Methods. A nested case-control study of HPV16 positive women was performed in a prospective cohort from Guanacaste, Costa Rica designed to study the natural history of HPV and cervical neoplasia. Controls encompassed 31 women with transient infections; there were 44 cases, including 31 women with CIN3 and 13 with cervical cancer. DNA samples from exfoliated cervical cells were treated with bisulfite and four regions (E6, E2, L2 and L1) were amplified with barcoded primers and tested by NGS. CpG methylation was quantified using a bioinformatics pipeline. Results. Median methylation levels were significantly different between the CIN3 + cases versus controls in the E2, L2, and L1 regions. Methyl-haplotypes, specifically in 5 CpG sites included in the targeted L2 region, with the pattern "- - + - +" had the highest Area Under the Curve value (AUC = 88.40%) observed for CIN3 vs. controls. The most significant CpG site, L2 4277, determined by bisulfite NGS had an AUC = 78.62%. Conclusions. This study demonstrates that NGS of bisulfite treated HPV DNA is a useful and efficient technique to survey rnethylation patterns in HPV16. This procedure provides quantitative information on both individual CpG sites and methyl-haplotypes that identify women with elevated present or subsequent risk for HPV16 CIN3 and cancer. (C) 2015 Elsevier Inc. All rights reserved. C1 [Frimer, Marina; Goldberg, Gary L.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Div Gynecol Oncol, Bronx, NY USA. [Sun, Chang; Chen, Zigui; Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [McAndrew, Thomas; Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. [Smith, Benjamin; Harari, Ariana; Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Mirabello, Lisa; Wentzensen, Nicolas; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rodriguez, Ana C.] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. RP Frimer, M (reprint author), Albert Einstein Coll Med, 1695 Eastchester Rd,Suite 601, Bronx, NY 10461 USA. EM mfrimer@montefiore.org RI Chen, Zigui/E-8490-2017 FU National Cancer Institute [CA78527]; Albert Einstein Cancer Center from the National Cancer Institute [P30CA013330]; Einstein-Montefiore Center for AIDS - NIH [AI-51519] FX This work was supported in part by the National Cancer Institute (CA78527), the Albert Einstein Cancer Center (P30CA013330) from the National Cancer Institute, and the Einstein-Montefiore Center for AIDS funded by the NIH (AI-51519). The authors acknowledge the women who participated in this study and the Guanacaste Project staff. NR 40 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2015 VL 138 IS 1 BP 94 EP 100 DI 10.1016/j.ygyno.2015.05.001 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CL3HN UT WOS:000356841100016 PM 26001326 ER PT J AU Jiang, DK Ma, XP Yu, HJ Cao, GW Ding, DL Chen, HT Huang, HX Gao, YZ Wu, XP Long, XD Zhang, HX Zhang, YJ Gao, Y Chen, TY Ren, WH Zhang, PY Shi, ZQ Jiang, W Wan, B Saiyin, H Yin, JH Zhou, YF Zhai, Y Lu, PX Zhang, HW Gu, XL Tan, AH Wang, JB Zuo, XB Sun, LD Liu, JO Yi, Q Mo, ZN Zhou, GQ Liu, Y Sun, JL Shugart, YY Zheng, SL Zhang, XJ Xu, JF Yu, L AF Jiang, De-Ke Ma, Xiao-Pin Yu, Hongjie Cao, Guangwen Ding, Dong-Lin Chen, Haitao Huang, Hui-Xing Gao, Yu-Zhen Wu, Xiao-Pan Long, Xi-Dai Zhang, Hongxing Zhang, Youjie Gao, Yong Chen, Tao-Yang Ren, Wei-Hua Zhang, Pengyin Shi, Zhuqing Jiang, Wei Wan, Bo Saiyin, Hexige Yin, Jianhua Zhou, Yuan-Feng Zhai, Yun Lu, Pei-Xin Zhang, Hongwei Gu, Xiaoli Tan, Aihua Wang, Jin-Bing Zuo, Xian-Bo Sun, Liang-Dan Liu, Jun O. Yi, Qing Mo, Zengnan Zhou, Gangqiao Liu, Ying Sun, Jielin Shugart, Yin Yao Zheng, S. Lilly Zhang, Xue-Jun Xu, Jianfeng Yu, Long TI Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B SO HEPATOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; SCLEROSIS SUSCEPTIBILITY LOCI; MACULAR DEGENERATION; HEPATOCELLULAR-CARCINOMA; VIRUS INFECTION; KAWASAKI-DISEASE; IMMUNE-SYSTEM; RISK LOCI; HLA-DO; POLYMORPHISM AB Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], P-meta=1.28 x 10(-34); and rs422951 [T320A] in NOTCH4, P-meta=5.33 x 10(-16)); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, P-meta=1.04 x 10(-23)); and one noncoding variant (rs2853953 near HLA-C, P-meta=5.06 x 10(-20)). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, P-meta=2.95 x 10(-15)). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 x 10(-71)P(meta)9.92 x 10(-7)). Conclusion: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease. (Hepatology 2015;62:118-128) C1 [Jiang, De-Ke; Ma, Xiao-Pin; Ding, Dong-Lin; Chen, Haitao; Huang, Hui-Xing; Zhang, Pengyin; Shi, Zhuqing; Jiang, Wei; Wan, Bo; Saiyin, Hexige; Zheng, S. Lilly; Xu, Jianfeng; Yu, Long] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200438, Peoples R China. [Jiang, De-Ke; Chen, Haitao; Zhang, Pengyin; Shi, Zhuqing; Zheng, S. Lilly; Xu, Jianfeng] Fudan Univ, Sch Life Sci, Key Lab Contemporary Anthropol, Minist Educ, Shanghai 200433, Peoples R China. [Jiang, De-Ke; Chen, Haitao; Zhang, Pengyin; Shi, Zhuqing; Xu, Jianfeng] Fudan Univ, Sch Life Sci, Ctr Genet Epidemiol, Shanghai 200433, Peoples R China. [Jiang, De-Ke; Chen, Haitao; Zhang, Pengyin; Shi, Zhuqing; Xu, Jianfeng] Fudan Univ, Sch Publ Hlth, Ctr Genet Translat Med & Prevent, Shanghai 200433, Peoples R China. [Jiang, De-Ke; Sun, Jielin; Zheng, S. Lilly] Wake Forest Univ, Sch Med, Ctr Canc Genom, Winston Salem, NC 27109 USA. [Yu, Hongjie] Zhejiang Univ, Coll life Sci, James D Watson Inst Genome Sci, Hangzhou 310003, Zhejiang, Peoples R China. [Cao, Guangwen; Yin, Jianhua; Zhang, Hongwei] Second Mil Med Univ, Dept Epidemiol, Shanghai, Peoples R China. [Gao, Yu-Zhen] Soochow Univ, Coll Med, Dept Forens Med, Suzhou, Peoples R China. [Wu, Xiao-Pan; Liu, Ying] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [Wu, Xiao-Pan; Liu, Ying] Peking Union Med Coll, Sch Basic Med, Beijing 100021, Peoples R China. [Long, Xi-Dai; Zhou, Yuan-Feng] Youjiang Med Coll Nationalities, Dept Pathol, Youjiang, Guangxi, Peoples R China. [Zhang, Hongxing; Zhai, Yun; Gu, Xiaoli; Zhou, Gangqiao] Beijing Inst Radiat Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing, Peoples R China. [Zhang, Youjie; Gao, Yong; Tan, Aihua; Mo, Zengnan] Guangxi Med Univ, Affiliated Hosp 1, Inst Urol & Nephrol, Nanning, Peoples R China. [Zhang, Youjie; Gao, Yong; Tan, Aihua; Mo, Zengnan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning, Peoples R China. [Chen, Tao-Yang; Lu, Pei-Xin] Qidong Peoples Hosp, Qidong Liver Canc Inst, Qidong, Peoples R China. [Ren, Wei-Hua] Zhengzhou Univ, Luoyang Cent Hosp, Luoyang, Peoples R China. [Zuo, Xian-Bo; Sun, Liang-Dan; Zhang, Xue-Jun] Anhui Med Univ, Hosp 1, Inst Dermatol, Hefei, Peoples R China. [Zuo, Xian-Bo; Sun, Liang-Dan; Zhang, Xue-Jun] Anhui Med Univ, Hosp 1, Dept Dermatol, Hefei, Peoples R China. [Zuo, Xian-Bo; Sun, Liang-Dan; Zhang, Xue-Jun] Minist Natl Sci & Technol, State Key Lab Incubat Base Dermatol, Hefei, Peoples R China. [Liu, Jun O.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Yi, Qing] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Yi, Qing] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Houston, TX 77030 USA. [Yi, Qing] Univ Texas MD Anderson Canc Ctr, Ctr Canc Immunol Res, Houston, TX 77030 USA. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Zheng, S. Lilly; Xu, Jianfeng] NorthShore Univ Hlth Syst, Program Personalized Canc Care, Evanston, IL USA. [Yu, Long] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. RP Jiang, DK (reprint author), Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200438, Peoples R China. EM dekejiang@fudan.edu.cn; jxu@wakehealth.edu; longyu@fudan.edu.cn RI Zhang, Youjie/F-7346-2016 OI Zhang, Youjie/0000-0002-6035-8536 FU National Natural Science Foundation of China for Creative Research Groups [30024001]; National Key Sci-Tech Special Project of China [2008ZX10002-020, 2013ZX10002010]; Shanghai Municipal Science and Technology Commission; National Natural Science Foundation of China [31071193, 31100895, 81472618]; Director Foundation of the State Key Laboratory of Genetic Engineering; State Key Laboratory of Genetic Engineering, Fudan University; Fund from Chang-An Capital; Tianying S.T Group Co., Ltd.; Beijing Xinhong Investment Group Co. Ltd.; Fong's Family Foundation; Fong Shu Fook Tong Foundation; MOE Foundation of Cheung Kong Scholars Program; Fudan University; Huashan Hospital, Fudan University; Fudan-VARI Center for Genetic Epidemiology, Fudan University; Fund from Dasan Li; Fund from Tseng Tao Chen FX The study is supported by the National Natural Science Foundation of China for Creative Research Groups (30024001; to L.Y.), the National Key Sci-Tech Special Project of China (2008ZX10002-020 and 2013ZX10002010; to L.Y.), the Project of the Shanghai Municipal Science and Technology Commission (to L.Y.), the National Natural Science Foundation of China (31071193 [to L.Y.], 31100895, and 81472618 [to D.-K.J.]), Director Foundation of the State Key Laboratory of Genetic Engineering (to L.Y.), the Research Fund of the State Key Laboratory of Genetic Engineering, Fudan University (to L.Y.), the Fund from Chang-An Capital (to L.Y.), the Fund from Tianying S.T Group Co., Ltd. (to L.Y.), the Fund from Beijing Xinhong Investment Group Co. Ltd. (to L.Y.), the Fund from Runhua Fang, Dasan Li, and Tseng Tao Chen (to L.Y.), Fong's Family Foundation and Fong Shu Fook Tong Foundation (to L.Y.), MOE Foundation of Cheung Kong Scholars Program (to J.L. and Q.Y.), Outstanding Young Scholar Project of Fudan University (to D.-K.J.), as well as an intramural research grant for new young teachers from Fudan University (to D.-K.J.), an intramural research grant for promotion of the scientific research ability of young teachers from Fudan University (to D.-K.J.), an intramural research grant from Huashan Hospital, Fudan University (to J.X.), and an intramural research grant from Fudan-VARI Center for Genetic Epidemiology, Fudan University (to J.X.). NR 43 TC 5 Z9 6 U1 5 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2015 VL 62 IS 1 BP 118 EP 128 DI 10.1002/hep.27794 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CL3QH UT WOS:000356864800018 PM 25802187 ER PT J AU Jao, J Freimanis, L Mussi-Pinhata, MM Cohen, RA Monteiro, JP Cruz, ML Sperling, RS Branch, A Siberry, GK AF Jao, Jennifer Freimanis, Laura Mussi-Pinhata, Marisa M. Cohen, Rachel A. Monteiro, Jacqueline P. Cruz, Maria L. Sperling, Rhoda S. Branch, Andrea Siberry, George K. CA NISDI LILAC Protocol TI Low vitamin D status among pregnant Latin American and Caribbean women with HIV Infection SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Caribbean; HIV; Latin America; Pregnancy; Vitamin D ID 25-HYDROXYVITAMIN D CONCENTRATION; D DEFICIENCY; D SUPPLEMENTATION; D INSUFFICIENCY; MOTHERS; POPULATION; RISK; PREVALENCE; METABOLISM; TANZANIA AB Objective: To evaluate the prevalence and predictors of low vitamin D status among pregnant women with HIV infection. Methods: The present cross-sectional study analyzed repository specimens collected at 12-34 weeks of pregnancy among women enrolled across 17 sites in Latin America and the Caribbean between 2002 and 2009. Logistic regression modeling was used to identify factors associated with low vitamin D status (25-hydroxyvitamin D <30 ng/mL). Results: Among 715 women, 218 (30.5%) were vitamin D deficient (<20 ng/mL) and 252 (35.2%) were insufficient (21-29 ng/mL). Factors associated with low vitamin D status included residence in subtropical latitudes (adjusted odds ratio [aOR] 1.97,95% confidence interval [CI] 1.35-2.88), assessment during non-summer seasons (autumn: aOR 1.85, 95% CI 1.20-2.86; spring: 43,2.65-6.95; winter: 10.82, 5.74-20.41), employment (aOR 1.56, 95% CI 1.06-238), and assessment before 20 weeks of pregnancy (aOR 1.89, 95% CI 1.18-3.06). Factors protective against low vitamin D status were CD4 count below 200 cells per mm(3) (aOR 0.45, 95% CI 0.26-0.77) and protease inhibitors (aOR 0.62, 95% CI 0.40-0.95). Conclusion: Low vitamin D status was prevalent among pregnant women with HIV infection. Further studies are warranted to identify the impact of low maternal vitamin D status. (C) 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Jao, Jennifer; Branch, Andrea] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Jao, Jennifer; Sperling, Rhoda S.] Icahn Sch Med Mt Sinai, Dept Obstet Gynecol & Reprod Sci, New York, NY 10029 USA. [Freimanis, Laura; Cohen, Rachel A.] Westat Corp, Rockville, MD USA. [Mussi-Pinhata, Marisa M.; Monteiro, Jacqueline P.] Univ Sao Paulo, Fac Med, BR-14049 Ribeirao Preto, Brazil. [Cruz, Maria L.] Hosp Fed Servidores Estado, Serv Doencas Infecciosas & Parasitarias, Rio De Janeiro, Brazil. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. RP Jao, J (reprint author), Icahn Sch Med Mt Sinai, Dept Med, One Gustave L Levy Pl,Box 1087, New York, NY 10029 USA. EM jenniferjao@mssm.edu RI Monteiro, Jacqueline/F-6987-2012 FU National Institutes of Health [N01-HD-3-3345, HHSN267200800001C, N01-HD-8-0001]; Abbott Laboratories; NICHD [K23HD070760] FX The present study was supported by the National Institutes of Health (Eunice Kennedy Shriver NICHD contract N01-HD-3-3345 [2002-2007] and NICHD contract HHSN267200800001C [NICHD control N01-HD-8-0001] [2007-2012]) and by Abbott Laboratories. J.J. is supported by NICHD K23HD070760. NR 33 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD JUL PY 2015 VL 130 IS 1 BP 54 EP 58 DI 10.1016/j.ijgo.2015.01.017 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CL5DH UT WOS:000356979500013 PM 25912414 ER PT J AU Wintermark, M Luby, M Bornstein, NM Demchuk, A Fiehler, J Kudo, K Lees, KR Liebeskind, DS Michel, P Nogueira, RG Parsons, MW Sasaki, M Wardlaw, JM Wu, O Zhang, WW Zhu, GM Warach, SJ AF Wintermark, Max Luby, Marie Bornstein, Natan M. Demchuk, Andrew Fiehler, Jens Kudo, Kohsuke Lees, Kennedy R. Liebeskind, David S. Michel, Patrik Nogueira, Raul G. Parsons, Mark W. Sasaki, Makoto Wardlaw, Joanna M. Wu, Ona Zhang, Weiwei Zhu, Guangming Warach, Steven J. TI International survey of acute Stroke imaging used to make revascularization treatment decisions SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE CT; MRI; penumbra; perfusion imaging; stroke; vascular imaging ID ACUTE ISCHEMIC-STROKE; ENDOVASCULAR TREATMENT; TRIAL AB BackgroundTo assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. MethodsSTroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies. ResultsWe received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (IV) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) . ConclusionThere were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning. C1 [Wintermark, Max] Stanford Univ, Dept Radiol, Neuroradiol, Palo Alto, CA 94304 USA. [Luby, Marie] NINDS, NIH, Bethesda, MD 20892 USA. [Luby, Marie; Warach, Steven J.] UT Southwestern Med Ctr, Dept Neurol & Neurotherapeut, Seton UT Southwestern Clin Res Inst Austin, Austin, TX USA. [Bornstein, Natan M.] Tel Aviv Univ, Sackler Fac Med, Dept Neurol, Elias Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Demchuk, Andrew] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Demchuk, Andrew] Univ Calgary, Hotchkiss Brain Inst, Dept Radiol, Calgary, AB, Canada. [Fiehler, Jens] Univ Med Ctr Hamburg Eppendorf, Dept Neuroradiol, Hamburg, Germany. [Kudo, Kohsuke] Hokkaido Univ Hosp, Dept Diagnost Radiol, Sapporo, Hokkaido 060, Japan. [Lees, Kennedy R.] Univ Glasgow, Western Infirm, Univ Dept Med & Therapeut, Glasgow G11 6NT, Lanark, Scotland. [Liebeskind, David S.] Univ Calif Los Angeles, Dept Neurol, Stroke Ctr, Los Angeles, CA 90024 USA. [Michel, Patrik] Univ Lausanne, CHU Vaudois, Lausanne, Switzerland. [Nogueira, Raul G.] Emory Univ, Sch Med, Marcus Stroke & Neurosci Ctr, Atlanta, GA USA. [Parsons, Mark W.] Univ Newcastle, Dept Neurol, John Hunter Hosp, Med Res Inst, Newcastle, NSW 2300, Australia. [Sasaki, Makoto] Iwate Med Univ, Inst Biomed Sci, Yahaba, Iwate, Japan. [Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Brain Res Imaging Ctr, Div Neuroimaging Sci, Edinburgh, Midlothian, Scotland. [Wu, Ona] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Wu, Ona] Harvard Univ, Sch Med, Boston, MA USA. [Zhang, Weiwei; Zhu, Guangming] Beijing PLA, Mil Gen Hosp, Dept Neurol, Beijing, Peoples R China. RP Wintermark, M (reprint author), UVA Dept Radiol, Neuroradiol Div, Radiol Neurol Neurosurg & Biomed Engn, Box 800170, Charlottesville, VA 22908 USA. EM Max.Wintermark@gmail.com RI Michel, Patrik/Q-2275-2016; OI Michel, Patrik/0000-0003-4954-7579; Wintermark, Max/0000-0002-6726-3951 FU Intramural NIH HHS [Z99 NS999999] NR 7 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD JUL PY 2015 VL 10 IS 5 BP 759 EP 762 DI 10.1111/ijs.12491 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CL1QD UT WOS:000356718000030 PM 25833105 ER PT J AU Klauer, SG Ehsani, JP McGehee, DV Manser, M AF Klauer, Sheila G. Ehsani, Johnathon P. McGehee, Daniel V. Manser, Michael TI The Effect of Secondary Task Engagement on Adolescents' Driving Performance and Crash Risk SO JOURNAL OF ADOLESCENT HEALTH LA English DT Review ID TRIGGERED VIDEO INTERVENTION; TEENAGE DRIVERS; NOVICE; BEHAVIOR; DISTRACTION AB Purpose: The purpose of this review was to synthesize the evidence of the effects of secondary task engagement on novice adolescent's driving performance and crash risk. Methods: Searches of multiple databases were conducted using search terms related to secondary task engagement and teenage drivers. Articles were selected for inclusion if they were: written in English, an empirical study assessing the impact of secondary task engagement on driving, and included study participants who were licensed drivers between the ages of 14 and 17 years (if research was conducted in the United States) or within 18 months licensure in other countries. Thirty-eight abstracts were reviewed. Results: Fifteen studies met the inclusion criteria. Most studies examined the effects of electronic device use as the secondary task. Effects were assessed using crash databases, simulator, instrumented vehicle, and naturalistic driving studies. Texting resulted in increased lane deviations and eyes off road time in simulated driving, whereas talking on a cell phone had little effect. Naturalistic studies, which use vehicle instrumentation to measure actual driving, found secondary tasks that required drivers to look away from the forward roadway also increased the risk of crashes and near-crashes for young novice drivers, whereas tasks that did not require eyes to be off the forward roadway (e.g., talking on cell phone) had no effect on crash risk. Conclusions: Methodological differences in the definition and measurement of driving performance make it difficult to directly compare findings, even among the limited number of studies conducted. Despite this, results suggest that secondary tasks degrade driving performance and increase risk only when they require drivers to look away from the forward roadway. Future research needs to focus more explicitly on the ways in which secondary task engagement influences drivers' behavior (e.g., interfering with information acquisition or manual control of the vehicle). This, along with the use of standard measures across studies, would build a more useful body of literature on this topic. (C) 2015 Society for Adolescent Health and Medicine. All rights reserved. C1 [Klauer, Sheila G.] Virginia Tech, Transportat Inst, Blacksburg, VA 24061 USA. [Ehsani, Johnathon P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [McGehee, Daniel V.] Univ Iowa, Publ Policy Ctr, Iowa City, IA USA. [Manser, Michael] Texas A&M Transportat Inst, College Stn, TX USA. RP Klauer, SG (reprint author), Virginia Tech, Transportat Inst, Blacksburg, VA 24061 USA. EM cklauer@vtti.vt.edu RI Emchi, Karma/Q-1952-2016 FU NIH Office of Disease Prevention FX The authors are grateful to Mr. Larry Thompson, Librarian, College of Engineering, Virginia Tech who conducted the literature search. Sincere appreciation also to Dr. Rob Foss and Whitney Atkins for their technical editing of this article. This work was funded in part by the NIH Office of Disease Prevention. NR 35 TC 2 Z9 2 U1 4 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2015 VL 57 IS 1 SU S BP S36 EP S43 DI 10.1016/j.jadohealth.2015.03.014 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA CL2KS UT WOS:000356773200005 PM 26112736 ER PT J AU Ouimet, MC Pradhan, AK Brooks-Russell, A Ehsani, JP Berbiche, D Simons-Morton, BG AF Ouimet, Marie Claude Pradhan, Anuj K. Brooks-Russell, Ashley Ehsani, Johnathon P. Berbiche, Djamal Simons-Morton, Bruce G. TI Young Drivers and Their Passengers: A Systematic Review of Epidemiological Studies on Crash Risk SO JOURNAL OF ADOLESCENT HEALTH LA English DT Review ID 16-AND 17-YEAR-OLD DRIVERS; OLDER DRIVERS; TEENAGE PASSENGERS; VEHICLE; INJURY; COLLISION; SAFETY; RATES; AGE AB Purpose: A systematic review of the literature was conducted to appraise the evidence from epidemiological studies of crash risk in young drivers accompanied by passengers, compared with solo driving. Methods: Databases searched were the Cochrane Library, Embase, Scopus, Transportation Research Information Services, and Web of Science for studies published between January 1, 1989 and August 1, 2013. Epidemiological studies were selected for review if they focused on crashes of young drivers (<= 24 years old) and included both a no-passenger comparison group and some measure of exposure to enable calculation of estimates. Results: Fifteen articles (17 studies) were selected; seven studies reported on fatal crashes and 10 on nonfatal or combined fatal/nonfatal crashes. Studies on fatal crashes showed increased risk, compared with solo driving, for young drivers with at least one passenger (significant estimates ranging from 1.24 to 1.89) and two or more passengers versus solo driving (1.70-2.92). Increased risk was also found for fatal crashes and for combined or nonfatal crashes with male versus female passengers (1.53-2.66) and for younger versus older drivers (1.42-3.14). Conclusions: Results more clearly indicated an increased risk for passenger presence in fatal crashes than that in nonfatal or combined fatal/nonfatal crashes. Findings of this review, based on correlational studies, support licensing policies that limit the presence and number of young passengers for young drivers. (C) 2015 Society for Adolescent Health and Medicine. All rights reserved. C1 [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ J4K 0A8, Canada. [Ouimet, Marie Claude; Berbiche, Djamal] Charles Lemoyne Hosp, Res Ctr, Longueuil, PQ, Canada. [Pradhan, Anuj K.] Univ Michigan, Transportat Res Inst, Ann Arbor, MI 48109 USA. [Brooks-Russell, Ashley] Univ Colorado, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Aurora, CO USA. [Ehsani, Johnathon P.; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Ouimet, MC (reprint author), Univ Sherbrooke, Fac Med & Hlth Sci, 150,Pl Charles Le Moyne,Suite 200, Longueuil, PQ J4K 0A8, Canada. EM marie.claude.ouimet@usherbrooke.ca RI kiaie, robabeh/I-2157-2016; kiaie, fatemeh/I-6083-2016; OI kiaie, robabeh/0000-0001-5251-3201; Pradhan, Anuj/0000-0002-7612-4208; Simons-Morton, Bruce/0000-0003-1099-6617 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Quebec Health Research Fund (Fonds de Recherche du QuebecdSante) FX This research was supported in part by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. M.C.O. was supported through a career award from the Quebec Health Research Fund (Fonds de Recherche du QuebecdSante). NR 28 TC 2 Z9 2 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2015 VL 57 IS 1 SU S BP S24 EP + DI 10.1016/j.jadohealth.2015.03.010 PG 18 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA CL2KS UT WOS:000356773200004 PM 26112735 ER PT J AU Chiao, D Ksendzovsky, A Buell, T Sheehan, J Newman, S Wintermark, M AF Chiao, David Ksendzovsky, Alexander Buell, Thomas Sheehan, Jason Newman, Steven Wintermark, Max TI Intraventricular migration of silicone oil: A mimic of traumatic and neoplastic pathology SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Complications; Extraocular; Imaging; Intraocular; Intraventricular; Oil; Silicone ID SYSTEM AB We describe an 80-year-old woman with intraventricular silicone oil mimicking traumatic pathology upon presentation to the emergency department after a ground-level fall. Intraventricular migration of silicone oil from prior intraocular endotamponade is rare having only been described in a handful of case reports. While it has a unique and characteristic appearance on imaging, intraventricular silicone oil can be confused with intraventricular hemorrhage or calcified ventricular neoplasms. Recognition and differentiation of intraventricular silicone oil from more sinister pathology is essential for the radiologist, neurologist and neurosurgeon and can be done with routine head CT scan. We discuss the imaging findings of intraventricular silicone oil and review the current understanding of this unusual phenomenon. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Chiao, David] Univ Virginia, Dept Radiol & Med Imaging, Neuroradiol Div, Charlottesville, VA 22908 USA. [Ksendzovsky, Alexander; Buell, Thomas; Sheehan, Jason; Newman, Steven] Univ Virginia, Dept Neurosurg, Charlottesville, VA 22908 USA. [Newman, Steven] Univ Virginia, Dept Opthalmol, Charlottesville, VA 22908 USA. [Ksendzovsky, Alexander] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Wintermark, Max] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. RP Chiao, D (reprint author), Univ Virginia, Dept Radiol & Med Imaging, Neuroradiol Div, 1215 Lee St,POB 800170, Charlottesville, VA 22908 USA. EM dsc5z@virginia.edu OI Wintermark, Max/0000-0002-6726-3951 NR 16 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD JUL PY 2015 VL 22 IS 7 BP 1205 EP 1207 DI 10.1016/j.jocn.2015.02.003 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK9KE UT WOS:000356558200031 PM 25863996 ER PT J AU Thacker, SG Rousset, X Esmail, S Zarzour, A Jin, XT Collins, HL Sampson, M Stonik, J Demosky, S Malide, DA Freeman, L Vaisman, BL Kruth, HS Adelman, SJ Remaley, AT AF Thacker, Seth G. Rousset, Xavier Esmail, Safiya Zarzour, Abdalrahman Jin, Xueting Collins, Heidi L. Sampson, Maureen Stonik, John Demosky, Stephen Malide, Daniela A. Freeman, Lita Vaisman, Boris L. Kruth, Howard S. Adelman, Steven J. Remaley, Alan T. TI Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lecithin:cholesterol acyltransferase; scavenger receptor class B member I; knockout ID HIGH-DENSITY-LIPOPROTEIN; RECEPTOR-DEFICIENT MICE; CORONARY-ARTERY-DISEASE; APOLIPOPROTEIN-E; TRANSGENIC MICE; CARDIOVASCULAR-DISEASE; EFFLUX CAPACITY; HUMAN LECITHIN; LECITHINCHOLESTEROL ACYLTRANSFERASE; ERYTHROCYTE-MEMBRANE AB LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over-and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab (-/-)] mice, which have a secondary defect in cholesterol esterification. Scarab (-/-) xLCAT-null [Lcat (-/-)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 +/- 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab (-/-) x LCAT -transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 +/- 0.005). Plasma from Scarab (-/-) x LCAT -Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab (-/-) x LCAT -Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab (-/-) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles. C1 [Thacker, Seth G.; Rousset, Xavier; Esmail, Safiya; Zarzour, Abdalrahman; Stonik, John; Demosky, Stephen; Freeman, Lita; Vaisman, Boris L.; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Jin, Xueting; Kruth, Howard S.] NHLBI, Expt Atherosclerosis Sect, Ctr Mol, NIH, Bethesda, MD 20892 USA. [Malide, Daniela A.] NHLBI, Light Microscopy Core, NIH, Bethesda, MD 20892 USA. [Collins, Heidi L.; Adelman, Steven J.] Vasc Strategies LLC, Plymouth Meeting, PA 19462 USA. [Sampson, Maureen] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NHLBI, Lipoprot Metab Sect, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov FU intramural National Heart, Lung, and Blood Institute, National Institutes of Health funds FX This research was supported by intramural National Heart, Lung, and Blood Institute, National Institutes of Health funds. NR 83 TC 7 Z9 7 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2015 VL 56 IS 7 BP 1282 EP 1295 DI 10.1194/jlr.M048629 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CL3FB UT WOS:000356834700006 PM 25964513 ER PT J AU Vitiello, B Lazzaretto, D Yershova, K Abikoff, H Paykina, N McCracken, JT McGough, JJ Kollins, SH Greenhill, LL Wigal, S Wigal, T Riddle, MA AF Vitiello, Benedetto Lazzaretto, Deborah Yershova, Kseniya Abikoff, Howard Paykina, Natalya McCracken, James T. McGough, James J. Kollins, Scott H. Greenhill, Laurence L. Wigal, Sharon Wigal, Tim Riddle, Mark A. TI Pharmacotherapy of the Preschool ADHD Treatment Study (PATS) Children Growing Up SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; preschoolers; medication; stimulant ID ATTENTION-DEFICIT/HYPERACTIVITY-DISORDER; ANTIPSYCHOTIC USE; METHYLPHENIDATE; CONTINUITY AB Objective: To describe the long-term psychopharmacological treatment of children first diagnosed with attention-deficit/hyperactivity disorder (ADHD) as preschoolers. Method: In a systematic, prospective, naturalistic followup, 206 (68.0%) of the 303 children who participated in the Preschool ADHD Treatment Study (PATS) were reassessed 3 years (mean age 7.4 years) and 179 (59.1%) were reassessed 6 years (mean age 10.4 years) after completion of the controlled study. Pharmacotherapy and clinical data were obtained from the parents. Pharmacotherapy was defined as use of a specific class of medication for at least 50% of the days in the previous 6 months. Results: At year 3, a total of 34.0% of the participants were on no pharmacotherapy, 41.3% were on stimulant monotherapy, 9.2% were on atomoxetine alone or with a stimulant, 8.3% were on an antipsychotic usually together with a stimulant, and the remaining 7.2% were on other pharmacotherapy; overall, 65.0% were on an indicated ADHD medication. At year 6, a total of 26.8% of the participants were on no pharmacotherapy, 40.2% were on stimulant monotherapy, 4.5% were on atomoxetine alone or with a stimulant, 13.4% were on an antipsychotic, and 15.1% were on other pharmacotherapy; overall, 70.9% were on an indicated ADHD medication. Antipsychotic treatment was associated with more comorbidity, in particular disruptive behavior disorders and pervasive development disorders, and a lower level of functioning. Conclusion: In this study, the long-term pharmacotherapy of preschoolers with ADHD was heterogeneous. Although stimulant medication continued to be used by most children, about 1 child in 4 was off medication, and about 1 in 10 was on an antipsychotic. C1 [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Yershova, Kseniya; Paykina, Natalya; Greenhill, Laurence L.] Columbia Univ, Med Ctr, New York, NY USA. [Yershova, Kseniya; Paykina, Natalya; Greenhill, Laurence L.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Abikoff, Howard] NYU, Sch Med, New York, NY USA. [McCracken, James T.; McGough, James J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Kollins, Scott H.] Duke Univ, Sch Med, Durham, NC USA. [Wigal, Sharon; Wigal, Tim] Univ Calif Irvine, Irvine, CA USA. [Riddle, Mark A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Vitiello, B (reprint author), NIMH, DSIR, Room 7147,6001 Execut Blvd,MSC 9633, Bethesda, MD 20892 USA. EM bvitiell@nih.gov FU NIMH; Duke University Medical Center [U01MH60848]; Johns Hopkins University [U01 MH60642]; New York University Child Study Center [U01 MH60943]; NYSPI/Columbia University [U01 MH60833]; University of California, Irvine [U01 MH60833]; University of California, Los Angeles [U01 MH60900]; National Institutes of Health (NIH); American Physician Institute for Advanced Professional Studies; Multi-Health Systems, School Specialty/Premier, Inc.; Guilford Press; Roche; Seaside Pharmaceuticals; NIH; NeuroSigma, Inc.; Purdue Pharma LP; Shire Pharmaceuticals; Akili Interactive; Alcobra Pharmaceuticals; Atentiv; Ironshore Pharmaceuticals; Arbor Pharmaceuticals; NEOS Pharmaceuticals; Purdue Canada; Rhodes Pharmaceuticals; Sunovion Pharmaceuticals; Tris Pharma; National Institutes of Health (NIDA, NIEHS); Center for Scientific Review; Environmental Protection Agency; American Academy of Child and Adolescent Psychiatry; REACH Institute; Klingenstein Third Generation Foundation; Health Information Technology Laboratory; Forest; Ironshore; NextWave Pharmaceuticals; Noven; NuTec; Pfizer; Purdue Pharma; Rho; LLP; Shire; Sunovion; Tris Pharma Reviews FX This research was supported by a cooperative agreement between NIMH and the following institutions Duke University Medical Center (U01MH60848), Johns Hopkins University (U01 MH60642), New York University Child Study Center (U01 MH60943), NYSPI/Columbia University (U01 MH60833), University of California, Irvine (U01 MH60833), and University of California, Los Angeles (U01 MH60900).; Dr. Vitiello has received salary support from the National Institutes of Health (NIH), income from private practice, and consultant fees from the American Physician Institute for Advanced Professional Studies. Dr. Abikoff has received an NIMH research grant and royalties from Multi-Health Systems, School Specialty/Premier, Inc., and Guilford Press. Dr. McCracken has received NIMH research grant and contract funds, consultant income from Roche, research contract support from Seaside Pharmaceuticals and Roche, speaker honoraria from the Tourette Syndrome Association, and study drug and placebo from Shire Dr. McGough has received grant or research support from NIH, NeuroSigma, Inc., Purdue Pharma LP, and Shire Pharmaceuticals. He has served as consultant to Akili Interactive Labs, Merck, Neurovance, and Sunovion. He has presented expert testimony for Shire Pharmaceuticals. Dr. Kollins has received research support and/or consulting fees from the following sources: Akili Interactive, Alcobra Pharmaceuticals, Atentiv, Ironshore Pharmaceuticals, Arbor Pharmaceuticals, NEOS Pharmaceuticals, Purdue Canada, Rhodes Pharmaceuticals, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Tris Pharma, the National Institutes of Health (NIDA, NIEHS), the Center for Scientific Review, and the Environmental Protection Agency Dr. Greenhill has received honoraria or consultation fees from the American Academy of Child and Adolescent Psychiatry, the REACH Institute, the Klingenstein Third Generation Foundation, and the Health Information Technology Laboratory, and has been on the scientific advisory board of Quotient I Pearson NCS Systems. Dr. S. Wigal is co-owner of Avida, Inc., and has served as a consultant/on the speaker or advisory boards for and/or has received grant/research support from Forest, Ironshore, NextWave Pharmaceuticals, Noven, NuTec, Pfizer, Purdue Pharma, Rho, Rhodes Pharmaceuticals, LLP, Shire, Sunovion, and Tris Pharma. Dr. T. Wigal is co-owner of Avida, Inc., and has served as a consultant/on the speaker or advisory boards for and/or has received grant/research support from Forest, Ironshore, NextWave Pharmaceuticals, Noven, NuTec, Pfizer, Purdue Pharma, Rho, Rhodes Pharmaceuticals, LLP, Shire, Sunovion, Tris Pharma Reviews, and the Environmental Protection Agency Dr Riddle has received research support from NIMH, medication from Bristol Myers Squibb for an NIMH-sponsored research study, and honoraria from the REACH Institute. Ms. Lazzaretto has received professional contra et funds from NIMH. Dr. Yershova and Ms. Paykina report no biomedical financial interests or potential conflicts of interest NR 19 TC 2 Z9 2 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2015 VL 54 IS 7 BP 550 EP 556 DI 10.1016/j.jaac.2015.04.004 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CL5ER UT WOS:000356983100007 PM 26088659 ER PT J AU Verlinden, M Jansen, PW Veenstra, R Jaddoe, VWV Hofman, A Verhulst, FC Shaw, P Tiemeier, H AF Verlinden, Marina Jansen, Pauline W. Veenstra, Rene Jaddoe, Vincent W. V. Hofman, Albert Verhulst, Frank C. Shaw, Philip Tiemeier, Henning TI Preschool Attention-Deficit/Hyperactivity and Oppositional Defiant Problems as Antecedents of School Bullying SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bullying; victimization; children; ADHD; ODD ID DEFICIT-HYPERACTIVITY DISORDER; EARLY ELEMENTARY-SCHOOL; ONSET CONDUCT PROBLEMS; DISRUPTIVE BEHAVIOR; PEER VICTIMIZATION; YOUTH VIOLENCE; SOCIAL-SKILLS; ADULT HEALTH; GENERATION R; CHILDHOOD AB Objective: To examine whether early manifestations of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) increase children's later risk of bullying or victimization. Method: Using a population-based, prospective cohort, our multi-informant approach comprised reports of parents, teachers, and peers. ADHD and ODD behavioral problems at ages 1.5, 3, and 5 years were determined from parental reports on the Child Behavior Checklist. Later bullying behavior at school was reported by teachers using a questionnaire (n = 3,192, mean age 6.6 years), and by peer/self-reports using peer nominations (n = 1,098, mean age 7.6 years). We examined the following: whether problem behavior scores at age 1.5, 3, or 5 years predicted a risk of bullying involvement; and whether high or increasing behavioral problems throughout ages 1.5 to 5 years were associated with bullying involvement at school. Analyses were adjusted for a range of child and maternal covariates. Results: Behavioral problems at a young age each predicted later bullying involvement at school. For example, higher ADHD problem scores at age 3 years were associated with the risks of becoming a bully or a bully-victim (ORBULLY = 1.20, 95% CI = 1.07-1.35 [teacher report], ORBULLY-VICTIM = 1.28, 95% CI = 1.14-1.43 [teacher report], and ORBULLY-VICTIM = 1.35, 95% CI = 1.03-1.78 [peer/self-report]). Children whose behavioral problem scores were high or increased over time consistently had elevated risks of becoming a bully or a bully-victim. Conclusion: Behavioral problems at a young age may predispose children to bullying involvement in early elementary school. C1 [Verlinden, Marina; Jansen, Pauline W.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; Tiemeier, Henning] Erasmus MC, Rotterdam, Netherlands. [Verlinden, Marina; Jaddoe, Vincent W. V.] Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands. [Jansen, Pauline W.] Erasmus Univ, Inst Psychol, NL-3000 DR Rotterdam, Netherlands. [Veenstra, Rene] Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. [Shaw, Philip] NHGRI, Neurobehav Clin Res Sect, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Tiemeier, H (reprint author), Erasmus MC, Dept Child & Adolescent Psychiat, POB 2060, NL-3000 CB Rotterdam, Netherlands. EM h.tiemeier@erasmusmc.nl RI Veenstra, Rene/G-6696-2011 OI Veenstra, Rene/0000-0001-6686-6307 FU Erasmus Medical Center Rotterdam; Netherlands Organization for Health Research and Development (NWO-ZonMw Geestkracht) [10.000.1003]; Netherlands Organization for Scientific Research [VIDI01.7.106.370]; Sophia Foundation for Medical Research SSWO [602]; Intramural Program of the National Institutes of Health FX The Generation R Study is conducted by the Erasmus Medical Center Rotterdam, the Municipal Health Service Rotterdam Area, and the Stichting Trombosedienst en Ansenlaboratorium Rijnmond (STAR), Rotterdam, the Netherlands. Generation R is made possible by financial support from the Erasmus Medical Center Rotterdam, and the Netherlands Organization for Health Research and Development (NWO-ZonMw Geestkracht 10.000.1003). Additional grants were obtained from the Netherlands Organization for Scientific Research (VIDI01.7.106.370 to H.T.), and from the Sophia Foundation for Medical Research SSWO (grant 602 to P.W.J.).; Dr. Verhulst has received remuneration as contributing author of the Achenbach System of Empirically Based Assessment (ASEBA). Dr. Shaw has received grant or research support from the Intramural Program of the National Institutes of Health. Drs. Verlinden, Jansen, Veenstra, Jaddoe, Hofman, and Tiemeier report no biomedical financial interests or potential conflicts of interest. NR 48 TC 1 Z9 1 U1 7 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2015 VL 54 IS 7 BP 571 EP 579 DI 10.1016/j.jaac.2015.05.002 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CL5ER UT WOS:000356983100010 PM 26088662 ER PT J AU Telford, WG AF Telford, William G. TI Near infrared lasers in flow cytometry SO METHODS LA English DT Article DE Flow cytometry; Laser; Near-infrared; Alexa Fluor dyes ID DYES; IMMUNOFLUORESCENCE; FLUORESCENCE; EXCITATION; DIODES; PROBES; RED AB Technology development in flow cytometry has closely tracked laser technology, the light source that flow cytometers almost exclusively use to excite fluorescent probes. The original flow cytometers from the 1970s and 1980s used large water-cooled lasers to produce only one or two laser lines at a time. Modern cytometers can take advantage of the revolution in solid state laser technology to use almost any laser wavelength ranging from the ultraviolet to the near infrared. Commercial cytometers can now be equipped with many small solid state lasers, providing almost any wavelength needed for cellular analysis. Flow cytometers are now equipped to analyze 20 or more fluorescent probes simultaneously, requiring multiple laser wavelengths. Instrument developers are now trying to increase this number by designing fluorescent probes that can be excited by laser wavelength at the "edges" of the visible light range, in the near ultraviolet and near-infrared region. A variety of fluorescent probes have been developed that excite with violet and long wavelength ultraviolet light; however, the near-infrared range (660-800 nm) has yet seen only exploitation in flow cytometry. Fortunately, near-infrared laser diodes and other solid state laser technologies appropriate for flow cytometry have been in existence for some time, and can be readily incorporated into flow cytometers to accelerate fluorescent probe development. The near infrared region represents one of the last "frontiers" to maximize the number of fluorescent probes that can be analyzed by flow cytometry. In addition, near infrared fluorescent probes used in biomedical tracking and imaging could also be employed for flow cytometry with the correct laser wavelengths. This review describes the available technology, including lasers, fluorescent probes and detector technology optimal for near infrared signal detection. Published by Elsevier Inc. C1 NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Telford, WG (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM telfordw@mail.nih.gov FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX The author expresses his gratitude to Molecular Probes Life Technologies, most notably Jolene Bradford and Gayle Buller, for their technical advice regarding NIR fluorochromes. James Jackson at Power Technologies, Inc. provided invaluable consultation on NIR laser diodes. This work was supported by intramural research funds awarded by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. NR 27 TC 4 Z9 4 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JUL 1 PY 2015 VL 82 BP 12 EP 20 DI 10.1016/j.ymeth.2015.03.010 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CL4GN UT WOS:000356910700003 PM 25814439 ER PT J AU McAlees, JW Whitehead, GS Harley, ITW Cappelletti, M Rewerts, CL Holdcroft, AM Divanovic, S Wills-Karp, M Finkelman, FD Karp, CL Cook, DN AF McAlees, J. W. Whitehead, G. S. Harley, I. T. W. Cappelletti, M. Rewerts, C. L. Holdcroft, A. M. Divanovic, S. Wills-Karp, M. Finkelman, F. D. Karp, C. L. Cook, D. N. TI Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation SO MUCOSAL IMMUNOLOGY LA English DT Article ID ALLERGIC-ASTHMA; ENDOTOXIN EXPOSURE; EPITHELIAL-CELLS; MICE; LUNG; HYPERRESPONSIVENESS; LIPOPOLYSACCHARIDE; SEVERITY; SPUTUM; IL-17 AB Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by T helper type 2 (Th2)-driven eosinophilia, whereas others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4(fl/fl) mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens. C1 [McAlees, J. W.; Harley, I. T. W.; Cappelletti, M.; Rewerts, C. L.; Holdcroft, A. M.; Divanovic, S.; Wills-Karp, M.; Finkelman, F. D.; Karp, C. L.] Cincinnati Childrens Hosp Res Fdn, Div Immunobiol, Cincinnati, OH USA. [Whitehead, G. S.; Cook, D. N.] NIEHS, Lab Resp Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Finkelman, F. D.] Cincinnati Vet Affairs Med Ctr, Dept Med, Cincinnati, OH USA. [Finkelman, F. D.] Univ Cincinnati, Sch Med, Dept Internal Med, Div Allergy Immunol & Rheumatol, Cincinnati, OH USA. [Karp, C. L.] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Cook, DN (reprint author), NIEHS, Lab Resp Biol, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM cookd@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); NIEHS; NIH [R01 AI088372, R01 HL094576, F32 HL110497] FX We thank Matt Edin and Michael Fessler (NIEHS) for critical reading of the manuscript and Traci Stankiewicz and Elizabeth Donelan (CCHMC) for technical assistance. This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and the NIEHS (to D.N.C.), NIH R01 AI088372 and R01 HL094576 (to C.L.K.), and F32 HL110497 (to J.W.M.). NR 45 TC 13 Z9 13 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2015 VL 8 IS 4 BP 863 EP 873 DI 10.1038/mi.2014.117 PG 11 WC Immunology SC Immunology GA CL3QP UT WOS:000356865700015 PM 25465099 ER PT J AU Tiniakou, E Mammen, AL AF Tiniakou, Eleni Mammen, Andrew L. TI NECROTIZING MYOPATHY CAUSED BY CENTRAL HYPOTHYROIDISM SO MUSCLE & NERVE LA English DT Letter C1 [Tiniakou, Eleni] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Mammen, Andrew L.] Natl Inst Musculoskeletal & Arthrit & Skin Dis, NIH, Bethesda, MD USA. RP Tiniakou, E (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NR 5 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 2015 VL 52 IS 1 BP 152 EP 153 DI 10.1002/mus.24637 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK8OQ UT WOS:000356498000027 PM 25808401 ER PT J AU Yadav, H Rane, SG AF Yadav, Hariom Rane, Sushil G. TI Dietary fatty acids: Friends or foes? SO OBESITY LA English DT Editorial Material C1 [Yadav, Hariom; Rane, Sushil G.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Rane, SG (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM ranes@mail.nih.gov OI Yadav, Hariom/0000-0003-4504-1597 NR 5 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2015 VL 23 IS 7 BP 1329 EP 1329 DI 10.1002/oby.21141 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CL4AD UT WOS:000356893400002 PM 26110889 ER PT J AU Zhang, SS Chen, GZ Li, N Dai, MY Chen, C Wang, PH Tang, HR Hoopes, SL Zeldin, DC Wang, DW Xu, XZ AF Zhang, Shasha Chen, Guangzhi Li, Ning Dai, Meiyan Chen, Chen Wang, Peihua Tang, Huiru Hoopes, Samantha L. Zeldin, Darryl C. Wang, Dao Wen Xu, Xizhen TI CYP2J2 overexpression ameliorates hyperlipidemia via increased fatty acid oxidation mediated by the AMPK pathway SO OBESITY LA English DT Article ID ACTIVATED PROTEIN-KINASE; HUMAN HEPG2 CELLS; REDUCES INSULIN-RESISTANCE; FRUCTOSE-TREATED RATS; INDUCED DIABETIC MICE; VASCULAR DYSFUNCTION; SIGNALING PATHWAYS; ENDOTHELIAL-CELLS; ARACHIDONIC-ACID; DIET AB ObjectiveThe study aims to investigate the effect of cytochrome P450 2J2 (CYP2J2) overexpression on hyperlipidemia in mice and further to explore its effect on fatty acid oxidation in vivo and in vitro. MethodsThe effects and mechanisms of endothelial-specific CYP2J2 transgene (Tie2-CYP2J2-Tr) on lipid and fatty acid metabolism were investigated in high-fat diet (HFD) -treated mice. HepG2, LO2 cells, and HUVECs were exposed to 0.4 mM free fatty acid (FFA) for 24 h and used as a model to investigate the roles of CYP2J2 overexpression and epoxyeicosatrienoic acids (EETs) on fatty acid -oxidation in vitro. ResultsTie2-CYP2J2-Tr mice had significantly lower plasma and liver triglycerides, lower liver cholesterol and fatty acids, and reduced HFD-induced lipid accumulation. CYP2J2 overexpression resulted in activation of the hepatic and endothelial AMPK, increased ACC phosphorylation, and increased expression of CPT-1 and PPAR, which were all reduced by HFD treatment. In FFA-treated HepG2, LO2, and HUVECs, both CYP2J2 overexpression and EETs significantly decreased lipid accumulation and increased fatty acid oxidation via activating the AMPK and PPAR pathways. ConclusionsEndothelial-specific CYP2J2 overexpression alleviates HFD-induced hyperlipidemia in vivo. CYP2J2 ameliorates FFA-induced dyslipidemia via increased fatty acid oxidation mediated by the AMPK and PPAR pathways. C1 [Zhang, Shasha; Chen, Guangzhi; Dai, Meiyan; Chen, Chen; Wang, Peihua; Wang, Dao Wen; Xu, Xizhen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med,Inst Hypertens, Wuhan 430074, Peoples R China. [Li, Ning; Tang, Huiru] Univ Chinese Acad Sci, State Key Lab Magnet Resonance & Atom & Mol Phys, Key Lab Magnet Resonance Biol Syst, Wuhan Ctr Magnet Resonance,Wuhan Inst Phys & Math, Wuhan, Peoples R China. [Hoopes, Samantha L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med,Inst Hypertens, Wuhan 430074, Peoples R China. EM dwwang@tjh.tjmu.edu.cn; xzxu@tjh.tjmu.edu.cn RI Tang, Huiru/F-9849-2011 OI Tang, Huiru/0000-0002-7139-2756 FU 973 program [2012CB517801]; National Nature Science Foundation Committee of China [81400369, 81471021]; Program for Innovative Research Team of Chinese Ministry of Education [IRT14R20] FX This work was supported by the 973 program (Grant No. 2012CB517801), National Nature Science Foundation Committee of China (Grant Nos. 81400369 and 81471021) and Program for Innovative Research Team of Chinese Ministry of Education (No. IRT14R20). NR 37 TC 6 Z9 6 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2015 VL 23 IS 7 BP 1401 EP 1413 DI 10.1002/oby.21115 PG 13 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CL4AD UT WOS:000356893400013 PM 26053032 ER PT J AU Xiao, CY Goldgof, M Gavrilova, O Reitman, ML AF Xiao, Cuiying Goldgof, Margalit Gavrilova, Oksana Reitman, Marc L. TI Anti-obesity and metabolic efficacy of the 3-adrenergic agonist, CL316243, in mice at thermoneutrality compared to 22 degrees C SO OBESITY LA English DT Article ID BROWN ADIPOSE-TISSUE; ENERGY-EXPENDITURE; BETA(3)-ADRENOCEPTOR AGONISTS; RECEPTOR AGONIST; INDUCED OBESITY; THERMOGENESIS; HOMEOSTASIS; FAT; BALANCE; RATS AB ObjectiveMice are typically housed at environmental temperatures below thermoneutrality, whereas humans live near thermoneutrality. This difference affects energy physiology and, potentially, anti-obesity drug efficacy. Here 3-adrenergic agonist treatment at thermoneutrality (30 degrees C) versus room temperature (22 degrees C) is compared. MethodsMale C57BL/6J mice were singly housed at 30 degrees C or 22 degrees C and treated with vehicle or CL316243, a 3-agonist, for 4 weeks. Food intake, energy expenditure, body and adipose weight, brown adipose activity, white adipose browning, and glucose tolerance were evaluated. CL316243 treatment was studied in both chow- and high-fat diet-fed mice. ResultsMice at 30 degrees C, compared to 22 degrees C, had reduced food intake, metabolic rate, and brown adipose activity, as well as increased adiposity. At both temperatures, CL316243 treatment increased brown adipose activation and energy expenditure and improved glucose tolerance. At 30 degrees C, CL316243 increased energy expenditure disproportionately to changes in food intake, thus reducing adiposity, while at 22 degrees C these changes were matched, yielding unchanged adiposity. ConclusionsCL316243 treatment can have beneficial metabolic effects in the absence of adiposity changes. In addition, the interaction between environmental temperature and CL316243 treatment is different from the interaction between environmental temperature and 2,4-dinitrophenol treatment reported previously, suggesting that each drug mechanism must be examined to understand the effect of environmental temperature on drug efficacy. C1 [Xiao, Cuiying; Goldgof, Margalit; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH [DK075062, DK075064] FX This research was supported by the Intramural Research Program (DK075062, DK075064) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH. NR 40 TC 7 Z9 7 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2015 VL 23 IS 7 BP 1450 EP 1459 DI 10.1002/oby.21124 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CL4AD UT WOS:000356893400018 PM 26053335 ER PT J AU Kelly, NR Shomaker, LB Pickworth, CK Brady, SM Courville, AB Bernstein, S Schvey, NA Demidowich, AP Galescu, O Yanovski, SZ Tanofsky-Kraff, M Yanovski, JA AF Kelly, Nichole R. Shomaker, Lauren B. Pickworth, Courtney K. Brady, Sheila M. Courville, Amber B. Bernstein, Shanna Schvey, Natasha A. Demidowich, Andrew P. Galescu, Ovidiu Yanovski, Susan Z. Tanofsky-Kraff, Marian Yanovski, Jack A. TI A prospective study of adolescent eating in the absence of hunger and body mass and fat mass outcomes SO OBESITY LA English DT Article ID WEIGHT-GAIN; HISPANIC CHILDREN; SELF-REGULATION; ADULT OBESITY; FOOD-INTAKE; HIGH-RISK; GIRLS; OVERWEIGHT; COMPENSATION; PREDICTORS AB ObjectiveEating in the absence of hunger (EAH) refers to the consumption of palatable foods in a sated state. It has been proposed that EAH promotes excess weight gain in youth; yet there are limited prospective data to support this hypothesis. We examined whether EAH at baseline predicted increases in body mass (BMI and BMIz) and fat mass (kg) 1 year later among adolescent boys and girls. MethodsEAH was assessed as adolescents' consumption of palatable snack foods following eating to satiety from an ad libitum lunch buffet. Parents also completed a questionnaire about their children's EAH. Body composition was assessed using air displacement plethysmography. ResultsOf 196 adolescents assessed for EAH at baseline, 163 (83%) were re-evaluated 1 year later. Accounting for covariates, which included respective baseline values for each dependent variable, race, height, age, sex, and pubertal stage, there were no significant associations between baseline observed or parent-reported EAH and change in adolescent BMI, BMIz, or fat mass. Results did not differ by sex, child weight status, or maternal weight status. ConclusionsNo evidence was found to support the hypothesis that EAH is a unique endophenotype for adolescent weight or fat gain. C1 [Kelly, Nichole R.; Shomaker, Lauren B.; Pickworth, Courtney K.; Brady, Sheila M.; Schvey, Natasha A.; Demidowich, Andrew P.; Galescu, Ovidiu; Yanovski, Susan Z.; Tanofsky-Kraff, Marian; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Kelly, Nichole R.; Shomaker, Lauren B.] Colorado State Univ, Ft Collins, CO 80523 USA. [Courville, Amber B.; Bernstein, Shanna] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Schvey, Natasha A.; Tanofsky-Kraff, Marian] USUHS, Dept Med & Clin Psychol, Bethesda, MD USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, NIH, DHHS, 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,DHHS, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Galescu, Ovidiu/0000-0003-0948-645X FU NIH Intramural Research Program Grant from NICHD [1ZIAHD000641]; NIH Bench to Bedside Program; Office of Behavioral and Social Sciences Research; NIH National Research Service Award [F32HD056762]; NICHD [K99/R00HD069516] FX NIH Intramural Research Program Grant 1ZIAHD000641 (J. Yanovski) from NICHD with supplemental funding from the NIH Bench to Bedside Program and the Office of Behavioral and Social Sciences Research; NIH National Research Service Award F32HD056762 and Pathway to Independence Award K99/R00HD069516 (L. Shomaker) from NICHD. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the DHHS, USUHS, or the U.S. Department of Defense. NR 33 TC 0 Z9 0 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2015 VL 23 IS 7 BP 1472 EP 1478 DI 10.1002/oby.21110 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CL4AD UT WOS:000356893400020 PM 26052830 ER PT J AU Aslibekyan, S Demerath, EW Mendelson, M Zhi, D Guan, W Liang, L Sha, J Pankow, JS Liu, C Irvin, MR Fornage, M Hidalgo, B Lin, LA Stanton Thibeault, K Bressler, J Tsai, MY Grove, ML Hopkins, PN Boerwinkle, E Borecki, IB Ordovas, JM Levy, D Tiwari, HK Absher, DM Arnett, DK AF Aslibekyan, Stella Demerath, Ellen W. Mendelson, Michael Zhi, Degui Guan, Weihua Liang, Liming Sha, Jin Pankow, James S. Liu, Chunyu Irvin, Marguerite R. Fornage, Myriam Hidalgo, Bertha Lin, Li-An Stanton Thibeault, Krista Bressler, Jan Tsai, Michael Y. Grove, Megan L. Hopkins, Paul N. Boerwinkle, Eric Borecki, Ingrid B. Ordovas, Jose M. Levy, Daniel Tiwari, Hemant K. Absher, Devin M. Arnett, Donna K. TI Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference SO OBESITY LA English DT Article ID MONOUNSATURATED FATTY-ACIDS; LIPID-LOWERING DRUGS; DIET-INDUCED OBESITY; DNA METHYLATION; GENE; EXPRESSION; PATTERNS; CANCER; POLYMORPHISMS; ADIPOGENESIS AB ObjectiveTo conduct an epigenome-wide analysis of DNA methylation and obesity traits. MethodsDNA methylation was quantified in CD4+ T-cells using the Illumina Infinium HumanMethylation450 array in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. Methylation at individual cytosine-phosphate-guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T-cell purity, smoking, and family structure, was modeled. ResultsEpigenome-wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n=2,377) and the Atherosclerosis Risk in Communities study (n=2,097), were found. Top findings were in CPT1A (meta-analysis P=2.7 x 10(-43) for BMI and 9.9 x 10(-23) for WC), PHGDH (meta-analysis P=2.0 x 10(-15) for BMI and 4.0 x 10(-9) for WC), CD38 (meta-analysis P=6.3 x 10(-11) for BMI and 1.6 x 10(-12) for WC), and long intergenic non-coding RNA 00263 (meta-analysis P=2.2 x 10(-16) for BMI and 8.9 x 10(-14) for WC), regions with biologically plausible relationships to adiposity. ConclusionsThis large-scale epigenome-wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications. C1 [Aslibekyan, Stella; Sha, Jin; Irvin, Marguerite R.; Hidalgo, Bertha; Arnett, Donna K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Demerath, Ellen W.; Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Mendelson, Michael; Liang, Liming; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Mendelson, Michael; Liang, Liming; Liu, Chunyu; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Mendelson, Michael] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Zhi, Degui; Tiwari, Hemant K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Guan, Weihua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Liu, Chunyu] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam; Lin, Li-An; Bressler, Jan; Grove, Megan L.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Stanton Thibeault, Krista; Absher, Devin M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Tsai, Michael Y.] Univ Minnesota, Div Lab Med & Pathol, Minneapolis, MN USA. [Hopkins, Paul N.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Borecki, Ingrid B.] Washington Univ, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc, Dept Epidemiol Atherothrombosis & Imaging, Madrid, Spain. [Ordovas, Jose M.] Inst Madrileno Estudios Avanzados Alimentac, Madrid, Spain. [Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Aslibekyan, S (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. EM saslibek@uab.edu RI Mendelson, Michael/I-2874-2014; Lin, LiAn/C-5819-2017; OI Mendelson, Michael/0000-0001-7590-3958; Lin, LiAn/0000-0003-2731-1346; Pankow, James/0000-0001-7076-483X FU National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) [U01HL072524-04]; NHLBI [N01HC25195, HHSN2682011 00005C, HHSN268201100006C, HHSN268201100007C, HHSN268 201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; NHLBI (National Human Genome Research Institute) [U01HG004402]; NHLBI (NIH) [HHSN268200625226C]; NIH [UL1RR025005]; NIH Roadmap for Medical Research FX The authors thank the staff and participants of ARIC, FHS, and GOLDN for their important contributions. The work on the GOLDN study has been funded by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI), grant U01HL072524-04. The Framingham Heart Study is supported by NHLBI contract N01HC25195. The ARIC study is carried out as a collaborative study supported by NHLBI contracts (HHSN2682011 00005C, HHSN268201100006C, HHSN268201100007C, HHSN268 201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure for ARIC was partly supported by grant UL1RR025005, a component of the NIH and specifically the NIH Roadmap for Medical Research. Support for the ARIC exome chip genotyping was provided by Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium through the NIH American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). NR 39 TC 15 Z9 16 U1 5 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2015 VL 23 IS 7 BP 1493 EP 1501 DI 10.1002/oby.21111 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CL4AD UT WOS:000356893400023 PM 26110892 ER PT J AU Glaser, TS Doss, LE Shih, G Nigam, D Sperduto, RD Ferris, FL Agron, E Clemons, TE Chew, EY AF Glaser, Tanya S. Doss, Lauren E. Shih, Grace Nigam, Divya Sperduto, Robert D. Ferris, Frederick L., III Agron, Elvira Clemons, Traci E. Chew, Emily Y. CA Age-Related Eye Disease Study Res TI The Association of Dietary Lutein plus Zeaxanthin and B Vitamins with Cataracts in the Age-Related Eye Disease Study AREDS Report No. 37 SO OPHTHALMOLOGY LA English DT Article ID BEAVER DAM EYE; ULTRAVIOLET-LIGHT EXPOSURE; SUBCAPSULAR LENS OPACITIES; TERM NUTRIENT INTAKE; REPORT NO. 4; RISK-FACTORS; RANDOMIZED-TRIAL; CLINICAL-TRIAL; VISUAL IMPAIRMENT; EPITHELIAL-CELLS AB Purpose: To evaluate whether dietary intake of luteiin/zeaxanthin and B vitamins is associated with cataract prevalence and incidence. Design: Clinic-based, baseline cross-sectional and prospective cohort study designs. Participants: Three thousand one hundred fifteen patients (6129 eyes) enrolled in the Age-Related Eye Disease Study 55 to 80 years of age followed up for mean of 9.6 years. Methods: Participants completed baseline food frequency questionnaires. Baseline and annual lens photographs were graded centrally. Multivariate models controlling for previously identified risk factors for cataracts tested for the association of cataracts with reported dietary intake, using the lowest quintile as reference. Main Outcome Measures: Cataract surgery, cataract status (type and severity) at baseline, and development of cataracts. Results: At baseline, increased dietary riboflavin and B12 were associated inversely with nuclear and cortical lens opacities. In comparisons of persons with and without cataract, persons with the highest riboflavin intake versus those with the lowest intake had the following associations: mild nuclear cataract: odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63-0.97; moderate nuclear cataract: OR, 0.62; 95% CI, 0.43-0.90; and mild cortical cataract: OR, 0.80; 95% CI, 0.65-0.99. For B12, the results were: mild nuclear cataract: OR, 0.78; 95% CI, 0.63-0.96; moderate nuclear cataract: OR, 0.62; 95% CI, 0.43-0.88; and mild cortical cataract: OR, 0.77; 95% CI, 0.63-0.95. Highest dietary B6 intake was associated with a decreased risk of moderate nuclear lens opacity developing compared with the lowest quintile (OR, 0.67; 95% CI, 0.45-0.99). Highest dietary intake levels of niacin and B12 were associated with a decreased risk of development of mild nuclear or mild cortical cataracts in participants not taking Centrum (Pfizer, New York, NY) multivitamins. For participants taking multivitamins during the study, the highest intake of dietary folate was associated with an increased risk of mild posterior subcapsular lens opacity development. No statistically significant associations were found between lutein plus zeaxanthin intake and presence at baseline or development of nuclear or cortical lens opacity outcomes. Conclusions: These findings are consistent with earlier studies suggesting that dietary intake of B vitamins may affect the occurrence of age-related lens opacities. Further investigations are warranted. (C) 2015 by the American Academy of Ophthalmology. C1 [Glaser, Tanya S.; Doss, Lauren E.; Shih, Grace; Nigam, Divya; Ferris, Frederick L., III; Agron, Elvira; Chew, Emily Y.] NEI, NIH, Bethesda, MD 20814 USA. [Sperduto, Robert D.; Clemons, Traci E.] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, NIH, 10 Ctr Dr,MSC 1204,BG 10-CRC Room 3-2531, Bethesda, MD 20814 USA. EM echew@nei.nih.gov FU National Eye Institute, National Institutes of Health, Bethesda, Maryland [NOI-EY-0-2127]; National Institutes of Health (NIH) Medical Research Scholars Program; NIH; Pfizer, Inc.; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute; Howard Hughes Medical Institute (HHMI-NIH scholars program) FX Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (contract no.: NOI-EY-0-2127); the National Institutes of Health (NIH) Medical Research Scholars Program (T.S.G., L.E.D.), a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from Pfizer, Inc., The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors (for a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program); and the Howard Hughes Medical Institute (HHMI-NIH scholars program; G.S.). NR 53 TC 2 Z9 2 U1 1 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2015 VL 122 IS 7 BP 1471 EP 1479 DI 10.1016/j.ophtha.2015.04.007 PG 9 WC Ophthalmology SC Ophthalmology GA CL0HI UT WOS:000356621700028 PM 25972257 ER PT J AU Kelly, NR Cotter, EW Tanofsky-Kraff, M Mazzeo, SE AF Kelly, Nichole R. Cotter, Elizabeth W. Tanofsky-Kraff, Marian Mazzeo, Suzanne E. TI Racial Variations in Binge Eating, Body Image Concerns, and Compulsive Exercise Among Men SO PSYCHOLOGY OF MEN & MASCULINITY LA English DT Article DE race/ethnicity; binge eating; body dissatisfaction; exercise; men ID SELF-REPORT QUESTIONNAIRE; AMERICAN COLLEGE-STUDENTS; POPULATION-BASED SAMPLE; EDE-Q NORMS; AFRICAN-AMERICAN; ADOLESCENT GIRLS; ASIAN-AMERICAN; DISORDER SYMPTOMS; COMMUNITY SAMPLE; MASCULINE NORMS AB Binge eating in young men is associated with obesity and metabolic dysfunction, as well as disordered eating attitudes and behaviors. Although preliminary research suggests that Asian American males might be more likely to binge eat and report body image concerns compared with men of other races/ethnicities, few studies have investigated racial variations in this disordered eating behavior and its correlates. The goal of the current study was to examine binge eating, body image concerns, drive for muscularity, and compulsive exercise in a sample of Black, Asian American, and White men (N = 365). Results suggest that men who reported binge eating also reported higher body mass, male body image concerns, internalization of the male body ideal, and compulsive exercise than men who did not engage in binge eating. Asian American men endorsed higher body image concerns relative to White and Black men. Furthermore, compulsive exercise was particularly high among Asian American men with binge eating. Although additional research is needed to examine potential variations in binge eating, body image, and compulsive exercise in diverse racial and ethnic groups, results suggest that Asian American men might be at higher risk for disordered eating attitudes and behaviors consistent with a desire to achieve a muscular body type. Future research should examine cultural factors, such as acculturation, that might contribute to these potentially harmful cognitions and behaviors. C1 [Kelly, Nichole R.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Kelly, Nichole R.; Tanofsky-Kraff, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Cotter, Elizabeth W.] Amer Univ, Sch Educ Teaching & Hlth, Washington, DC 20016 USA. [Mazzeo, Suzanne E.] Virginia Commonwealth Univ, Dept Psychol & Pediat, Richmond, VA 23284 USA. RP Kelly, NR (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM nichole.kelly@nih.gov NR 112 TC 8 Z9 8 U1 13 U2 24 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1524-9220 EI 1939-151X J9 PSYCHOL MEN MASCULIN JI Psychol. Men Masculinity PD JUL PY 2015 VL 16 IS 3 BP 326 EP 336 DI 10.1037/a0037585 PG 11 WC Psychology, Social SC Psychology GA CK9YE UT WOS:000356594700010 ER PT J AU Zhang, YP Zhao, XS Zhang, B Zhang, LL Ni, CP Hao, N Shi, CB Porr, C AF Zhang, Yin-Ping Zhao, Xin-Shuang Zhang, Bei Zhang, Lu-Lu Ni, Chun-Ping Hao, Nan Shi, Chang-Bei Porr, Caroline TI Cross-cultural adaptation and psychometric assessment of the Chinese version of the comprehensive needs assessment tool for cancer caregivers (CNAT-C) SO QUALITY OF LIFE RESEARCH LA English DT Article DE Caregiver; Cancer; Needs assessment; Culturally appropriate survey instruments ID QUALITY-OF-LIFE; CONFIRMATORY FACTOR-ANALYSIS; VALIDATION; BURDEN; RELIABILITY; GUIDELINES; SCALE AB The comprehensive needs assessment tool for cancer caregivers (CNAT-C) is a systematic and comprehensive needs assessment tool for the family caregivers. The purpose of this project was twofold: (1) to adapt the CNAT-C to Mainland China's cultural context and (2) to evaluate the psychometric properties of the newly adapted Chinese CNAT-C. Cross-cultural adaptation of the original CNAT-C was performed according to published guidelines. A pilot study was conducted in Mainland China with 30 Chinese family cancer caregivers. A subsequent validation study was conducted with 205 Chinese cancer caregivers from Mainland China. Construct validity was determined through exploratory and confirmatory factor analyses. Reliability was determined using internal consistency and test-retest reliability. The split-half coefficient for the overall Chinese CNAT-C scale was 0.77. Principal component analysis resulted in an eight-factor structure explaining 68.11 % of the total variance. The comparative fit index (CFI) was 0.91 from the modified model confirmatory factor analysis. The Chi-square divided by degrees of freedom was 1.98, and the root mean squared error of approximation (RMSEA) was 0.079. In relation to the known-group validation, significant differences were found in the Chinese CNAT-C scale according to various caregiver characteristics. Internal consistency was high for the Chinese CNAT-C reaching a Cronbach alpha value of 0.94. Test-retest reliability was 0.85. The newly adapted Chinese CNAT-C scale possesses adequate validity, test-retest reliability, and internal consistency and therefore may be used to ascertain holistic health and support needs of cancer patients' family caregivers in Mainland China. C1 [Zhang, Yin-Ping; Zhao, Xin-Shuang; Zhang, Bei; Zhang, Lu-Lu] Xi An Jiao Tong Univ, Dept Nursing, Hlth Sci Ctr, Xian 710061, Peoples R China. [Ni, Chun-Ping] Mental Hlth Inst, Ctr Clin, Bethesda, MD 20892 USA. [Hao, Nan] Xi An Jiao Tong Univ, Dept Oncol, Attached Hosp 1, Xian 710061, Peoples R China. [Shi, Chang-Bei] Shaanxi Prov Tumor Hosp, Dept Radiotherapy, Xian 710061, Peoples R China. [Porr, Caroline] Mem Univ, Sch Nursing, St John, NF A1B 3V6, Canada. RP Zhang, YP (reprint author), Xi An Jiao Tong Univ, Dept Nursing, Hlth Sci Ctr, 76 West Yanta Rd, Xian 710061, Peoples R China. EM cathyzh@mail.xjtu.edu.cn FU Xi'an Jiaotong Graduate Fund; National Natural Science Foundation of China [81100628] FX Authors were partially supported by the grants from Xi'an Jiaotong Graduate Fund, and the National Natural Science Foundation of China (81100628). We thank all the study participants for volunteering to participate in the study. We would also like to thank Dr. Qian Chen from Philadelphia College in the USA for the manuscript editing. NR 25 TC 0 Z9 0 U1 2 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD JUL PY 2015 VL 24 IS 7 BP 1607 EP 1614 DI 10.1007/s11136-014-0891-5 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CL4XM UT WOS:000356960500005 PM 25702265 ER PT J AU Bourdon-Lacombe, JA Moffat, ID Deveau, M Husain, M Auerbach, S Krewski, D Thomas, RS Bushel, PR Williams, A Yauk, CL AF Bourdon-Lacombe, Julie A. Moffat, Ivy D. Deveau, Michelle Husain, Mainul Auerbach, Scott Krewski, Daniel Thomas, Russell S. Bushel, Pierre R. Williams, Andrew Yauk, Carole L. TI Technical guide for applications of gene expression profiling in human health risk assessment of environmental chemicals SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Human health risk assessment; Toxicogenomics; Chemical mode of action; Hazard assessment; Risk characterization ID CONDENSATES IN-VITRO; HUMAN CANCER-RISK; RNA-SEQ; MECHANISTIC ASSESSMENT; TOXICOGENOMIC ANALYSIS; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; NEXT-GENERATION; GENOMIC DATA; HUMAN TOXOME AB Toxicogenomics promises to be an important part of future human health risk assessment of environmental chemicals. The application of gene expression profiles (e.g., for hazard identification, chemical prioritization, chemical grouping, mode of action discovery, and quantitative analysis of response) is growing in the literature, but their use in formal risk assessment by regulatory agencies is relatively infrequent. Although additional validations for specific applications are required, gene expression data can be of immediate use for increasing confidence in chemical evaluations. We believe that a primary reason for the current lack of integration is the limited practical guidance available for risk assessment specialists with limited experience in genomics. The present manuscript provides basic information on gene expression profiling, along with guidance on evaluating the quality of genomic experiments and data, and interpretation of results presented in the form of heat maps, pathway analyses and other common approaches. Moreover, potential ways to integrate information from gene expression experiments into current risk assessment are presented using published studies as examples. The primary objective of this work is to facilitate integration of gene expression data into human health risk assessments of environmental chemicals. Crown Copyright (C) 2015 Published by Elsevier Inc. All rights reserved. C1 [Bourdon-Lacombe, Julie A.; Moffat, Ivy D.; Deveau, Michelle] Hlth Canada, Water & Air Qual Bur, Ottawa, ON K1A 0L2, Canada. [Husain, Mainul; Williams, Andrew; Yauk, Carole L.] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Auerbach, Scott] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Krewski, Daniel] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON, Canada. [Thomas, Russell S.] US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Bushel, Pierre R.] NIEHS, Biostat & Computat Biol Branch, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Moffat, ID (reprint author), Hlth Canada, Water & Air Qual Bur, 269 Laurier Ave, Ottawa, ON K1A 0L2, Canada. EM Ivy.Moffat@hc-sc.gc.ca OI Thomas, Russell/0000-0002-2340-0301; Yauk, Carole/0000-0003-4919-876X NR 100 TC 8 Z9 9 U1 4 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD JUL PY 2015 VL 72 IS 2 BP 292 EP 309 DI 10.1016/j.yrtph.2015.04.010 PG 18 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CL4DN UT WOS:000356902900016 PM 25944780 ER PT J AU Santen, RJ Demers, LM Ziegler, RG AF Santen, Richard J. Demers, Laurence M. Ziegler, Regina G. TI Workshop on measuring estrogen exposure and metabolism: Summary of the presentations SO STEROIDS LA English DT Editorial Material C1 [Santen, Richard J.] Univ Virginia Hlth Sci Syst, Dept Med, Div Endocrinol & Metab, Charlottesville, VA 22908 USA. [Demers, Laurence M.] Penn State Univ, Sch Med, Dept Pathol, Hershey, PA USA. [Demers, Laurence M.] Penn State Univ, Sch Med, Dept Med, Hershey, PA USA. [Ziegler, Regina G.] NIH, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Santen, RJ (reprint author), Univ Virginia Hlth Sci Syst, Dept Med, Div Endocrinol & Metab, Charlottesville, VA 22908 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD JUL PY 2015 VL 99 SI SI BP 1 EP 7 DI 10.1016/j.steroids.2014.12.012 PN A PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CL5FH UT WOS:000356984700001 PM 25554577 ER PT J AU Ziegler, RG Fuhrman, BJ Moore, SC Matthews, CE AF Ziegler, Regina G. Fuhrman, Barbara J. Moore, Steven C. Matthews, Charles E. TI Epidemiologic studies of estrogen metabolism and breast cancer SO STEROIDS LA English DT Review DE Breast cancer; Estradiol; Estrogen metabolites; Hormonal carcinogenesis; 2-hydroxyestrone; 16 alpha-hydroxyestrone ID TANDEM MASS-SPECTROMETRY; 15 URINARY ESTROGENS; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; ASSAY REPRODUCIBILITY; ENDOGENOUS ESTROGENS; PHYSICAL-ACTIVITY; SERUM ESTROGENS; RISK; ESTRADIOL AB Early epidemiologic studies of estrogen metabolism measured only 2-hydroxyestrone and 16 alpha-hydroxyestrone and relied on direct enzyme immunoassays without purification steps. Eight breast cancer studies have used these assays with prospectively collected blood or urine samples. Results were inconsistent, and generally not statistically significant; but the assays had limited specificity, especially at the low concentrations characteristic of postmenopausal women. To facilitate continued testing in population-based studies of the multiple laboratory-based hypotheses about the roles of estrogen metabolites, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to measure concurrently all 15 estrogens and estrogen metabolites in human serum and urine, as unconjugated and total (glucuronidated + sulfated + unconjugated) concentrations. The assay has high sensitivity (lower limit of quantitation similar to 1-2 pmol/L), reproducibility (coefficients of variation generally <= 5%), and accuracy. Three prospective studies utilizing this comprehensive assay have demonstrated that enhanced 2-hydroxylation of parent estrogens (estrone + estradiol) is associated with reduced risk of postmenopausal breast cancer. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort, the serum ratio of 2-hydroxylation pathway metabolites to parent estrogens was associated with a 28% reduction in breast cancer risk across extreme deciles (p-trend = .05), after adjusting for unconjugated estradiol and breast cancer risk factors. Incorporating this ratio into a risk prediction model already including unconjugated estradiol improved absolute risk estimates substantially (by >= 14%) in 36% of the women, an encouraging result that needs replication. Additional epidemiologic studies of the role of estrogen metabolism in the etiology of hormone-related diseases and continued improvement of estrogen metabolism assays are justified. Published by Elsevier Inc. C1 [Ziegler, Regina G.; Fuhrman, Barbara J.; Moore, Steven C.; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Ziegler, RG (reprint author), NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, 9609 Med Ctr Dr,Room 7E588,MSC 9773, Bethesda, MD 20892 USA. EM Regina.Ziegler@nih.gov RI Moore, Steven/D-8760-2016; matthews, charles/E-8073-2015; OI Moore, Steven/0000-0002-8169-1661; matthews, charles/0000-0001-8037-3103; Fuhrman, Barbara/0000-0002-1777-9888 NR 47 TC 14 Z9 14 U1 1 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD JUL PY 2015 VL 99 SI SI BP 67 EP 75 DI 10.1016/j.steroids.2015.02.015 PN A PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CL5FH UT WOS:000356984700012 PM 25725255 ER PT J AU Stanczyk, FZ Mathews, BW Sherman, ME AF Stanczyk, Frank Z. Mathews, Brett W. Sherman, Mark E. TI Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: A critical appraisal of current science SO STEROIDS LA English DT Review DE Breast; Estrogens; Androgens; Tissue; Cancerous; Benign ID POSTMENOPAUSAL WOMEN; ADIPOSE-TISSUE; 17-BETA-HYDROXYSTEROID DEHYDROGENASE; SUBCELLULAR-DISTRIBUTION; ENDOGENOUS CONCENTRATION; ESTROGEN CONCENTRATIONS; AROMATASE ACTIVITIES; ESTRADIOL LEVELS; TUMOR; EXPRESSION AB A systematic review of the literature on sex steroid measurement in breast tissue identified only 19 articles meeting the following criteria: menopausal status given; steroids measured in tissue homogenates by conventional RIA with a purification step or by mass spectrometry; and values reported per g tissue or per g protein. Twelve articles were analyzed in detail for: ratios of sex steroid hormone levels in cancerous or benign tissues to blood levels, stratified by menopausal status; ratios between the different hormone levels within tissues or within blood; and difference in these ratios between tissue and blood compartments. Estrogen and androgen concentrations varied greatly in benign and cancerous tissues and in blood between individuals. Postmenopausal, but not premenopausal, estradiol concentrations were significantly higher in cancerous compared to benign breast tissue. The estradiol/estrone ratio was lowest in premenopausal benign tissue, and substantially higher in premenopausal cancerous tissue and postmenopausal benign and cancerous tissues. Estradiol and estrone levels were considerably higher in tissue than in plasma in both premenopausal and postmenopausal women. Androgen levels were generally higher in the benign than the cancerous tissue, and tissue androgen levels were higher than in plasma, suggesting in situ aromatization of androgens to estrogens in breast cancer tissue. Limited available data on levels of hydroxylated estrogens in breast tissue compared to corresponding levels in plasma or urine were reviewed, but due to the paucity of studies no conclusions can presently be drawn regarding the relationship of the 2-hydroxyestrone:16 alpha-hydroxyestrone ratio to breast cancer risk and genotoxic effects of 4-hydroxylated estrogens. Finally, data on hormone levels in breast adipose tissue were analyzed; high levels of androstenedione and testosterone and significant estrone and estradiol levels in breast adipocytes from postmenopausal breast cancer patients are consistent with an obesity-inflammation-aromatase axis occurring locally in breast tissue. The controversies regarding the source of intratumoral estrogens in the breast are summarized. Published by Elsevier Inc. C1 [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Mathews, Brett W.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Stanczyk, FZ (reprint author), Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, 1321 N Mission Rd, Los Angeles, CA 90033 USA. EM fstanczyk@att.net OI Mathews, Brett/0000-0001-6325-6714 NR 30 TC 9 Z9 9 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD JUL PY 2015 VL 99 SI SI BP 91 EP 102 DI 10.1016/j.steroids.2014.12.011 PN A PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CL5FH UT WOS:000356984700015 PM 25554581 ER PT J AU Foster, MC Inker, LA Hsu, CY Eckfeldt, JH Levey, AS Pavkov, ME Myers, BD Bennett, PH Kimmel, PL Vasan, RS Coresh, J Nelson, RG AF Foster, Meredith C. Inker, Lesley A. Hsu, Chi-yuan Eckfeldt, John H. Levey, Andrew S. Pavkov, Meda E. Myers, Bryan D. Bennett, Peter H. Kimmel, Paul L. Vasan, Ramachandran S. Coresh, Josef Nelson, Robert G. CA CKD Biomarkers Consortium TI Filtration Markers as Predictors of ESRD and Mortality in Southwestern American Indians With Type 2 Diabetes SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Beta-trace protein (BTP); beta-2 microglobulin (B2M); end-stage renal disease (ESRD); type 2 diabetes mellitus; diabetic kidney failure; mortality; filtration markers; glomerular filtration rate (GFR); kidney function; Pima Indians; CKD Biomarkers Consortium ID BETA-TRACE PROTEIN; STAGE RENAL-DISEASE; CYSTATIN-C; SERUM CREATININE; AFRICAN-AMERICANS; KIDNEY-FUNCTION; MEASURED GFR; RISK; PROGRESSION; NEPHROPATHY AB Background: A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether b-trace protein (BTP) and b2-microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known. Study Design: Longitudinal cohort study. Setting & Participants: 250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). Predictors: Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFR(cr)) or cystatin C level (eGFR(cys)). Outcomes & Measurements: Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M level to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C statistics, continuous net reclassification improvement, and relative integrated discrimination improvement (RIDI). Results: During a median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP level remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M level was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M level to established markers increased the C statistic for mortality but only weakly when assessed by either continuous net reclassification improvement or RIDI; none was improved for ESRD by the addition of these markers. Limitations: Small sample size, single measurements of markers. Conclusions: In Pima Indians with type 2 diabetes, BTP and, to a lesser extent, B2M levels were associated with ESRD. B2M level was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M level in a multimarker approach leads to improved risk prediction for mortality in this population. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. C1 [Foster, Meredith C.; Inker, Lesley A.; Levey, Andrew S.] Tufts Med Ctr, Boston, MA USA. [Hsu, Chi-yuan] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Eckfeldt, John H.] Univ Minnesota, Minneapolis, MN USA. [Pavkov, Meda E.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Myers, Bryan D.] Stanford Univ, Stanford, CA 94305 USA. [Bennett, Peter H.; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Nelson, RG (reprint author), NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970 FU NIDDK grants [U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689]; Intramural Research Program of the NIDDK; National Heart, Lung and Blood Institute grant [T32 HL007024] FX The CKD Biomarkers Consortium is funded by NIDDK grants U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, and U01DK085689 and by the Intramural Research Program of the NIDDK. Dr Foster was supported in part by National Heart, Lung and Blood Institute grant T32 HL007024. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. NR 27 TC 7 Z9 7 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2015 VL 66 IS 1 BP 75 EP 83 DI 10.1053/j.ajkd.2015.01.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CL1UO UT WOS:000356730600016 PM 25773485 ER PT J AU Kasiske, BL Anderson-Haag, T Israni, AK Kalil, RS Kimmel, PL Kraus, ES Kumar, R Posselt, AA Pesavento, TE Rabb, H Steffes, MW Snyder, JJ Weir, MR AF Kasiske, Bertram L. Anderson-Haag, Teresa Israni, Ajay K. Kalil, Roberto S. Kimmel, Paul L. Kraus, Edward S. Kumar, Rajiv Posselt, Andrew A. Pesavento, Todd E. Rabb, Hamid Steffes, Michael W. Snyder, Jon J. Weir, Matthew R. TI A Prospective Controlled Study of Living Kidney Donors: Three-Year Follow-up SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease (CKD); renal insufficiency; unilateral nephrectomy; glomerular filtration rate (GFR); kidney function; patient safety; parathyroid hormone (PTH); uric acid; homocysteine; potassium; hemoglobin; mineral and bone disorders; living kidney donation; kidney transplantation; Assessing Long Term Outcomes in Living Kidney Donors (ALTOLD) ID GLOMERULAR-FILTRATION-RATE; LONG-TERM CONSEQUENCES; SERUM URIC-ACID; RENAL-FUNCTION; INSULIN-RESISTANCE; BLOOD-PRESSURE; MINERAL METABOLISM; COLLABORATIVE METAANALYSIS; UNILATERAL NEPHRECTOMY; CARDIOVASCULAR-DISEASE AB Background: There have been few prospective controlled studies of kidney donors. Understanding the pathophysiologic effects of kidney donation is important for judging donor safety and improving our understanding of the consequences of reduced kidney function in chronic kidney disease. Study Design: Prospective, controlled, observational cohort study. Setting & Participants: 3-year follow-up of kidney donors and paired controls suitable for donation at their donor's center. Predictor: Kidney donation. Outcomes: Medical history, vital signs, glomerular filtration rate, and other measurements at 6, 12, 24, and 36 months after donation. Results: At 36 months, 182 of 203 (89.7%) original donors and 173 of 201 (86.1%) original controls continue to participate in follow-up visits. The linear slope of the glomerular filtration rate measured by plasma iohexol clearance declined 0.36 +/- 7.55 mL/min per year in 194 controls, but increased 1.47 +/- 5.02 mL/min per year in 198 donors (P = 0.005) between 6 and 36 months. Blood pressure was not different between donors and controls at any visit, and at 36 months, all 24-hour ambulatory blood pressure parameters were similar in 126 controls and 135 donors (mean systolic blood pressure, 120.0 +/- 11.2 [SD] vs 120.7 +/- 9.7 mm Hg [P = 0.6]; mean diastolic blood pressure, 73.4 +/- 7.0 vs 74.5 +/- 6.5 mm Hg [P = 0.2]). Mean arterial pressure nocturnal dipping was manifest in 11.2% +/- 6.6% of controls and 11.3% +/- 6.1% of donors (P = 0.9). Urinary protein-creatinine and albumin-creatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower, in donors compared with controls. Limitations: Possible bias resulting from an inability to select controls screened to be as healthy as donors, short follow-up duration, and dropouts. Conclusions: Kidney donors manifest several of the findings of mild chronic kidney disease. However, at 36 months after donation, kidney function continues to improve in donors, whereas controls have expected age-related declines in function. (C) 2015 by the National Kidney Foundation, Inc. C1 [Kasiske, Bertram L.; Anderson-Haag, Teresa; Israni, Ajay K.] Hennepin Cty Med Ctr, Dept Med, Minneapolis, MN 55415 USA. [Kasiske, Bertram L.; Anderson-Haag, Teresa; Israni, Ajay K.] Univ Minnesota, Minneapolis, MN USA. [Kalil, Roberto S.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Kraus, Edward S.; Rabb, Hamid] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Kumar, Rajiv] Mayo Clin, Dept Med, Rochester, MN USA. [Posselt, Andrew A.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Pesavento, Todd E.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Steffes, Michael W.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Snyder, Jon J.] Minneapolis Med Res Fdn Inc, Sci Registry Transplant Recipients, Minneapolis, MN USA. [Weir, Matthew R.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. RP Kasiske, BL (reprint author), Hennepin Cty Med Ctr, Dept Med, 701 Pk Ave, Minneapolis, MN 55415 USA. EM bkasiske@cdrg.org FU National Institutes of Health (NIH) [U01 DK066013]; Minneapolis Medical Research Foundation, Minneapolis, MN FX This study was funded by the National Institutes of Health (NIH) under the cooperative agreement U01 DK066013. The NIH participated in the interpretation of data, writing the report, and the decision to submit the report for publication. This study was also supported by the Minneapolis Medical Research Foundation, Minneapolis, MN, which did not participate in any aspect of the study. NR 53 TC 16 Z9 16 U1 0 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2015 VL 66 IS 1 BP 114 EP 124 DI 10.1053/j.ajkd.2015.01.019 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA CL1UO UT WOS:000356730600021 PM 25795073 ER PT J AU Powell-Wiley, TM Cooper-McCann, R Ayers, C Berrigan, D Lian, M McClurkin, M Ballard-Barbash, R Das, SR Hoehner, CM Leonard, T AF Powell-Wiley, Tiffany M. Cooper-McCann, Rebecca Ayers, Colby Berrigan, David Lian, Min McClurkin, Michael Ballard-Barbash, Rachel Das, Sandeep R. Hoehner, Christine M. Leonard, Tammy TI Change in Neighborhood Socioeconomic Status and Weight Gain Dallas Heart Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID BODY-MASS INDEX; SAMPLE SELECTION BIAS; PHYSICAL-ACTIVITY; LONGITUDINAL ASSOCIATIONS; SPECIFICATION ERROR; BUILT ENVIRONMENT; RISK BEHAVIORS; OBESITY; HEALTH; DEPRIVATION AB Introduction: Despite a proposed connection between neighborhood environment and obesity, few longitudinal studies have examined the relationship between change in neighborhood socioeconomic deprivation, as defined by moving between neighborhoods, and change in body weight. The purpose of this study is to examine the longitudinal relationship between moving to more socioeconomically deprived neighborhoods and weight gain as a cardiovascular risk factor. Methods: Weight (kilograms) was measured in the Dallas Heart Study (DHS), a multiethnic cohort aged 18-65 years, at baseline (2000-2002) and 7-year follow-up (2007-2009, N=1,835). Data were analyzed in 2013-2014. Geocoded addresses were linked to Dallas County, TX, census block groups. A block group-level neighborhood deprivation index (NDI) was created. Multilevel difference-indifference models with random effects and a Heckman correction factor (HCF) determined weight change relative to NDI change. Results: Forty-nine percent of the DHS population moved (263 to higher NDI, 586 to lower NDI, 47 within same NDI), with blacks more likely to move than whites or Hispanics (p<0.01), but similar baseline BMI and waist circumference were observed in movers versus non-movers (p>0.05). Adjusting for HCF, sex, race, and time-varying covariates, those who moved to areas of higher NDI gained more weight compared to those remaining in the same or moving to a lower NDI (0.64 kg per 1-unit NDI increase, 95% CI=0.09, 1.19). Impact of NDI change on weight gain increased with time (p=0.03). Conclusions: Moving to more-socioeconomically deprived neighborhoods was associated with weight gain among DHS participants. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Powell-Wiley, Tiffany M.; McClurkin, Michael] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Cooper-McCann, Rebecca] NIH, Ctr Clin, Off Clin Res Training & Med Educ, Bethesda, MD 20892 USA. [Berrigan, David; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Ayers, Colby; Das, Sandeep R.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Med, Dallas, TX 75390 USA. [Leonard, Tammy] Univ Dallas, Dept Econ, Irving, TX USA. [Lian, Min] Washington Univ, Sch Med, Dept Med, Div Gen Med Sci, St Louis, MO 63110 USA. RP Powell-Wiley, TM (reprint author), NHLBI, Div Intramural Res, Cardiovasc & Pulm Branch, NIH, Bldg 10 CRC,Rm 5E3340, Bethesda, MD 20892 USA. EM powelltm2@mail.nih.gov OI Leonard, Tammy/0000-0002-8621-9358 FU Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) at NIH; Division of Intramural Research of NHLBI at NIH [HHSN268201300173P]; NIH Medical Research Scholars Program; NIH; Pfizer Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute; Mr. and Mrs. Joel S. Marcus FX Funding support for Dr. Powell-Wiley and Mr. McClurkin is provided by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) at NIH. Funding support for Mr. Ayers is provided through a professional services contract (contract number HHSN268201300173P) through the Division of Intramural Research of NHLBI at NIH. Funding support for Ms. Cooper-McCann is provided through NIH Medical Research Scholars Program, a public-private partnership supported jointly by NIH and generous contributions to the Foundation for NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc., Mr. and Mrs. Joel S. Marcus, the Howard Hughes Medical Institute, and other private donors. NR 44 TC 1 Z9 1 U1 4 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2015 VL 49 IS 1 BP 72 EP 79 DI 10.1016/j.amepre.2015.01.013 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CK6UI UT WOS:000356363400011 PM 25960394 ER PT J AU Cortes, A Maksymowych, WP Wordsworth, BP Inman, RD Danoy, P Rahman, P Stone, MA Corr, M Gensler, LS Gladman, D Morgan, A Marzo-Ortega, H Ward, MM Learch, TJ Reveille, JD Brown, MA Weisman, MH AF Cortes, A. Maksymowych, W. P. Wordsworth, B. P. Inman, R. D. Danoy, P. Rahman, P. Stone, M. A. Corr, M. Gensler, Lianne S. Gladman, D. Morgan, A. Marzo-Ortega, H. Ward, M. M. Learch, T. J. Reveille, J. D. Brown, M. A. Weisman, M. H. CA SPARCC Spondyloarthrit Res TASC Australo-Anglo-Amer TI Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GENOME-WIDE ASSOCIATION; DISEASE SEVERITY; HLA-B27 HOMOZYGOSITY; MINERAL DENSITY; SUSCEPTIBILITY; RISK; LOCI; SPONDYLOARTHRITIS; PROGRESSION AB Objective To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). Method We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 50 and 30 UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. Results Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p= 1.2x10(-5)), which lies within RANK (receptor activator of NF kappa B), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p= 2.6x10(-3)). There was no observed association between radiographic severity and HLA-B*27. Conclusions These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS. C1 [Cortes, A.; Danoy, P.; Brown, M. A.] Univ Queensland, Translat Res Inst, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Maksymowych, W. P.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Wordsworth, B. P.] Nuffield Orthopaed Ctr, NIHR Oxford Musculoskeletal Biomed Res Unit, Oxford Comprehens Biomed Res Ctr, Oxford OX3 7LD, England. [Inman, R. D.] Toronto Western Hosp, Div Rheumatol, Toronto, ON M5T 2S8, Canada. [Rahman, P.] Mem Univ Newfoundland, St John, NF, Canada. [Stone, M. A.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Corr, M.] Univ San Diego, Sch Med, San Diego, CA 92110 USA. [Gensler, Lianne S.] Univ Calif San Francisco, Div Rheumatol, Dept Med, San Francisco, CA USA. [Gladman, D.] Univ Toronto, Div Rheumatol, Toronto, ON, Canada. [Gladman, D.] Toronto Western Res Inst, Toronto, ON, Canada. [Gladman, D.] Univ Hlth Network, Psoriat Arthrit Program, Toronto, ON, Canada. [Morgan, A.; Marzo-Ortega, H.] Univ Leeds, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds Inst Rheumat & Musculoskeletal Med, Leeds Teaching Hosp Trust, Leeds, W Yorkshire, England. [Ward, M. M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Learch, T. J.; Weisman, M. H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Reveille, J. D.] Univ Texas Hlth Sci Ctr Houston, Dept Rheumatol & Clin Immunogenet, Houston, TX 77030 USA. RP Brown, MA (reprint author), Univ Queensland, Translat Res Inst, Princess Alexandra Hosp, Diamantina Inst, 37 Kent Rd, Woolloongabba, Qld 4102, Australia. EM matt.brown@uq.edu.au FU US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [P01-052915]; Intramural Research Program, NIAMS/NIH; National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship; Arthritis Research UK [19536] FX This study was funded by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915. MMW is supported by the Intramural Research Program, NIAMS/NIH. MAB was funded by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship. Recruitment of patients to this study was in part funded by a project grant from Arthritis Research UK (19536). WPM is a medical scientist of Alberta Innovates Health Solutions. NR 35 TC 11 Z9 12 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2015 VL 74 IS 7 BP 1387 EP 1393 DI 10.1136/annrheumdis-2013-204835 PG 7 WC Rheumatology SC Rheumatology GA CK2EZ UT WOS:000356024700010 PM 24651623 ER PT J AU Carmona-Rivera, C Zhao, WP Yalavarthi, S Kaplan, MJ AF Carmona-Rivera, Carmelo Zhao, Wenpu Yalavarthi, Srilakshmi Kaplan, Mariana J. TI Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2 SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID PEPTIDYLARGININE DEIMINASE INHIBITION; NETTING NEUTROPHILS; MEMBRANE-VESICLES; TISSUE INHIBITORS; ATHEROSCLEROSIS; CELLS; MACROPHAGES; MATRIX-METALLOPROTEINASE-9; EXPRESSION; NEPHRITIS AB Rationale The structural and functional integrity of the endothelium is crucial in maintaining vascular homeostasis and preventing atherosclerosis. Patients with systemic lupus erythematosus (SLE) have an increased risk of developing endothelial dysfunction and premature cardiovascular disease. Neutrophil extracellular trap (NET) formation is increased in SLE and has been proposed to contribute to endothelial damage, but the mechanism remains unclear. Objective To determine the mechanism by which enhanced NET formation by low-density granulocytes (LDGs) in SLE contributes to endothelial damage and disrupts the endothelium. Results The putative role of NET-externalised matrix metalloproteinases (MMPs) in altering the functional integrity of the endothelium was examined. MMP-9 externalised by lupus LDGs during NET formation specifically impaired murine aortic endothelium-dependent vasorelaxation and induced endothelial cell apoptosis. Endothelial dysfunction correlated with the activation of endothelial MMP-2 by MMP-9 present in NETs, while inhibition of MMP-2 activation restored endothelium-dependent function and decreased NET-induced vascular cytotoxicity. Moreover, immunogenic complexes composed of MMP-9 and anti-MMP-9 were identified in SLE sera. These complexes, as well as anti-MMP- 9 autoantibodies, induced NETosis and enhanced MMP-9 activity. Conclusions These observations implicate activation of endothelial MMP-2 by MMP-9 contained in NETs as an important player in endothelial dysfunction, and MMP-9 as a novel self-antigen in SLE. These results further support that aberrant NET formation plays pathogenic roles in SLE. C1 [Carmona-Rivera, Carmelo; Zhao, Wenpu; Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Yalavarthi, Srilakshmi] Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA. RP Kaplan, MJ (reprint author), NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 6D-47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov FU National Institutes of Health through the Intramural Research Program at NIAMS; PHS [HL088419, T32AR007080] FX This work was supported by the National Institutes of Health through the Intramural Research Program at NIAMS and by PHS grants HL088419 and T32AR007080. NR 39 TC 40 Z9 41 U1 3 U2 16 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2015 VL 74 IS 7 BP 1417 EP 1424 DI 10.1136/annrheumdis-2013-204837 PG 8 WC Rheumatology SC Rheumatology GA CK2EZ UT WOS:000356024700014 PM 24570026 ER PT J AU Teicher, BA Tomaszewski, JE AF Teicher, Beverly A. Tomaszewski, Joseph E. TI Proteasome inhibitors Commentary SO BIOCHEMICAL PHARMACOLOGY LA English DT Editorial Material DE Proteasome; Bortezomib; Carfilzomib; Ixazomib citrate; MLN9708 ID MULTIPLE-MYELOMA CELLS; PHASE-I TRIAL; HEMATOLOGIC MALIGNANCIES; CHEMOTHERAPEUTIC-AGENTS; ANTITUMOR-ACTIVITY; CANCER-THERAPY; TUMOR-GROWTH; KAPPA-B; PS-341; IXAZOMIB AB Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. C1 [Teicher, Beverly A.; Tomaszewski, Joseph E.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. RP Teicher, BA (reprint author), NCI, DCTD, RM 4-W602,MSC 9735,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM Beverly.Teicher@nih.gov; teicherba@mail.nih.gov NR 63 TC 21 Z9 22 U1 3 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUL 1 PY 2015 VL 96 IS 1 BP 1 EP 9 DI 10.1016/j.bcp.2015.04.008 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK9MD UT WOS:000356563300001 PM 25935605 ER PT J AU Lukkahatai, N Walitt, B Espina, A Wang, D Saligan, LN AF Lukkahatai, Nada Walitt, Brian Espina, Alexandra Wang, Dan Saligan, Leorey N. TI Comparing Genomic Profiles of Women With and Without Fibromyalgia SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE genomic profile; fibromyalgia; pain; fatigue ID FATIGUE SYNDROME/MYALGIC ENCEPHALOMYELITIS; PREMATURE CENTROMERE DIVISION; GENE-EXPRESSION; ANTICENTROMERE ANTIBODIES; AUTOIMMUNE-DISEASES; MULTIPLE-SCLEROSIS; SYSTEMIC-SCLEROSIS; MODERATE EXERCISE; SHOCK-PROTEIN; CENP-A AB Background: Fibromyalgia syndrome (FMS), a chronic musculoskeletal condition characterized by diffuse pain, fatigue, sleep impairment, and cognitive dysfunction, is associated with significant functional disability. Its underlying biological mechanisms are unknown. This study investigated differentially expressed genes between women with FMS and healthy volunteers. Methods: Women who met the 1990 or 2010 American College of Rheumatology fibromyalgia criteria were compared to age- and race-matched pain-free healthy women. Peripheral blood samples were collected, and a full genome microarray gene expression analysis was performed. One-way analysis of variance was used to identify differentially expressed genes using the filtering criterion of 1% false discovery rate. Analysis of canonical pathways associated with these genes was performed. Confirmatory quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay verified microarray results. Independent t-tests compared gene and protein expression between groups. Result: Participants were 54 women with FMS and 25 controls. Expression arrays from a subset of women with FMS (n = 29) and controls (n = 20) showed upregulation of 12 genes (>1.8-fold change, p < .05) in the FMS sample. Differentially expressed genes were related to B-cell development, primary immunodeficiency signaling, and mitotic roles of polo-like kinase. CENPK and HSP90AA1 were the most differentially expressed genes (p < .01). Conclusion: Activity of interrelated pathways related to immune response, and homeostasis appears to be relevant to the experience of FMS. Replication and exploration of the relationship between gene expression and symptom severity will help determine clinical relevance of these findings. C1 [Lukkahatai, Nada] Univ Nevada, Sch Nursing, Las Vegas, NV 89154 USA. [Lukkahatai, Nada; Walitt, Brian; Espina, Alexandra; Wang, Dan; Saligan, Leorey N.] NINR, NIH, Bethesda, MD 20892 USA. [Walitt, Brian] Washington Hosp Ctr, Rheumatol Sect, Washington, DC 20010 USA. RP Saligan, LN (reprint author), NINR, Div Intramural Res, NIH, 3 Ctr Dr,Bldg 3,Room 5E14, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov FU MedStar grant [NCT00888563]; Division of Intramural Research of the NINR; Division of Intramural Research of the NINR, National Institutes of Health, Bethesda, MD (Office of Human Subject Research and Protection Approval) [4966]; Georgetown Howard Universities Center for Clinical and Translational Science through MedStar Research Institute [NCT00888563] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part of a collaborative activity of NINR and the Medstar Research Institute as approved by the Office of Human Subjects Research (OHSR) of the National Institutes of Health (OHSR IRB-Exempt #4966) and is funded in part by a MedStar grant (NCT00888563) and the Division of Intramural Research of the NINR. This study is fully supported by the Division of Intramural Research of the NINR, National Institutes of Health, Bethesda, MD (Office of Human Subject Research and Protection Approval #4966), and the Georgetown Howard Universities Center for Clinical and Translational Science through the MedStar Research Institute grant (NCT00888563). NR 53 TC 2 Z9 2 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD JUL PY 2015 VL 17 IS 4 SI SI BP 373 EP 383 DI 10.1177/1099800415589785 PG 11 WC Nursing SC Nursing GA CK7TU UT WOS:000356437200004 PM 26015072 ER PT J AU Gill, JM Lee, H Baxter, T Reddy, SY Barr, T Kim, HS Wang, D Mysliwiec, V AF Gill, Jessica M. Lee, Hyunhwa Baxter, Tristin Reddy, Swarnalatha Y. Barr, Taura Kim, Hyung-suk Wang, Dan Mysliwiec, Vincent TI A Diagnosis of Insomnia Is Associated With Differential Expression of Sleep-Regulating Genes in Military Personnel SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE insomnia; military; gene expression; urotensin ID SUDDEN UNEXPLAINED DEATH; TRAUMATIC BRAIN-INJURY; EYE-MOVEMENT SLEEP; NARCOLEPSY; DISORDER; DURATION; HYPERTENSION; DEPRESSION; DROSOPHILA; SOLDIERS AB Sleep disturbance is a common and disturbing symptom in military personnel, with many individuals progressing to the development of insomnia, which is characterized by increased arousals, wakefulness after sleep onset, and distorted sleep architecture. The molecular mechanisms underlying insomnia remain elusive, limiting future therapeutic development to address this critical issue. We examined whole gene expression profiles associated with insomnia. We compared subjects with insomnia (n = 25) to controls (n = 13) without insomnia using microarray gene expression profiles obtained from peripheral samples of whole blood obtained from military personnel. Compared to controls, participants with insomnia had differential expression of 44 transcripts from 43 identified genes. Among the identified genes, urotensin 2 was downregulated by more than 6 times in insomnia participants, and the fold-change remained significant after controlling for depression, posttraumatic stress disorder, and medication use. Urotensin 2 is involved in regulation of orexin A and B activity and rapid eye movement during sleep. These findings suggest that differential expression of these sleep-regulating genes contributes to symptoms of insomnia and, specifically, that switching between rapid eye movement and nonrapid eye movement sleep stages underlies insomnia symptoms. Future work to identify therapeutic agents that are able to regulate these pathways may provide novel treatments for insomnia. C1 [Gill, Jessica M.; Kim, Hyung-suk; Wang, Dan] NINR, NIH, Bethesda, MD 20892 USA. [Lee, Hyunhwa] Univ Nevada, Sch Nursing, Las Vegas, NV 89154 USA. [Baxter, Tristin; Mysliwiec, Vincent] Madigan Army Med Ctr, Tacoma, WA 98431 USA. [Reddy, Swarnalatha Y.] NINR, Bethesda, MD 20892 USA. [Barr, Taura] W Virginia Univ, Morgantown, WV 26506 USA. RP Gill, JM (reprint author), NINR, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM gillj@mail.nih.gov RI Reddy, Swarna/G-5349-2013 FU Center for Neuroscience and Regenerative Medicine [60855]; National Institute of Nursing Research FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded, in part, by the Center for Neuroscience and Regenerative Medicine (grant #60855) and by the by the intramural research program of the National Institute of Nursing Research. Additionally, Taura Barr is a 2012 Robert Wood Johnson Foundation Nurse Faculty Scholar. NR 43 TC 3 Z9 3 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD JUL PY 2015 VL 17 IS 4 SI SI BP 384 EP 392 DI 10.1177/1099800415575343 PG 9 WC Nursing SC Nursing GA CK7TU UT WOS:000356437200005 PM 25767060 ER PT J AU Stanfill, AG Conley, Y Cashion, A Thompson, C Homayouni, R Cowan, P Hathaway, D AF Stanfill, Ansley Grimes Conley, Yvette Cashion, Ann Thompson, Carol Homayouni, Ramin Cowan, Patricia Hathaway, Donna TI Neurogenetic and Neuroimaging Evidence for a Conceptual Model of Dopaminergic Contributions to Obesity SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE dopamine; obesity; BMI; genetics ID D2 RECEPTOR GENE; MONOAMINE-OXIDASE; IN-VIVO; FUNCTIONAL POLYMORPHISM; DORSAL STRIATUM; WEIGHT-GAIN; HUMAN BRAIN; FOOD; ASSOCIATION; AVAILABILITY AB As the incidence of obesity continues to rise, clinicians and researchers alike are seeking explanations for why some people become obese while others do not. While caloric intake and physical activity most certainly play a role, some individuals continue to gain weight despite careful attention to these factors. Increasing evidence suggests that genetics may play a role, with one potential explanation being genetic variability in genes within the neurotransmitter dopamine pathway. This variability can lead to a disordered experience with the rewarding properties of food. This review of literature examines the extant knowledge about the relationship between obesity and the dopaminergic reward pathways in the brain, with particularly strong evidence provided from neuroimaging and neurogenetic data. Pubmed, Google Scholar, and Cumulative Index to Nursing and Allied Health Literature searches were conducted with the search terms dopamine, obesity, weight gain, food addiction, brain regions relevant to the mesocortical and mesolimbic (reward) pathways, and relevant dopaminergic genes and receptors. These terms returned over 200 articles. Other than a few sentinel articles, articles were published between 1993 and 2013. These data suggest a conceptual model for obesity that emphasizes dopaminergic genetic contributions as well as more traditional risk factors for obesity, such as demographics (age, race, and gender), physical activity, diet, and medications. A greater understanding of variables contributing to weight gain and obesity is imperative for effective clinical treatment. C1 [Stanfill, Ansley Grimes] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. [Stanfill, Ansley Grimes; Cowan, Patricia; Hathaway, Donna] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Conley, Yvette] Univ Pittsburgh, Pittsburgh, PA USA. [Cashion, Ann] NIH, Bethesda, MD 20892 USA. [Thompson, Carol] Univ Kentucky, Lexington, KY USA. [Homayouni, Ramin] Univ Memphis, Memphis, TN 38152 USA. RP Stanfill, AG (reprint author), Univ Pittsburgh, 3500 Victoria St,Victoria Bldg, Pittsburgh, PA 15261 USA. EM Stanfill@pitt.edu FU NIH/NINR [1F31NR013812, T32 NR009759]; Southern Nursing Research Society 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 by NIH/NINR grant 1F31NR013812 (PI: Stanfill, cosponsors: Hathaway and Conley; by the NIH/NINR grant T32 NR009759 (PI: Conley), and by the Southern Nursing Research Society Dissertation award (PI: Stanfill). NR 60 TC 0 Z9 0 U1 1 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD JUL PY 2015 VL 17 IS 4 SI SI BP 413 EP 421 DI 10.1177/1099800414565170 PG 9 WC Nursing SC Nursing GA CK7TU UT WOS:000356437200008 PM 25576324 ER PT J AU Kurnat-Thoma, EL Pangilinan, F Matteini, AM Wong, B Pepper, GA Stabler, SP Guralnik, JM Brody, LC AF Kurnat-Thoma, Emma L. Pangilinan, Faith Matteini, Amy M. Wong, Bob Pepper, Ginette A. Stabler, Sally P. Guralnik, Jack M. Brody, Lawrence C. TI Association of Transcobalamin II (TCN2) and Transcobalamin II-Receptor (TCblR) Genetic Variations With Cobalamin Deficiency Parameters in Elderly Women SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE cobalamin; vitamin B12 deficiency; transcobalamin; genetic association; pernicious anemia; older adults ID ONE-CARBON METABOLISM; DWELLING OLDER WOMEN; B-VITAMIN TREATMENT; MOBILITY DIFFICULTY; SERUM CREATININE; INCREASED RISK; HUMAN PLASMA; FOLIC-ACID; FRAILTY; HEALTH AB Cobalamin (vitamin B12) deficiency is a subtle progressive clinical disorder, affecting nearly 1 in 5 individuals > 60 years old. This deficiency is produced by age-related decreases in nutrient absorption, medications that interfere with vitamin B12 absorption, and other comorbidities. Clinical heterogeneity confounds symptom detection for elderly adults, as deficiency sequelae range from mild fatigue and weakness to debilitating megaloblastic anemia and permanent neuropathic injury. A better understanding of genetic factors that contribute to cobalamin deficiency in the elderly would allow for targeted nursing care and preventive interventions. We tested for associations of common variants in genes involved in cobalamin transport and homeostasis with metabolic indicators of cobalamin deficiency (homocysteine and methylmalonic acid) as well as hematologic, neurologic, and functional performance features of cobalamin deficiency in 789 participants of the Women's Health and Aging Studies. Although not significant when corrected for multiple testing, eight single nucleotide polymorphisms (SNPs) in two genes, transcobalamin II (TCN2) and the transcobalamin II-receptor (TCblR), were found to influence several clinical traits of cobalamin deficiency. The three most significant findings were the identified associations involving missense coding SNPs, namely, TCblR G220R (rs2336573) with serum cobalamin, TCN2 S348F (rs9621049) with homocysteine, and TCN2 P259R (rs1801198) with red blood cell mean corpuscular volume. These SNPs may modify the phenotype in older adults who are more likely to develop symptoms of vitamin B12 malabsorption. C1 [Kurnat-Thoma, Emma L.; Pangilinan, Faith; Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Kurnat-Thoma, Emma L.] NINR, NIH, Bethesda, MD 20892 USA. [Matteini, Amy M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kurnat-Thoma, Emma L.; Wong, Bob; Pepper, Ginette A.] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Stabler, Sally P.] Univ Colorado, Sch Med, Div Hematol, Denver, CO USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Brody, LC (reprint author), NHGRI, NIH, Louis B Stokes Labs, 50 South Dr,Bldg 50,Room 5305, Bethesda, MD 20892 USA. EM lbrody@mail.nih.gov FU National Human Genome Research Institute; National Institute on Aging (National Institutes of Health); National Institute of Nursing Research 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 by Intramural Research Programs of the National Human Genome Research Institute and the National Institute on Aging (National Institutes of Health). Dr. Kurnat-Thoma was supported by a predoctoral Intramural Research Training Award from the National Institute of Nursing Research. NR 65 TC 0 Z9 0 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD JUL PY 2015 VL 17 IS 4 SI SI BP 444 EP 454 DI 10.1177/1099800415569506 PG 11 WC Nursing SC Nursing GA CK7TU UT WOS:000356437200012 PM 25657319 ER PT J AU Siddiqui, S Sarro, Y Diarra, B Diallo, H Guindo, O Dabitao, D Tall, M Hammond, A Kassambara, H Goita, D Dembele, P Traore, B Hengel, R Nason, M Warfield, J Washington, J Polis, M Diallo, S Dao, S Koita, O Lane, HC Catalfamo, M Tounkara, A AF Siddiqui, S. Sarro, Y. Diarra, B. Diallo, H. Guindo, O. Dabitao, D. Tall, M. Hammond, A. Kassambara, H. Goita, D. Dembele, P. Traore, B. Hengel, R. Nason, M. Warfield, J. Washington, J. Polis, M. Diallo, S. Dao, S. Koita, O. Lane, H. C. Catalfamo, M. Tounkara, A. TI Tuberculosis specific responses following therapy for TB: Impact of HIV co-infection SO CLINICAL IMMUNOLOGY LA English DT Article DE Tuberculosis; CD4+T cells; HIV ID RECONSTITUTION INFLAMMATORY SYNDROME; CELL CYTOKINE RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; IFN-GAMMA; PULMONARY TUBERCULOSIS; GREATER-THAN-350 CELLS/MM(3); IMMUNE ACTIVATION; INTERFERON-GAMMA AB 0 Characterizing perturbations in the immune response to tuberculosis in HIV can develop insights into the pathogenesis of coinfection. HIV+ TB+ and TB monoinfected (TB+) subjects recruited from clinics in Bamako prior to initiation of TB treatment were evaluated at time-points following initiation of therapy. Flow cytometry assessed CD4+/CD8+ T cell subsets and activation markers CD38/HLA-DR. Antigen specific responses to TB proteins were assessed by intracellular cytokine detection and proliferation. HIV+ TB+ subjects had significantly higher markers of immune activation in the CD4+ and CD8+ T cells compared to TB+ subjects. HIV+ TB+ had tower numbers of TB-specific CD4+ T cells at baseline. Plasma IFN gamma levels were similar between HIV+ TB+ and TB+ subjects. No differences were observed in in-vitro proliferative capacity to TB antigens between HIV+ TB+ and TB+ subjects. Subjects with HIV+ TB+ coinfection demonstrate in vivo expansion of TB-specific CD4+ T cells. Immunodeficiency associated with CD4+ T cell depletion may be less significant compared to immunosuppression associated with HIV viremia or untreated TB infection. Published by Elsevier Inc. C1 [Siddiqui, S.; Sarro, Y.; Diarra, B.; Diallo, H.; Guindo, O.; Dabitao, D.; Tall, M.; Hammond, A.; Kassambara, H.; Goita, D.; Dembele, P.; Traore, B.; Hengel, R.; Nason, M.; Warfield, J.; Washington, J.; Polis, M.; Diallo, S.; Dao, S.; Koita, O.; Lane, H. C.; Catalfamo, M.; Tounkara, A.] NIAID, Collaborat Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Siddiqui, S (reprint author), NIAID, Collaborat Clin Res Branch, NIH, Rm 1167,Bldg 6700B,Rockledge Dr, Bethesda, MD 20892 USA. EM ssiddiqui@niaid.nih.gov OI Traore, Brehima/0000-0001-9075-9157 FU University of Bamako, Faculty of Medicine; intramural program of the NIAID/NIH FX The intramural program of the NIAID/NIH in collaboration with the University of Bamako, Faculty of Medicine, supported this work. NR 43 TC 1 Z9 2 U1 2 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2015 VL 159 IS 1 BP 1 EP 12 DI 10.1016/j.clim.2015.04.002 PG 12 WC Immunology SC Immunology GA CK9MQ UT WOS:000356564600001 PM 25889622 ER PT J AU Ren, JQ Wang, H Tran, K Civini, S Jin, P Castiello, L Feng, J Kuznetsov, SA Robey, PG Sabatino, M Stroncek, DF AF Ren, Jiaqiang Wang, Huan Tran, Katherine Civini, Sara Jin, Ping Castiello, Luciano Feng, Ji Kuznetsov, Sergei A. Robey, Pamela G. Sabatino, Marianna Stroncek, David F. TI Human bone marrow stromal cell confluence: effects on cell characteristics and methods of assessment SO CYTOTHERAPY LA English DT Article DE bone marrow stromal cells; cellular therapy; confluence; gene expression profiling; microRNA ID MESENCHYMAL STEM-CELLS; ANTIINFLAMMATORY PROTEIN TSG-6; OSTEOGENIC DIFFERENTIATION; ISCHEMIC CARDIOMYOPATHY; REPLICATIVE SENESCENCE; MYOCARDIAL-INFARCTION; MICRORNA EXPRESSION; ADHESION MOLECULES; PROGENITOR CELLS; MSC SUBSETS AB Background aims. Ex vivo expansion and serial passage of human bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) is required to obtain sufficient quantities for clinical therapy. The BMSC confluence criteria used to determine passage and harvest timing vary widely, and the impact of confluence on BMSC properties remains controversial. The effects of confluence on BMSC properties were studied and confluence-associated markers were identified. Methods. BMSC characteristics were analyzed as they grew from 50% to 100% confluence, including viability, population doubling time, apoptosis, colony formation, immunosuppression, surface marker expression, global gene expression and microRNA expression. In addition, culture supernatant protein, glucose, lactate and pH levels were analyzed. Results. Confluence-dependent changes were detected in the expression of several cell surface markers: 39 culture supernatant proteins, 26 microRNAs and 2078 genes. Many of these surface markers, proteins, microRNAs and genes have been reported to be important in BMSC function. The pigment epithelium-derived factor/vascular endothelial growth factor ratio increased with confluence, but 80% and 100% confluent BMSCs demonstrated a similar level of immunosuppression of mixed lymphocyte reactions. In addition, changes in lactate and glucose levels correlated with BMSC density. Conclusions. BMSC characteristics change as confluence increases. 100% confluent BMSCs may have compromised pro-angiogenesis properties but may retain their immunomodulatory properties. Supernatant lactate and glucose levels can be used to estimate confluence and ensure consistency in passage and harvest timing. Flow cytometry or microRNA expression can be used to confirm that the BMSCs have been harvested at the appropriate confluence. C1 [Ren, Jiaqiang; Wang, Huan; Tran, Katherine; Civini, Sara; Jin, Ping; Castiello, Luciano; Feng, Ji; Sabatino, Marianna; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Kuznetsov, Sergei A.; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov RI Castiello, Luciano/K-8616-2016; Robey, Pamela/H-1429-2011 OI Castiello, Luciano/0000-0001-7146-3158; Robey, Pamela/0000-0002-5316-5576 FU NIH Bone Marrow Stromal Cell Transplantation Center (BMSCTC); Department of Transfusion Medicine, Clinical Center NIH FX The authors thank the staff of the Cell Processing Laboratory, Department of Transfusion Medicine, Clinical Center, NIH for their support of these studies. We also thank Dr Francesco Marincola and Dr Ena Wang (Department of Transfusion Medicine, Clinical Center, NIH, now at Sidra Medical and Research Center, Qtar) for useful discussions and comments on the manuscript. This work was funded by NIH Bone Marrow Stromal Cell Transplantation Center (BMSCTC) and the Department of Transfusion Medicine, Clinical Center NIH. NR 72 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUL PY 2015 VL 17 IS 7 BP 897 EP 911 DI 10.1016/j.jcyt.2015.03.607 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CL0KS UT WOS:000356632200007 PM 25882666 ER PT J AU Schernthaner, G Schernthaner-Reiter, MH AF Schernthaner, G. Schernthaner-Reiter, M. H. TI How attractive is the combination of a sodium glucose co-transporter 2 inhibitor with a dipeptidyl peptidase 4 inhibitor in the treatment of type 2 diabetes? SO DIABETES OBESITY & METABOLISM LA English DT Editorial Material ID METFORMIN PLUS SULFONYLUREA; ADD-ON THERAPY; GLYCEMIC CONTROL; DAPAGLIFLOZIN; TRIAL; EMPAGLIFLOZIN; CANAGLIFLOZIN; LINAGLIPTIN; MANAGEMENT C1 [Schernthaner, G.] Rudolfstiftung Hosp Vienna, Dept Med 1, A-1030 Vienna, Austria. [Schernthaner-Reiter, M. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Schernthaner, G (reprint author), Rudolfstiftung Hosp Vienna, Juchgasse 25, A-1030 Vienna, Austria. EM guntram.schernthaner@meduniwien.ac.at OI Schernthaner-Reiter, Marie Helene/0000-0002-7972-7610 NR 13 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 EI 1463-1326 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD JUL PY 2015 VL 17 IS 7 BP 613 EP 615 DI 10.1111/dom.12478 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CK9XG UT WOS:000356592200001 PM 26018554 ER PT J AU Papaneri, AB Johnson, RF Wada, J Bollinger, L Jahrling, PB Kuhn, JH AF Papaneri, Amy B. Johnson, Reed F. Wada, Jiro Bollinger, Laura Jahrling, Peter B. Kuhn, Jens H. TI Middle East respiratory syndrome: obstacles and prospects for vaccine development SO EXPERT REVIEW OF VACCINES LA English DT Review DE betacoronavirus; Coronaviridae; coronavirus; MERS-CoV; Middle East respiratory syndrome; Nidovirales; nidovirus ID SYNDROME CORONAVIRUS INFECTION; SARS-LIKE CORONAVIRUS; TO-HUMAN TRANSMISSION; PAPAIN-LIKE PROTEASE; HEALTH-CARE WORKER; MERS-COV INFECTION; SAUDI-ARABIA; DROMEDARY CAMELS; NEUTRALIZING ANTIBODIES; SPIKE PROTEIN AB The recent emergence of Middle East respiratory syndrome (MERS) highlights the need to engineer new methods for expediting vaccine development against emerging diseases. However, several obstacles prevent pursuit of a licensable MERS vaccine. First, the lack of a suitable animal model for MERS complicates the in vivo testing of candidate vaccines. Second, due to the low number of MERS cases, pharmaceutical companies have little incentive to pursue MERS vaccine production as the costs of clinical trials are high. In addition, the timeline from bench research to approved vaccine use is 10 years or longer. Using novel methods and cost-saving strategies, genetically engineered vaccines can be produced quickly and cost-effectively. Along with progress in MERS animal model development, these obstacles can be circumvented or at least mitigated. C1 [Papaneri, Amy B.; Johnson, Reed F.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, Div Intramural Res, NIH, Frederick, MD USA. [Wada, Jiro; Bollinger, Laura; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD 20817 USA. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 20817 USA. EM kuhnjens@mail.nih.gov OI Papaneri, Amy/0000-0003-2144-2441 FU US National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research; Battelle Memorial Institute; NIAID [HHSN272200700016I] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. This work was supported, in part, by the US National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research, and in part through Battelle Memorial Institute's prime contract with NIAID under Contract No. HHSN272200700016I. J Wada and L Bollinger performed this work as employees of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are as follows: JH Kuhn, an employee of Tunnell Government Services, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 145 TC 6 Z9 6 U1 2 U2 23 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUL PY 2015 VL 14 IS 7 BP 949 EP 962 DI 10.1586/14760584.2015.1036033 PG 14 WC Immunology SC Immunology GA CK7WF UT WOS:000356445300006 PM 25864502 ER PT J AU Li, Q Kim, Y Suktitipat, B Hetmanski, JB Marazita, ML Duggal, P Beaty, TH Bailey-Wilson, JE AF Li, Qing Kim, Yoonhee Suktitipat, Bhoom Hetmanski, Jacqueline B. Marazita, Mary L. Duggal, Priya Beaty, Terri H. Bailey-Wilson, Joan E. TI Gene-Gene Interaction Among WNT Genes for Oral Cleft in Trios SO GENETIC EPIDEMIOLOGY LA English DT Article DE complex disease; family-based study; machine learning ID GENOME-WIDE ASSOCIATION; STATISTICAL-METHODS; LIP; PALATE; MICE; MORPHOGENESIS; VARIANTS AB Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (CL/P) have identified multiple genes as important in the etiology of this common birth defect. We performed a candidate gene/pathway analysis explicitly considering gene-gene (G x G) interaction to further explore the etiology of CL/P. Animal models have shown the WNT signaling pathway plays an important role in mid-facial development, and various genes in this pathway have been associated with nonsyndromic CL/P in previous studies. We propose a combined approach to search for possible G x G interactions using machine learning and regression-based methods to test for interactions between genes in the WNT family, and between these genes and other genes identified by GWAS in case-parent trios. Using this combined approach of regression-based and machine learning methods in CL/P case-parent trios, we found robust evidence of G x G interaction between markers in WNT5B and MAFB (empiric P-values = 0.0076 among Asian trios and P-values = 0.018 among European trios). Additional evidence for epistatic interaction between markers in WNT5A, IRF6, and C1orf107 was seen among Asian trios, and markers in the 8q24 region and WNT5B among European trios. (C) 2015 Wiley Periodicals, Inc. C1 [Li, Qing; Kim, Yoonhee; Suktitipat, Bhoom; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD 21224 USA. [Suktitipat, Bhoom] Mahidol Univ, Fac Med, Siriraj Hosp, Dept Biochem, Bangkok 10700, Thailand. [Hetmanski, Jacqueline B.; Duggal, Priya; Beaty, Terri H.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Pittsburgh, PA USA. RP Bailey-Wilson, JE (reprint author), NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD 21224 USA. EM jebw@mail.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920; Suktitipat, Bhoom/0000-0001-8034-7757 FU National Institute for Dental and Craniofacial Research [U01-DE-018993]; NHGRI; National Human Genome Research Institute, National Institutes of Health; NIH [HHSN268200782096C]; NIH, National Institute of Environmental Health Sciences (AJW); [R01-DE-014581]; [R37-DE08559]; [R01-DE09886]; [R01-DE012472]; [R01-DE014677]; [R01-DE016148]; [P50-DE016215]; [R21-DE016930]; [R01-HD390661]; [R01-DE016877] FX The data for this international cleft consortium were a collaborative effort among many groups, and we acknowledge the invaluable contributions of J. C. Murray (University of Iowa), R. G. Munger (Utah State University), A. J. Wilcox (NIEHS), R. T. Lie (University of Bergen), Y.-H. Wu-Chou (Chang Gung Memorial Hospital), H. Wang (Peking University), X. Ye (Wuhan University), S. Huang (Peking Medical College), V. Yeow (KKWCH), S. S. Chong (National University of Singapore), S. H. Jee (Yonsei University), B. Shi (West China School of Stomatology, Sichuan University), and A. F. Scott (Johns Hopkins). We sincerely thank all of the families at each of the original recruitment sites for participating in this study, and we gratefully acknowledge the invaluable assistance of clinical, field, and laboratory staff who contributed to making this work possible. Funding to support data collection, genotyping, and analysis came from several sources, some to individual investigators and some to the consortium itself. The consortium for GWAS genotyping and analysis was supported by the National Institute for Dental and Craniofacial Research through U01-DE-018993; "International Consortium to Identify Genes & Interactions Controlling Oral Clefts," 2007-2009; T. H. Beaty, PI. This project was part of the gene, environment association studies consortium (GENEVA) funded by NHGRI to enhance communication and collaboration among investigators conducting genome-wide studies for a variety of complex diseases. The current analyses were also supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Our group benefited greatly from the work of the Coordinating Center (directed by B. Weir and C. Laurie of the University of Washington) in data cleaning and preparation of these case-parent trios for submission to the Database for Genotypes and Phenotypes (dbGaP: http://www.ncbi.nlm.nih.gov/). We also acknowledge the leadership of T. Manolio of NHGRI and E. Harris of NIDCR. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), funded through a federal contract from NIH to Johns Hopkins University (contract number HHSN268200782096C). Funding for individual investigators and the replication studies include: R01-DE-014581 (T.H.B.), R37-DE08559 (J.C.M., M.L.M.), R01-DE09886 (M.L.M.), R01-DE012472 (M.L.M.), R01-DE014677 (M.L.M.), R01-DE016148 (M.L.M.), P50-DE016215 (J.C.M., M.L.M.), R21-DE016930 (M.L.M.), R01-HD390661 and R01-DE016877 (R.G.M.). Smile Train Foundation supported data collection in Chengdu. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (AJW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Dental and Craniofacial Research, nor the National Institutes of Health. NR 28 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2015 VL 39 IS 5 BP 385 EP 394 DI 10.1002/gepi.21888 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CK6UM UT WOS:000356363800007 PM 25663376 ER PT J AU Portnoy, DB Loud, JT Han, PKJ Mai, PL Greene, MH AF Portnoy, David B. Loud, Jennifer T. Han, Paul K. J. Mai, Phuong L. Greene, Mark H. TI Effects of False-Positive Cancer Screenings and Cancer Worry on Risk-Reducing Surgery Among BRCA1/2 Carriers SO HEALTH PSYCHOLOGY LA English DT Article DE BRCA1/2; risk perception; cancer worry; false-positive; cancer screening; risk-reducing surgery ID QUALITY-OF-LIFE; BREAST-CANCER; OVARIAN-CANCER; MUTATION CARRIERS; PROPHYLACTIC OOPHORECTOMY; SALPINGO-OOPHORECTOMY; INFLUENZA VACCINATION; HEALTH BEHAVIOR; FAMILY-HISTORY; WOMEN AB Objective: Female BRCA1/2 mutation carriers are at increased risk of breast and ovarian cancer. Annual breast and semiannual ovarian cancer screening is recommended for early detection, which frequently leads to false-positive test results (FPTR). FPTR may influence cancer risk perceptions and worry, which in turn may affect an individual's decision to undergo risk-reducing bilateral salpingo-oophorectomy (RRSO) or risk-reducing bilateral mastectomy (RRBM). The purpose of this study was to examine: (a) the effect of false-positive breast and ovarian cancer screening test results on perceived cancer risk and cancer worry, and (b) the joint effects of FPTR, risk perceptions, and worry on the choice of risk-reducing surgery among BRCA1/2 mutation carriers undergoing an intensive cancer screening protocol. Method: BRCA1/2 mutation carriers (N = 170) reported cancer risk perceptions and cancer worry during a prospective 4-year screening protocol (2001-2007) at the U.S. National Cancer Institute. FPTR and risk-reducing surgeries were objectively recorded. Results: FPTR at baseline were associated with transient elevations in worry; cumulative FPTR across the entire study were not associated with opting for risk-reducing surgery. However, cancer-specific worry was a strong predictor of surgery (RRSO: OR = 6.15; RRBM: OR = 4.27). Conclusions: In women at inherited risk of breast and ovarian cancer, FPTR were not associated with large increases in cancer risk perception, cancer worry, or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery and warrants consideration when counseling high-risk women regarding risk-reducing interventions. C1 [Portnoy, David B.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training & Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Loud, Jennifer T.; Mai, Phuong L.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04102 USA. RP Portnoy, DB (reprint author), US FDA, Ctr Tobacco Prod, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457; Han, Paul/0000-0003-0165-1940 FU Intramural Research Program of the NIH; National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH and the National Cancer Institute. The views expressed do not necessarily reflect those of the Food and Drug Administration or the Federal Government. The authors wish to acknowledge Ruthann Giusti, Sheila Prindiville, and June Peters for their contributions to the original design and implementation of the Breast Imaging Study. NR 46 TC 1 Z9 1 U1 0 U2 2 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 JUL PY 2015 VL 34 IS 7 BP 709 EP 717 DI 10.1037/hea0000156 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA CK9XO UT WOS:000356593100003 PM 25243716 ER PT J AU Taber, JM Klein, WMP Ferrer, RA Lewis, KL Biesecker, LG Biesecker, BB AF Taber, Jennifer M. Klein, William M. P. Ferrer, Rebecca A. Lewis, Katie L. Biesecker, Leslie G. Biesecker, Barbara B. TI Dispositional Optimism and Perceived Risk Interact to Predict Intentions to Learn Genome Sequencing Results SO HEALTH PSYCHOLOGY LA English DT Article DE dispositional optimism; perceived risk; genetics; genomics; comparative risk ID BREAST-CANCER RISK; INFORMATION AVOIDANCE; PSYCHOLOGICAL DISTRESS; DECISION-MAKING; HEALTH BEHAVIOR; FAMILY-HISTORY; PERCEPTIONS; BELIEFS; WORRY; SUSCEPTIBILITY AB Objective: Dispositional optimism and risk perceptions are each associated with health-related behaviors and decisions and other outcomes, but little research has examined how these constructs interact, particularly in consequential health contexts. The predictive validity of risk perceptions for health-related information seeking and intentions may be improved by examining dispositional optimism as a moderator, and by testing alternate types of risk perceptions, such as comparative and experiential risk. Method: Participants (n = 496) had their genomes sequenced as part of a National Institutes of Health pilot cohort study (ClinSeq (R)). Participants completed a cross-sectional baseline survey of various types of risk perceptions and intentions to learn genome sequencing results for differing disease risks (e.g., medically actionable, nonmedically actionable, carrier status) and to use this information to change their lifestyle/health behaviors. Results: Risk perceptions (absolute, comparative, and experiential) were largely unassociated with intentions to learn sequencing results. Dispositional optimism and comparative risk perceptions interacted, however, such that individuals higher in optimism reported greater intentions to learn all 3 types of sequencing results when comparative risk was perceived to be higher than when it was perceived to be lower. This interaction was inconsistent for experiential risk and absent for absolute risk. Independent of perceived risk, participants high in dispositional optimism reported greater interest in learning risks for nonmedically actionable disease and carrier status, and greater intentions to use genome information to change their lifestyle/health behaviors. Conclusions: The relationship between risk perceptions and intentions may depend on how risk perceptions are assessed and on degree of optimism. C1 [Taber, Jennifer M.; Klein, William M. P.; Ferrer, Rebecca A.] NCI, NIH, Bethesda, MD 20892 USA. [Lewis, Katie L.; Biesecker, Leslie G.; Biesecker, Barbara B.] NHGRI, NIH, Bethesda, MD USA. RP Taber, JM (reprint author), NCI, 9609 Med Ctr Dr,Room 3E642, Bethesda, MD 20892 USA. EM jennifer.taber@nih.gov FU National Human Genome Research Institute FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute. NR 61 TC 3 Z9 3 U1 5 U2 12 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 JUL PY 2015 VL 34 IS 7 BP 718 EP 728 DI 10.1037/hea0000159 PG 11 WC Psychology, Clinical; Psychology SC Psychology GA CK9XO UT WOS:000356593100004 PM 25313897 ER PT J AU Edelman, EJ Tate, JP Fiellin, DA Brown, ST Bryant, K Gandhi, N Gibert, CL Goetz, MB Gordon, KS Rodriguez-Barradas, MC Braithwaite, RS Rimland, D Justice, AC AF Edelman, E. J. Tate, J. P. Fiellin, D. A. Brown, S. T. Bryant, K. Gandhi, N. Gibert, C. L. Goetz, M. B. Gordon, K. S. Rodriguez-Barradas, M. C. Braithwaite, R. S. Rimland, D. Justice, A. C. TI Impact of defined clinical population and missing data on temporal trends in HIV viral load estimation within a health care system SO HIV MEDICINE LA English DT Article DE community viral load; epidemiological methods; HIV; population surveillance; quality of health care ID OF-VETERANS-AFFAIRS; MEDICAL-CARE; COHORT; INFORMATION; ENGAGEMENT; MORTALITY; INDEX AB ObjectivesCommunity viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Health Administration (VA) to determine trends in the health care system viral load (HSVL) and its sensitivity to varying definitions of the clinical population and assumptions regarding missing data. MethodsWe included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with at least one documented CD4 count, HIV-1 RNA or antiretroviral prescription (n=37318). We created 6-month intervals including patients with at least one visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load. ResultsThe clinical population size varied by definition, increasing from 16000-19000 patients in 2000 to 23000-26000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or the past 2 years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97800 HIV-1 RNA copies/mL in 2000 to 2000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322300 to 9900 copies/mL. HSVL was underestimated when using only current data in each interval. ConclusionsThe CVL concept can be applied to a health care system, providing a measure of health care quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data. C1 [Edelman, E. J.; Tate, J. P.; Fiellin, D. A.; Justice, A. C.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Edelman, E. J.; Fiellin, D. A.; Justice, A. C.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT 06520 USA. [Tate, J. P.; Gordon, K. S.; Justice, A. C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Brown, S. T.] James J Peters VA Med Ctr, Bronx, NY USA. [Brown, S. T.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Bryant, K.] NIAAA, Bethesda, MD USA. [Gandhi, N.] Emory Rollins Sch Publ Hlth, Atlanta, GA USA. [Gandhi, N.; Rimland, D.] Emory Univ, Sch Med, Atlanta, GA USA. [Gibert, C. L.] Washington DC VA Med Ctr, Washington, DC USA. [Gibert, C. L.] George Washington Univ, Sch Med, Washington, DC USA. [Goetz, M. B.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Goetz, M. B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rodriguez-Barradas, M. C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, M. C.] Baylor Coll Med, Houston, TX 77030 USA. [Braithwaite, R. S.] NYU, Sch Med, New York, NY USA. [Rimland, D.] Atlanta Vet Affairs Med Ctr, Decatur, GA USA. RP Edelman, EJ (reprint author), Yale Univ, Sch Med, Gen Internal Med, POB 208025, New Haven, CT 06520 USA. EM ejennifer.edelman@yale.edu OI Goetz, Matthew/0000-0003-4542-992X; Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502 FU NIAAA NIH HHS [U01-AA020790, U10 AA013566, U10-AA13566, U01 AA020790, U24 AA020794, U24-AA020794]; NIAID NIH HHS [K24 AI114444, P30AI050409]; NIDA NIH HHS [K12 DA033312, K12DA033312-01A1]; PHS HHS [K24114444-01] NR 38 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD JUL PY 2015 VL 16 IS 6 BP 346 EP 354 DI 10.1111/hiv.12219 PG 9 WC Infectious Diseases SC Infectious Diseases GA CK9XL UT WOS:000356592700003 PM 25688937 ER PT J AU Wang, ZM Rajaraman, P Melin, BS Chung, CC Zhang, WJ McKean-Cowdin, R Michaud, D Yeager, M Ahlbom, A Albanes, D Andersson, U Freeman, LEB Buring, JE Butler, MA Carreon, T Feychting, M Gapstur, SM Gaziano, JM Giles, GG Hallmans, G Henriksson, R Hoffman-Bolton, J Inskip, PD Kitahara, CM Marchand, LL Linet, MS Li, SC Peters, U Purdue, MP Rothman, N Ruder, AM Sesso, HD Severi, G Stampfer, M Stevens, VL Visvanathan, K Wang, SS White, E Zeleniuch-Jacquotte, A Hoover, R Fraumeni, JF Chatterjee, N Hartge, P Chanock, SJ AF Wang, Zhaoming Rajaraman, Preetha Melin, Beatrice S. Chung, Charles C. Zhang, Weijia McKean-Cowdin, Roberta Michaud, Dominique Yeager, Meredith Ahlbom, Anders Albanes, Demetrius Andersson, Ulrika Freeman, Laura E. Beane Buring, Julie E. Butler, Mary Ann Carreon, Tania Feychting, Maria Gapstur, Susan M. Gaziano, J. Michael Giles, Graham G. Hallmans, Goran Henriksson, Roger Hoffman-Bolton, Judith Inskip, Peter D. Kitahara, Cari M. Marchand, Loic Le Linet, Martha S. Li, Shengchao Peters, Ulrike Purdue, Mark P. Rothman, Nathaniel Ruder, Avima M. Sesso, Howard D. Severi, Gianluca Stampfer, Meir Stevens, Victoria L. Visvanathan, Kala Wang, Sophia S. White, Emily Zeleniuch-Jacquotte, Anne Hoover, Robert Fraumeni, Joseph F. Chatterjee, Nilanjan Hartge, Patricia Chanock, Stephen J. TI Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data SO HUMAN MUTATION LA English DT Article DE glioma; TP53; rare SNP; TCGA ID GENOME-WIDE ASSOCIATION; SQUAMOUS-CELL CARCINOMA; NERVOUS-SYSTEM TUMORS; POLYADENYLATION SIGNAL; CANCER SUSCEPTIBILITY; SNPS; RARE AB We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10(-11)), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximate to 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. (C) 2015 Wiley Periodicals, Inc. C1 [Wang, Zhaoming; Rajaraman, Preetha; Chung, Charles C.; Yeager, Meredith; Albanes, Demetrius; Freeman, Laura E. Beane; Inskip, Peter D.; Kitahara, Cari M.; Linet, Martha S.; Li, Shengchao; Purdue, Mark P.; Rothman, Nathaniel; Hoover, Robert; Fraumeni, Joseph F.; Chatterjee, Nilanjan; Hartge, Patricia; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Wang, Zhaoming; Chung, Charles C.; Yeager, Meredith; Li, Shengchao] Leidos Biomed Res Inc, Canc Genom Res Lab, Gaithersburg, MD USA. [Melin, Beatrice S.; Andersson, Ulrika; Henriksson, Roger] Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden. [Zhang, Weijia] Icahn Sch Med Mt Sinai, Dept Med Bioinformat Core, New York, NY 10029 USA. [McKean-Cowdin, Roberta] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Michaud, Dominique] Brown Univ, Dept Epidemiol, Div Biol & Med, Providence, RI 02912 USA. [Michaud, Dominique] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Ahlbom, Anders; Feychting, Maria] Karolinska Inst, Inst Environm Med, Div Epidemiol, S-10401 Stockholm, Sweden. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Harvard Univ, Sch Med, Boston, MA USA. [Butler, Mary Ann; Carreon, Tania; Ruder, Avima M.] NIOSH, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Ctr Geriatr Res Educ & Clin, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med Nutr Res, Umea, Sweden. [Hoffman-Bolton, Judith; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Marchand, Loic Le] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Peters, Ulrike; White, Emily] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Peters, Ulrike; White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Stampfer, Meir] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Visvanathan, Kala] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Zeleniuch-Jacquotte, Anne] NYU Sch Med, Dept Environm Med, Div Epidemiol, New York, NY USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr Rm 7E412,MSC 9776, Bethesda, MD 20892 USA. EM wangzha@mail.nih.gov; chanocks@mail.nih.gov RI Purdue, Mark/C-9228-2016; Kitahara, Cari/R-8267-2016; OI Purdue, Mark/0000-0003-1177-3108; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU NCI; NIH [N01-CO-12400]; Department of Health and Human Services FX Contract grant sponsors: NCI; NIH; Department of Health and Human Services; NCI; NIH (N01-CO-12400). NR 18 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUL PY 2015 VL 36 IS 7 BP 684 EP 688 DI 10.1002/humu.22799 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CK8NT UT WOS:000356495700005 PM 25907361 ER PT J AU Munoz-Price, LS Banach, DB Bearman, G Gould, JM Leekha, S Morgan, DJ Palmore, TN Rupp, ME Weber, DJ Wiemken, TL AF Munoz-Price, L. Silvia Banach, David B. Bearman, Gonzalo Gould, Jane M. Leekha, Surbhi Morgan, Daniel J. Palmore, Tara N. Rupp, Mark E. Weber, David J. Wiemken, Timothy L. TI Isolation Precautions for Visitors SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID INTENSIVE-CARE-UNIT; INFLUENZA-A; HEALTH-CARE; MYCOBACTERIUM-TUBERCULOSIS; NOSOCOMIAL TRANSMISSION; HOSPITAL VISITOR; OUTBREAK; INFECTION; CONTAINMENT; NOROVIRUS C1 [Munoz-Price, L. Silvia] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Banach, David B.] Yale Univ, Sch Med, New Haven, CT USA. [Bearman, Gonzalo] Virginia Commonwealth Univ, Richmond, VA USA. [Gould, Jane M.] Drexel Univ, Coll Med, Christophers Hosp Children, Philadelphia Dept Publ Hlth, Philadelphia, PA 19104 USA. [Leekha, Surbhi] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Morgan, Daniel J.] Univ Maryland, Baltimore, MD 21201 USA. [Palmore, Tara N.] NIH, Bethesda, MD 20892 USA. [Rupp, Mark E.] Univ Nebraska Med Ctr, Omaha, NE USA. [Weber, David J.] Univ N Carolina, Chapel Hill, NC USA. [Wiemken, Timothy L.] Univ Louisville, Louisville, KY 40292 USA. RP Munoz-Price, LS (reprint author), 8701 Watertown Plank Rd,POB 26509, Milwaukee, WI 53226 USA. EM smunozprice@mcw.edu FU SHEA Research Network FX This study was supported in part by the SHEA Research Network. NR 44 TC 2 Z9 2 U1 2 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2015 VL 36 IS 7 BP 747 EP 758 DI 10.1017/ice.2015.67 PG 12 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CK8UE UT WOS:000356513400001 PM 26017347 ER PT J AU Brown, P Farrell, M AF Brown, Paul Farrell, Michael TI A Practical Approach to Avoiding Iatrogenic Creutzfeldt-Jakob Disease (CJD) from Invasive Instruments SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Review ID SPONGIFORM ENCEPHALOPATHY; TRANSMISSION AB Potential Creutzfeldt-Jakob disease instrument-contamination events continue to occur, causing widespread hospital and patient concern. We propose the use of a combination of diagnostic tests (ie, spinal fluid for 14-3-3 protein or nasal brushing for misfolded prion protein) and instrument handling procedures (ie, using a regional set of dedicated instruments), which if applied to all patients admitted with symptoms of either dementia or cerebellar disease, should eliminate the risk of iatrogenic instrument infection. C1 [Brown, Paul] NIH, Bethesda, MD 20892 USA. [Farrell, Michael] Beaumont Hosp, Neuropathol, Dublin 9, Ireland. RP Brown, P (reprint author), 7815 Exeter Rd, Bethesda, MD USA. EM paulwbrown@comcast.net NR 14 TC 7 Z9 7 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2015 VL 36 IS 7 BP 844 EP 848 DI 10.1017/ice.2015.53 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CK8UE UT WOS:000356513400016 PM 25850546 ER PT J AU Brown, P Farrell, M AF Brown, Paul Farrell, Michael TI A New Practical Diagnostic Test for Creutzfeldt-Jakob Disease SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Letter C1 [Brown, Paul] NIH, Bethesda, MD 20892 USA. [Farrell, Michael] Beaumont Hosp, Dept Neuropathol, Dublin 9, Ireland. RP Brown, P (reprint author), 7815 Exeter Rd, Bethesda, MD 20814 USA. EM paulwbrown@comcast.net NR 3 TC 2 Z9 2 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2015 VL 36 IS 7 BP 849 EP 849 DI 10.1017/ice.2015.109 PG 1 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CK8UE UT WOS:000356513400017 PM 25998792 ER PT J AU Terwilliger, A Swick, MC Pflughoeft, KJ Pomerantsev, A Lyons, CR Koehler, TM Maresso, A AF Terwilliger, Austen Swick, Michelle C. Pflughoeft, Kathryn J. Pomerantsev, Andrei Lyons, C. Rick Koehler, Theresa M. Maresso, Anthony TI Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins SO JOURNAL OF BACTERIOLOGY LA English DT Article ID PORPHYROMONAS-GINGIVALIS; OLIGOPEPTIDE PERMEASE; HEME ACQUISITION; GENOME SEQUENCE; CULTURE-MEDIUM; IGA PROTEASE; VIRULENCE; STRAIN; BACTERIA; GENE AB Bacteria sustain an infection by acquiring nutrients from the host to support replication. The host sequesters these nutrients as a growth-restricting strategy, a concept termed "nutritional immunity." Historically, the study of nutritional immunity has centered on iron uptake because many bacteria target hemoglobin, an abundant circulating protein, as an iron source. Left unresolved are the mechanisms that bacteria use to attain other nutrients from host sources, including amino acids. We employed a novel medium designed to mimic the chemical composition of human serum, and we show here that Bacillus anthracis, the causative agent of anthrax disease, proteolyzes human hemoglobin to liberate essential amino acids which enhance its growth. This property can be traced to the actions of InhA1, a secreted metalloprotease, and extends to at least three other serum proteins, including serum albumin. The results suggest that we must also consider proteolysis of key host proteins to be a way for bacterial pathogens to attain essential nutrients, and we provide an experimental framework to determine the host and bacterial factors involved in this process. IMPORTANCE The mechanisms by which bacterial pathogens acquire nutrients during infection are poorly understood. Here we used a novel defined medium that approximates the chemical composition of human blood serum, blood serum mimic (BSM), to better model the nutritional environment that pathogens encounter during bacteremia. Removing essential amino acids from BSM revealed that two of the most abundant proteins in blood-hemoglobin and serum albumin-can satiate the amino acid requirement for Bacillus anthracis, the causative agent of anthrax. We further demonstrate that hemoglobin is proteolyzed by the secreted protease InhA1. These studies highlight that common blood proteins can be a nutrient source for bacteria. They also challenge the historical view that hemoglobin is solely an iron source for bacterial pathogens. C1 [Terwilliger, Austen; Maresso, Anthony] Baylor Coll Med, Mol Virol & Microbiol Dept, Houston, TX 77030 USA. [Swick, Michelle C.; Pflughoeft, Kathryn J.; Koehler, Theresa M.] Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. [Pomerantsev, Andrei] NIAID, Microbial Pathogenesis Sect, Bethesda, MD 20892 USA. [Lyons, C. Rick] Colorado State Univ, Infect Dis Res Complex, Ft Collins, CO 80523 USA. RP Maresso, A (reprint author), Baylor Coll Med, Mol Virol & Microbiol Dept, Houston, TX 77030 USA. EM maresso@bcm.edu FU National Institute of Allergy and Infectious Diseases [R01 AI097- 167, RO1 AI33537] FX This work was supported by research grants R01 AI097- 167 to A.M. and RO1 AI33537 to T.M.K. from the National Institute of Allergy and Infectious Diseases. NR 65 TC 5 Z9 5 U1 2 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 2015 VL 197 IS 14 BP 2400 EP 2411 DI 10.1128/JB.00073-15 PG 12 WC Microbiology SC Microbiology GA CK8YP UT WOS:000356526600016 PM 25962917 ER PT J AU Quesada, P Whitby, D Benavente, Y Miley, W Labo, N Chichareon, S Trong, N Shin, HR Anh, PTH Thomas, J Matos, E Herrero, R Munoz, N Molano, M Franceschi, S de Sanjose, S AF Quesada, Paloma Whitby, Denise Benavente, Yolanda Miley, Wendell Labo, Nazzarena Chichareon, Saibua Nguyen Trong Shin, Hai-Rim Pham Thi Hoang Anh Thomas, Jaiyeola Matos, Elena Herrero, Rolando Munoz, Nubia Molano, Monica Franceschi, Silvia de Sanjose, Silvia TI Hepatitis C virus seroprevalence in the general female population from 8 countries SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE Hepatitis C virus; Seroprevalence; Sexual behaviour ID INFECTION; PREVALENCE; BURDEN AB Background: Hepatitis C virus (HCV) infection is a significant global health issue because it is widespread and persistent and can cause serious liver diseases. Objectives: The aim of this study is to estimate HCV prevalence in women from the general population in different geographical areas worldwide and to assess the potential role of sexual behaviour in the virus transmission. Study design: Each participating centre recruited a random sample of women from the general population aged from less than 20 to more than 75 years. The study included 8130 women from 8 countries with information on sociodemographic factors, reproductive and sexual behaviour, smoking habit and HPV DNA through individual interviews. A blood sample was also collected to perform serological tests. We estimated the prevalence ratios associated to HCV to evaluate the effect of sexual behaviour in viral transmission. Results: Women were reactive to a minimum of two HCV antigens, including at least one non structural protein were considered as positive (33% of the samples were classified as positive, 40% as negative, and 27% as indeterminate (N = 402), that were considered as not positive). The age-adjusted HCV seroprevalence varied significantly by regions (0.3% in Argentina to 21.1% in Nigeria). We found no association between HCV prevalence and age, educational level, smoking habit and any of the available variables for sexual behaviour and reproductive history. Conclusions: This large study showed heterogeneous distribution of HCV seroprevalence in female and provides evidence of the null impact of sexual behaviour in HCV transmission. (C) 2015 Elsevier B.V. All rights reserved. C1 [Quesada, Paloma; Benavente, Yolanda; de Sanjose, Silvia] Inst Catala Oncol, IDIBELL, Unit Infect & Canc UNIC, Lhospitalet De Llobregat, Spain. [Whitby, Denise; Miley, Wendell; Labo, Nazzarena] Leidos Biomed Inc, Frederick Natl Lab Canc Res, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick, MD USA. [Benavente, Yolanda; de Sanjose, Silvia] CIBER Epidemiol & Salud Publ, Madrid, Spain. [Chichareon, Saibua] Prince Songkla Univ, Dept Obstet & Gynecol, Hat Yai, Songkhla, Thailand. [Nguyen Trong; Pham Thi Hoang Anh] Hung Vuong Hosp, Dept Neonatol, Ho Chi Minh City, Vietnam. [Shin, Hai-Rim; Franceschi, Silvia] Int Agcy Res Canc, F-69372 Lyon, France. [Thomas, Jaiyeola] Louisiana State Univ, Hlth Sci Ctr, Baton Rouge, LA 70803 USA. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, RA-1053 Buenos Aires, DF, Argentina. [Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Munoz, Nubia; Molano, Monica] Inst Nacl Cancerol, Bogota, Colombia. [Shin, Hai-Rim] Natl Canc Ctr, Goyang, South Korea. [Shin, Hai-Rim] WHO Western Pacific Reg Off, Noncommunicable Dis & Hlth Promot, Manila, Philippines. RP de Sanjose, S (reprint author), CIBERESP Inst Catala Oncol, Canc Epidemiol Res Programme IDIBELL, Unit Infect & Canc, Av Gran Via Hosp, Lhospitalet De Llobregat 08908, Spain. EM s.sanjose@iconcologia.net RI de Sanjose Llongueras, Silvia/H-6339-2014 FU National Cancer Institute at National Institutes of Health [N01-CO-12400]; Instituto de Salud Carlos III (Spanish Government) [CIBER ESP 06/0673]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR Generalitat de Catalunya, Catalonian Government) [2014SGR756] FX This work was partially supported by the National Cancer Institute at the National Institutes of Health (grant number N01-CO-12400); the Instituto de Salud Carlos III (Spanish Government) (grant CIBER ESP 06/0673) and the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR Generalitat de Catalunya, Catalonian Government) (grant number 2014SGR756). NR 15 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD JUL PY 2015 VL 68 BP 89 EP 93 DI 10.1016/j.jcv.2015.05.005 PG 5 WC Virology SC Virology GA CK3FF UT WOS:000356101300019 PM 26071344 ER PT J AU Harper, M Weis, C Pleil, JD Blount, BC Miller, A Hoover, MD Jahn, S AF Harper, Martin Weis, Christopher Pleil, Joachim D. Blount, Benjamin C. Miller, Aubrey Hoover, Mark D. Jahn, Steven TI Commentary on the contributions and future role of occupational exposure science in a vision and strategy for the discipline of exposure science SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Review DE education; exposure science; exposure assessment; exposome; risk ID ENVIRONMENTAL EXPOSURE; HEALTH-RISKS; BISPHENOL-A; EXPOSOME; POPULATION; EXPERIENCE; INDUSTRY; EXHAUST; BRITAIN; WORKERS AB Exposure science is a holistic concept without prejudice to exposure source. Traditionally, measurements aimed at mitigating environmental exposures have not included exposures in the workplace, instead considering such exposures to be an internal affair between workers and their employers. Similarly, occupational (or industrial) hygiene has not typically accounted for environmental contributions to poor health at work. Many persons spend a significant amount of their lifetime in the workplace, where they maybe exposed to more numerous chemicals at higher levels than elsewhere in their environment. In addition, workplace chemical exposures and other exogenous stressors may increase epigenetic and germline modifications that are passed on to future generations. We provide a brief history of the development of exposure science from its roots in the assessment of workplace exposures, including an appendix where we detail current resources for education and training in exposure science offered through occupational hygiene organizations. We describe existing successful collaborations between occupational and environmental practitioners in the field of exposure science, which may serve as a model for future interactions. Finally, we provide an integrated vision for the field of exposure science, emphasizing interagency collaboration, the need for complete exposure information in epidemiological studies, and the importance of integrating occupational, environmental, and residential assessments. Our goal is to encourage communication and spur additional collaboration between the fields of occupational and environmental exposure assessment. Providing a more comprehensive approach to exposure science is critical to the study of the "exposome", which conceptualizes the totality of exposures throughout a person's life, not only chemical, but also from diet, stress, drugs, infection, and so on, and the individual response. C1 [Harper, Martin] NIOSH, Exposure Assessment Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. [Weis, Christopher; Miller, Aubrey] NIEHS, Off Director, Bethesda, MD USA. [Pleil, Joachim D.] US EPA, Methods Dev & Applicat Branch, Natl Exposure Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Blount, Benjamin C.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, CDC, Atlanta, GA USA. [Hoover, Mark D.] NIOSH, Div Resp Dis Studies, Morgantown, WV 26505 USA. [Jahn, Steven] Jahn Ind Hyg, Aiken, SC USA. RP Harper, M (reprint author), NIOSH, Exposure Assessment Branch, Hlth Effects Lab Div, 1095 Willowdale Rd,MS-3030, Morgantown, WV 26505 USA. EM mharper@cdc.gov FU Intramural CDC HHS [CC999999] NR 51 TC 3 Z9 3 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD JUL-AUG PY 2015 VL 25 IS 4 BP 381 EP 387 DI 10.1038/jes.2014.91 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CK8TT UT WOS:000356512100003 PM 25670022 ER PT J AU Thomas, D Frascella, J Hall, T Smith, W Compton, W Koroshetz, W Briggs, J Grady, P Somerman, M Volkow, N AF Thomas, D. Frascella, J. Hall, T. Smith, W. Compton, W. Koroshetz, W. Briggs, J. Grady, P. Somerman, M. Volkow, N. TI Reflections on the role of opioids in the treatment of chronic pain: a shared solution for prescription opioid abuse and pain SO JOURNAL OF INTERNAL MEDICINE LA English DT Editorial Material ID LOW-BACK-PAIN; EDUCATION C1 [Thomas, D.; Frascella, J.; Hall, T.] NIDA, Div Clin Neurosci & Behav Res, Bethesda, MD 20892 USA. [Smith, W.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Compton, W.; Volkow, N.] NIDA, Off Director, Bethesda, MD 20892 USA. [Koroshetz, W.] NINDS, Off Director, Bethesda, MD 20892 USA. [Briggs, J.] Natl Ctr Complementary & Integrat Hlth, Off Director, Bethesda, MD USA. [Grady, P.] NINR, Off Director, Bethesda, MD 20892 USA. [Somerman, M.] Natl Inst Dent & Craniofacial Res, Off Director, Bethesda, MD USA. RP Thomas, D (reprint author), NIDA, Div Clin Neurosci & Behav Res, 6001 Executive Blvd, Bethesda, MD 20892 USA. EM dthomas1@nida.nih.gov NR 15 TC 5 Z9 5 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-6820 EI 1365-2796 J9 J INTERN MED JI J. Intern. Med. PD JUL PY 2015 VL 278 IS 1 BP 92 EP 94 DI 10.1111/joim.12345 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CK6VP UT WOS:000356367000010 PM 25556772 ER PT J AU Lukas, VA Fishbein, KW Reiter, DA Lin, PC Schneider, E Spencer, RG AF Lukas, Vanessa A. Fishbein, Kenneth W. Reiter, David A. Lin, Ping-Chang Schneider, Erika Spencer, Richard G. TI Sensitivity and specificity of univariate MRI analysis of experimentally degraded cartilage under clinical imaging conditions SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE osteoarthritis; bovine nasal cartilage; quantitative MRI; classification; sensitivity; specificity ID HUMAN ARTICULAR-CARTILAGE; PROTEOGLYCAN DEPLETION; MAGNETIZATION-TRANSFER; RELAXATION-TIMES; T-2 RELAXATION; OSTEOARTHRITIS; T2; DEGRADATION; DIFFUSION; GLYCOSAMINOGLYCANS AB BackgroundTo evaluate the sensitivity and specificity of classification of pathomimetically degraded bovine nasal cartilage at 3 Tesla and 37 degrees C using univariate MRI measurements of both pure parameter values and intensities of parameter-weighted images. MethodsPre- and posttrypsin degradation values of T-1, T-2, T-2*, magnetization transfer ratio (MTR), and apparent diffusion coefficient (ADC), and corresponding weighted images, were analyzed. Classification based on the Euclidean distance was performed and the quality of classification was assessed through sensitivity, specificity and accuracy (ACC). ResultsThe classifiers with the highest accuracy values were ADC (ACC = 0.82 0.06), MTR (ACC = 0.78 +/- 0.06), T-1 (ACC = 0.99 +/- 0.01), T-2 derived from a three-dimensional (3D) spin-echo sequence (ACC = 0.74 +/- 0.05), and T-2 derived from a 2D spin-echo sequence (ACC = 0.77 +/- 0.06), along with two of the diffusion-weighted signal intensities (b = 333 s/mm(2): ACC = 0.80 +/- 0.05; b = 666 s/mm(2): ACC = 0.85 +/- 0.04). In particular, T-1 values differed substantially between the groups, resulting in atypically high classification accuracy. The second-best classifier, diffusion weighting with b = 666 s/mm(2), as well as all other parameters evaluated, exhibited substantial overlap between pre- and postdegradation groups, resulting in decreased accuracies. ConclusionClassification according to T-1 values showed excellent test characteristics (ACC = 0.99), with several other parameters also showing reasonable performance (ACC > 0.70). Of these, diffusion weighting is particularly promising as a potentially practical clinical modality. As in previous work, we again find that highly statistically significant group mean differences do not necessarily translate into accurate clinical classification rules. J. Magn. Reson. Imaging 2015;42:136-144. (c) 2014 Wiley Periodicals, Inc. C1 [Lukas, Vanessa A.; Fishbein, Kenneth W.; Reiter, David A.; Spencer, Richard G.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Lin, Ping-Chang] Howard Univ, Coll Med, Dept Radiol, Washington, DC USA. [Schneider, Erika] Cleveland Clin Fdn, Imaging Inst, Cleveland, OH 44195 USA. RP Spencer, RG (reprint author), 251 Bayview Blvd,Suite 04B116, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov RI Lin, Ping-Chang/C-9811-2009; OI Lin, Ping-Chang/0000-0003-0918-4072; Fishbein, Kenneth/0000-0002-6353-4603 FU National Institutes of Health, National Institute on Aging, Intramural Research Program FX Contract grant sponsor: The National Institutes of Health, National Institute on Aging, Intramural Research Program. NR 40 TC 1 Z9 1 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUL PY 2015 VL 42 IS 1 BP 136 EP 144 DI 10.1002/jmri.24773 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL0IN UT WOS:000356625500016 PM 25327944 ER PT J AU Venkatesh, BA Donekal, S Yoneyama, K Wu, CL Fernandes, VRS Rosen, BD Shehata, ML McClelland, R Bluemke, DA Lima, JAC AF Venkatesh, Bharath Ambale Donekal, Sirisha Yoneyama, Kihei Wu, Colin Fernandes, Veronica R. S. Rosen, Boaz D. Shehata, Monda L. McClelland, Robyn Bluemke, David A. Lima, Joao A. C. TI Regional myocardial functional patterns: Quantitative tagged magnetic resonance imaging in an adult population free of cardiovascular risk factors: The multi-ethnic study of atherosclerosis (MESA) SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE tagged MRI; myocardial strain; torsion; reference values; left ventricular deformation ID LEFT-VENTRICULAR FUNCTION; HARMONIC PHASE MRI; ASYMPTOMATIC INDIVIDUALS; STRAIN; HYPERTENSION; TORSION; AGE; EVENTS; SEX AB PurposeTo characterize the left ventricular (LV) regional deformation patterns and identify normal values of left ventricular strains from tagged magnetic resonance imaging (MRI) in a population with low-risk-factor (LRF) exposure. Materials and MethodsTagged CMR on three LV short axis slices was performed in participants of the MESA study who were free of cardiovascular disease at baseline. Images were analyzed by the harmonic phase imaging method to obtain: peak torsion, circumferential (Ecc) and radial (Err) strains, and systolic (SRs) and early-diastolic (SRe) strain rates. An LRF group was created from the overall population based on strict exclusion criteria (n = 129) based on risk factors and events observed over a 10-year follow-up. ResultsThe normative prediction intervals for the averaged peak Ecc (%) and torsion (deg/cm) measures were: in 45-59-year-old women: (-20.8, -13.2) and (2.1, 6.3); 60-84-year-old women: (-20.6, -12.8) and (2.2, 6.9); 45-59-year-old men: (-21.3, -13.5) and (1.9, 5.7); 60-84-year-old men: (-20.5, -12.5) and (1.5, 5.2). In general, African-Americans (Ecc = -15.9, torsion = 3.3) had lower strains as compared to Chinese (Ecc = -17.1, torsion = 3.9), while Caucasians and Hispanics were intermediate and not significantly different. Circumferential shortening increased spatially from the epicardium to the endocardium (-16.9 to -18.2 at the mid-ventricle) and from the base to the apex (-15.1 to -17.5 at the midwall). ConclusionThe present study provides reference ranges and deformation patterns of deformation values from a large healthy population free of cardiovascular disease at baseline. J. Magn. Reson. Imaging 2015;42:153-159. (c) 2014 Wiley Periodicals, Inc. C1 [Venkatesh, Bharath Ambale; Donekal, Sirisha; Yoneyama, Kihei; Fernandes, Veronica R. S.; Rosen, Boaz D.; Shehata, Monda L.; Lima, Joao A. C.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Wu, Colin; Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [McClelland, Robyn] Univ Washington, Seattle, WA 98195 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ Hosp, Med & Radiol, 600 North Wolfe St,Blalock 524D1, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute, USA [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168] FX Contract grant sponsor: National Heart, Lung, and Blood Institute, USA; Contract grant numbers: N01-HC-95159 through N01-HC95168. NR 25 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUL PY 2015 VL 42 IS 1 BP 153 EP 159 DI 10.1002/jmri.24749 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL0IN UT WOS:000356625500018 PM 25223588 ER PT J AU Hunter, K AF Hunter, Kent TI The role of individual inheritance in tumor progression and metastasis SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Review DE Metastasis; Solid tumors; Cancer-related deaths ID BREAST-CANCER METASTASIS; PROSTATE-CANCER; CELL CARCINOMA; CLONAL ORIGIN; SURVIVAL; PROGNOSIS; SIPA1; EVOLUTION; GENES; PREDISPOSITION AB Metastasis, the dissemination and growth of tumor cells at secondary sites, is the primary cause of patient mortality from solid tumors. Metastasis is an extremely complex, inefficient process requiring contributions of not only the tumor cell but also local and distant environmental factors, at both the cellular and molecular level. Variation in the function of any of the steps in the metastatic cascade may therefore have profound implications for the ultimate course of the disease. In addition to the somatic and cellular heterogeneity that can affect cancer outcome, an individual's specific ancestry or genetic background can also significantly influence metastatic progression. These inherited variants not only encoded for metastatic susceptibility but also provided a window to study critical factors that are not easily accessible with current technologies. Furthermore, investigations into inherited metastatic susceptibility enable identification of important molecular and cellular processes that are not subject to mutation and are consequently not detectable by standard cancer genome sequencing strategies. Incorporation of inherited variation into metastasis research therefore provides methods to more comprehensively investigate the etiology of the lethal consequences of tumor progression. C1 NCI, Lab Canc Biol & Genet, CCR, NIH, Bethesda, MD 20892 USA. RP Hunter, K (reprint author), NCI, Lab Canc Biol & Genet, CCR, NIH, Bldg 37 Room 5046C,37 Convent Dr, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX I would like to apologize to the many colleagues whose work was not referenced here due to space constraints. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 46 TC 2 Z9 3 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 EI 1432-1440 J9 J MOL MED JI J. Mol. Med. PD JUL PY 2015 VL 93 IS 7 BP 719 EP 725 DI 10.1007/s00109-015-1299-6 PG 7 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA CK9AC UT WOS:000356530700003 PM 26054921 ER PT J AU Moody, TW Nuche-Berenguer, B Moreno, P Jensen, RT AF Moody, Terry W. Nuche-Berenguer, Bernardo Moreno, Paola Jensen, Robert T. TI CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE CCK; Gastrin; CI-988; EGFR transactivation; Lung cancer proliferation ID GROWTH-FACTOR RECEPTOR; MULTIPLE SIGNALING PATHWAYS; PANCREATIC ACINAR-CELLS; CCK2 RECEPTOR; TYROSINE PHOSPHORYLATION; GASTRIN RECEPTORS; CLONAL GROWTH; B RECEPTORS; CHOLECYSTOKININ; ACTIVATION AB Cholecystokinin (CCK) receptors are G-protein coupled receptors (GPCR) which are present on lung cancer cells. CCK-8 stimulates the proliferation of lung cancer cells, whereas the CCK2R receptor antagonist CI-988 inhibits proliferation. GPCR for some gastrointestinal hormones/neurotransmitters mediate lung cancer growth by causing epidermal growth factor receptor (EGFR) transactivation. Here, the role of CCK/gastrin and CI-988 on EGFR transactivation and lung cancer proliferation was investigated. Addition of CCK-8 or gastrin-17 (100 nM) to NCI-H727 human lung cancer cells increased EGFR Tyr(1068) phosphorylation after 2 min. The ability of CCK-8 to cause EGFR tyrosine phosphorylation was blocked by CI-988, gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), and tiron (superoxide scavenger). CCK-8 nonsulfated and gastrin-17 caused EGFR transactivation and bound with high affinity to NCI-H727 cells, suggesting that the CCK2R is present. CI-988 inhibited the ability of CCK-8 to cause ERK phosphorylation and elevate cytosolic Ca2+. CI-988 or gefitinib inhibited the basal growth of NCI-H727 cells or that stimulated by CCK-8. The results indicate that CCK/gastrin may increase lung cancer proliferation in an EGFR-dependent manner. C1 [Moody, Terry W.] NCI, Dept Hlth & Human Serv, Ctr Canc Res, Off Director, Bethesda, MD 20892 USA. [Nuche-Berenguer, Bernardo; Moreno, Paola; Jensen, Robert T.] Natl Inst Diabet Digest & Kidney Dis, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, Dept Hlth & Human Serv, Ctr Canc Res, Off Director, 9609 Med Ctr Dr,Room 2 W-130, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov FU NIH intramural program of NIDDK; NIH intramural program of NCI FX The authors thank Dr. J. Hughes for the CI-988 and Dr. D. Chan for the helpful discussions. This research is supported by the NIH intramural programs of NIDDK and NCI. NR 45 TC 1 Z9 1 U1 5 U2 6 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 JUL PY 2015 VL 56 IS 3 BP 663 EP 672 DI 10.1007/s12031-015-0533-6 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CL0BN UT WOS:000356603600020 PM 25761747 ER PT J AU Morens, DM Taubenberger, JK AF Morens, David M. Taubenberger, Jeffery K. TI A forgotten epidemic that changed medicine: measles in the US Army, 1917-18 SO LANCET INFECTIOUS DISEASES LA English DT Review ID HEMOLYTIC STREPTOCOCCI; BACTERIAL PNEUMONIA; SUGAR FERMENTATIONS; PANDEMIC INFLUENZA; LOBAR PNEUMONIA; SCARLET FEVER; UNITED-STATES; EMPYEMA; INFECTIONS; PATHOLOGY AB A US army-wide measles outbreak in 1917-18 resulted in more than 95 000 cases and more than 3000 deaths. An outbreak investigation implicated measles and streptococcal co-infections in most deaths, and also characterised a parallel epidemic of primary streptococcal pneumonia in soldiers without measles. For the first time, the natural history and pathogenesis of these diseases was able to be well characterised by a broad-interdisciplinary research effort with hundreds of military and civilian physicians and scientists representing disciplines such as internal medicine, pathology, microbiology, radiology, surgery, preventive medicine, and rehabilitation medicine. A clear conceptualisation of bronchopneumonia resulting from viral-bacterial interactions between pathogens was developed, and prevention and treatment approaches were developed and optimised in real time. These approaches were used in the 1918 influenza pandemic, which began as the measles epidemic waned. The outbreak findings remain relevant to the understanding and medical management of severe pneumonia. C1 [Morens, David M.] NIAID, Offc Director, NIH, Bethesda, MD 20892 USA. [Taubenberger, Jeffery K.] NIAID, NIH, Div Intramural Res, Infect Dis Lab,Viral Pathogenesis & Evolut Sect, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, Offc Director, NIH, 31 Ctr Dr,Room 7A03, Bethesda, MD 20892 USA. EM dm270q@nih.gov FU US National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This research was supported by the intramural research funds of the US National Institutes of Health and the National Institute of Allergy and Infectious Diseases. We thank James Musser for sharing information about streptococcal phylogenetics and pathogenesis, Daniel Mollura for discussing with us radiological aspects of army medicine of the 1917-19 era, Ken Maguire (Camp Zachary Taylor Historical Society) for providing photographic images related to the epidemics and for research support. We thank Jeffrey Reznick, the staff of the History of Medical Division, National Library of Medicine, and Betty Murgolo and the Document Delivery team at the National Institute of Health Library. NR 121 TC 4 Z9 4 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2015 VL 15 IS 7 BP 852 EP 861 DI 10.1016/S1473-3099(15)00109-7 PG 10 WC Infectious Diseases SC Infectious Diseases GA CL0HT UT WOS:000356622900037 PM 26070967 ER PT J AU Lambrechts, L Ferguson, NM Harris, E Holmes, EC McGraw, EA O'Neill, SL Ooi, EE Ritchie, SA Ryan, PA Scott, TW Simmons, CP Weaver, SC AF Lambrechts, Louis Ferguson, Neil M. Harris, Eva Holmes, Edward C. McGraw, Elizabeth A. O'Neill, Scott L. Ooi, Eng E. Ritchie, Scott A. Ryan, Peter A. Scott, Thomas W. Simmons, Cameron P. Weaver, Scott C. TI Assessing the epidemiological effect of wolbachia for dengue control SO LANCET INFECTIOUS DISEASES LA English DT Article ID AEDES-AEGYPTI MOSQUITOS; CYTOPLASMIC INCOMPATIBILITY; VIRUS TRANSMISSION; KAMPHAENG-PHET; HUMAN MOVEMENT; POPULATION; INFECTION; CHILDREN; TRAP; ESTABLISHMENT AB Dengue viruses cause more human morbidity and mortality than any other arthropod-borne virus. Dengue prevention relies mainly on vector control; however, the failure of traditional methods has promoted the development of novel entomological approaches. Although use of the intracellular bacterium wolbachia to control mosquito populations was proposed 50 years ago, only in the past decade has its use as a potential agent of dengue control gained substantial interest. Here, we review evidence that supports a practical approach for dengue reduction through field release of wolbachia-infected mosquitoes and discuss the additional studies that have to be done before the strategy can be validated and implemented. A crucial next step is to assess the efficacy of wolbachia in reducing dengue virus transmission. We argue that a cluster randomised trial is at this time premature because choice of wolbachia strain for release and deployment strategies are still being optimised. We therefore present a pragmatic approach to acquiring preliminary evidence of efficacy through various complementary methods including a prospective cohort study, a geographical cluster investigation, virus phylogenetic analysis, virus surveillance in mosquitoes, and vector competence assays. This multipronged approach could provide valuable intermediate evidence of efficacy to justify a future cluster randomised trial. C1 [Lambrechts, Louis] Inst Pasteur, CNRS, Dept Genomes & Genet, Insect Virus Interact Grp,URA 3012, F-75724 Paris 15, France. [Ferguson, Neil M.] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Outbreak Anal & Modelling, Sch Publ Hlth, London, England. [Harris, Eva] Univ Calif Berkeley, Sch Publ Hlth, Div Infect Dis & Vaccinol, Berkeley, CA 94720 USA. [Holmes, Edward C.] Univ Sydney, Charles Perkins Ctr, Sch Biol Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [McGraw, Elizabeth A.; O'Neill, Scott L.; Ryan, Peter A.] Monash Univ, Sch Biol Sci, Melbourne, Vic 3004, Australia. [Ooi, Eng E.] Duke Natl Univ Singapore, Grad Sch Med, Program Emerging Infect Dis, Singapore, Singapore. [Ritchie, Scott A.] James Cook Univ, Sch Publ Hlth & Trop Med & Rehabilitat Sci, Cairns, Qld, Australia. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD USA. [Simmons, Cameron P.] Oxford Univ Clin Res, Ctr Trop Med, Ho Chi Minh City, Vietnam. [Simmons, Cameron P.] Univ Oxford, Ctr Trop Med, Nuffi Dept Med, Oxford, England. [Simmons, Cameron P.] Univ Melbourne, Nossal Inst Global Hlth, Carlton, Vic 3053, Australia. [Weaver, Scott C.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Weaver, Scott C.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. RP Lambrechts, L (reprint author), Inst Pasteur, CNRS, Dept Genomes & Genet, Insect Virus Interact Grp,URA 3012, F-75724 Paris 15, France. EM louis.lambrechts@pasteur.fr RI Lambrechts, Louis/A-2057-2010; Ferguson, Neil/B-8578-2008; O'Neill, Scott/B-3568-2009; Weaver, Scott/D-6490-2011; OI Lambrechts, Louis/0000-0001-5958-2138; Holmes, Edward/0000-0001-9596-3552; Ferguson, Neil/0000-0002-1154-8093; O'Neill, Scott/0000-0002-4131-3615; Ooi, Eng Eong/0000-0002-0520-1544; Simmons, Cameron P./0000-0002-9039-7392 FU Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative of the Bill & Melinda Gates Foundation FX We thank Stephanie James and Fil M Randazzo for their insights, and two anonymous reviewers for helpful comments. This work was supported by a grant from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative of the Bill & Melinda Gates Foundation. NR 38 TC 11 Z9 11 U1 9 U2 37 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUL PY 2015 VL 15 IS 7 BP 862 EP 866 DI 10.1016/S1473-3099(15)00091-2 PG 5 WC Infectious Diseases SC Infectious Diseases GA CL0HT UT WOS:000356622900038 PM 26051887 ER PT J AU Harouni, AA Gharib, AM Osman, NF Morse, C Heller, T Abd-Elmoniem, KZ AF Harouni, Ahmed A. Gharib, Ahmed M. Osman, Nael F. Morse, Caryn Heller, Theo Abd-Elmoniem, Khaled Z. TI Assessment of liver fibrosis using fast strain-encoded MRI driven by inherent cardiac motion SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE strain-encoded MRI; SENC; liver stiffness; fibrosis; liver motion ID MAGNETIC-RESONANCE ELASTOGRAPHY; ULTRASOUND VIBROMETRY SDUV; TRANSIENT ELASTOGRAPHY; NONINVASIVE ASSESSMENT; SAMPLING VARIABILITY; MYOCARDIAL MOTION; HEPATIC-FIBROSIS; TISSUE ELASTICITY; BREAST MRI; TRACKING AB PurposeAn external driver-free MRI method for assessment of liver fibrosis offers a promising noninvasive tool for diagnosis and monitoring of liver disease. Lately, the heart's intrinsic motion and MR tagging have been utilized for the quantification of liver strain. However, MR tagging requires multiple breath-hold acquisitions and substantial postprocessing. In this study, we propose the use of a fast strain-encoded (FSENC) MRI method to measure the peak strain (S-p) in the liver's left lobe, which is in close proximity and caudal to the heart. Additionally, we introduce a new method of measuring heart-induced shear wave velocity (SWV) inside the liver. MethodsPhantom and in vivo experiments (11 healthy subjects and 11 patients with liver fibrosis) were conducted. Reproducibility experiments were performed in seven healthy subjects. ResultsPeak liver strain, S-p, decreased significantly in fibrotic liver compared with healthy liver (6.46% 2.27% vs 12.49% +/- 1.76%; P < 0.05). Heart-induced SWV increased significantly in patients compared with healthy subjects (0.15 +/- 0.04 m/s vs 0.63 +/- 0.32 m/s; P < 0.05). Reproducibility analysis yielded no significant difference in Sp (P = 0.47) or SWV (P = 0.56). ConclusionAccelerated external driver-free noninvasive assessment of left liver lobe strain and SWV is feasible using strain-encoded MRI. The two measures significantly separate healthy subjects from patients with fibrotic liver. Magn Reson Med 74:106-114, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Harouni, Ahmed A.] Natl Inst Biomed Imaging & Bioengn, Imaging Sci Training Program, NIH, Bethesda, MD USA. [Gharib, Ahmed M.; Abd-Elmoniem, Khaled Z.] NIDDK, Biomed & Metab Imaging Branch, NIH, Bethesda, MD 20892 USA. [Osman, Nael F.] Johns Hopkins Univ, Sch Med, Div MR Res, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Morse, Caryn] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, Liver Dis, NIH, Bethesda, MD 20892 USA. RP Gharib, AM (reprint author), NIH, Building10,Room 3-5340,MSC 1263,10 Ctr Dr, Bethesda, MD 20892 USA. EM agharib@mail.nih.gov RI Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008; OI Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702; Morse, Caryn/0000-0002-1177-4365 NR 51 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2015 VL 74 IS 1 BP 106 EP 114 DI 10.1002/mrm.25379 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK7XZ UT WOS:000356451500012 ER PT J AU Ding, Y Xue, H Ahmad, R Chang, TC Ting, ST Simonetti, OP AF Ding, Yu Xue, Hui Ahmad, Rizwan Chang, Ti-chiun Ting, Samuel T. Simonetti, Orlando P. TI Paradoxical effect of the signal-to-noise ratio of GRAPPA calibration lines: A quantitative study SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE GRAPPA; condition number; signal to noise ratio; real-time MRI ID RECONSTRUCTION; REGULARIZATION; MATRICES AB PurposeIntuitively, GRAPPA auto-calibration signal (ACS) lines with higher signal-to-noise ratio (SNR) may be expected to boost the accuracy of kernel estimation and increase the SNR of GRAPPA reconstructed images. Paradoxically, Sodickson and his colleagues pointed out that using ACS lines with high SNR may actually lead to lower SNR in the GRAPPA reconstructed images. A quantitative study of how the noise in the ACS lines affects the SNR of the GRAPPA reconstructed images is presented. MethodsIn a phantom, the singular values of the GRAPPA encoding matrix and the root-mean-square error of GRAPPA reconstruction were evaluated using multiple sets of ACS lines with variant SNR. In volunteers, ACS lines with high and low SNR were estimated, and the SNR of corresponding TGRAPPA reconstructed images was evaluated. ResultsWe show that the condition number of the GRAPPA kernel estimation equations is proportional to the SNR of the ACS lines. In dynamic image series reconstructed with TGRAPPA, high SNR ACS lines result in reduced SNR if appropriate regularization is not applied. ConclusionNoise has a similar effect to Tikhonov regularization. Without appropriate regularization, a GRAPPA kernel estimated from ACS lines with higher SNR amplifies random noise in the GRAPPA reconstruction. Magn Reson Med 74:231-239, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Ding, Yu; Ahmad, Rizwan; Ting, Samuel T.; Simonetti, Orlando P.] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. [Xue, Hui] NHLBI, Magnet Resonance Technol Program, NIH, Bethesda, MD 20892 USA. [Ahmad, Rizwan] Ohio State Univ, Dept Elect & Comp Engn, Columbus, OH 43210 USA. [Chang, Ti-chiun] Siemens Corp Res, Princeton, NJ USA. [Ting, Samuel T.; Simonetti, Orlando P.] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA. [Simonetti, Orlando P.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Simonetti, Orlando P.] Ohio State Univ, Dept Radiol, Columbus, OH 43210 USA. RP Xue, H (reprint author), NHLBI, Magnet Resonance Technol Program, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hui.xue@nih.gov FU National Heart, Lung, And Blood Institute [R01HL102450]; Siemens Healthcare FX Grant sponsor: The National Heart, Lung, And Blood Institute; Grant number: R01HL102450; Grant sponsor: Siemens Healthcare. NR 19 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2015 VL 74 IS 1 BP 231 EP 239 DI 10.1002/mrm.25385 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK7XZ UT WOS:000356451500024 ER PT J AU Choi, EY Lim, JH Neuwirth, A Economopoulou, M Chatzigeorgiou, A Chung, KJ Bittner, S Lee, SH Langer, H Samus, M Kim, H Cho, GS Ziemssen, T Bdeir, K Chavakis, E Koh, JY Boon, L Hosur, K Bornstein, SR Meuth, SG Hajishengallis, G Chavakis, T AF Choi, E. Y. Lim, J-H Neuwirth, A. Economopoulou, M. Chatzigeorgiou, A. Chung, K-J Bittner, S. Lee, S-H Langer, H. Samus, M. Kim, H. Cho, G-S Ziemssen, T. Bdeir, K. Chavakis, E. Koh, J-Y Boon, L. Hosur, K. Bornstein, S. R. Meuth, S. G. Hajishengallis, G. Chavakis, T. TI Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination SO MOLECULAR PSYCHIATRY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INFLAMMATORY CELL RECRUITMENT; BLOOD-BRAIN-BARRIER; MULTIPLE-SCLEROSIS; T-CELLS; ANTIGEN PRESENTATION; DEL-1; EAE; EXPRESSION; DISEASE AB Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders. C1 [Choi, E. Y.; Lee, S-H; Kim, H.; Cho, G-S] Univ Ulsan, Coll Med, CDRC, Dept Biomed Sci, Seoul 138736, South Korea. [Choi, E. Y.; Lee, S-H; Kim, H.; Cho, G-S] Univ Ulsan, Coll Med, CDRC, Dept Pharmacol, Seoul 138736, South Korea. [Choi, E. Y.; Langer, H.; Chavakis, T.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Choi, E. Y.; Lim, J-H; Neuwirth, A.; Chatzigeorgiou, A.; Chung, K-J; Chavakis, T.] Tech Univ Dresden, Fac Med, Dept Clin Pathobiochem, D-01062 Dresden, Germany. [Choi, E. Y.; Chatzigeorgiou, A.; Samus, M.; Bornstein, S. R.; Chavakis, T.] Tech Univ Dresden, Fac Med, Dept Internal Med 3, D-01062 Dresden, Germany. [Economopoulou, M.] Tech Univ Dresden, Fac Med, Clin Ophthalmol, D-01062 Dresden, Germany. [Bittner, S.; Meuth, S. G.] Univ Munster, Dept Neurol, D-48149 Munster, Germany. [Langer, H.] Univ Tubingen, Med Klin 3, Tubingen, Germany. [Ziemssen, T.] Tech Univ Dresden, Fac Med, Dept Neurol, D-01062 Dresden, Germany. [Bdeir, K.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Chavakis, E.] Goethe Univ Frankfurt, Dept Internal Med, D-60054 Frankfurt, Germany. [Koh, J-Y] Univ Ulsan, Coll Med, Dept Neurol, Seoul 138736, South Korea. [Boon, L.] Bioceros, Utrecht, Netherlands. [Hosur, K.; Hajishengallis, G.] Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Chavakis, T.] Tech Univ Dresden, Fac Med, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany. [Chavakis, T.] Ctr Regenerat Therapies Dresden, Dresden, Germany. RP Choi, EY (reprint author), Univ Ulsan, Coll Med, CDRC, Dept Biomed Sci, 88 Olymp Roh,43 Gil, Seoul 138736, South Korea. EM choieun@ulsan.ac.kr RI Koh, Jae-Young/C-9014-2011; OI Koh, Jae-Young/0000-0002-4318-495X; Samus, Maryna/0000-0002-5397-2183 FU National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology of Korea [2011-0014447, 2008-0062286]; Novartis Foundation for Therapeutical Research; US NIH Extramural Program [DE021685, DE017138]; NIH Intramural Research Program, National Cancer Institute; Deutsche Forschungsgemeinschaft [CH279/5-1]; European Commission International Reintegration Grant [2010-268108]; European Research Council (ENDHOMRET); Else Kroner-Fresenius-Stiftung; Excellence Cluster Cardiopulmonary System (DFG) [Exc147-1]; German Centre for Cardiovascular Research (BMBF); LOEWE Center for Gene and Cell Therapy (Hessen, Germany) FX This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology of Korea (2011-0014447 and 2008-0062286 to EYC), from the Novartis Foundation for Therapeutical Research (to TC and EYC), from the US NIH Extramural Program (DE021685 and DE017138 to GH), the NIH Intramural Research Program, National Cancer Institute (to TC), the Deutsche Forschungsgemeinschaft (CH279/5-1 to TC), by a European Commission International Reintegration Grant (2010-268108, ANTIINFLDEL to TC) and the European Research Council (ENDHOMRET to TC). EC was supported by the Else Kroner-Fresenius-Stiftung, the Excellence Cluster Cardiopulmonary System (DFG; Exc147-1), the German Centre for Cardiovascular Research (BMBF) and the LOEWE Center for Gene and Cell Therapy (Hessen, Germany). We thank S Grossklaus and M Schuster for technical assistance, T Quertermous and R Kundu (Department of Medicine, Stanford University, Stanford, CA, USA) for providing Del-1-/- mice, Amgen for the IL-17RA-/- mice, the imaging core facility of the MTZ-Technische Universitat Dresden for help with imaging and Yongqing Zhang, Elin Lehrmann and Kevin G Becker (National Institute of Aging, NIH, Baltimore, MD, USA) for assistance with gene expression analysis. NR 50 TC 8 Z9 8 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 2015 VL 20 IS 7 BP 880 EP 888 DI 10.1038/mp.2014.146 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CL0EI UT WOS:000356611800011 PM 25385367 ER PT J AU Fitzgerald, PJ Pinard, CR Camp, MC Feyder, M Sah, A Bergstrom, HC Graybeal, C Liu, Y Schluter, OM Grant, SG Singewald, N Xu, W Holmes, A AF Fitzgerald, P. J. Pinard, C. R. Camp, M. C. Feyder, M. Sah, A. Bergstrom, H. C. Graybeal, C. Liu, Y. Schlueter, O. M. Grant, S. G. Singewald, N. Xu, W. Holmes, A. TI Durable fear memories require PSD-95 SO MOLECULAR PSYCHIATRY LA English DT Article ID ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTEX; TIME-DEPENDENT REORGANIZATION; REMOTE SPATIAL MEMORY; BASOLATERAL AMYGDALA; POSTSYNAPTIC DENSITY; SYNAPTIC PLASTICITY; DORSAL HIPPOCAMPUS; MOLECULAR-MECHANISMS; ASSOCIATIVE MEMORY AB Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95(GK)), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95(GK) mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories. C1 [Fitzgerald, P. J.; Pinard, C. R.; Camp, M. C.; Feyder, M.; Bergstrom, H. C.; Graybeal, C.; Holmes, A.] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Sah, A.; Singewald, N.] Univ Innsbruck, Dept Pharmacol & Toxicol, Inst Pharm, A-6020 Innsbruck, Austria. [Sah, A.; Singewald, N.] Univ Innsbruck, CMBI, A-6020 Innsbruck, Austria. [Liu, Y.; Xu, W.] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Schlueter, O. M.] European Neurosci Inst, Gottingen, Germany. [Grant, S. G.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Grant, S. G.] Univ Edinburgh, Ctr Neuroregenerat, Edinburgh, Midlothian, Scotland. RP Holmes, A (reprint author), 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM Courtney.Pinard@nih.gov OI Bergstrom, Hadley/0000-0003-3677-1619 FU NIAAA Intramural Research Program; Austrian Science Fund (FWF) [P22931-B18, Sonderforschungsbereich (SFB F4410-B19)]; NIH [MH080310]; JPB foundation; Simons Seed Grant at MIT FX We are very grateful to Katie Kaugars for technical assistance. Research supported by NIAAA Intramural Research Program (AH), the Austrian Science Fund (FWF): P22931-B18 and Sonderforschungsbereich (SFB F4410-B19; NS), NIH MH080310 JPB foundation (WX) and a Simons Seed Grant at MIT (WX). NR 95 TC 11 Z9 11 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 2015 VL 20 IS 7 BP 901 EP 912 DI 10.1038/mp.2014.161 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CL0EI UT WOS:000356611800013 PM 25510511 ER PT J AU Swaminathan, S Klemm, L Park, E Papaemmanuil, E Ford, A Kweon, SM Trageser, D Hasselfeld, B Henke, N Mooster, J Geng, HM Schwarz, K Kogan, SC Casellas, R Schatz, DG Lieber, MR Greaves, MF Muschen, M AF Swaminathan, Srividya Klemm, Lars Park, Eugene Papaemmanuil, Elli Ford, Anthony Kweon, Soo-Mi Trageser, Daniel Hasselfeld, Brian Henke, Nadine Mooster, Jana Geng, Huimin Schwarz, Klaus Kogan, Scott C. Casellas, Rafael Schatz, David G. Lieber, Michael R. Greaves, Mel F. Mueschen, Markus TI Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia SO NATURE IMMUNOLOGY LA English DT Article ID CYTIDINE DEAMINASE AID; B-CELL DEVELOPMENT; CHROMOSOME TRANSLOCATIONS; MONOZYGOTIC TWINS; CLASS SWITCH; DAY-CARE; RECOMBINATION; GENE; ACTIVATION; EXPRESSION AB Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood. C1 [Swaminathan, Srividya; Klemm, Lars; Park, Eugene; Geng, Huimin; Kogan, Scott C.; Mueschen, Markus] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Klemm, Lars] Univ Freiburg, Fac Biol, Freiburg, Germany. [Park, Eugene] Univ Cambridge, Dept Haematol, Cambridge, England. [Papaemmanuil, Elli] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England. [Ford, Anthony; Greaves, Mel F.] Inst Canc Res, Ctr Evolut & Canc, London, England. [Kweon, Soo-Mi; Trageser, Daniel; Hasselfeld, Brian; Lieber, Michael R.] Univ So Calif, Los Angeles, CA USA. [Henke, Nadine; Mooster, Jana] Univ Dusseldorf, Dusseldorf, Germany. [Schwarz, Klaus] Univ Ulm, Inst Transfus Med, D-89069 Ulm, Germany. [Casellas, Rafael] NIAMS, Genom & Immun, NIH, Bethesda, MD USA. [Schatz, David G.] Yale Univ, New Haven, CT USA. RP Muschen, M (reprint author), Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. EM markus.muschen@ucsf.edu OI Nickel, Nadine/0000-0002-0609-0735 FU National Cancer Institute of the US National Institutes of Health [R01CA137060, R01CA139032, R01CA157644, R01CA169458, R01CA172558]; Leukemia and Lymphoma Society [1479-11, 6132-09, 6097-10, 6221-12]; William Lawrence and Blanche Hughes Foundation; California Institute for Regenerative Medicine [TR2-01816]; Leukaemia, Lymphoma Research UK; Cancer Research UK [CRUK 18131]; Wellcome Trust [WT105104/Z/14/Z, WT101880AIA] FX We thank J.L. Wiemels and C. Gawad for encouragement and critical discussions; D.B. Kohn (University of California, Los Angeles) for the envelope and packaging vectors for lentivirus and retrovirus productions; and H. Hanenberg (Indiana University) for the plasmid pCL6-IRES-eGFP-wo. Supported by the National Cancer Institute of the US National Institutes of Health (R01CA137060, R01CA139032, R01CA157644, R01CA169458 and R01CA172558 to M.M.), the Leukemia and Lymphoma Society (1479-11, 6132-09, 6097-10 and 6221-12 to M.M.), the William Lawrence and Blanche Hughes Foundation, the California Institute for Regenerative Medicine (TR2-01816 to M.M.), Leukaemia, Lymphoma Research UK (M.F.G. and A.F.), Cancer Research UK (CRUK 18131 to M.M.) and The Wellcome Trust (WT105104/Z/14/Z to M.F.G. and WT101880AIA to M.M.). NR 54 TC 31 Z9 31 U1 4 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2015 VL 16 IS 7 BP 766 EP + DI 10.1038/ni.3160 PG 11 WC Immunology SC Immunology GA CK7WH UT WOS:000356445600013 PM 25985233 ER PT J AU Wager, TD Atlas, LY AF Wager, Tor D. Atlas, Lauren Y. TI The neuroscience of placebo effects: connecting context, learning and health SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID IRRITABLE-BOWEL-SYNDROME; BEHAVIORALLY CONDITIONED IMMUNOSUPPRESSION; PREFRONTAL-SUBCORTICAL PATHWAYS; VENTROLATERAL ORBITAL CORTEX; ROSTRAL VENTROMEDIAL MEDULLA; AUTONOMIC NERVOUS-SYSTEM; PERIAQUEDUCTAL GRAY; PARKINSONS-DISEASE; INDIVIDUAL-DIFFERENCES; NUCLEUS-ACCUMBENS AB Placebo effects are beneficial effects that are attributable to the brain-mind responses to the context in which a treatment is delivered rather than to the specific actions of the drug. They are mediated by diverse processes - including learning, expectations and social cognition - and can influence various clinical and physiological outcomes related to health. Emerging neuroscience evidence implicates multiple brain systems and neurochemical mediators, including opioids and dopamine. We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind-brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs. C1 [Wager, Tor D.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Atlas, Lauren Y.] NIH, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20982 USA. RP Wager, TD (reprint author), Univ Colorado, Dept Psychol & Neurosci, 345 UCB, Boulder, CO 80309 USA. EM Tor.Wager@Colorado.edu FU Intramural Research Program of the US National Institutes of Health's National Center for Complementary and Integrative Health; [NIMH 2R01MH076136]; [R01DA027794] FX The authors thank J. Sills and E. Hitchcock for research support, the members of the Cognitive and Affective Neuroscience Lab, S. Maier and L. Watkins for helpful discussions, and L. Ruzic for help with the summary in Figure 3. This work was funded by grants NIMH 2R01MH076136 and R01DA027794 (to T.D.W.). This work was also supported in part by the Intramural Research Program of the US National Institutes of Health's National Center for Complementary and Integrative Health. NR 215 TC 29 Z9 29 U1 10 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2015 VL 16 IS 7 BP 403 EP 418 DI 10.1038/nrn3976 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CK9UV UT WOS:000356585900008 PM 26087681 ER PT J AU Heilig, M Carlezon, WA AF Heilig, Markus Carlezon, William A., Jr. TI Circumspectives: The Replacements SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material C1 [Heilig, Markus] Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. [Carlezon, William A., Jr.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA USA. RP Heilig, M (reprint author), NIAAA, Ctr Social & Affect Neurosci, Dept Clin & Expt Med, LCTS, 10 Ctr Dr, Bethesda, MD 20892 USA. EM markus.heilig@liu.se NR 6 TC 0 Z9 0 U1 0 U2 1 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 JUL PY 2015 VL 40 IS 8 BP 1813 EP 1814 DI 10.1038/npp.2015.82 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CK4IE UT WOS:000356186700001 PM 26068571 ER PT J AU Fink, LHL Anastasio, NC Fox, RG Rice, KC Moeller, FG Cunningham, KA AF Fink, Latham H. L. Anastasio, Noelle C. Fox, Robert G. Rice, Kenner C. Moeller, F. Gerard Cunningham, Kathryn A. TI Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID REACTION-TIME-TASK; HEAD-TWITCH RESPONSE; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; DOPAMINERGIC MECHANISMS; RAT-BRAIN; ADULT-RAT; BEHAVIOR; AGONIST; PERFORMANCE AB Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT2AR receptor (5-HT2AR) promote and 5-HT2AR antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT2AR, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT2AR antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT2AR binding density in frontal cortex ([H-3]-ketanserin radioligand binding). Elevated mPFC 5-HT2AR protein expression concomitant with augmented association of the 5-HT2AR with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT2AR ligands and associated distinct 5-HT2AR protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT2AR system. C1 [Fink, Latham H. L.; Anastasio, Noelle C.; Fox, Robert G.; Cunningham, Kathryn A.] Univ Texas Med Branch, Ctr Addict Res, Galveston, TX 77555 USA. [Fink, Latham H. L.; Anastasio, Noelle C.; Fox, Robert G.; Cunningham, Kathryn A.] Univ Texas Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA. [Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD USA. [Rice, Kenner C.] NIAAA, Bethesda, MD USA. [Moeller, F. Gerard] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA USA. RP Cunningham, KA (reprint author), Univ Texas Med Branch, Dept Pharmacol & Toxicol, UTMB Ctr Addict Res, 301 Univ Blvd,Route 1031, Galveston, TX 77555 USA. EM kcunning@utmb.edu FU NIDA [F30 DA034488, T32 007287, P20 DA024157, P50 DA0333935, K05 DA020087, K99 DA033374]; Center for Addiction Research at the University of Texas Medical Branch; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX We thank Dr Charles D Nichols and Dr Kenneth M Johnson for providing assistance and advice for the radioligand binding studies. This work was supported by NIDA grants F30 DA034488 (to LHLF), T32 007287 (to LHLF), P20 DA024157 (to KAC), P50 DA0333935 (to KAC), K05 DA020087 (to KAC), and K99 DA033374 (to NCA), and the Center for Addiction Research at the University of Texas Medical Branch. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. NR 70 TC 4 Z9 4 U1 2 U2 11 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 JUL PY 2015 VL 40 IS 8 BP 1957 EP 1968 DI 10.1038/npp.2015.46 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CK4IE UT WOS:000356186700016 PM 25666313 ER PT J AU Fedota, JR Sutherland, MT Salmeron, BJ Ross, TJ Hong, LE Stein, EA AF Fedota, John R. Sutherland, Matthew T. Salmeron, Betty Jo Ross, Thomas J. Hong, L. Elliot Stein, Elliot A. TI Reward Anticipation Is Differentially Modulated by Varenicline and Nicotine in Smokers SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID RECEPTOR PARTIAL AGONIST; SMOKING-CESSATION; COGNITIVE CONTROL; ATTENTIONAL BIAS; DRUG-ADDICTION; FRONTAL-CORTEX; CUE REACTIVITY; ACTIVATION; FMRI; SYSTEMS AB Recidivism rates for cigarette smokers following treatment often exceed 80%. Varenicline is the most efficacious pharmacotherapy currently available with cessation rates of 25-35% following a year of treatment. Although the in vivo binding properties are well known, varenicline's neurobiological mechanisms of action are still poorly understood. Varenicline acts as a nicotinic receptor partial agonist or antagonist depending on the presence or absence of nicotine and has been implicated in the reduction of reward signaling more broadly. The current study probed anticipatory reward processing using a revised monetary incentive delay task during fMRI in cohorts of smokers and non-smokers who completed a two-drug, placebo-controlled, double-blind crossover study. All participants underwent similar to 17 days of order-balanced varenicline and placebo pill administration and were scanned under each condition wearing a transdermal nicotine or placebo patch. Consistent with nicotine's ability to enhance the rewarding properties of nondrug stimuli, acute nicotine administration enhanced activation in response to reward-predicting monetary cues in both smokers and non-smokers. In contrast, varenicline reduced gain magnitude processing, but did so only in smokers. These results suggest that varenicline's downregulation of anticipatory reward processing in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation. C1 [Fedota, John R.; Salmeron, Betty Jo; Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Sutherland, Matthew T.] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [Hong, L. Elliot] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. RP Fedota, JR (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM john.fedota@nih.gov RI Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse (NIDA) Intramural Research Program; National Institutes of Health [K01-DA037819, R01-MH085646, R01-DA027680, P50-MH103222]; Mitsubishi; Your Energy Systems LLC; Pfizer FX This study was supported by the National Institute on Drug Abuse (NIDA) Intramural Research Program (JRF, MTS, BJS, TJR, and EAS). Additional funding was received from the National Institutes of Health grant K01-DA037819 (MTS). LEH receives support from the National Institute of Health grants R01-MH085646, R01-DA027680, and P50-MH103222, and unrestricted research funding from Mitsubishi, Your Energy Systems LLC, and Pfizer. Pfizer is the manufacturer of varenicline. NR 49 TC 4 Z9 4 U1 1 U2 14 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 JUL PY 2015 VL 40 IS 8 BP 2038 EP 2046 DI 10.1038/npp.2015.54 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CK4IE UT WOS:000356186700023 PM 25742873 ER PT J AU Li, YY Krahn, JM Flake, GP Umbach, DM Li, LP AF Li, Yuanyuan Krahn, Juno M. Flake, Gordon P. Umbach, David M. Li, Leping TI Toward predicting metastatic progression of melanoma based on gene expression data SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE metastasis; metastatic progression; biomarker; melanoma; classification; GA; KNN ID CANCER GENOME ATLAS; S100 PROTEINS; SAMPLE CLASSIFICATION; IMMUNE-RESPONSE; BREAST-CANCER; GA/KNN METHOD; MIR-205; COMPLEMENT; METALLOPROTEINASES; PROLIFERATION AB Primary and metastatic melanoma tumors share the same cell origin, making it challenging to identify genomic biomarkers that can differentiate them. Primary tumors themselves can be heterogeneous, reflecting ongoing genomic changes as they progress toward metastasizing. We developed a computational method to explore this heterogeneity and to predict metastatic progression of the primary tumors. We applied our method separately to gene expression and to microRNA (miRNA) expression data from 450 primary and metastatic skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA). Metastatic progression scores from RNA-seq data were significantly associated with clinical staging of patients' lymph nodes, whereas scores from miRNA-seq data were significantly associated with Clark's level. The loss of expression of many characteristic epithelial lineage genes in primary SKCM tumor samples was highly correlated with predicted progression scores. We suggest that those genes/miRNAs might serve as putative biomarkers for SKCM metastatic progression. C1 [Li, Yuanyuan; Umbach, David M.; Li, Leping] NIEHS, Biostat & Computat Biol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Krahn, Juno M.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Flake, Gordon P.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Li, LP (reprint author), NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM li3@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES101765] FX We are grateful to John Demchok (National Cancer Institute) for his assistance on questions related to the clinical data. We thank Mike Resnick, Paul Wade, and Shyamal Peddada for comments and suggestions and the reviewers for their constructive comments that improved our manuscript. We thank the Computational Biology Facility at NIEHS and the Biowulf at NIH for computing time. This research was supported by Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES101765). NR 52 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JUL PY 2015 VL 28 IS 4 DI 10.1111/pcmr.12374 PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA CK6UA UT WOS:000356362600012 ER PT J AU Fourie, NH Jolly, CJ Phillips-Conroy, JE Brown, JL Bernstein, RM AF Fourie, Nicolaas H. Jolly, Clifford J. Phillips-Conroy, Jane E. Brown, Janine L. Bernstein, Robin M. TI Variation of hair cortisol concentrations among wild populations of two baboon species (Papio anubis, P-hamadryas) and a population of their natural hybrids SO PRIMATES LA English DT Article DE Hair; Cortisol; Baboons; Hybrids; Behavior; Stress ID MULTILEVEL SOCIETY; SOCIAL SUPPORT; CEREBROSPINAL-FLUID; GREETING BEHAVIOR; RHESUS MACAQUES; STRESS-RESPONSE; CHACMA BABOONS; RECEPTOR GENE; PRIMATE; GLUCOCORTICOIDS AB Male olive (Papio anubis) and hamadryas (P. hamadryas) baboons have distinctive sociobehavioral and physical characteristics. In the Awash National Park, Ethiopia, a hybrid population at the contact zone between these two species, exhibits heterogeneous sociobehavioral and physical characteristics. The ambiguity of the hybrid social environment and disruption of parental stress genotypes may be sources of physiological stress for hybrids. We examined levels of chronic stress among males of the three populations and tested the prediction that chronic cortisol levels would be higher among the hybrids. Animals were captured, sampled, and released during the wet season, and a hair sample was taken for assay. Cortisol was extracted from 182 hair samples with methanol and quantified by ELISA. We included age, age class, rainfall variation, and species affiliation in models examining variation in hair cortisol levels. Species and age significantly contributed to models explaining variation in hair cortisol. Infant hypercortisolism was observed in all three groups, and a decline in cortisol through juvenile and adolescent stages, with a subsequent rise in adulthood. This rise occurred earliest in hamadryas, corroborating other evidence of the precocious development of hamadryas baboons. As expected, hybrids had significantly elevated hair cortisol compared with olive baboons and hamadryas, irrespective of age, except for very young animals. Infant hypercortisolism was also less pronounced among hybrids. Species differences and age-related differences in cortisol levels suggest a dysregulated cortisol phenotype in hybrids, and possibly reflect some form of hybrid disadvantage. More work will be required to disentangle the effects of genetic factors and the social environment. C1 [Fourie, Nicolaas H.] NINR, Biobehav Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Jolly, Clifford J.] NYU, Dept Anthropol, New York, NY 10003 USA. [Phillips-Conroy, Jane E.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Phillips-Conroy, Jane E.] Washington Univ, Dept Anthropol, St Louis, MO 63130 USA. [Brown, Janine L.] Smithsonian Conservat Biol Inst, Ctr Species Survival, Front Royal, VA 22630 USA. [Bernstein, Robin M.] Univ Colorado, Dept Anthropol, Boulder, CO 80309 USA. RP Fourie, NH (reprint author), NINR, Biobehav Branch, Intramural Res Program, NIH, Room 2N104,10 Ctr Dr, Bethesda, MD 20892 USA. EM fourienh@mail.nih.gov OI Fourie, Nicolaas/0000-0002-5167-8570 NR 102 TC 7 Z9 7 U1 1 U2 20 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0032-8332 EI 1610-7365 J9 PRIMATES JI Primates PD JUL PY 2015 VL 56 IS 3 BP 259 EP 272 DI 10.1007/s10329-015-0469-z PG 14 WC Zoology SC Zoology GA CK9BU UT WOS:000356536000008 PM 25903227 ER PT J AU Kim, JH Ku, B Lee, KS Kim, SJ AF Kim, Ju Hee Ku, Bonsu Lee, Kyung S. Kim, Seung Jun TI Structural analysis of the polo-box domain of human Polo-like kinase 2 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE polo-box domain; Polo-like kinase 2; tumor suppressor; structure; cell cycle ID CENTRIOLE DUPLICATION; CELL-PROLIFERATION; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; CANCER-THERAPY; RECOGNITION; INHIBITION; PLK1 AB Polo-like kinases (Plks) are the key regulators of cell cycle progression, the members of which share a kinase domain and a polo-box domain (PBD) that serves as a protein-binding module. While Plk1 is a promising target for antitumor therapy, Plk2 is regarded as a tumor suppressor even though the two Plks commonly recognize the S-pS/T-P motif through their PBD. Herein, we report the crystal structure of the PBD of Plk2 at 2.7 angstrom. Despite the overall structural similarity with that of Plk1 reflecting their high sequence homology, the crystal structure also contains its own features including the highly ordered loop connecting two subdomains and the absence of 3(10)-helices in the N-terminal region unlike the PBD of Plk1. Based on the three-dimensional structure, we furthermore could model its interaction with two types of phosphopeptides, one of which was previously screened as the optimal peptide for the PBD of Plk2. Proteins 2015; 83:1201-1208. (c) 2015 Wiley Periodicals, Inc. C1 [Kim, Ju Hee; Ku, Bonsu; Kim, Seung Jun] Korea Res Inst Biosci & Biotechnol, Funct Genom Res Ctr, Taejon 305806, South Korea. [Lee, Kyung S.] Natl Canc Inst, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), Korea Res Inst Biosci & Biotechnol, Funct Genom Res Ctr, Taejon 305806, South Korea. EM ksj@kribb.re.kr FU National Research Foundation of Korea [20110030027]; Korea Research Institute of Bioscience and Biotechnology Research Initiative Program FX Grant sponsor: National Research Foundation of Korea; Grant number: 20110030027; Grant sponsor: Korea Research Institute of Bioscience and Biotechnology Research Initiative Program. NR 37 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD JUL PY 2015 VL 83 IS 7 BP 1201 EP 1208 DI 10.1002/prot.24804 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CK7TI UT WOS:000356435500001 PM 25846005 ER PT J AU Fenton, SE AF Fenton, Suzanne E. TI A special issue dedicated to a complex tissue SO REPRODUCTIVE TOXICOLOGY LA English DT Editorial Material ID MAMMARY-GLAND DEVELOPMENT; BISPHENOL-A; RODENT; EXPOSURES; CHEMICALS; PUBERTY; GROWTH; RATS C1 [Fenton, Suzanne E.] NIEHS, Natl Toxicol Program NTP Lab, Div NTP, NIH, Res Triangle Pk, NC 27709 USA. RP Fenton, SE (reprint author), 111 TW Alexander Dr,Bldg 101,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov NR 32 TC 0 Z9 0 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2015 VL 54 SI SI BP 1 EP 5 DI 10.1016/j.reprotox.2015.05.004 PG 5 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK7GR UT WOS:000356401300001 PM 25986312 ER PT J AU Forman, MR Winn, DM Collman, GW Rizzo, J Birnbaum, LS AF Forman, Michele R. Winn, Deborah M. Collman, Gwen W. Rizzo, Jeanne Birnbaum, Linda S. TI Environmental exposures, breast development and cancer risk: Through the looking glass of breast cancer prevention SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Environment; Prevention; Breast development; Breast cancer; Life course ID BIRTH-WEIGHT; PREECLAMPSIA; ASSOCIATION; GENDER; WOMEN AB This review summarizes the report entitled: Breast Cancer and the Environment: Prioritizing Prevention, highlights research gaps and the importance of focusing on early life exposures for breast development and breast cancer risk. (C) 2014 Elsevier Inc. All rights reserved. C1 [Forman, Michele R.] Univ Texas Austin, Austin, TX 78712 USA. [Winn, Deborah M.] NCI, NIH, Bethesda, MD 20892 USA. [Collman, Gwen W.; Birnbaum, Linda S.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Rizzo, Jeanne] Breast Canc Fund, San Francisco, CA 94109 USA. RP Forman, MR (reprint author), Univ Texas Austin, Austin, TX 78712 USA. EM mforman@austin.utexas.edu NR 16 TC 7 Z9 7 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2015 VL 54 SI SI BP 6 EP 10 DI 10.1016/j.reprotox.2014.10.019 PG 5 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK7GR UT WOS:000356401300002 PM 25499721 ER PT J AU Tucker, DK Macon, MB Strynar, MJ Dagnino, S Andersen, E Fenton, SE AF Tucker, Deirdre K. Macon, Madisa B. Strynar, Mark J. Dagnino, Sonia Andersen, Erik Fenton, Suzanne E. TI The mammary gland is a sensitive pubertal target in CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Perfluorooctanoic acid; Mammary gland; Puberty; CD-1; C57Bl/6; Vaginal opening; Estrous cycle ID LACTATING MICE; BREAST-CANCER; MOUSE STRAINS; PREGNANCY; MEDIATE; TISSUES; BALB/C; FLUIDS; PUPS AB Perfluorooctanoic acid (PFOA) is a developmental toxicant in mice, with varied strain outcomes depending on dose and period of exposure. The impact of PFOA on female mouse pubertal development at low doses (<= 1 mg/kg) has yet to be determined. Therefore, female offspring from CD-1 and C57Bl/6 dams exposed to PFOA, creating serum concentrations similar to humans, were examined for pubertal onset, including mammary gland development. Pups demonstrated a shorter PFOA elimination half-life than that reported for adult mice. Prenatal exposure to PFOA caused significant mammary developmental delays in female offspring in both strains. Delays started during puberty and persisted into young adulthood; severity was dose-dependent. Also an evaluation of female serum hormone levels and pubertal timing onset revealed no effects of PFOA compared to controls in either strain. These data suggest that the mammary gland is more sensitive to early low level PFOA exposures compared to other pubertal endpoints, regardless of strain. Published by Elsevier Inc. C1 [Tucker, Deirdre K.; Macon, Madisa B.] Univ N Carolina, Sch Med, Curriculum Toxicol, Chapel Hill, NC 27599 USA. [Tucker, Deirdre K.; Macon, Madisa B.; Fenton, Suzanne E.] NIEHS, Natl Toxicol Program Lab, Div NTP, NIH, Res Triangle Pk, NC 27709 USA. [Strynar, Mark J.] US EPA, Methods Dev & Applicat Branch, Human Exposure & Atmospher Sci Div, Natl Exposure Res Lab,Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Dagnino, Sonia] US EPA, Natl Exposure Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Andersen, Erik] US EPA, Exposure Measurements & Anal Branch, Human Exposure & Atmospher Sci Div, Natl Exposure Res Lab,Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Fenton, SE (reprint author), NIEHS, POB 12233,Bldg 101,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences, NIH; Intramural Research Training Award; NIEHS; NIH; Curriculum of Toxicology at UNC Chapel Hill, Chapel Hill, NC, USA FX This work was supported by the National Toxicology Program, National Institute of Environmental Health Sciences, NIH. Deirdre Katrese Tucker was funded by an Intramural Research Training Award, NIEHS, NIH and the Curriculum of Toxicology at UNC Chapel Hill, Chapel Hill, NC, USA. NR 55 TC 10 Z9 10 U1 3 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2015 VL 54 SI SI BP 26 EP 36 DI 10.1016/j.reprotox.2014.12.002 PG 11 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK7GR UT WOS:000356401300005 PM 25499722 ER PT J AU Hines, EP Mendola, P von Ehrenstein, OS Ye, XY Calafat, AM Fenton, SE AF Hines, Erin P. Mendola, Pauline von Ehrenstein, Ondine S. Ye, Xiaoyun Calafat, Antonia M. Fenton, Suzanne E. TI Concentrations of environmental phenols and parabens in milk, urine and serum of lactating North Carolina women SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Biomonitoring; BPA; Breast milk; Lactation; MAMA Study; Parabens phenols; Serum; Urine ID TANDEM MASS-SPECTROMETRY; HPLC-MS/MS METHOD; POLYBROMINATED DIPHENYL ETHERS; NUTRITION EXAMINATION SURVEY; BISPHENOL-A CONCENTRATIONS; MALE REPRODUCTIVE-SYSTEM; PERSONAL CARE PRODUCTS; HUMAN BREAST-MILK; NATIONAL-HEALTH; RISK-ASSESSMENT AB Phenols and parabens show some evidence for endocrine disruption in laboratory animals. The goal of the Methods Advancement for Milk Analysis (MAMA) Study was to develop or adapt methods to measure parabens (methyl, ethyl, butyl, propyl) and phenols (bisphenol A (BPA), 2,4- and 2,5-dichlorophenol, benzophenone-3, triclosan) in urine, milk and serum twice during lactation, to compare concentrations across matrices and with endogenous biomarkers among 34 North Carolina women. These non-persistent chemicals were detected in most urine samples (53-100%) and less frequently in milk or serum; concentrations differed by matrix. Although urinary parabens, triclosan and dichlorophenols concentrations correlated significantly at two time points, those of BPA and benzophenone-3 did not, suggesting considerable variability in those exposures. These pilot data suggest that nursing mothers are exposed to phenols and parabens; urine is the best measurement matrix; and correlations between chemical and endogenous immune-related biomarkers merit further investigation. Published by Elsevier Inc. C1 [Hines, Erin P.] US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. [Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. [von Ehrenstein, Ondine S.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA USA. [Ye, Xiaoyun; Calafat, Antonia M.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. [Fenton, Suzanne E.] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. RP Hines, EP (reprint author), US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. EM hines.erin@epa.gov; pauline.mendola@nih.gov; ovehren@ucla.edu; xay5@cdc.gov; aic7@cdc.gov; fentonse@niehs.nih.gov OI Hines, Erin Pias/0000-0002-2458-6267; Mendola, Pauline/0000-0001-5330-2844 FU National Children's Study Inter-Agency Coordinating Committee; Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Jack Reidy, Tao Jia, Xiaoliu Zhou, Amber Bishop, Charles Dodson, Pam Olive, and Richard Wang for technical assistance. The authors thank the Westat, Inc. recruiters (Andrea Ware, Bethany Bradford, Brian Karasek), U.S. EPA nursing staff (Deb Levin, Mary Ann Bassett, and Tracey Montilla), and the MAMA study participants, without whom this project would not have been a success. This project received partial extramural funding through the recommendation of the National Children's Study Inter-Agency Coordinating Committee. This research was supported, in part, by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 62 TC 16 Z9 16 U1 9 U2 48 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2015 VL 54 SI SI BP 120 EP 128 DI 10.1016/j.reprotox.2014.11.006 PG 9 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK7GR UT WOS:000356401300015 PM 25463527 ER PT J AU Stanko, JP Easterling, MR Fenton, SE AF Stanko, Jason P. Easterling, Michael R. Fenton, Suzanne E. TI Application of Sholl analysis to quantify changes in growth and development in rat mammary gland whole mounts SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Mammary gland; Endocrine disruptors; Sholl analysis; Reproductive; Developmental; Toxicology; Breast cancer; Rodent ID SPRAGUE-DAWLEY RATS; CARCINOMA IN-SITU; LONG-EVANS RATS; BISPHENOL-A; BREAST-CANCER; FEMALE RATS; QUANTITATIVE ASSESSMENT; PERINATAL EXPOSURE; UTERO EXPOSURE; IMAGE-ANALYSIS AB Studies that utilize the rodent mammary gland (MG) as an endpoint for assessing the developmental toxicity of chemical exposures typically employ either basic dimensional measurements or developmental scoring of morphological characteristics as a means to quantify MG development. There are numerous means by which to report these developmental changes, leading to inconsistent translation across laboratories. The Sholl analysis is a method historically used for quantifying neuronal dendritic patterns. The present study describes the use of the Shall analysis to quantify MG branching characteristics. Using this method, we were able to detect significant differences in branching density in MG of peripubertal female Sprague Dawley rats that had been exposed to vehicle or a potent estrogen. These data suggest the Sholl analysis can be an effective tool for quantitatively measuring an important characteristic of MG development and for examining associations between MG growth and density and adverse effects in the breast. Published by Elsevier Inc. C1 [Stanko, Jason P.; Fenton, Suzanne E.] NIEHS, Natl Toxicol Program Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Easterling, Michael R.] Social & Sci Syst Inc, Durham, NC 27713 USA. RP Fenton, SE (reprint author), NTPL DNTP NIEHS, 111 TW Alexander Dr,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999, ZIA ES102785-04] NR 40 TC 2 Z9 2 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2015 VL 54 SI SI BP 129 EP 135 DI 10.1016/j.reprotox.2014.11.004 PG 7 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK7GR UT WOS:000356401300016 PM 25463529 ER PT J AU Teitelbaum, SL Belpoggi, F Reinlib, L AF Teitelbaum, Susan L. Belpoggi, Fiorella Reinlib, Les TI Advancing research on endocrine disrupting chemicals in breast cancer: Expert panel recommendations SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Endocrine disrupting chemicals; Breast cancer; Mammary gland biology; Windows of susceptibility ID IN-UTERO EXPOSURE; PHTHALATES INDUCE PROLIFERATION; MAMMARY-GLAND DEVELOPMENT; SEVESO WOMENS HEALTH; ESTROGEN-RECEPTOR; BISPHENOL-A; SIGNALING PATHWAY; CHILDRENS HEALTH; CRITICAL WINDOWS; DIOXIN EXPOSURE AB Breast cancer incidence continues to increase in the US and Europe, a reflection of the growing influence of environment factors that interact with personal genetics. The US Environmental Protection Agency estimates that there are approximately 10,000 endocrine disrupting chemicals among the common daily exposures that could affect the risk of disease. The daunting tasks of identifying, characterizing, and elucidating the mechanisms of endocrine disrupting chemicals in breast cancer need to be addressed to produce a comprehensive model that will facilitate preventive strategies and public policy. An expert panel met to describe and bring attention to needs linking common environmental exposures, critical windows of exposure, and optimal times of assessment in investigating breast cancer risk. The group included investigators with extensive experience in the use of rodent models and in leading population studies and produced a set of recommendations for effective approaches to gaining insights into the environmental origins of breast cancer across the lifespan. Published by Elsevier Inc. C1 [Teitelbaum, Susan L.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Belpoggi, Fiorella] Ramazzini Inst, Cesare Maltoni Canc Res Ctr, Bologna, Italy. [Reinlib, Les] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27713 USA. RP Reinlib, L (reprint author), NIEHS, Div Extramural Res, NIH, 530 Davis Dr,Room 3072, Res Triangle Pk, NC 27713 USA. EM reinlib@niehs.nih.gov FU NIEHS; Breast Cancer and the Environment Research Program (BCERP) of the National Institute of Environmental Health Sciences; National Cancer Institute (NCI) [U01ES019459] FX This report summarizes the ideas and recommendations discussed at the "Meeting on Gene-Environment Interactions of Endocrine Disrupting Chemicals in Breast Cancer" held May 18-19, 2014 at the Ramazzini Institute, Bentivoglio, Bologna, Italy, which kindly supported the meeting. The key meeting speakers were: Fiorella Belpoggi (co-Chair), Ramazzini Institute, Bologna; Susan L. Teitelbaum (co-Chair), Icahn School of Medicine, Mount Sinai, New York; Suzanne Fenton, Division of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park (RTP), North Carolina US; Fabiana Manservisi Ramazzini Institute, Bologna; Michela Padovani, Ramazzini Institute, Bologna; Les Reinlib, Division of Extramural Research & Training, NIEHS, NIH, RTP. This work was supported in part by NIEHS. SL Teitelbaum was supported by the Breast Cancer and the Environment Research Program (BCERP) of the National Institute of Environmental Health Sciences and the National Cancer Institute (NCI), award number U01ES019459. NR 67 TC 5 Z9 5 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL PY 2015 VL 54 SI SI BP 141 EP 147 DI 10.1016/j.reprotox.2014.12.015 PG 7 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK7GR UT WOS:000356401300018 PM 25549947 ER PT J AU Kuschner, ES Eisenberg, IW Orionzi, B Simmons, WK Kenworthy, L Martin, A Wallace, GL AF Kuschner, Emily S. Eisenberg, Ian W. Orionzi, Bako Simmons, W. Kyle Kenworthy, Lauren Martin, Alex Wallace, Gregory L. TI A preliminary study of self-reported food selectivity in adolescents and young adults with autism spectrum disorder SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Autism; Food; Taste; Sensory; Adolescent; Adult ID GASTROINTESTINAL SYMPTOMS; DIAGNOSTIC INTERVIEW; ADAPTIVE-BEHAVIOR; NUTRIENT INTAKE; HUMAN BRAIN; CHILDREN; DISABILITIES; RESPONSES; DEFICITS; TASTE AB Although it is well-established that picky eating is a common feature of early development in autism spectrum disorder (ASD), far less is known about food selectivity during adolescence and adulthood. Using portions of the Adult/Adolescent Sensory Profile, food selectivity self-ratings were obtained from 65 high-functioning adolescents/young adults with ASD and compared to those of 59 typically developing controls matched on age, IQ and sex ratio. Individuals with ASD reported preferring familiar foods (food neophobia) and disliking foods with particular textures and strong flavors. Providing linkage to everyday behavior, parent ratings of daily living skills were lower among individuals with ASD and food neophobia than among those without food neophobia. Food selectivity continues to be an important issue for adolescents/young adults with ASD. (c) 2015 Elsevier LtdElsevier Ltd. All rights reserved. C1 [Kuschner, Emily S.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Eisenberg, Ian W.; Orionzi, Bako; Martin, Alex; Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD USA. [Simmons, W. Kyle] Laureate Inst Brain Res, Tulsa, OK USA. [Kenworthy, Lauren] Childrens Natl Med Ctr, Washington, DC USA. [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, Washington, DC 20052 USA. RP Wallace, GL (reprint author), George Washington Univ, Dept Speech & Hearing Sci, 2115 G St NW,Hall Govt 201, Washington, DC 20052 USA. EM gwallac1@gwu.edu RI Simmons, William/K-8925-2015; OI Simmons, William/0000-0002-0399-9003; Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program at NIMH, NIH [1-ZIA-MH002920] FX This work was supported by the Intramural Research Program at NIMH, NIH under grant number 1-ZIA-MH002920. NR 61 TC 2 Z9 2 U1 7 U2 28 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 JUL PY 2015 VL 15-16 BP 53 EP 59 DI 10.1016/j.rasd.2015.04.005 PG 7 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA CL1XM UT WOS:000356738200006 PM 26309446 ER PT J AU Mattson, MP AF Mattson, Mark P. TI WHAT DOESN'T KILL YOU ... SO SCIENTIFIC AMERICAN LA English DT Article AB When asked why eating lots of fruits and vegetables can improve health, many people will point to the antioxidants in these foods. That reasoning is logical because major diseases such as cancer, cardiovascular disease and diabetes involve cell damage caused by chemicals called free radicals that antioxidants neutralize. C1 [Mattson, Mark P.] NIA, Lab Neurosci, Bethesda, MD 20892 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Neurosci, Baltimore, MD 21218 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 7 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD JUL PY 2015 VL 313 IS 1 BP 40 EP 45 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL0KY UT WOS:000356632800029 PM 26204714 ER PT J AU Delnevo, CD Giovenco, DP Ambrose, BK Corey, CG Conway, KP AF Delnevo, Cristine D. Giovenco, Daniel P. Ambrose, Bridget K. Corey, Catherine G. Conway, Kevin P. TI Preference for flavoured cigar brands among youth, young adults and adults in the USA SO TOBACCO CONTROL LA English DT Article ID TOBACCO PRODUCTS; UNITED-STATES; SMOKING; SMOKERS; ADOLESCENTS; PREVALENCE; CALIFORNIA; MARIJUANA; PATTERNS; STUDENTS AB Background While cigarette consumption in the USA continues to decline, cigar consumption has increased. Tobacco-trade publications suggest that flavoured cigars are driving the recent growth in cigar consumption. Limited survey data exist to explore flavoured cigar preferences among youth and adults. Methods This study used the 2010-2011 National Survey on Drug Use and Health (NSDUH) and Nielsen market scanner data. The NSDUH sample consisted of 6678 past 30-day cigar smokers who reported smoking a usual brand of cigars. NSDUH contains a measure on usual cigar brand smoked and was merged with Nielsen data to estimate the per cent of each cigar brand's market share that is flavoured. Results Multivariate analyses indicate that youth, young adults, females, blacks, cigarette smokers, blunt users and daily cigar smokers are significantly more likely to report a usual cigar brand that is flavoured. Preference for a usual brand that produces flavoured cigars decreases significantly with age. Conclusions This study finds recent growth in flavoured cigar consumption and preference among youth and young adults for cigar brands that are flavoured. These findings underscore the need to expand monitoring of product attributes as well as individual-level cigar use behaviours captured through population surveillance. C1 [Delnevo, Cristine D.; Giovenco, Daniel P.] Rutgers Sch Publ Hlth, Ctr Tobacco Surveillance & Evaluat Res, New Brunswick, NJ 08854 USA. [Ambrose, Bridget K.; Corey, Catherine G.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, Rockville, MD USA. RP Delnevo, CD (reprint author), Rutgers Sch Publ Hlth, Ctr Tobacco Surveillance & Evaluat Res, New Brunswick, NJ 08854 USA. OI Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C] FX This project has been funded in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under contract no. HHSN271201100027C. NR 39 TC 37 Z9 37 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD JUL PY 2015 VL 24 IS 4 BP 389 EP 394 DI 10.1136/tobaccocontrol-2013-051408 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL0BS UT WOS:000356604100019 PM 24721967 ER PT J AU Zhang, JW Ferre-D'Amare, AR AF Zhang, Jinwei Ferre-D'Amare, Adrian R. TI Structure and mechanism oftheT-box riboswitches SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review ID AMINOACYL-TRANSFER-RNAS; MEDIATED TRANSCRIPTION ANTITERMINATION; PHENYLALANINE TRANSFER-RNA; BACTERIAL GENE-EXPRESSION; BACILLUS-SUBTILIS; MESSENGER-RNA; SMALL MOLECULES; LEADER RNA; IN-VITRO; CRYSTAL-STRUCTURE AB In most Gram-positive bacteria, including many clinically devastating pathogens from genera such as Bacillus, Clostridium, Listeria, and Staphylococcus, T-box riboswitches sense and regulate intracellular availability of amino acids through a multipartite messenger RNA (mRNA)-transfer RNA (tRNA) interaction. The T-box mRNA leaders respond to nutrient starvation by specifically binding cognate tRNAs and sensing whether the bound tRNA is aminoacylated, as a proxy for amino acid availability. Based on this readout, T-boxes direct a transcriptional or translational switch to control the expression of downstream genes involved in various aspects of amino acid metabolism: biosynthesis, transport, aminoacylation, transamidation, and so forth. Two decades after its discovery, the structural and mechanistic underpinnings of the T-box riboswitch were recently elucidated, producing a wealth of insights into how two structured RNAs can recognize each other with robust affinity and exquisite selectivity. The T-box paradigm exemplifies how natural noncoding RNAs can interact not just through sequence complementarity but can add molecular specificity by precisely juxtaposing RNA structural motifs, exploiting inherently flexible elements and the biophysical properties of post-transcriptional modifications, ultimately achieving a high degree of shape complementarity through mutually induced fit. The T-box also provides a proof-of-principle that compact RNA domains can recognize minute chemical changes (such as tRNA aminoacylation) on another RNA. The unveiling of the structure and mechanism of the T-box system thus expands our appreciation of the range of capabilities and modes of action of structured noncoding RNAs, and hints at the existence of networks of noncoding RNAs that communicate through both, structural and sequence specificity. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Intramural NIH HHS [ZIA HL006102-03] NR 76 TC 2 Z9 3 U1 4 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-7004 EI 1757-7012 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD JUL-AUG PY 2015 VL 6 IS 4 BP 419 EP 433 DI 10.1002/wrna.1285 PG 15 WC Cell Biology SC Cell Biology GA CL0ET UT WOS:000356613200005 PM 25959893 ER PT J AU Chen, YW Fiscella, KA Bacharach, SZ Tanda, G Shaham, Y Calu, DJ AF Chen, Yu-Wei Fiscella, Kimberly A. Bacharach, Samuel Z. Tanda, Gianluigi Shaham, Yavin Calu, Donna J. TI Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history SO ADDICTION BIOLOGY LA English DT Article DE Conditioned place preference; aversion; dopamine; reinstatement; stress; sensory seeking; yohimbine ID STRESS-INDUCED REINSTATEMENT; CORTICOTROPIN-RELEASING-FACTOR; ANXIOGENIC DRUG YOHIMBINE; COCAINE-SEEKING BEHAVIOR; MEDIAL PREFRONTAL CORTEX; CONDITIONED PLACE PREFERENCE; ALCOHOL-SEEKING; HEROIN-SEEKING; INDUCED RELAPSE; NORADRENERGIC MECHANISMS AB Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here, we addressed two fundamental questions regarding yohimbine's effect on reinstatement of reward seeking: (1) whether the drug's effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine's effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine's effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine. C1 [Chen, Yu-Wei; Fiscella, Kimberly A.; Bacharach, Samuel Z.; Shaham, Yavin; Calu, Donna J.] NIDA, Behav Neurosci Res Branch, Biomed Res Ctr, NIH,DHHS, Baltimore, MD 21224 USA. [Tanda, Gianluigi] NIDA, Medicat Dev Program, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Calu, DJ (reprint author), NIDA, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM donna.calu@nih.gov RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Calu, Donna/0000-0003-2377-9494 FU National Institute on Drug Abuse FX We would like to acknowledge Mark Coggiano for his technical assistance with the microdialysis experiments. The work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 80 TC 6 Z9 6 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2015 VL 20 IS 4 BP 690 EP 700 DI 10.1111/adb.12164 PG 11 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA CK1TG UT WOS:000355989600006 PM 25065697 ER PT J AU Kwako, LE Schwandt, ML Sells, JR Ramchandani, VA Hommer, DW George, DT Sinha, R Heilig, M AF Kwako, Laura E. Schwandt, Melanie L. Sells, Joanna R. Ramchandani, Vijay A. Hommer, Daniel W. George, David T. Sinha, Rajita Heilig, Markus TI Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes SO ADDICTION BIOLOGY LA English DT Article DE Alcoholism; craving; cortisol; neuroendocrine; PTSD; stress ID CORTICOTROPIN-RELEASING-FACTOR; CORTISOL RESPONSE; CUE REACTIVITY; PRESSOR TASK; HPA AXIS; RELAPSE; ADDICTION; DRINKING; ABUSE; PTSD AB Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving. C1 [Kwako, Laura E.; Schwandt, Melanie L.; Sells, Joanna R.; Ramchandani, Vijay A.; Hommer, Daniel W.; George, David T.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Sinha, Rajita] Yale Univ, Sch Med, Dept Psychiat, Yale Stress Ctr, New Haven, CT USA. RP Kwako, LE (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,1-5330, Bethesda, MD 20892 USA. EM laura.kwako@nih.gov RI Schwandt, Melanie/L-9866-2016; OI Heilig, Markus/0000-0003-2706-2482 FU Division of Intramural Clinical and Biological Research, NIAAA FX This study was funded by the Division of Intramural Clinical and Biological Research, NIAAA. Thanks to Lauren Adams, Jessica Berman, Eric Markey, Victoria Brown, Keva Garg, and Byung Joon Park; Kristie Diamond, Debra Hill, Cheryl Jones, Monte Philips, and Erick Singley; and James Paterson, Judie Jones, Mary Ley, Jacqueline Goodson, and the 1SE Nursing Staff of the NIH Clinical Center. NR 48 TC 5 Z9 5 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2015 VL 20 IS 4 BP 733 EP 746 DI 10.1111/adb.12150 PG 14 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA CK1TG UT WOS:000355989600010 PM 24806358 ER PT J AU Evans, JD Juliano-Bult, D Lee, SY AF Evans, Jovier D. Juliano-Bult, Denise Lee, Su Yeon TI Health Disparities Research in Geriatric Mental Health: Commentary from the National Institute of Mental Health SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Editorial Material C1 [Evans, Jovier D.] NIMH, Div Translat Res, Rockville, MD 20852 USA. [Juliano-Bult, Denise] NIMH, Div Serv & Intervent Res, Rockville, MD 20852 USA. [Lee, Su Yeon] NIMH, Off Res Dispar & Global Mental Hlth, Rockville, MD 20852 USA. RP Evans, JD (reprint author), NIMH, Div Translat Res, 6001 Execut Blvd,MSC 9634,Room 7217, Rockville, MD 20852 USA. EM Jevans1@mail.nih.gov NR 14 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2015 VL 23 IS 7 BP 655 EP 657 DI 10.1016/j.jagp.2015.01.006 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA CK0WN UT WOS:000355926200001 PM 26055317 ER PT J AU Almli, LM Stevens, JS Smith, AK Kilaru, V Meng, Q Flory, J Abu-Amara, D Hammamieh, R Yang, RT Mercer, KB Binder, EB Bradley, B Hamilton, S Jett, M Yehuda, R Marmar, CR Ressler, KJ AF Almli, Lynn M. Stevens, Jennifer S. Smith, Alicia K. Kilaru, Varun Meng, Qian Flory, Janine Abu-Amara, Duna Hammamieh, Rasha Yang, Ruoting Mercer, Kristina B. Binder, Elizabeth B. Bradley, Bekh Hamilton, Steven Jett, Marti Yehuda, Rachel Marmar, Charles R. Ressler, Kerry J. TI A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE GWAS; PTSD; fMRI; meQTL; epigenetic ID POSTTRAUMATIC-STRESS-DISORDER; DNA METHYLATION; ASSOCIATION; SYMPTOMS; AMYGDALA; POLYMORPHISM; POPULATION; EXPRESSION; INVENTORY; RECEPTOR AB Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N=147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N=147, =31.34, P=1.28x10(-8)) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N=2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N=2006, P=0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N=157, P=0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N=53, P<0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder. (c) 2015 Wiley Periodicals, Inc. C1 [Almli, Lynn M.; Stevens, Jennifer S.; Smith, Alicia K.; Kilaru, Varun; Mercer, Kristina B.; Binder, Elizabeth B.; Bradley, Bekh; Ressler, Kerry J.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Meng, Qian] Univ Med Ctr, Dept Psychiat, New York, NY USA. [Flory, Janine; Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Mental Hlth Care Ctr, Bronx, NY USA. [Flory, Janine; Yehuda, Rachel] Traumat Stress Studies Div, New York, NY USA. [Abu-Amara, Duna; Marmar, Charles R.] NYU, Dept Psychiat, Steven & Alexandra Cohen Vet Ctr Posttraumat Stre, New York, NY 10016 USA. [Hammamieh, Rasha; Jett, Marti] US Army Ctr Environm Hlth Res, Integrat Syst Biol, Ft Detrick, MD USA. [Yang, Ruoting] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Binder, Elizabeth B.] Max Planck Inst Psychiat, Dept Translat Res Psychiat, D-80804 Munich, Germany. [Bradley, Bekh] Dept Vet Affairs Med Ctr, Mental Hlth Serv Line, Atlanta, GA USA. [Hamilton, Steven] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Ressler, Kerry J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Ressler, KJ (reprint author), Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. EM kressle@emory.edu FU National Institutes of Mental Health [MH071537, MH096764]; Department of Defense [W81XWH-09-2-0044, W911NF-09-1-0298]; Emory and Grady Memorial Hospital General Clinical Research Center; NIH National Centers for Research Resources [M01RR00039]; Howard Hughes Medical Institute; Steven and Alexandra Cohen Foundation; National Center for Advancing Translational Sciences [UL1TR000067] FX Grant sponsor: National Institutes of Mental Health; Grant numbers: MH071537, MH096764; Grant sponsor: Department of Defense; Grant numbers: W81XWH-09-2-0044, W911NF-09-1-0298; Grant sponsor: Emory and Grady Memorial Hospital General Clinical Research Center; Grant sponsor: NIH National Centers for Research Resources; Grant number: M01RR00039; Grant sponsor: Howard Hughes Medical Institute; Grant sponsor: Steven and Alexandra Cohen Foundation; Grant sponsor: National Center for Advancing Translational Sciences; Grant number: #UL1TR000067. NR 43 TC 12 Z9 12 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL PY 2015 VL 168 IS 5 BP 327 EP 336 DI 10.1002/ajmg.b.32315 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA CK2XW UT WOS:000356079700002 PM 25988933 ER PT J AU Trampush, JW Lencz, T Knowles, E Davies, G Guha, S Pe'er, I Liewald, DC Starr, JM Djurovic, S Melle, I Sundet, K Christoforou, A Reinvang, I Mukherjee, S DeRosse, P Lundervold, A Steen, VM John, M Espeseth, T Raikkonen, K Widen, E Palotie, A Eriksson, JG Giegling, I Konte, B Ikeda, M Roussos, P Giakoumaki, S Burdick, KE Payton, A Ollier, W Horan, M Scult, M Dickinson, D Straub, RE Donohoe, G Morris, D Corvin, A Gill, M Hariri, A Weinberger, DR Pendleton, N Iwata, N Darvasi, A Bitsios, P Rujescu, D Lahti, J Le Hellard, S Keller, MC Andreassen, OA Deary, IJ Glahn, DC Malhotra, AK AF Trampush, Joey W. Lencz, Todd Knowles, Emma Davies, Gail Guha, Saurav Pe'er, Itsik Liewald, David C. Starr, John M. Djurovic, Srdjan Melle, Ingrid Sundet, Kjetil Christoforou, Andrea Reinvang, Ivar Mukherjee, Semanti DeRosse, Pamela Lundervold, Astri Steen, Vidar M. John, Majnu Espeseth, Thomas Raikkonen, Katri Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Giegling, Ina Konte, Bettina Ikeda, Masashi Roussos, Panos Giakoumaki, Stella Burdick, Katherine E. Payton, Antony Ollier, William Horan, Mike Scult, Matthew Dickinson, Dwight Straub, Richard E. Donohoe, Gary Morris, Derek Corvin, Aiden Gill, Michael Hariri, Ahmad Weinberger, Daniel R. Pendleton, Neil Iwata, Nakao Darvasi, Ariel Bitsios, Panos Rujescu, Dan Lahti, Jari Le Hellard, Stephanie Keller, Matthew C. Andreassen, Ole A. Deary, Ian J. Glahn, David C. Malhotra, Anil K. TI Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE neurocognition; general cognitive ability; educational attainment; genetics; GWAS; proxy phenotype ID GENOME-WIDE-ASSOCIATION; HUMAN INTELLIGENCE; VARIANTS; HEIGHT; RISK; METAANALYSIS; PERFORMANCE; POPULATION; CHILDHOOD; ADULT AB Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability (g) in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P=1.47x10(-4)) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P=4.94x10(-7)), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P=1.65x10(-9)). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness. (c) 2015 Wiley Periodicals, Inc. C1 [Trampush, Joey W.; Lencz, Todd; Guha, Saurav; Mukherjee, Semanti; DeRosse, Pamela; John, Majnu; Malhotra, Anil K.] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA. [Trampush, Joey W.; Lencz, Todd; Mukherjee, Semanti; DeRosse, Pamela; John, Majnu; Malhotra, Anil K.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Trampush, Joey W.; Lencz, Todd; Malhotra, Anil K.] Hofstra North Shore LIJ Sch Med, Dept Psychiat, Hempstead, NY USA. [Knowles, Emma; Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Davies, Gail; Liewald, David C.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Pe'er, Itsik] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Andreassen, Ole A.] NorMent, KG Jebsen Ctr, Oslo, Norway. [Djurovic, Srdjan; Melle, Ingrid; Andreassen, Ole A.] Oslo Univ Hosp, Oslo, Norway. [Melle, Ingrid; Sundet, Kjetil; Andreassen, Ole A.] Univ Oslo, Oslo, Norway. [Christoforou, Andrea; Steen, Vidar M.; Le Hellard, Stephanie] Univ Bergen, Dept Clin Med, Dr Einar Martens Res Grp Biol Psychiat, KG Jebsen Ctr Psychosis Res, Bergen, Norway. [Christoforou, Andrea; Steen, Vidar M.; Le Hellard, Stephanie] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Reinvang, Ivar; Espeseth, Thomas] Univ Oslo, Dept Psychol, Oslo, Norway. [Lundervold, Astri] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, Bergen, Norway. [Lundervold, Astri] Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway. [Lundervold, Astri] Haraldsplass Deaconess Hosp, Kavli Res Ctr Aging & Dementia, Bergen, Norway. [Espeseth, Thomas] Oslo Univ Hosp, Div Mental Hlth & Addict, KG Jebsen Ctr Psychosis Res, Oslo, Norway. [Raikkonen, Katri; Lahti, Jari] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Widen, Elisabeth; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, Aarno] Univ Cent Hosp, Helsinki, Finland. [Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Giegling, Ina; Konte, Bettina; Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Ikeda, Masashi; Iwata, Nakao] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 47011, Japan. [Roussos, Panos; Burdick, Katherine E.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Giakoumaki, Stella] Univ Crete, Dept Psychol, Sch Social Sci, Iraklion, Greece. [Payton, Antony; Ollier, William] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England. [Horan, Mike] Univ Manchester, Sch Community Based Med, Neurodegenerat Res Grp, Manchester, Lancs, England. [Scult, Matthew; Hariri, Ahmad] Duke Univ, Dept Psychol & Neurosci, Neurogenet Lab, Durham, NC USA. [Dickinson, Dwight; Straub, Richard E.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Brain & Genes Cognit & Psych, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Straub, Richard E.; Weinberger, Daniel R.] Johns Hopkins Univ Med Campus, Lieber Inst Brain Dev, Baltimore, MD USA. [Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael] Trinity Coll Dublin, Trinity Coll Inst Neurosci, Dublin, Ireland. [Pendleton, Neil] Univ Manchester, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England. [Darvasi, Ariel] Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel. [Bitsios, Panos] Univ Crete, Fac Med, Dept Psychiat & Behav Sci, Iraklion, Crete, Greece. [Lahti, Jari] Folkhalsan Res Ctr, Inst Genet, Helsinki, Finland. [Keller, Matthew C.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. RP Trampush, JW (reprint author), Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM jtrampush@nshs.edu RI Melle, Ingrid /B-4858-2011; Roussos, Panos/J-7090-2013; Lencz, Todd/J-3418-2014; OI Melle, Ingrid /0000-0002-9783-548X; Donohoe, Gary/0000-0003-3037-7426; Roussos, Panos/0000-0002-4640-6239; Lencz, Todd/0000-0001-8586-338X; Eriksson, Johan/0000-0002-2516-2060; Sundet, Kjetil/0000-0003-2850-3673; Scult, Matthew/0000-0001-5554-8186; Corvin, Aiden/0000-0001-6717-4089; Gill, Michael/0000-0003-0206-5337; Pendleton, Neil/0000-0003-0794-2386; Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470; Payton, Antony/0000-0003-0335-152X FU National Institutes of Health [R01 MH079800, P50 MH080173, RC2 MH089964, R01 MH080912, K23 MH077807, K01 MH085812]; Health Research Board (Ireland); Science Foundation Ireland; Research Council of Norway [154313/V50, 177458/V50]; Bergen Research Foundation; University of Bergen; Research Council of Norway (FUGE, Psykisk Helse); Helse Vest RHF; Dr. Einar Martens Fund; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; UK Biotechnology and Biological Sciences Research Council (BBSRC); BBSRC; Medical Research Council (MRC); NSF Graduate Research Fellowship; NIDA [R01DA031579, R01DA033369]; NIH/NIMH Intramural Research Program; Lieber Institute for Brain Development; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research FX This work has been supported by grants from the National Institutes of Health (R01 MH079800 and P50 MH080173 to AKM; RC2 MH089964 to TL; R01 MH080912 to DCG; K23 MH077807 to KEB; K01 MH085812 to MCK). Dr. Donohoe is generously funded by the Health Research Board (Ireland) and Science Foundation Ireland. Data collection for the TOP cohort was supported by the Research Council of Norway, South-East Norway Health Authority. The NCNG study was supported by Research Council of Norway Grants 154313/V50 and 177458/V50. The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE, Psykisk Helse), Helse Vest RHF and Dr. Einar Martens Fund. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. For the LBC1936 cohort we thank the cohort participants and team members who contributed to this study. Phenotype collection was supported by Age UK (The Disconnected Mind project). Genotyping was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative(MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. The Duke Neurogenetic Study was supported by an NSF Graduate Research Fellowship to MS, Duke University, and NIDA grants R01DA031579 & R01DA033369. The NIMH Genes, Cognition and Psychosis Study was funded by the NIH/NIMH Intramural Research Program and the Lieber Institute for Brain Development. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California.; Finally, several publicly available datasets were included; we kindly thank the investigative teams and staffs of the Pediatric Imaging, Neurocognition, and Genetics (PING) study, the Alzheimer's Disease Neuroimaging Initiative (ADNI) project, and the studies who made their data available in dbGaP. NR 42 TC 8 Z9 8 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL PY 2015 VL 168 IS 5 BP 363 EP 373 DI 10.1002/ajmg.b.32319 PG 11 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA CK2XW UT WOS:000356079700006 PM 25951819 ER PT J AU Sloan, A Gona, P Johnson, AD AF Sloan, Arielle Gona, Philimon Johnson, Andrew D. TI Cardiovascular correlates of platelet count and volume in the Framingham Heart Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Platelets; Cholesterol; Cardiovascular diseases; Smoking; Platelet count; Platelet volume ID WHITE BLOOD-CELL; BODY-MASS INDEX; CIGARETTE-SMOKING; METABOLIC SYNDROME; MOLI-SANI; POPULATION; PARAMETERS; WOMEN; RISK; AGE AB Purpose: Platelet count and volume are inexpensive, routinely assayed biomarkers associated with cardiovascular health, but specific relationships among platelet indices, cardiovascular risk factors, and disease warrant further investigation. The purpose of this study was to understand associations among platelet count volume, and 20 cardiovascular health related variables in the Framingham Heart Study (FHS). Methods: Cross-sectional analyses were performed on platelet count and volume associations with cardiovascular health indicators in three FHS cohorts (original n = 964, offspring n = 2699, and third generation n = 2419) using multivariate linear regression analysis. Time-to-event analysis was used for cardiovascular disease related event incidences using Kaplan-Meier plots and Cox proportional hazards regression adjusted for age and sex. Results: Results were concordant with the hypothesis that higher platelet counts are associated with less favorable cardiovascular risk profiles, although mean platelet volume associations were weaker. In our analysis, increased platelet count across FHS cohorts was consistently associated with smoking, triglycerides, low-density lipoprotein, and total cholesterol levels. Some associations with platelet count appeared sex dependent. Conclusions: Significant associations of common blood platelet measurements are observed with sex and cardiovascular risk factors, namely smoking and lipids. Research is warranted to confirm these relationships in other cohorts, evaluate differences by ethnicity, and examine longitudinal effects on disease risk. Published by Elsevier Inc. C1 [Sloan, Arielle; Gona, Philimon; Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, NIH, Framingham, MA USA. [Sloan, Arielle] Brigham Young Univ, Dept Hlth Sci, Provo, UT 84602 USA. [Gona, Philimon] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Johnson, AD (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU NIH under National Heart, Lung, and Blood Institute Division of Intramural Research; National Heart, Lung, and Blood Institute [R01-HL-48157] FX Financial support for this research was provided by the NIH under the National Heart, Lung, and Blood Institute Division of Intramural Research. The collection of phenotype data was supported by the National Heart, Lung, and Blood Institute Framingham Heart Study (N01-HC-25195). Collection of PRPPC was supported by National Heart, Lung, and Blood Institute R01-HL-48157. NR 44 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUL PY 2015 VL 25 IS 7 BP 492 EP 498 DI 10.1016/j.annepidem.2015.01.010 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CJ8SG UT WOS:000355773200005 PM 25771288 ER PT J AU Kobayashi, K Hashimoto, M Honkakoski, P Negishi, M AF Kobayashi, Kaoru Hashimoto, Mari Honkakoski, Paavo Negishi, Masahiko TI Regulation of gene expression by CAR: an update SO ARCHIVES OF TOXICOLOGY LA English DT Review DE Constitutive androstane receptor; Cytochrome P450; Drug metabolism; Epidermal growth factor receptor; Liver injury; Glucose metabolism ID CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE-X-RECEPTOR; ORPHAN NUCLEAR RECEPTOR; RESPONSIVE ENHANCER MODULE; MOUSE PRIMARY HEPATOCYTES; INDUCED LIVER-INJURY; ACTIVE/ANDROSTANE RECEPTOR; GLUCOCORTICOID-RECEPTOR; CYP2B6 GENE; GAMMA COACTIVATOR-1-ALPHA AB The constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, is a well-known xenosensor that regulates hepatic drug metabolism and detoxification. CAR activation can be elicited by a large variety of xenobiotics, including phenobarbital (PB) which is not a directly binding CAR ligand. The mechanism of CAR activation is complex and involves translocation from the cytoplasm into the nucleus, followed by further activation steps in the nucleus. Recently, epidermal growth factor receptor (EGFR) has been identified as a PB-responsive receptor, and PB activates CAR by inhibiting the EGFR signaling. In addition to regulation of drug metabolism, activation of CAR has multiple biological end points such as modulation of xenobiotic-elicited liver injury, and the role of CAR in endobiotic functions such as glucose metabolism and cholesterol homeostasis is increasingly recognized. Thus, investigations on the molecular mechanism of CAR activation are critical for the real understanding of CAR-mediated processes. Here, we summarize the current understanding of mechanisms by which CAR activators regulate gene expression through cellular signaling pathways and the roles of CAR on xenobiotic-elicited hepatocellular carcinoma, liver injury, glucose metabolism and cholesterol homeostasis. C1 [Kobayashi, Kaoru; Hashimoto, Mari] Chiba Univ, Grad Sch Pharmaceut Sci, Lab Pharmacol & Toxicol, Chiba, Japan. [Honkakoski, Paavo; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Honkakoski, Paavo] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio, Finland. RP Kobayashi, K (reprint author), Chiba Univ, Grad Sch Pharmaceut Sci, Lab Pharmacol & Toxicol, Chiba, Japan. EM kaoruk@faculty.chiba-u.jp NR 101 TC 8 Z9 8 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD JUL PY 2015 VL 89 IS 7 BP 1045 EP 1055 DI 10.1007/s00204-015-1522-9 PG 11 WC Toxicology SC Toxicology GA CK3EQ UT WOS:000356099800005 PM 25975989 ER PT J AU Radoshitzky, SR Bao, YM Buchmeier, MJ Charrel, RN Clawson, AN Clegg, CS DeRisi, JL Emonet, S Gonzalez, JP Kuhn, JH Lukashevich, IS Peters, CJ Romanowski, V Salvato, MS Stenglein, MD de la Torre, JC AF Radoshitzky, Sheli R. Bao, Yimng Buchmeier, Michael J. Charrel, Remi N. Clawson, Anna N. Clegg, Christopher S. DeRisi, Joseph L. Emonet, Sebastien Gonzalez, Jean-Paul Kuhn, Jens H. Lukashevich, Igor S. Peters, Clarence J. Romanowski, Victor Salvato, Maria S. Stenglein, Mark D. de la Torre, Juan Carlos TI Past, present, and future of arenavirus taxonomy SO ARCHIVES OF VIROLOGY LA English DT Article DE Arenavirid; Arenaviridae; Arenavirus; Bat virus; Bibdavirus; ICTV; Inclusion body disease; International Committee on Taxonomy of Viruses; Mammarenavirus; PASC; Reptarenavirus; Rodent virus; Snake virus; TaxoProp; Viral hemorrhagic fever; Virus classification; Virus nomenclature; Virus taxonomy ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; FINGER-Z-PROTEIN; OLD-WORLD ARENAVIRUSES; INCLUSION-BODY DISEASE; VIRAL-RNA SYNTHESIS; LASSA-VIRUS; PICHINDE VIRUS; WEST-AFRICA; PHYLOGENETIC ANALYSIS; FAMILY-ARENAVIRIDAE AB Until recently, members of the monogeneric family Arenaviridae (arenaviruses) have been known to infect only muroid rodents and, in one case, possibly phyllostomid bats. The paradigm of arenaviruses exclusively infecting small mammals shifted dramatically when several groups independently published the detection and isolation of a divergent group of arenaviruses in captive alethinophidian snakes. Preliminary phylogenetic analyses suggest that these reptilian arenaviruses constitute a sister clade to mammalian arenaviruses. Here, the members of the International Committee on Taxonomy of Viruses (ICTV) Arenaviridae Study Group, together with other experts, outline the taxonomic reorganization of the family Arenaviridae to accommodate reptilian arenaviruses and other recently discovered mammalian arenaviruses and to improve compliance with the Rules of the International Code of Virus Classification and Nomenclature (ICVCN). PAirwise Sequence Comparison (PASC) of arenavirus genomes and NP amino acid pairwise distances support the modification of the present classification. As a result, the current genus Arenavirus is replaced by two genera, Mammarenavirus and Reptarenavirus, which are established to accommodate mammalian and reptilian arenaviruses, respectively, in the same family. The current species landscape among mammalian arenaviruses is upheld, with two new species added for Lunk and Merino Walk viruses and minor corrections to the spelling of some names. The published snake arenaviruses are distributed among three new separate reptarenavirus species. Finally, a non-Latinized binomial species name scheme is adopted for all arenavirus species. In addition, the current virus abbreviations have been evaluated, and some changes are introduced to unequivocally identify each virus in electronic databases, manuscripts, and oral proceedings. C1 [Radoshitzky, Sheli R.] US Army Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Bao, Yimng] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Buchmeier, Michael J.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA. [Charrel, Remi N.] Aix Marseille Univ, Emergence Pathol Virales EPV UMR D 190, IRD, French Inst Res Dev,EHESP,French Sch Publ Hlth, F-13385 Marseille, France. [Clawson, Anna N.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [DeRisi, Joseph L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [DeRisi, Joseph L.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [DeRisi, Joseph L.] Univ Calif San Francisco, Dept Microbiol, San Francisco, CA 94143 USA. [Emonet, Sebastien] Echelon Rech Lyon, IRBA, Unite Virol, Lyon, France. [Gonzalez, Jean-Paul] Metabiota Inc, Emerging Dis & Biosecur, Washington, DC USA. [Lukashevich, Igor S.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Ctr Predict Med Biodef & Emerging Infect Dis, Louisville, KY 40292 USA. [Peters, Clarence J.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Romanowski, Victor] CONICET UNLP, CCT La Plata, Inst Biotecnol & Biol Mol, La Plata, Buenos Aires, Argentina. [Salvato, Maria S.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Stenglein, Mark D.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [de la Torre, Juan Carlos] Scripps Res Inst, Dept Immunol & Microbial Sci IMM 6, La Jolla, CA 92037 USA. [Charrel, Remi N.] Hosp Marseille, IHU Mediterranee Infect, APHM Publ Hosp Marseille, F-13385 Marseille, France. RP Radoshitzky, SR (reprint author), US Army Med Res Inst Infect Dis, 1425 Porter St, Frederick, MD 21702 USA. EM sheli.r.radoshitzky.ctr@mail.mil; juanct@scripps.edu RI Stenglein, Mark/E-3541-2017 OI Stenglein, Mark/0000-0002-0993-813X FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [HHSN272200700016I]; National Institutes of Health, National Library of Medicine FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the US Department of the Army, the US Department of Defense or of the institutions and companies affiliated with the authors. JHK performed this work as an employee of Tunnell Government Services, Inc., and ANC as the owner of Logos Consulting, Inc., both subcontractors to Battelle Memorial Institute under its prime contract with the National Institutes of Health/National Institute of Allergy and Infectious Diseases, under Contract No. HHSN272200700016I. YB's contribution was also supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 144 TC 21 Z9 21 U1 2 U2 20 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD JUL PY 2015 VL 160 IS 7 BP 1851 EP 1874 DI 10.1007/s00705-015-2418-y PG 24 WC Virology SC Virology GA CK3FA UT WOS:000356100800030 PM 25935216 ER PT J AU Zarate, CA Machado-Vieira, R AF Zarate, Carlos A., Jr. Machado-Vieira, Rodrigo TI Potential Pathways Involved in the Rapid Antidepressant Effects of Nitrous Oxide SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DISORDER; LITHIUM C1 [Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Intramural Res Program, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), 10 Ctr Dr,CRC,Unit 7 Southeast,Room 7-5342, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural NIH HHS [, ZIA MH002927-07] NR 10 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2015 VL 78 IS 1 BP 2 EP 4 DI 10.1016/j.biopsych.2015.04.007 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CK0WA UT WOS:000355924800003 PM 26051637 ER PT J AU Ogino, S Campbell, PT Nishihara, R Phipps, AI Beck, AH Sherman, ME Chan, AT Troester, MA Bass, AJ Fitzgerald, KC Irizarry, RA Kelsey, KT Nan, H Peters, U Poole, EM Qian, ZR Tamimi, RM Tchetgen, EJT Tworoger, SS Zhang, XH Giovannucci, EL van den Brandt, PA Rosner, BA Wang, ML Chatterjee, N Begg, CB AF Ogino, Shuji Campbell, Peter T. Nishihara, Reiko Phipps, Amanda I. Beck, Andrew H. Sherman, Mark E. Chan, Andrew T. Troester, Melissa A. Bass, Adam J. Fitzgerald, Kathryn C. Irizarry, Rafael A. Kelsey, Karl T. Nan, Hongmei Peters, Ulrike Poole, Elizabeth M. Qian, Zhi Rong Tamimi, Rulla M. Tchetgen, Eric J. Tchetgen Tworoger, Shelley S. Zhang, Xuehong Giovannucci, Edward L. van den Brandt, Piet A. Rosner, Bernard A. Wang, Molin Chatterjee, Nilanjan Begg, Colin B. TI Proceedings of the second international molecular pathological epidemiology (MPE) meeting SO CANCER CAUSES & CONTROL LA English DT Review DE Epidemiologic method; Molecular pathologic epidemiology; Personalized medicine; Systems biology; Translational epidemiology; Unique disease principle ID ISLAND METHYLATOR PHENOTYPE; COLORECTAL-CANCER RISK; LIFE-STYLE FACTORS; MICROSATELLITE INSTABILITY STATUS; DISEASE CLASSIFICATION DATA; EPITHELIAL OVARIAN-CANCER; UNIQUE TUMOR PRINCIPLE; BODY-MASS INDEX; BREAST-CANCER; FAMILY-HISTORY AB Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the Big Data to Knowledge, Genetic Associations and Mechanisms in Oncology, and Precision Medicine Initiative of the US National Institute of Health. The MPE meeting series can help advance transdisciplinary population science and optimize training and education systems for twenty-first century medicine and public health. C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Ogino, Shuji; Nishihara, Reiko; Bass, Adam J.; Qian, Zhi Rong] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02215 USA. [Ogino, Shuji; Nishihara, Reiko; Fitzgerald, Kathryn C.; Tamimi, Rulla M.; Tchetgen, Eric J. Tchetgen; Tworoger, Shelley S.; Giovannucci, Edward L.; Wang, Molin] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Nishihara, Reiko; Irizarry, Rafael A.; Tchetgen, Eric J. Tchetgen; Rosner, Bernard A.; Wang, Molin] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Nishihara, Reiko; Fitzgerald, Kathryn C.; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Phipps, Amanda I.; Peters, Ulrike] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Phipps, Amanda I.; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Beck, Andrew H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Beck, Andrew H.; Bass, Adam J.] Broad Inst, Cambridge, MA USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Sherman, Mark E.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Poole, Elizabeth M.; Tamimi, Rulla M.; Tworoger, Shelley S.; Zhang, Xuehong; Giovannucci, Edward L.; Rosner, Bernard A.; Wang, Molin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02215 USA. [Troester, Melissa A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Irizarry, Rafael A.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Kelsey, Karl T.] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. [Nan, Hongmei] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [van den Brandt, Piet A.] Maastricht Univ, Dept Epidemiol, NL-6200 MD Maastricht, Netherlands. [Begg, Colin B.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU US National Institute of Health (NIH) [R01 CA151993, K07 CA190673, R01 CA137178, K24 DK098311, K07 CA172298]; Dana-Farber Cancer Institute FX We thank all of the members of the program committee, the speakers, the discussants, and the other participants of the Second International MPE Meeting on December 4-5, 2014 in Boston, MA, USA. We thank the Dana-Farber Cancer Institute (Edward J. Benz, Jr., President and CEO) for providing the meeting venue and the Department of Pathology, the Brigham and Women's Hospital (Jeffrey A. Golden, Chairperson), and Enzymatics, Inc., for providing meals and refreshments, respectively. We also thank the Department of Pathology, the Brigham and Women's Hospital (Jeffrey A. Golden, Chairperson); the Department of Epidemiology, the Harvard T.H. Chan School of Public Health (Michelle A. Williams, Chairperson); the Dana-Farber Harvard Cancer Center (Giovanni Parmigiani, Meir J. Stampfer, Lorelei A. Mucci, Deborah Schrag, and Charles S. Fuchs; Program Leaders); and the Channing Division of Network Medicine, the Department of Medicine, the Brigham and Women's Hospital (Edwin K. Silverman, Division Chief) for providing morale supports and helping in announcements. This work was supported in part by grants from the US National Institute of Health (NIH) [R01 CA151993 (to SO), K07 CA190673 (to RN), R01 CA137178 (to ATC), K24 DK098311 (to ATC), and K07 CA172298 (to AIP)], and the friends of the Dana-Farber Cancer Institute (to SO). ATC is Damon Runyon Clinical Investigator. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders (including Enzymatics, Inc.) did not have any role in planning the meeting, the decision to submit the manuscript for publication, or the writing of the manuscript. Use of Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC)-approved symbols for genes and gene products: We use symbols approved by HGNC and described at www.genenames.org; those include BRAF, CD274, ERBB2, ESR1, FASN, KRAS, MLH1, PDCD1LG2, PGR, PIK3CA, and VHL. Gene names are italicized, while names of gene products are non-italicized. Non-official names are described in parenthesis where helpful. NR 148 TC 18 Z9 18 U1 9 U2 27 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUL PY 2015 VL 26 IS 7 BP 959 EP 972 DI 10.1007/s10552-015-0596-2 PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CK2DN UT WOS:000356020900001 PM 25956270 ER PT J AU Lin, J Zahm, SH Shriver, CD Purdue, M McGlynn, KA Zhu, KM AF Lin, Jie Zahm, Shelia H. Shriver, Craig D. Purdue, Mark McGlynn, Katherine A. Zhu, Kangmin TI Survival among Black and White patients with renal cell carcinoma in an equal-access health care system SO CANCER CAUSES & CONTROL LA English DT Article DE Renal cell carcinoma; Racial disparity; Survival; Equal access; Hazard ratio ID RACIAL DISPARITY; KIDNEY CANCER; CLINICAL CHARACTERISTICS; PROGNOSTIC-FACTORS; PROSTATE-CANCER; UNITED-STATES; COLON-CANCER; LUNG-CANCER; RACE; OUTCOMES AB Unequal access to health care may be a reason for shorter survival among Black patients with renal cell carcinoma (RCC) than among their White counterparts. No studies have investigated survival disparity among RCC patients in an equal-access health care delivery system. This study aimed to examine racial differences in survival among clear cell RCC patients in the Department of Defense's (DoD) Military Health System (MHS), which provides equal access to care to all persons. The study used the DoD's Automated Central Tumor Registry to identify 2056 White patients and 370 Black patients diagnosed with clear cell RCC between 1988 and 2004. The subjects were followed through 2007 with a median follow-up time of 4.8 years. Kaplan-Meier survival curves were compared and a Cox model was used to estimate the hazard ratios (HRs) associated with survival by race. During follow-up, 1,027 White and 158 Black patients died. The Kaplan-Meier curves showed that Black patients had more favorable overall survival than did White patients (log rank p = 0.031). After adjustment for demographic, tumor, and treatment variables, the Cox model showed no statistically significant racial difference overall (adjusted HR 1.07, 95 % CI 0.90-1.28) or stratified by age, sex or tumor stage. However, among patients who did not undergo surgery, Black patients had poorer survival than White patients. The lack of racial difference in survival among RCC patients in the MHS may be related to equal access to health care. Improved access could reduce the survival disparity among RCC patients in the general population. C1 [Lin, Jie; Shriver, Craig D.; Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, Div Mil Epidemiol & Populat Sci, John P Murtha Canc Ctr, Rockville, MD 20852 USA. [Zahm, Shelia H.; Purdue, Mark; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Gen Surg Serv, Bethesda, MD USA. [Shriver, Craig D.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Lin, J (reprint author), Walter Reed Natl Mil Med Ctr, Div Mil Epidemiol & Populat Sci, John P Murtha Canc Ctr, 11300 Rockville Pike,Suite 1120, Rockville, MD 20852 USA. EM jlin@murthacancercenter.org; kangmin.zhu@usuhs.edu FU John P. Murtha Cancer Center; Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under Henry M. Jackson Foundation for the Advancement of Military Medicine; National Cancer Institute FX This project was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine, and by the intramural research program of the National Cancer Institute. The authors thank the Joint Pathology Center (formerly Armed Forces Institute of Pathology) for providing the data. We thank Mr. Derek Brown for his input in statistical analysis. NR 30 TC 3 Z9 3 U1 5 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUL PY 2015 VL 26 IS 7 BP 1019 EP 1026 DI 10.1007/s10552-015-0594-4 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CK2DN UT WOS:000356020900006 PM 25956269 ER PT J AU Cookson, MR AF Cookson, Mark R. TI LRRK2 Pathways Leading to Neurodegeneration SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Autophagy; Genetics; Kinase activity; Mutations ID REPEAT KINASE 2; DISEASE-ASSOCIATED MUTATIONS; GENOME-WIDE ASSOCIATION; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; LEUCINE-RICH-REPEAT-KINASE-2 LRRK2; CYTOPLASMIC LOCALIZATION; DOMINANT PARKINSONISM; ENDOSOMAL TRAFFICKING; NEURONAL TOXICITY AB Mutations in LRRK2 are associated with inherited Parkinson's disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the pathophysiology of PD. C1 NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. For reasons of space, I unfortunately was not able to quote all of the primary literature and apologize to those colleagues whose work is mentioned in other reviews and not included directly here. NR 100 TC 9 Z9 9 U1 3 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD JUL PY 2015 VL 15 IS 7 AR 42 DI 10.1007/s11910-015-0564-y PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK5HC UT WOS:000356253200006 PM 26008812 ER PT J AU Pearl, PL Parviz, M Vogel, K Schreiber, J Theodore, WH Gibson, KM AF Pearl, Phillip L. Parviz, Mahsa Vogel, Kara Schreiber, John Theodore, William H. Gibson, K. Michael TI Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Review ID SEMIALDEHYDE DEHYDROGENASE-DEFICIENCY; GABA-METABOLISM; HYDROXYBUTYRIC ACID; SSADH DEFICIENCY; OXIDATIVE STRESS; HERITABLE DISORDER; CEREBRAL-CORTEX; MICE DEFICIENT; VIGABATRIN; PATIENT AB Inherited disorders of gamma-aminobutyric acid (GABA) metabolism include succinic semialdehyde dehydrogenase (SSADH) and gamma-aminobutyric acid transaminase (GABA-T) deficiencies. The clinical features, pathophysiology, diagnosis, and management of both, and an updated list of mutations in the ALDH5A1 gene, which cause SSADH deficiency, are discussed. A database of 112 individuals (71 children and adolescents, and 41 adults) indicates that developmental delay and hypotonia are the most common symptoms arising from SSADH deficiency. Furthermore, epilepsy is present in two-thirds of SSADH-deficient individuals by adulthood. Research with murine genetic models and human participants, using [C-11] flumazenil positron emission tomography (FMZ-PET) and transcranial magnetic stimulation, have led to therapeutic trials, and the identification of additional disruptions to GABA metabolism. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy, with enhanced activation of the mammalian target of rapamycin (mTOR) pathway. Details of known pathogenic mutations in the ALDH5A1 gene, three of which have not previously been reported, are summarized here. Investigations into disorders of GABA metabolism provide fundamental insights into the mechanisms underlying epilepsy, and support the importance of developing biomarkers and clinical trials. Comprehensive definition of phenotypes arising as a result of deficiencies in both SSADH and GABA-T may increase our understanding of the neurophysiological consequences of a hyper-GABAergic state. C1 [Pearl, Phillip L.; Parviz, Mahsa] Harvard Univ, Sch Med, Dept Neurol, Boston Childrens Hosp, Boston, MA 02115 USA. [Vogel, Kara; Gibson, K. Michael] Washington State Univ, Coll Pharm, Dept Expt & Syst Pharmacol, Spokane, WA USA. [Schreiber, John] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Theodore, William H.] NINDS, Clin Epilepsy Branch, NIH, Bethesda, MD 20892 USA. RP Pearl, PL (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston Childrens Hosp, Boston, MA 02115 USA. EM phillip.pearl@childrens.harvard.edu OI Parviz, Mahsa/0000-0003-1659-1119 FU NIH/NINDS [NCT02019667] FX Thank you to Shaye Moore and Elizabeth Jarvis for their technical assistance. Grant/research support was obtained from NIH/NINDS: NCT02019667 (PLP, JS, WHT, KMG). The authors have stated that they had no interests that might be perceived as posing a conflict or bias. NR 60 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD JUL PY 2015 VL 57 IS 7 BP 611 EP 617 DI 10.1111/dmcn.12668 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA CK2ZO UT WOS:000356084600009 ER PT J AU Bandini, L Danielson, M Esposito, LE Foley, JT Fox, MH Frey, GC Fleming, RK Krahn, G Must, A Porretta, DL Rodgers, AB Stanish, H Urv, T Vogel, LC Humphries, K AF Bandini, Linda Danielson, Melissa Esposito, Layla E. Foley, John T. Fox, Michael H. Frey, Georgia C. Fleming, Richard K. Krahn, Gloria Must, Aviva Porretta, David L. Rodgers, Anne Brown Stanish, Heidi Urv, Tiina Vogel, Lawrence C. Humphries, Kathleen TI Obesity in children with developmental and/or physical disabilities SO DISABILITY AND HEALTH JOURNAL LA English DT Editorial Material DE Obesity; Children; Physical disability; Developmental disability; Intellectual disability ID AUTISM SPECTRUM DISORDERS; CEREBRAL-PALSY; INTELLECTUAL DISABILITY; ENERGY-EXPENDITURE; MENTAL-RETARDATION; CHILDHOOD OBESITY; BODY-COMPOSITION; DOWN-SYNDROME; CARDIOVASCULAR FITNESS; ADOLESCENT OVERWEIGHT AB Children with developmental or physical disabilities, many of whom face serious health-related conditions, also are affected by the current obesity crisis. Although evidence indicates that children with disabilities have a higher prevalence of obesity than do children without disabilities, little is known of the actual magnitude of the problem in this population. To address this concern, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) held a conference on obesity in children with intellectual, developmental, or physical disabilities, bringing together scientists and practitioners in the fields of obesity and disability to foster collaboration, identify barriers to healthy weight status in populations with disabilities, propose avenues to solutions through research and practice, and develop a research agenda to address the problem. This article describes current knowledge about prevalence of obesity in this population, discusses factors influencing obesity risk, and summarizes recommendations for research presented at the conference. Published by Elsevier Inc. C1 [Bandini, Linda] Univ Massachusetts, Sch Med, Eunice Kennedy Shriver Ctr, Waltham, MA 02452 USA. [Bandini, Linda] Boston Univ, Dept Hlth Sci, Boston, MA 02215 USA. [Danielson, Melissa; Fox, Michael H.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Div Human Dev & Disabil, Atlanta, GA 30333 USA. [Esposito, Layla E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child Dev & Behav Branch, NIH, Rockville, MD 20892 USA. [Foley, John T.] SUNY Coll Cortland, Dept Phys Educ, Cortland, NY 13045 USA. [Frey, Georgia C.] Indiana Univ, Dept Kinesiol, Child Dev, Bloomington, IN 47405 USA. [Fleming, Richard K.; Stanish, Heidi] Univ Massachusetts, Dept Exercise & Hlth Sci, Boston, MA 02125 USA. [Krahn, Gloria] Oregon State Univ, Coll Publ Hlth & Human Sci, Barbara E Knudson Endowed Chair Family Policy, External Relat & Econ Dev, Corvallis, OR 97331 USA. [Must, Aviva] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Porretta, David L.] Ohio State Univ, Kinesiol, Columbus, OH 43210 USA. [Rodgers, Anne Brown] NICHD Consultant, Falls Church, VA 22046 USA. [Urv, Tiina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intellectual & Dev Disabil Branch, NIH, Bethesda, MD 20892 USA. [Vogel, Lawrence C.] Shriners Hosp Children, Chicago, IL 60707 USA. [Humphries, Kathleen] Univ Montana, Rural Inst Disabil, Missoula, MT 59812 USA. RP Esposito, LE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child Dev & Behav Branch, NIH, 6100 Execut Blvd, Rockville, MD 20892 USA. EM espositl@mail.nih.gov OI Danielson, Melissa/0000-0001-9461-0341 NR 70 TC 4 Z9 4 U1 3 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD JUL PY 2015 VL 8 IS 3 BP 309 EP 316 DI 10.1016/j.dhjo.2015.04.005 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA CJ8QM UT WOS:000355768600003 PM 26058685 ER PT J AU Prasad, V Oseran, A AF Prasad, Vinay Oseran, Andrew TI Do we need randomised trials for rare cancers? SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material ID CLINICAL-TRIALS; RESPONSE RATE; SURVIVAL C1 [Prasad, Vinay] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Oseran, Andrew] Georgetown Univ, Sch Med, Washington, DC 20057 USA. RP Prasad, V (reprint author), NCI, Med Oncol Serv, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 8 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2015 VL 51 IS 11 BP 1355 EP 1357 DI 10.1016/j.ejca.2015.04.015 PG 3 WC Oncology SC Oncology GA CJ8HR UT WOS:000355741300001 PM 25963018 ER PT J AU Pistis, G Porcu, E Vrieze, SI Sidore, C Steri, M Danjou, F Busonero, F Mulas, A Zoledziewska, M Maschio, A Brennan, C Lai, S Miller, MB Marcelli, M Urru, MF Pitzalis, M Lyons, RH Kang, HM Jones, CM Angius, A Iacono, WG Schlessinger, D McGue, M Cucca, F Abecasis, GR Sanna, S AF Pistis, Giorgio Porcu, Eleonora Vrieze, Scott I. Sidore, Carlo Steri, Maristella Danjou, Fabrice Busonero, Fabio Mulas, Antonella Zoledziewska, Magdalena Maschio, Andrea Brennan, Christine Lai, Sandra Miller, Michael B. Marcelli, Marco Urru, Maria Francesca Pitzalis, Maristella Lyons, Robert H. Kang, Hyun M. Jones, Chris M. Angius, Andrea Iacono, William G. Schlessinger, David McGue, Matt Cucca, Francesco Abecasis, Goncalo R. Sanna, Serena TI Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WIDE ASSOCIATION; MULTIPLE-SCLEROSIS; MINNESOTA CENTER; FAMILY RESEARCH; COVERAGE; DISEASE; POPULATION; TWIN AB The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost-effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study-specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating similar to 200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and IMPUTE-INFO metrics should be used to efficiently filter badly imputed rare variants. This study thus provides general guidelines for researchers planning large-scale genetic studies. C1 [Pistis, Giorgio; Porcu, Eleonora; Sidore, Carlo; Steri, Maristella; Danjou, Fabrice; Busonero, Fabio; Mulas, Antonella; Zoledziewska, Magdalena; Maschio, Andrea; Lai, Sandra; Pitzalis, Maristella; Angius, Andrea; Cucca, Francesco; Sanna, Serena] CNR, IRGB, Monserrato, Italy. [Pistis, Giorgio; Porcu, Eleonora; Vrieze, Scott I.; Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Kang, Hyun M.; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Pistis, Giorgio; Porcu, Eleonora; Sidore, Carlo; Mulas, Antonella; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Brennan, Christine; Lyons, Robert H.; Angius, Andrea] Univ Michigan, Sch Med, Sequencing Core, Ann Arbor, MI USA. [Miller, Michael B.; Iacono, William G.; McGue, Matt] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Marcelli, Marco; Urru, Maria Francesca; Jones, Chris M.] CRS4, Parco Tecnol Sardegna, Cagliari, Italy. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Sanna, S (reprint author), CNR, IRGB, Cittadella Univ Monserrato,SS 554 Km 4500, I-09042 Cagliari, Italy. EM serena.sanna@irgb.cnr.it RI Angius, Andrea/P-9549-2015; Danjou, Fabrice/D-1563-2014; OI Angius, Andrea/0000-0003-2596-6461; Danjou, Fabrice/0000-0002-4976-2327; Mulas, Antonella/0000-0002-6856-1483; Sidore, Carlo/0000-0001-7504-7477; sanna, serena/0000-0002-3768-1749; Pitzalis, Maristella/0000-0003-4975-6987; Steri, Anna Maristella/0000-0001-5869-3872 FU Intramural Research Program of the National Institute of Health, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]; National Human Genome Research Institute [HG005581, HG005552, HG006513, HG007022]; National Institute on Drug Abuse [DA 024417, DA 034606]; Italian FISM [2011/R/13] FX This work was supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging (N01-AG-1-2109 and HHSN271201100005C), National Human Genome Research Institute grants (HG005581, HG005552, HG006513 and HG007022 to GRA), the National Institute on Drug Abuse (DA 024417 and DA 034606) and the Italian FISM (2011/R/13 to FC). We thank Frederic Reinier, Riccardo Berutti, Rossano Atzeni, Goo Jun, Alan Kwong, Maria Valentini, Roberto Cusano, Manuela Oppo, Rosella Pilu and Brendan Tarrier for additional help on generating and managing sequencing data; Mariano Dei, Monia Lobina and Francesca Deidda for sample preparation; and Lidia Leoni, Carlo Podda and Antonio Concas for their technical support on the high-performance computing cluster at CRS4. NR 25 TC 12 Z9 12 U1 5 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUL PY 2015 VL 23 IS 7 BP 975 EP 983 DI 10.1038/ejhg.2014.216 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CK4DJ UT WOS:000356170700013 PM 25293720 ER PT J AU Goldman, SM Umbach, DM Kamel, F Tanner, CM AF Goldman, S. M. Umbach, D. M. Kamel, F. Tanner, C. M. TI Head injury, alpha-synuclein Rep1 and Parkinson's disease: a meta-analytic view of gene-environment interaction SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Letter DE alpha-synuclein; epidemiology; gene-environment interaction; genetic association study; Parkinson's disease; traumatic brain injury C1 [Goldman, S. M.; Tanner, C. M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Goldman, S. M.; Tanner, C. M.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Umbach, D. M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Kamel, F.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Goldman, SM (reprint author), San Francisco VA Med Ctr, 4150 Clement St,Box 127-P, San Francisco, CA 94121 USA. EM samuel.goldman@ucsf.edu OI Kamel, Freya/0000-0001-5052-6615 NR 3 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD JUL PY 2015 VL 22 IS 7 BP E75 EP E75 DI 10.1111/ene.12694 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK3BP UT WOS:000356090800002 PM 26060929 ER PT J AU Mukherjee, K Chio, TI Sackett, DL Bane, SL AF Mukherjee, Kamalika Chio, Tak Ian Sackett, Dan L. Bane, Susan L. TI Detection of oxidative stress-induced carbonylation in live mammalian cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Oxidative stress; Biomolecule carbonylation; Live cells; Fluorophore; Hydrazine; Microscopy; Plate reader ID PROTEIN CARBONYLATION; LIPID-PEROXIDATION; EXOGENOUS GLUTATHIONE; ABASIC SITES; DNA-DAMAGE; DISEASE; ASSAY; PROTECTION; CHEMISTRY; MOLECULE AB Oxidative stress is often associated with etiology and/or progression of disease conditions, such as cancer, neurodegenerative diseases, and diabetes. At the cellular level, oxidative stress induces carbonylation of biomolecules such as lipids, proteins, and DNA. The presence of carbonyl-containing biomolecules as a hallmark of these diseases provides a suitable target for diagnostic detection. Here, a simple, robust method for detecting cellular aldehydes and ketones in live cells using a fluorophore is presented. A hydrazine-functionalized synthetic fluorophore serves as an efficient nucleophile that rapidly reacts with reactive carbonyls in the cellular milieu. The product thus formed exhibits a wavelength shift in the emission maximum accompanied by an increase in emission intensity. The photochemical characteristics of the fluorophore enable the identification of the fluorophore-conjugated cellular biomolecules in the presence of unreacted dye, eliminating the need for removal of excess fluorophore. Moreover, this fluorophore is found to be nontoxic and is thus appropriate for live cell analysis. Utility of the probe is demonstrated in two cell lines, PC3 and A549. Carbonylation resulting from serum starvation and hydrogen peroxide-induced stress is detected in both cell lines using fluorescence microscopy and a fluorescence plate reader. The fluorescent signal originates from carbonylated proteins and lipids but not from oxidized DNA, and the majority of the fluorescence signal (>60%) is attributed to fluorophore-conjugated lipid oxidation products. This method should be useful for detecting cellular carbonylation in a high-content assay or high-throughput assay format. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mukherjee, Kamalika; Chio, Tak Ian; Bane, Susan L.] SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Bane, SL (reprint author), SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA. EM sbane@binghamton.edu RI Bane, Susan/C-1414-2013 OI Bane, Susan/0000-0002-4270-6314 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [R15 GM-102867]; NSF [CHE-0922815] FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by NIH Grant R15 GM-102867. The Regional NMR Facility (600 MHz instrument) at Binghamton University is supported by NSF (CHE-0922815). The authors thank Dr. Abhijit Banerjee for synthesizing coumarin hydrazine and coumarin amine, Dr. Ozlem Dilek for synthesizing coumarin aldehyde, Mr. David Tuttle for photographing the gels and for expert assistance with image processing, Professor Rebecca Kissling for scientific discussion and assistance with organic synthesis, and Professor Ming An for the generous gift of A549 cells. NR 51 TC 4 Z9 4 U1 3 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2015 VL 84 BP 11 EP 21 DI 10.1016/j.freeradbiomed.2015.03.011 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CK0LK UT WOS:000355896500002 PM 25801292 ER PT J AU Carnesecchi, S Rougemont, AL Doroshow, JH Nagy, M Mouche, S Gumy-Pause, F Szanto, I AF Carnesecchi, S. Rougemont, A. -L. Doroshow, J. H. Nagy, M. Mouche, S. Gumy-Pause, F. Szanto, I. TI The NADPH oxidase NOX5 protects against apoptosis in ALK-positive anaplastic large-cell lymphoma cell lines SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Reactive oxygen species; NOX5; Anaplastic large-cell lymphoma; Karpas-299; Apoptosis; Free radicals ID REACTIVE OXYGEN; TYROSINE KINASE; NPM-ALK; HUMAN CANCER; EXPRESSION; BIOLOGY; PATHWAY; MECHANISM; TISSUE; DEATH AB Reactive oxygen species (ROS) are key modulators of apoptosis and carcinogenesis. One of the important sources of ROS is NADPH oxidases (NOXs). The isoform NOX5 is highly expressed in lymphoid tissues, but it has not been detected in any common Hodgkin or non-Hodgkin lymphoma cell lines. In diverse, nonlymphoid malignant cells NOX5 exerts an antiapoptotic effect. Apoptosis suppression is the hallmark feature of a rare type of lymphoma, termed anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and a major factor in the therapy resistance and relapse of ALK(+) ALCL tumors. We applied RT-PCR and Western blot analysis to detect NOX5 expression in three ALK(+) ALCL cell lines (Karpas-299, SR-786, SUP-M2). We investigated the role of NOX5 in apoptosis by small-interfering RNA (siRNA)-mediated gene silencing and chemical inhibition of NOX5 using FACS analysis and examining caspase 3 cleavage in Karpas-299 cells. We used immunohistochemistry to detect NOX5 in ALK(+) ALCL pediatric tumors. NOX5 mRNA was uniquely detected in ALK(+) ALCL cells, whereas cell lines of other lymphoma classes were devoid of NOX5. Transfection of NOX5-specific siRNA and chemical inhibition of NOX5 abrogated calcium-induced superoxide production and increased caspase 3-mediated apoptosis in Karpas-299 cells. Immunohistochemistry revealed focal NOX5 reactivity in pediatric ALK(+) ALCL tumor cells. These results indicate that NOX5-derived ROS contribute to apoptosis blockage in ALK(+) ALCL cell lines and suggest NOX5 as a potential pharmaceutical target to enhance apoptosis and thus to suppress tumor progression and prevent relapse in pediatric ALK(+) ALCL patients that resist classical therapeutic approaches. (C) 2015 Elsevier Inc. All rights reserved. C1 [Carnesecchi, S.; Mouche, S.; Szanto, I.] Univ Geneva, Dept Cellular Physiol & Metab, CH-1211 Geneva 4, Switzerland. [Carnesecchi, S.; Nagy, M.] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. [Rougemont, A. -L.] Univ Hosp Geneva, Div Clin Pathol, Geneva, Switzerland. [Szanto, I.] Univ Hosp Geneva, Dept Internal Med Specialties, Geneva, Switzerland. [Doroshow, J. H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gumy-Pause, F.] CANSEARCH, Dept Pediat, Res Lab, Hematol Oncol Unit, Geneva, Switzerland. RP Szanto, I (reprint author), Univ Hosp Geneva, Dept Internal Med Specialties, Geneva, Switzerland. EM ildiko.szanto@unige.ch FU Fondation Georges Lemaitre, Geneva, Switzerland FX We thank Nathalie Lin-Marq (University of Geneva) for excellent technical help. This work was supported by a grant from the Fondation Georges Lemaitre, Geneva, Switzerland, allocated to I.S. NR 61 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL PY 2015 VL 84 BP 22 EP 29 DI 10.1016/j.freeradbiomed.2015.02.027 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CK0LK UT WOS:000355896500003 PM 25797883 ER PT J AU Pathak, A Pemov, A McMaster, ML Dewan, R Ravichandran, S Pak, E Dutra, A Lee, HJ Vogt, A Zhang, XJ Yeager, M Anderson, S Kirby, M Caporaso, N Greene, MH Goldin, LR Stewart, DR AF Pathak, Anand Pemov, Alexander McMaster, Mary L. Dewan, Ramita Ravichandran, Sarangan Pak, Evgenia Dutra, Amalia Lee, Hyo Jung Vogt, Aurelie Zhang, Xijun Yeager, Meredith Anderson, Stacie Kirby, Martha Caporaso, Neil Greene, Mark H. Goldin, Lynn R. Stewart, Douglas R. CA NCI DCEG Canc Genomics Res Grp NCI DCEG Canc Sequencing Working TI Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family SO HUMAN GENETICS LA English DT Article ID GROWTH-FACTOR RECEPTOR; UBIQUITIN LIGASE ACTIVITY; C-CBL; MYELOID NEOPLASMS; PROTEIN LIGASE; TYROSINE; ACTIVATION; VARIANTS; AUTOINHIBITION; C-CBL/SLI-1 AB Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that arises from malignant transformation of the stem cell compartment and results in increased production of myeloid cells. Somatic and germline variants in CBL (Casitas B-lineage lymphoma proto-oncogene) have been associated with JMML. We report an incompletely penetrant CBL Y371C mutation discovered by whole-exome sequencing in three individuals with JMML in a large pedigree with 35 years of follow-up. The Y371 residue is highly evolutionarily conserved among CBL orthologs and paralogs. In silico bioinformatics prediction programs suggested that the Y371C mutation is highly deleterious. Protein structural modeling revealed that the Y371C mutation abrogated the ability of the CBL protein to adopt a conformation that is required for ubiquitination. Clinically, the three mutation-positive JMML individuals exhibited variable clinical courses; in two out of three, primary hematologic abnormalities persisted into adulthood with minimal clinical symptoms. The penetrance of the CBL Y371C mutation was 30 % for JMML and 40 % for all leukemia. Of the 8 mutation carriers in the family with available photographs, only one had significant dysmorphic features; we found no evidence of a clinical phenotype consistent with a "CBL syndrome". Although CBL Y371C has been previously reported in familial JMML, we are the first group to follow a complete pedigree harboring this mutation for an extended period, revealing additional information about this variant's penetrance, function and natural history. C1 [Pathak, Anand; Pemov, Alexander; Dewan, Ramita; Greene, Mark H.; Stewart, Douglas R.] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, NIH, Bethesda, MD 20892 USA. [McMaster, Mary L.; Caporaso, Neil; Goldin, Lynn R.] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Ravichandran, Sarangan] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Pak, Evgenia; Dutra, Amalia] NHGRI, Cytogenet & Microscopy Core, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Lee, Hyo Jung; Vogt, Aurelie; Zhang, Xijun; Yeager, Meredith] NCI, Div Canc Epidemiol & Genet, Canc Genom Res Lab, NIH, Rockville, MD USA. [Anderson, Stacie; Kirby, Martha] NHGRI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. RP Pathak, A (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, NIH, 9609 Med Ctr Dr Rm 6E450, Bethesda, MD 20892 USA. EM pathaka@mail.nih.gov; drstewart@mail.nih.gov RI Tobias, Geoffrey/M-4135-2016 OI Tobias, Geoffrey/0000-0002-2878-8253 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This Project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 46 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JUL PY 2015 VL 134 IS 7 BP 775 EP 787 DI 10.1007/s00439-015-1550-9 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA CK0YD UT WOS:000355930700008 PM 25939664 ER PT J AU Lathrop, SK Binder, KA Starr, T Cooper, KG Chong, A Carmody, AB Steele-Mortimer, O AF Lathrop, Stephanie K. Binder, Kelsey A. Starr, Tregei Cooper, Kendal G. Chong, Audrey Carmody, Aaron B. Steele-Mortimer, Olivia TI Replication of Salmonella enterica Serovar Typhimurium in Human Monocyte-Derived Macrophages SO INFECTION AND IMMUNITY LA English DT Article ID III SECRETION SYSTEM; PATHOGENICITY ISLAND 2; BACTERIAL VIRULENCE; TYPE-2 MACROPHAGES; IFN-GAMMA; IN-VITRO; INDUCTION; SURVIVAL; MURINE; GENES AB Salmonella enterica serovar Typhimurium is a common cause of food-borne gastrointestinal illness, but additionally it causes potentially fatal bacteremia in some immunocompromised patients. In mice, systemic spread and replication of the bacteria depend upon infection of and replication within macrophages, but replication in human macrophages is not widely reported or well studied. In order to assess the ability of Salmonella Typhimurium to replicate in human macrophages, we infected primary monocyte-derived macrophages (MDM) that had been differentiated under conditions known to generate different phenotypes. We found that replication in MDM depends greatly upon the phenotype of the cells, as M1-skewed macrophages did not allow replication, while M2a macrophages and macrophages differentiated with macrophage colony-stimulating factor (M-CSF) alone (termed M0) did. We describe how additional conditions that alter the macrophage phenotype or the gene expression of the bacteria affect the outcome of infection. In M0 MDM, the temporal expression of representative genes from Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2) and the importance of the PhoP/Q two-component regulatory system are similar to what has been shown in mouse macrophages. However, in contrast to mouse macrophages, where replication is SPI2 dependent, we observed early SPI2-independent replication in addition to later SPI2-dependent replication in M0 macrophages. Only SPI2-dependent replication was associated with death of the host cell at later time points. Altogether, our results reveal a very nuanced interaction between Salmonella and human macrophages. C1 [Lathrop, Stephanie K.; Binder, Kelsey A.; Starr, Tregei; Cooper, Kendal G.; Chong, Audrey; Steele-Mortimer, Olivia] NIAID, Rocky Mt Labs, Lab Intracellular Parasites, NIH, Hamilton, MT 59840 USA. [Carmody, Aaron B.] NIAID, Rocky Mt Labs, Res Technol Branch, NIH, Hamilton, MT 59840 USA. RP Steele-Mortimer, O (reprint author), NIAID, Rocky Mt Labs, Lab Intracellular Parasites, NIH, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 58 TC 5 Z9 5 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2015 VL 83 IS 7 BP 2661 EP 2671 DI 10.1128/IAI.00033-15 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CK5EB UT WOS:000356244000007 PM 25895967 ER PT J AU Rajaram, K Giebel, AM Toh, E Hu, S Newman, JH Morrison, SG Kari, L Morrison, RP Nelson, DE AF Rajaram, Krithika Giebel, Amanda M. Toh, Evelyn Hu, Shuai Newman, Jasmine H. Morrison, Sandra G. Kari, Laszlo Morrison, Richard P. Nelson, David E. TI Mutational Analysis of the Chlamydia muridarum Plasticity Zone SO INFECTION AND IMMUNITY LA English DT Article ID OBLIGATE INTRACELLULAR PATHOGEN; GENITAL-TRACT INFECTION; GAMMA IMMUNE EVASION; GENE KNOCKOUT MICE; GENOME SEQUENCE; IN-VIVO; TRYPTOPHAN SYNTHASE; ESCHERICHIA-COLI; HOST-CELLS; TRACHOMATIS AB Pathogenically diverse Chlamydia spp. can have surprisingly similar genomes. Chlamydia trachomatis isolates that cause trachoma, sexually transmitted genital tract infections (chlamydia), and invasive lymphogranuloma venereum (LGV) and the murine strain Chlamydia muridarum share 99% of their gene content. A region of high genomic diversity between Chlamydia spp. termed the plasticity zone (PZ) may encode niche-specific virulence determinants that dictate pathogenic diversity. We hypothesized that PZ genes might mediate the greater virulence and gamma interferon (IFN-gamma) resistance of Chlamydia muridarum compared to Chlamydia trachomatis in the murine genital tract. To test this hypothesis, we isolated and characterized a series of Chlamydia muridarum PZ nonsense mutants. Strains with nonsense mutations in chlamydial cytotoxins, guaBA-add, and a phospholipase D homolog developed normally in cell culture. Two of the cytotoxin mutants were less cytotoxic than the wild type, suggesting that the cytotoxins may be functional. However, none of the PZ nonsense mutants exhibited increased IFN-gamma sensitivity in cell culture or were profoundly attenuated in a murine genital tract infection model. Our results suggest that Chlamydia muridarum PZ genes are transcribed-and some may produce functional proteins-but are dispensable for infection of the murine genital tract. C1 [Rajaram, Krithika; Giebel, Amanda M.] Indiana Univ, Dept Biol, Bloomington, IN USA. [Toh, Evelyn; Hu, Shuai; Nelson, David E.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Newman, Jasmine H.] Indiana Univ, Dept Biochem & Mol Biol, Bloomington, IN USA. [Morrison, Sandra G.; Morrison, Richard P.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. [Kari, Laszlo] NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT USA. RP Nelson, DE (reprint author), Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. EM nelsonde@indiana.edu FU National Institutes of Health [RO1AI099278, R21AI099307]; National Institutes of General Medical Sciences [1P20GM103625] FX This work was supported by grants RO1AI099278 and R21AI099307 from the National Institutes of Health (D.E.N.) and in part by grant 1P20GM103625 from the National Institutes of General Medical Sciences (R.P.M.). NR 56 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2015 VL 83 IS 7 BP 2870 EP 2881 DI 10.1128/IAI.00106-15 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CK5EB UT WOS:000356244000027 PM 25939505 ER PT J AU Dastgheyb, SS Villaruz, AE Le, KY Tan, VY Duong, AC Chatterjee, SS Cheung, GYC Joo, HS Hickok, NJ Otto, M AF Dastgheyb, Sana S. Villaruz, Amer E. Le, Katherine Y. Tan, Vee Y. Duong, Anthony C. Chatterjee, Som S. Cheung, Gordon Y. C. Joo, Hwang-Soo Hickok, Noreen J. Otto, Michael TI Role of Phenol-Soluble Modulins in Formation of Staphylococcus aureus Biofilms in Synovial Fluid SO INFECTION AND IMMUNITY LA English DT Article ID PROSTHETIC-JOINT INFECTIONS; QUORUM-SENSING SYSTEM; AGR; EPIDERMIDIS; ARTHRITIS; PEPTIDES; ORIGIN; MICE AB Staphylococcus aureus is a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (> 1 mm). We found that while specific S. aureus surface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction of S. aureus surface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms of S. aureus infection, and have important implications for antistaphy lococcal therapeutic strategies. C1 [Dastgheyb, Sana S.; Villaruz, Amer E.; Le, Katherine Y.; Tan, Vee Y.; Duong, Anthony C.; Chatterjee, Som S.; Cheung, Gordon Y. C.; Joo, Hwang-Soo; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Dastgheyb, Sana S.; Hickok, Noreen J.] Thomas Jefferson Univ, Dept Orthoped Surg, Philadelphia, PA 19107 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Dastgheyb, Sana/0000-0001-8275-1614; Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) [ZIA AI000904-13]; NIH [HD06153, DE019901]; T32 NIH training grant [T32-AR-052273] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) (ZIA AI000904-13, to M.O.). This study was also supported by NIH grants HD06153 and DE019901 to N.J.H., and S.S.D. was supported by a T32 NIH training grant (T32-AR-052273). NR 44 TC 11 Z9 11 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2015 VL 83 IS 7 BP 2966 EP 2975 DI 10.1128/IAI.00394-15 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CK5EB UT WOS:000356244000037 PM 25964472 ER PT J AU Guyer, AE Jarcho, JM Perez-Edgar, K Degnan, KA Pine, DS Fox, NA Nelson, EE AF Guyer, Amanda E. Jarcho, Johanna M. Perez-Edgar, Koraly Degnan, Kathryn A. Pine, Daniel S. Fox, Nathan A. Nelson, Eric E. TI Temperament and Parenting Styles in Early Childhood Differentially Influence Neural Response to Peer Evaluation in Adolescence SO JOURNAL OF ABNORMAL CHILD PSYCHOLOGY LA English DT Article DE Behavioral inhibition; Social anxiety; Parenting; Peer rejection; Brain function ID VENTROLATERAL PREFRONTAL CORTEX; GENERALIZED ANXIETY DISORDER; BEHAVIORAL-INHIBITION; DEPRESSIVE SYMPTOMS; SOCIAL ANXIETY; COGNITIVE CONTROL; CONTEXT; SENSITIVITY; REJECTION; STRESS AB Behavioral inhibition (BI) is a temperament characterized by social reticence and withdrawal from unfamiliar or novel contexts and conveys risk for social anxiety disorder. Developmental outcomes associated with this temperament can be influenced by children's caregiving context. The convergence of a child's temperamental disposition and rearing environment is ultimately expressed at both the behavioral and neural levels in emotional and cognitive response patterns to social challenges. The present study used functional neuroimaging to assess the moderating effects of different parenting styles on neural response to peer rejection in two groups of adolescents characterized by their early childhood temperament (M (age) = 17.89 years, N = 39, 17 males, 22 females; 18 with BI; 21 without BI). The moderating effects of authoritarian and authoritative parenting styles were examined in three brain regions linked with social anxiety: ventrolateral prefrontal cortex (vlPFC), striatum, and amygdala. In youth characterized with BI in childhood, but not in those without BI, diminished responses to peer rejection in vlPFC were associated with higher levels of authoritarian parenting. In contrast, all youth showed decreased caudate response to peer rejection at higher levels of authoritative parenting. These findings indicate that BI in early life relates to greater neurobiological sensitivity to variance in parenting styles, particularly harsh parenting, in late adolescence. These results are discussed in relation to biopsychosocial models of development. C1 [Guyer, Amanda E.] Univ Calif Davis, Dept Human Ecol, Ctr Mind & Brain, Davis, CA 95618 USA. [Jarcho, Johanna M.; Pine, Daniel S.; Nelson, Eric E.] NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Perez-Edgar, Koraly] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Degnan, Kathryn A.; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. RP Guyer, AE (reprint author), Univ Calif Davis, Dept Human Ecol, Ctr Mind & Brain, 267 Cousteau Pl, Davis, CA 95618 USA. EM aeguyer@ucdavis.edu OI Jarcho, Johanna/0000-0001-9075-6968; Nelson, Eric/0000-0002-3376-2453; Perez-Edgar, Koraly/0000-0003-4051-9563 FU National Institute of Mental Health (NIMH) [MH080076, MH074454] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH), an NIMH Seymour S. Kety Memorial Award (AEG), and NIMH grants MH080076 (AEG) and MH074454 (NAF). The authors thank all of the families who participated in the study. NR 62 TC 5 Z9 5 U1 7 U2 30 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0627 EI 1573-2835 J9 J ABNORM CHILD PSYCH JI J. Abnorm. Child Psychol. PD JUL PY 2015 VL 43 IS 5 BP 863 EP 874 DI 10.1007/s10802-015-9973-2 PG 12 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA CK3CN UT WOS:000356093600006 PM 25588884 ER PT J AU Zhu, YY Hernandez, LM Dong, Y Himes, JH Hirschfeld, S Forman, MR AF Zhu, Yeyi Hernandez, Ladia M. Dong, Yongquan Himes, John H. Hirschfeld, Steven Forman, Michele R. TI Longer breastfeeding duration reduces the positive relationships among gestational weight gain, birth weight and childhood anthropometrics SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID BODY-MASS INDEX; METABOLIC SYNDROME; MATERNAL RECALL; 1ST YEAR; OBESITY; GROWTH; INFANTS; LIFE; ASSOCIATION; HEIGHT AB Background The relationship between gestational weight gain (GWG) and childhood growth remains controversial. An examination on whether infant feeding practices mediate this relationship may improve our understanding of it. Methods We investigated whether the relationships among GWG, birth weight and childhood anthropometrics were mediated through infant feeding practices (breastfeeding duration and age at introduction of solid foods) in a cross-sectional multiethnic study of 1387 mothers and their children aged 0-5.9 years in the USA (2011-2012). Child anthropometrics included age-specific and sex-specific z-scores for weight-for-age (WAZ), height/length-for-age (HAZ), weight-for-height/length (WHZ) and body mass index-for-age (BMIZ); and ulnar length, a marker for limb growth. We used structural equation modelling to calculate standardised path coefficients and total, direct and indirect associations of GWG, birth weight and infant feeding practices with child anthropometrics. Results Maternal GWG had a positive indirect association with all anthropometrics mediated via birth weight, whereas longer breastfeeding duration reduced the positive associations of GWG and birth weight with WAZ, WHZ and BMIZ in non-Hispanics (beta=-0.077, -0.064 and -0.106, respectively). Longer breastfeeding duration and introducing solid foods at a later age were positively associated with ulnar length (beta=0.023 and 0.030, respectively) but not HAZ, suggesting a distinct association, for the first time, with limb growth. Conclusions Findings suggest that promoting longer breastfeeding duration among women with excessive GWG who had high birthweight newborns may mitigate the potential for their offspring to develop obesity. In addition, findings reinforce the importance of promoting appropriate GWG and preventing high birth weight, which are positively associated with childhood anthropometrics. C1 [Zhu, Yeyi; Hernandez, Ladia M.; Dong, Yongquan; Forman, Michele R.] Univ Texas Austin, Dept Nutr Sci, Austin, TX 78712 USA. [Himes, John H.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Zhu, YY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM yeyi.zhu@nih.gov RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA [HHSN275200800020C] FX This work was supported by a contract award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA (HHSN275200800020C). NR 40 TC 5 Z9 5 U1 4 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD JUL PY 2015 VL 69 IS 7 BP 632 EP 638 DI 10.1136/jech-2014-204794 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK4BS UT WOS:000356164200006 PM 25680365 ER PT J AU Zabieglo, K Majewski, P Majchrzak-Gorecka, M Wlodarczyk, A Grygier, B Zegar, A Kapinska-Mrowiecka, M Naskalska, A Pyrc, K Dubin, A Wahl, SM Cichy, J AF Zabieglo, Katarzyna Majewski, Pawel Majchrzak-Gorecka, Monika Wlodarczyk, Agnieszka Grygier, Beata Zegar, Aneta Kapinska-Mrowiecka, Monika Naskalska, Antonina Pyrc, Krzysztof Dubin, Adam Wahl, Sharon M. Cichy, Joanna TI The inhibitory effect of secretory leukocyte protease inhibitor (SLPI) on formation of neutrophil extracellular traps SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE serine; inflammation; autoimmune disease; skin; psoriasis ID PROTEINASE-INHIBITOR; HOST-DEFENSE; PSORIASIS; ELASTASE; INFLAMMATION; RELEASE; CELLS; INFECTIONS; GRANULES; MICE AB Neutrophil extracellular traps (NETs), web-like DNA structures, provide efficient means of eliminating invading microorganisms but can also present a potential threat to its host because it is a likely source of autoantigens or by promoting bystander tissue damage. Therefore, it is important to identify mechanisms that inhibit NET formation. Neutrophil elastase (NE)dependent chromatin decondensation is a key event in the release of NETs release. We hypothesized that inhibitors of NE, secretory leukocyte protease inhibitor (SLPI) and alpha(1)-proteinase inhibitor (alpha(1)-PI), has a role in restricting NET generation. Here, we demonstrate that exogenous human SLPI, but not alpha(1)-PI markedly inhibited NET formation in human neutrophils. The ability of exogenous SLPI to attenuate NET formation correlated with an inhibition of a core histone, histone 4 (H4), cleavage, and partial dependence on SLPI-inhibitory activity against NE. Moreover, neutrophils from SLPI (/) mice were more efficient at generating NETs than were neutrophils from wild-type mice in vitro, and in experimental psoriasis in vivo. Finally, endogenous SLPI colocalized with NE in the nucleus of human neutrophils in vitro, as well as in vivo in inflamed skin of patients with psoriasis. Together, these findings support a controlling role for SLPI in NET generation, which is of potential relevance to infectious and autoinflammatory diseases. C1 [Zabieglo, Katarzyna; Majewski, Pawel; Majchrzak-Gorecka, Monika; Wlodarczyk, Agnieszka; Grygier, Beata; Zegar, Aneta; Cichy, Joanna] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Immunol, PL-30387 Krakow, Poland. [Pyrc, Krzysztof] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Microbiol, PL-30387 Krakow, Poland. [Dubin, Adam] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Analyt Biochem, PL-30387 Krakow, Poland. [Naskalska, Antonina; Pyrc, Krzysztof] Jagiellonian Univ, Malopolska Ctr Biotechnol, PL-30387 Krakow, Poland. [Kapinska-Mrowiecka, Monika] Zeromski Hosp, Dept Dermatol, Krakow, Poland. [Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, Cellular Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. RP Cichy, J (reprint author), Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Immunol, Gronostajowa 7 St, PL-30387 Krakow, Poland. EM joanna.cichy@uj.edu.pl RI Wlodarczyk, Agnieszka/K-3460-2015; OI Pyrc, Krzysztof/0000-0002-3867-7688 FU Polish National Science Center [2011/02/A/NZ5/00337]; Foundation for Polish Science Grant [TEAM/2010-5]; European Union within a European Regional Development Fund Award; European Union [POIG.02.01.00-12-064/08]; Polish Ministry of Science and Higher Education; Intramural Research Program of the U.S. National Institutes of Health National Institute of Dental and Craniofacial Research FX This work was supported in part by the Polish National Science Center Grant 2011/02/A/NZ5/00337 and the Foundation for Polish Science Grant TEAM/2010-5 and was cofinanced by the European Union within a European Regional Development Fund Award (to J.C.). The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficiary of structural funds from the European Union (Grant POIG.02.01.00-12-064/08) and a partner with the Leading National Research Center (KNOW) supported by the Polish Ministry of Science and Higher Education. This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health National Institute of Dental and Craniofacial Research (to S.M.W.). NR 40 TC 10 Z9 10 U1 2 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2015 VL 98 IS 1 BP 99 EP 106 DI 10.1189/jlb.4AB1114-543R PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA CK5FJ UT WOS:000356247700010 PM 25917460 ER PT J AU Raskolnikov, D George, AK Rais-Bahrami, S Turkbey, B Siddiqui, MM Shakir, NA Okoro, C Rothwax, JT Walton-Diaz, A Sankineni, S Su, D Stamatakis, L Merino, MJ Choyke, PL Wood, BJ Pinto, PA AF Raskolnikov, Dima George, Arvin K. Rais-Bahrami, Soroush Turkbey, Baris Siddiqui, M. Minhaj Shakir, Nabeel A. Okoro, Chinonyerem Rothwax, Jason T. Walton-Diaz, Annerleim Sankineni, Sandeep Su, Daniel Stamatakis, Lambros Merino, Maria J. Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI The Role of Magnetic Resonance Image Guided Prostate Biopsy in Stratifying Men for Risk of Extracapsular Extension at Radical Prostatectomy SO JOURNAL OF UROLOGY LA English DT Article DE prostate; adenocarcinoma; neoplasm staging; risk; prognosis ID TRANSRECTAL ULTRASOUND BIOPSY; CANCER-DETECTION; SPECIMENS; DISEASE; COIL; MRI AB Purpose: Magnetic resonance imaging detects extracapsular extension by prostate cancer with excellent specificity but low sensitivity. This limits surgical planning, which could be modified to account for focal extracapsular extension with image directed guidance for wider excision. In this study we evaluate the performance of multiparametric magnetic resonance imaging in extracapsular extension detection and determine which preoperative variables predict extracapsular extension on final pathology when multiparametric magnetic resonance imaging predicts organ confined disease. Materials and Methods: From May 2007 to March 2014, 169 patients underwent pre-biopsy multiparametric magnetic resonance imaging, magnetic resonance imaging/transrectal ultrasound fusion guided biopsy, extended sextant 12-core biopsy and radical prostatectomy at our institution. A subset of 116 men had multiparametric magnetic resonance imaging negative for extracapsular extension and were included in the final analysis. Results: The 116 men with multiparametric magnetic resonance imaging negative for extracapsular extension had a median age of 61 years (IQR 57-66) and a median prostate specific antigen of 5.51 ng/ml (IQR 3.91-9.07). The prevalence of extracapsular extension was 23.1% in the overall population. Sensitivity, specificity, and positive and negative predictive values of multiparametric magnetic resonance imaging for extracapsular extension were 48.7%, 73.9%, 35.9% and 82.8%, respectively. On multivariate regression analysis only patient age (p = 0.002) and magnetic resonance imaging/transrectal ultrasound fusion guided biopsy Gleason score (p = 0.032) were independent predictors of extracapsular extension on final radical prostatectomy pathology. Conclusions: Because of the low sensitivity of multiparametric magnetic resonance imaging for extracapsular extension, further tools are necessary to stratify men at risk for occult extracapsular extension that would otherwise only become apparent on final pathology. Magnetic resonance imaging/transrectal ultrasound fusion guided biopsy Gleason score can help identify which men with prostate cancer have extracapsular extension that may not be detectable by imaging. C1 [Raskolnikov, Dima; George, Arvin K.; Rais-Bahrami, Soroush; Siddiqui, M. Minhaj; Shakir, Nabeel A.; Okoro, Chinonyerem; Rothwax, Jason T.; Walton-Diaz, Annerleim; Su, Daniel; Stamatakis, Lambros; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Sankineni, Sandeep; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Center for Interventional Oncology; NIH Medical Research Scholars Program; NIH; Pfizer Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Center for Interventional Oncology. The NIH and Philips Healthcare have a cooperative research and development agreement, and share intellectual property in the field. Also supported by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from Pfizer Inc., the Doris Duke Charitable Foundation, Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list visit http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 29 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2015 VL 194 IS 1 BP 105 EP 111 DI 10.1016/j.juro.2015.01.072 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CK2AQ UT WOS:000356012100026 PM 25623751 ER PT J AU Nickel, JC Stephens, A Landis, JR Chen, J Mullins, C van Bokhoven, A Lucia, MS Melton-Kreft, R Ehrlichk, GD AF Nickel, J. Curtis Stephens, Alisa Landis, J. Richard Chen, Jun Mullins, Chris van Bokhoven, Adrie Lucia, M. Scott Melton-Kreft, Rachael Ehrlichk, Garth D. CA MAPP Res Network TI Search for Microorganisms in Men with Urologic Chronic Pelvic Pain Syndrome: A Culture-Independent Analysis in the MAPP Research Network SO JOURNAL OF UROLOGY LA English DT Article DE microbiota; infection; prostatitis; chronic pain; pelvic pain ID POLYMERASE-CHAIN-REACTION; CHRONIC PROSTATITIS; DNA-SEQUENCES; BACTERIAL; IDENTIFICATION; INFECTION AB Purpose: We used next-generation, state-of-the-art, culture independent methodology to survey urine microbiota of males with urologic chronic pelvic pain syndrome and control participants enrolled in the MAPP Network to investigate a possible microbial etiology. Materials and Methods: Male patients with urologic chronic pelvic pain syndrome and matched controls were asked to provide initial, midstream and post-prostatic massage urine specimens. Specimens were analyzed with Ibis T-5000 Universal Biosensor technology to provide comprehensive identification of bacterial and select fungal species. Differences between urologic chronic pelvic pain syndrome and control study participants for the presence of species or species variation in a higher taxonomic grouping (genus) were evaluated using permutational multivariate analysis of variance and logistic regression. Results: Initial and midstream urine specimens were obtained from 110 (post-prostatic massage urine in 67) participants with urologic chronic pelvic pain syndrome and 115 (post-prostatic massage urine in 62) controls. Overall 78, 73 and 54 species (42, 39 and 27 genera) were detected in initial, midstream and post-prostatic massage urine specimens, respectively. Mean (SD) initial, midstream and post-prostatic massage urine species count per person was 1.62 (1.28), 1.38 (1.36) and 1.33 (1.24) for cases, and 1.75 (1.32), 1.23 (1.15) and 1.56 (0.97) for controls, respectively. Overall species and genus composition differed significantly between participants with urologic chronic pelvic pain syndrome and controls in initial stream urine (p = 0.002 species level, p = 0.004 genus level), with Burkholderia cenocepacia overrepresented in urologic chronic pelvic pain syndrome. No significant differences were observed at any level in midstream or post-prostatic massage urine samples. Conclusions: Assessment of baseline culture-independent microbiological data from male subjects enrolled in the MAPP Network has identified overrepresentation of B. cenocepacia in urologic chronic pelvic pain syndrome. Future studies are planned to further evaluate microbiota associations with variable and changing urologic chronic pelvic pain syndrome symptom patterns. C1 [Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON K7L 2V7, Canada. [Stephens, Alisa; Landis, J. Richard] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Ehrlichk, Garth D.] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. [Ehrlichk, Garth D.] Drexel Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Melton-Kreft, Rachael] Ctr Excellence Biofilm Res, Allegheny Hlth Network, Pittsburgh, PA USA. [Chen, Jun] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Mullins, Chris] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [van Bokhoven, Adrie; Lucia, M. Scott] Univ Colorado, Dept Pathol, Aurora, CO USA. RP Nickel, JC (reprint author), Queens Univ, Dept Urol, Kingston, ON K7L 2V7, Canada. EM jcn@queensu.ca FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health MAPP Network Awards [U01DK82370, U01DK82342, U01DK82315, U01DK82344, U01DK82325, U01DK82345, U01DK82333, U01DK82316] FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health MAPP Network Awards U01DK82370, U01DK82342, U01DK82315, U01DK82344, U01DK82325, U01DK82345, U01DK82333 and U01DK82316. NR 28 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2015 VL 194 IS 1 BP 127 EP 135 DI 10.1016/j.juro.2015.01.037 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CK2AQ UT WOS:000356012100035 PM 25596358 ER PT J AU Jansen, IE Bras, JM Lesage, S Schulte, C Gibbs, JR Nalls, MA Brice, A Wood, NW Morris, H Hardy, JA Singleton, AB Gasser, T Heutink, P Sharma, M AF Jansen, Iris E. Bras, Jose M. Lesage, Suzanne Schulte, Claudia Gibbs, J. Raphael Nalls, Mike A. Brice, Alexis Wood, Nicholas W. Morris, Huw Hardy, John A. Singleton, Andrew B. Gasser, Thomas Heutink, Peter Sharma, Manu CA IPDGC TI CHCHD2 and Parkinson's disease SO LANCET NEUROLOGY LA English DT Letter ID GENOME-WIDE ASSOCIATION; LOCI C1 [Jansen, Iris E.; Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Jansen, Iris E.; Schulte, Claudia; Gasser, Thomas; Heutink, Peter] German Ctr Neurodegenerat Dis, Tubingen, Germany. [Bras, Jose M.; Wood, Nicholas W.] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Lesage, Suzanne; Brice, Alexis] Univ Paris 06, Univ Sorbonne, INSERM, CNRS, Paris, France. [Lesage, Suzanne; Brice, Alexis] Inst Cerveau & Moelle Epiniere, Paris, France. [Lesage, Suzanne; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [Schulte, Claudia; Gasser, Thomas; Heutink, Peter; Sharma, Manu] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Gibbs, J. Raphael; Nalls, Mike A.; Singleton, Andrew B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Morris, Huw] UCL, Natl Hosp Neurol & Neurosurg, London, England. [Hardy, John A.] UCL, Rita Lila Weston Inst, London, England. [Sharma, Manu] Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Ctr Genet Epidemiol, D-70276 Tubingen, Germany. RP Jansen, IE (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. EM manu.sharma@uni-tuebingen.de RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Lubbe, Steven/L-8261-2013; Morris, Huw/B-8527-2008; Wood, Nicholas/C-2505-2009 OI Morris, Huw/0000-0002-5473-3774; Wood, Nicholas/0000-0002-9500-3348 FU Medical Research Council; Wellcome Trust NR 4 TC 15 Z9 15 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD JUL PY 2015 VL 14 IS 7 BP 678 EP 679 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CK4LS UT WOS:000356195900008 PM 26067110 ER PT J AU Oezcan, A Turkbey, B Choyke, PL Akin, O Aras, O Mun, SK AF Oezcan, Alpay Tuerkbey, Baris Choyke, Peter L. Akin, Oguz Aras, Oemer Mun, Seong K. TI Interactive Feature Space Explorer(C) for multi-modal magnetic resonance imaging SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Computer-aided detection and diagnosis; Multi-modal imaging; Multi-parametric imaging; Cancer imaging; Prostate cancer; Renal cancer ID COMPUTER-AIDED DIAGNOSIS; APPARENT DIFFUSION-COEFFICIENT; PROSTATE-CANCER; MULTIPARAMETRIC MRI; MULTISPECTRAL MRI; GLEASON SCORE; IMAGES; LOCALIZATION; SEGMENTATION; DIFFERENTIATION AB Wider information content of multi-modal biomedical imaging is advantageous for detection, diagnosis and prognosis of various pathologies. However, the necessity to evaluate a large number images might hinder these advantages and reduce the efficiency. Herein, a new computer aided approach based on the utilization of feature space (FS) with reduced reliance on multiple image evaluations is proposed for research and routine clinical use. The method introduces the physician experience into the discovery process of FS biomarkers for addressing biological complexity, e.g., disease heterogeneity. This, in turn, elucidates relevant biophysical information which would not be available when automated algorithms are utilized. Accordingly, the prototype platform was designed and built for interactively investigating the features and their corresponding anatomic loci in order to identify pathologic FS regions. While the platform might be potentially beneficial in decision support generally and specifically for evaluating outlier cases, it is also potentially suitable for accurate ground truth determination in FS for algorithm development. Initial assessments conducted on two different pathologies from two different institutions provided valuable biophysical perspective. Investigations of the prostate magnetic resonance imaging data resulted in locating a potential aggressiveness biomarker in prostate cancer. Preliminary findings on renal cell carcinoma imaging data demonstrated potential for characterization of disease subtypes in the FS. (C) 2015 Elsevier Inc. All rights reserved. C1 [Oezcan, Alpay; Mun, Seong K.] Virginia Polytech Inst & State Univ, Arlington Innovat Ctr Hlth Res, Arlington, VA 22203 USA. [Tuerkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Akin, Oguz; Aras, Oemer] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Oezcan, A (reprint author), Virginia Polytech Inst & State Univ, Arlington Innovat Ctr Hlth Res, 900 N Glebe Rd, Arlington, VA 22203 USA. EM alpay@vt.edu; turkbeyi@mail.nih.gov; pchoyke@mail.nih.gov; akino@mskcc.org; araso@mskcc.org; munsk@vt.edu FU Prostate Cancer Imaging, NCI Intramural [ZIA BC 010655] FX This work is partially funded by the grant Prostate Cancer Imaging, NCI Intramural ZIA BC 010655. Special thanks to Michelle Albert Knutsen and Jim Quirk for their comments and feedback. Ibrahim Alpay Ozcan dedicates the manuscript to the memory of Ibrahim Hakki Ozcan, Afsin Baysal, Atilla Selcen, Hasan Cahit Sahin and Ahmet Rasim Bulut. NR 56 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUL PY 2015 VL 33 IS 6 BP 804 EP 815 DI 10.1016/j.mri.2015.03.007 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK3MX UT WOS:000356121300011 ER PT J AU Rouault, TA AF Rouault, Tracey A. TI Iron-sulfur proteins hiding in plain sight SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PARAMAGNETIC-RESONANCE; GENOMIC INTEGRITY; DNA METABOLISM; CLUSTERS; DEHYDROGENASE; SPECTROSCOPY; INSIGHTS; ENZYMES C1 NICHHD, Eunice Kennedy Shriver, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Eunice Kennedy Shriver, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov NR 25 TC 10 Z9 11 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUL PY 2015 VL 11 IS 7 BP 442 EP 445 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK6JO UT WOS:000356334600002 PM 26083061 ER PT J AU Abbasi, SA Hundley, WG Bluemke, DA Jerosch-Herold, M Blankstein, R Petersen, SE Rider, OJ Lima, JAC Allison, MA Murthy, VL Shah, RV AF Abbasi, S. A. Hundley, W. G. Bluemke, D. A. Jerosch-Herold, M. Blankstein, R. Petersen, Steffen E. Rider, Oliver J. Lima, J. A. C. Allison, M. A. Murthy, V. L. Shah, R. V. TI Visceral adiposity and left ventricular remodeling: The Multi-Ethnic Study of Atherosclerosis SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE Obesity; Cardiac magnetic resonance imaging; Visceral adiposity; Remodeling ID CARDIOVASCULAR RISK-FACTORS; INCIDENT HEART-FAILURE; INSULIN-RESISTANCE; WEIGHT-LOSS; SYSTOLIC FUNCTION; OBESE CHILDREN; MASS; MESA; DYSFUNCTION; FAT AB Background and aims: Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the MultiEthnic Study of Atherosclerosis (MESA). Methods and results: We performed a post-hoc analysis on 1151 participants from MESA with cardiac magnetic resonance quantification of LV mass and LV mass-to-volume ratio (LVMV, an index of concentricity) and computed tomographic-derived SQ and VF area. Multivariable regression models to estimate association between height-indexed SQ and VF area (per cm(2)/m) with height-indexed LV mass (per height(2.7)) and LVMV were constructed, adjusted for clinical, biochemical, and demographic covariates. We found that both VF and SQ area were associated with height-indexed LV mass (rho = 0.36 and 0.12, P < 0.0001, respectively), while only VF area was associated with LVMV (rho = 0.28, P < 0.0001). Individuals with above-median VF had lower LV ejection fraction, greater indexed LV volumes and mass, and higher LVMV (all P < 0.001). In multivariable models adjusted for weight, VF (but not SQ) area was associated with LV concentricity and LV mass index, across both sexes. Conclusion: Visceral adiposity is independently associated with LV concentricity, a precursor to heart failure. Further study into the role of VF in LV remodeling as a potential therapeutic target is warranted. (C) 2015 Elsevier B.V. All rights reserved. C1 [Blankstein, R.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Noninvas Cardiovasc Imaging Program, Boston, MA 02115 USA. [Jerosch-Herold, M.; Blankstein, R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Hundley, W. G.] Wake Forest Univ Hlth Sci, Dept Internal Med Cardiol, Winston Salem, NC USA. [Bluemke, D. A.] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Lima, J. A. C.] Johns Hopkins Sch Med, Inst Heart & Vasc, Div Cardiol, Baltimore, MD USA. [Allison, M. A.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Murthy, V. L.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Murthy, V. L.] Univ Michigan, Dept Radiol, Div Nucl Med, Ann Arbor, MI 48109 USA. [Shah, R. V.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Abbasi, S. A.] Brown Univ, Warren Alpert Med Sch, Dept Med, Div Cardiol, Providence, RI 02912 USA. [Petersen, Steffen E.] Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, London, England. [Rider, Oliver J.] Univ Oxford, Dept Cardiovasc Med, Oxford, England. RP Murthy, VL (reprint author), Univ Michigan, Ann Arbor Med Radiol, 1500 E Med Ctr Dr,SPC 5873, Ann Arbor, MI 48109 USA. EM vlmurthy@med.umich.edu; rshah1@bidmc.harvard.edu RI Murthy, Venkatesh/B-3448-2013; Petersen, Steffen/A-8389-2011; OI Murthy, Venkatesh/0000-0002-7901-1321; Petersen, Steffen/0000-0003-4622-5160; Bluemke, David/0000-0002-8323-8086; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95168, N01-HC-95169]; NCRR [UL1-TR-000040, UL1-RR-025005]; American Heart Association FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR. Dr. Shah is supported by an American Heart Association Fellow-to-Faculty Award. NR 30 TC 8 Z9 8 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 EI 1590-3729 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD JUL PY 2015 VL 25 IS 7 BP 667 EP 676 DI 10.1016/j.numecd.2015.03.016 PG 10 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA CK5BV UT WOS:000356238000007 PM 26033394 ER PT J AU Jones, RR Barone-Adesi, F Koutros, S Lerro, CC Blair, A Lubin, J Heltshe, SL Hoppin, JA Alavanja, MCR Freeman, LEB AF Jones, Rena R. Barone-Adesi, Francesco Koutros, Stella Lerro, Catherine C. Blair, Aaron Lubin, Jay Heltshe, Sonya L. Hoppin, Jane A. Alavanja, Michael C. R. Freeman, Laura E. Beane TI Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study: an updated analysis SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID NON-HODGKINS-LYMPHOMA; LUNG-CANCER; UNITED-STATES; OXIDATIVE STRESS; RISK-FACTORS; COHORT; EXPRESSION; KIDNEY; CELLS; LIVER AB Objective Diazinon, a common organophosphate insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. Methods Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with >= 10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). Results We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; P-trend=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; P-trend=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RRLT days=1.77; 95% CI 0.90 to 3.51; P-trend=0.09; RRIW days 1.37; 95% CI 0.64 to 2.92; P-trend=0.50), as were risks for aggressive prostate cancer (N=656). Conclusions Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation. C1 [Jones, Rena R.; Koutros, Stella; Lerro, Catherine C.; Blair, Aaron; Lubin, Jay; Alavanja, Michael C. R.; Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Barone-Adesi, Francesco] Univ London, Populat Hlth Res Inst, London, England. [Heltshe, Sonya L.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. RP Jones, RR (reprint author), NCI, Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,Room 6E116, Rockville, MD 20850 USA. EM rena.jones@nih.gov RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU intramural research programme of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01CP010119] FX This research was supported by the intramural research programme of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01CP010119). NR 36 TC 9 Z9 10 U1 1 U2 13 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JUL PY 2015 VL 72 IS 7 BP 496 EP 503 DI 10.1136/oemed-2014-102728 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK5WR UT WOS:000356298200007 PM 25907210 ER PT J AU Tanaka, N Takahashi, S Zhang, Y Krausz, KW Smith, PB Patterson, AD Gonzalez, FJ AF Tanaka, Naoki Takahashi, Shogo Zhang, Yuan Krausz, Kristopher W. Smith, Philip B. Patterson, Andrew D. Gonzalez, Frank J. TI Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE ER stress; Lipotoxicity; ATGL; PGC1 alpha; PPAR alpha ID FATTY LIVER-DISEASE; ENDOPLASMIC-RETICULUM STRESS; ACTIVATED RECEPTOR-ALPHA; PPAR-ALPHA; NONALCOHOLIC STEATOHEPATITIS; ANTIDIABETIC ACTIONS; FGF21; MICE; EXPRESSION; FIBROBLAST-GROWTH-FACTOR-21 AB Fibroblast growth factor 21 (FGF21) is a modulator of energy homeostasis and is increased in human nonalcoholic liver disease (NAFLD) and after feeding of methionine- and choline-deficient diet (MCD), a conventional inducer of murine nonalcoholic steatohepatitis (NASH). However, the significance of FGF21 induction in the occurrence of MCD-induced NASH remains undetermined. C57BL/6J Fgf21-null and wild-type mice were treated with MCD for 1 week. Hepatic Fgf21 mRNA was increased early after commencing MCD treatment independent of peroxisome proliferator-activated receptor (PPAR) a and farnesoid X receptor. While no significant differences in white adipose lipolysis were seen in both genotypes, hepatic triglyceride (TG) contents were increased in Fgf21-null mice, likely due to the up-regulation of genes encoding CD36 and phosphatidic acid phosphatase 2a/2c, involved in fatty acid (FA) uptake and diacylglycerol synthesis, respectively, and suppression of increased mRNAs encoding camitine palmitoyl-CoA transferase 1 alpha, PPAR gamma coactivator 1 alpha, and adipose TG lipase, which are associated with lipid clearance in the liver. The MCD-treated Fgf21-null mice showed increased hepatic endoplasmic reticulum (ER) stress. Exposure of primary hepatocytes to palmitic acid elevated the mRNA levels encoding DNA damage-inducible transcript 3, an indicator of ER stress, and FGF21 in a PPAR alpha-independent manner, suggesting that lipid-induced ER stress can enhance hepatic FGF21 expression. Collectively, FGF21 is elevated in the early stage of MCD-induced NASH likely to minimize hepatic lipid accumulation and ensuing ER stress. These results provide a possible mechanism on how FGF21 is increased in NAFLD/NASH. Published by Elsevier B.V. C1 [Tanaka, Naoki; Takahashi, Shogo; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tanaka, Naoki] Shinshu Univ, Grad Sch Med, Dept Metab Regulat, Matsumoto, Nagano 390, Japan. [Zhang, Yuan] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX USA. [Smith, Philip B.; Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Smith, Philip B.; Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health [U554 ES16015, 1R01ES022186-01] FX We thank Linda G. Byrd and John Buckley for providing technical assistance with the mouse studies. This study was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, U554 ES16015 and 1R01ES022186-01, National Institutes of Health. NR 46 TC 20 Z9 20 U1 1 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL PY 2015 VL 1852 IS 7 BP 1242 EP 1252 DI 10.1016/j.bbadis.2015.02.012 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CJ7YB UT WOS:000355715200003 PM 25736301 ER PT J AU Phillips, J Millum, J AF Phillips, John Millum, Joseph TI Valuing Stillbirths SO BIOETHICS LA English DT Article DE priority setting; global health; stillbirth; miscarriage; QALY; DALY ID FETAL PAIN; MORAL SIGNIFICANCE; ABORTION; DISEASE; HEALTH; SYPHILIS; INJURY; BURDEN; BIRTH; RISK AB Estimates of the burden of disease assess the mortality and morbidity that affect a population by producing summary measures of health such as quality-adjusted life years (QALYs) and disability-adjusted life years (DALYs). These measures typically do not include stillbirths (fetal deaths occurring during the later stages of pregnancy or during labor) among the negative health outcomes they count. Priority-setting decisions that rely on these measures are therefore likely to place little value on preventing the more than three million stillbirths that occur annually worldwide. In contrast, neonatal deaths, which occur in comparable numbers, have a substantial impact on burden of disease estimates and are commonly seen as a pressing health concern. In this article we argue in favor of incorporating unintended fetal deaths that occur late in pregnancy into estimates of the burden of disease. Our argument is based on the similarity between late-term fetuses and newborn infants and the assumption that protecting newborns is important. We respond to four objections to counting stillbirths: (1) that fetuses are not yet part of the population and so their deaths should not be included in measures of population health; (2) that valuing the prevention of stillbirths will undermine women's reproductive rights; (3) that including stillbirths implies that miscarriages (fetal deaths early in pregnancy) should also be included; and (4) that birth itself is in fact ethically significant. We conclude that our proposal is ethically preferable to current practice and, if adopted, is likely to lead to improved decisions about health spending. C1 [Phillips, John] Univ N Carolina, Philosophy, Chapel Hill, NC USA. RP Millum, J (reprint author), NIH, Ctr Clin, Dept Bioeth, Fogarty Int Ctr, Bldg 10,1C118,10 Ctr Dr, Bethesda, MD 20892 USA. EM joseph.millum@nih.gov FU National Institutes of Health Clinical Center FX This work was supported, in part, by intramural funds from the National Institutes of Health Clinical Center. NR 41 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD JUL PY 2015 VL 29 IS 6 BP 413 EP 423 DI 10.1111/bioe.12120 PG 11 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA CJ9YI UT WOS:000355859500006 PM 25395144 ER PT J AU Sinningen, K Albus, E Thiele, S Grossklaus, S Kurth, T Udey, MC Chavakis, T Hofbauer, LC Rauner, M AF Sinningen, Kathrin Albus, Elise Thiele, Sylvia Grossklaus, Sylvia Kurth, Thomas Udey, Mark C. Chavakis, Triantafyllos Hofbauer, Lorenz C. Rauner, Martina TI Loss of milk fat globule-epidermal growth factor 8 (MFG-E8) in mice leads to low bone mass and accelerates ovariectomy-associated bone loss by increasing osteoclastogenesis SO BONE LA English DT Article DE MFG-E8; Osteoblast; Osteoclast; Bone homeostasis ID ISCHEMIA-REPERFUSION INJURY; APOPTOTIC CELLS; FACTOR-VIII; INTESTINAL INFLAMMATION; OSTEOCYTE APOPTOSIS; DISEASE; MOUSE; IDENTIFICATION; CLEARANCE; ROLES AB Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that controls the engulfment of apoptotic cells and exerts inflammation-modulatory effects. Recently, it has been implicated in osteoclastogenesis and the pathogenesis of inflammatory periodontal bone loss, but its role in physiological bone homeostasis is still not well defined. Here, we evaluated the influence of MFG-E8 on osteoblasts and osteoclasts and its impact on bone remodeling in healthy and ovariectomized mice as a model for post-menopausal osteoporosis. Total and trabecular bone mineral densities at the lumbar spine in 6-week-old MFG-E8 KO mice were reduced by 11% (p < 0.05) and 17% (p < 0.01), respectively, as compared to wild-type (WT) mice. Accordingly, serum levels of the bone formation marker P1NP were decreased by 37% (p < 0.01) in MFG-E8 KO mice as were the ex vivo mineralization capacity and expression of osteoblast genes (Runx2, alkaline phosphatase, osteocalcin) in MFG-E8 KO osteoblasts. In contrast, serum bone resorption markers CTX1 and TRAP5b were increased by 30% and 60% (p < 0.05), respectively, in MFG-E8 KO mice. Furthermore, bone marrow macrophages from MFG-E8-KO mice differentiated more effectively into osteoclasts, as compared to WT cells. MFG-E8-deficient osteoclasts displayed increased bone resorption ex vivo, which could be reversed by the presence of recombinant MFG-E8. To determine the significance of the enhanced osteoclastogenesis in MFG-E8 KO mice, we performed an ovariectomy, which is associated with bone loss due to increased osteoclast activity. Indeed, MFG-E8 KO mice lost 12% more trabecular bone density than WT mice after ovariectomy. Together, these data indicate that MFG-E8 controls steady-state and pathological bone turnover and may therefore represent a new target gene in the treatment of bone diseases. (C) 2015 Elsevier Inc. All rights reserved. C1 [Sinningen, Kathrin; Albus, Elise; Thiele, Sylvia; Hofbauer, Lorenz C.; Rauner, Martina] Tech Univ Dresden, Dept Med 3, Div Endocrinol & Metab Bone Dis, D-01307 Dresden, Germany. [Grossklaus, Sylvia; Chavakis, Triantafyllos] Tech Univ Dresden, Inst Clin Chem & Lab Med, Dept Clin Pathobiochem, D-01307 Dresden, Germany. [Kurth, Thomas] Ctr Regenerat Therapies Dresden, Electron Microscopy Facil, Dresden, Germany. [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chavakis, Triantafyllos; Hofbauer, Lorenz C.] DFG Res Ctr Regenerat Therapies Dresden, Dresden, Germany. RP Rauner, M (reprint author), Tech Univ Dresden, Med Ctr, Dept Med 3, Div Endocrinol Diabet & Bone Dis, Fetscherstr 74, D-01307 Dresden, Germany. EM martina.rauner@uniklinikum-dresden.de RI Hofbauer, Lorenz/G-2490-2010 OI Hofbauer, Lorenz/0000-0002-8691-8423 FU Else Kroner Fresenius-Stiftung; German Rheumatology Society; Boehringer Ingelheim Fonds; German Research Foundation [RA1923/4-2, HO1875/8-2]; Center for Cancer Research, National Cancer Institute of the National Institutes of Health FX We would like to thank Patrick Bohme, Tina Dybek, and Nicole Pacyna for the excellent technical assistance. This work was supported by a grant from the Else Kroner Fresenius-Stiftung, the start-up grant of the German Rheumatology Society, the Boehringer Ingelheim Fonds, and the German Research Foundation (RA1923/4-2 and HO1875/8-2, Immunobone) to MR and LCH. MCU is supported by funds from the Center for Cancer Research, National Cancer Institute in the Intramural Research Program of the National Institutes of Health. NR 32 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD JUL PY 2015 VL 76 BP 107 EP 114 DI 10.1016/j.bone.2015.04.003 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ7ZE UT WOS:000355718100013 PM 25868798 ER PT J AU Liu, YM Shim, E Crespo-Mejias, Y Nguyen, P Gibbons, A Liu, D Shide, E Poirier, MC AF Liu, Yongmin Shim, Eunwoo Crespo-Mejias, Yasmin PhuongGiang Nguyen Gibbons, Alexander Liu, Daniel Shide, Eric Poirier, Miriam C. TI Cardiomyocytes are Protected from Antiretroviral Nucleoside Analog-Induced Mitochondrial Toxicity by Overexpression of PGC-1 alpha SO CARDIOVASCULAR TOXICOLOGY LA English DT Article DE NRTI; H9c2 cells; Zidovudine; Didanosine; Seahorse analyzer; Complex I ID REVERSE-TRANSCRIPTASE INHIBITORS; OXIDATIVE STRESS; PERINATAL EXPOSURE; PGC-1 COACTIVATORS; BIOGENESIS; DNA; DYSFUNCTION; CELLS; HEART; GENE AB The nucleoside reverse transcriptase inhibitors (NRTIs), used for treatment of the human immunodeficiency virus-1, compromise mitochondria in cardiomyocytes and other host cells, limiting the clinical use of these drugs. To explore underlying mechanisms, we overexpressed PGC-1 alpha, a master regulator of mitochondrial biogenesis, twofold in H9c2 rat cardiomyocyte cultures, hypothesizing that this might protect the mitochondria from damage induced by the NRTI combination zidovudine (AZT) and didanosine (ddI). The experimental groups, evaluated during 16 passages (P) of drug exposure, included: PGC-1 alpha-overexpressing cells with no exposure, or exposure to 50 A mu M AZT plus 50 A mu M ddI; and control cells with no exposure or exposure to the same doses of AZT and ddI. The AZT/ddI combination caused a growth inhibition of 15-20 % in control cells, but none in PGC-1 alpha cells. Apoptosis was highest in AZT/ddI-exposed control cells, and PGC-1 alpha overexpression protected cells from AZT/ddI-induced apoptosis. At P3, P6, P8, and P12, uncoupled mitochondrial oxygen consumption rate, determined by Seahorse 24 XF Analyzer, as higher in AZT/ddI-exposed PGC-1 alpha cells, compared to AZT/ddI-exposed control cells (p < 0.05 at all P). Complex I activity was higher in AZT/ddI-exposed PGC-1 alpha overexpressing cells than that in AZT/ddI-exposed control cells (p < 0.05), and reactive oxygen species levels were lower in PGC-1 alpha overexpressing cells than that in control cells (p < 0.05) when both were exposed to AZT/ddI. Taken together, these experiments show proof of concept that overexpression of PGC-1 alpha protects cardiomyocytes from NRTI-induced toxicity, and suggest that a pharmaceutical agent with similar activity may protect against NRTI-induced mitochondrial toxicity. C1 [Liu, Yongmin; Shim, Eunwoo; Crespo-Mejias, Yasmin; PhuongGiang Nguyen; Gibbons, Alexander; Liu, Daniel; Shide, Eric; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, CCR,NIH, Bethesda, MD 20892 USA. RP Liu, YM (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, CCR,NIH, Bldg 37,Rm 4032,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM yongminl@mail.nih.gov OI Nguyen, Phuonggiang/0000-0003-1638-1584 FU Center for Cancer Research, National Cancer Institute, NIH FX This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. We wish to thank Alexandra Michalowski for statistical support. NR 32 TC 1 Z9 2 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1530-7905 EI 1559-0259 J9 CARDIOVASC TOXICOL JI Cardiovasc. Toxicol. PD JUL PY 2015 VL 15 IS 3 BP 224 EP 231 DI 10.1007/s12012-014-9288-5 PG 8 WC Cardiac & Cardiovascular Systems; Toxicology SC Cardiovascular System & Cardiology; Toxicology GA CJ8TL UT WOS:000355776300004 PM 25377427 ER PT J AU Sclafani, V Paukner, A Suomi, SJ Ferrari, PF AF Sclafani, Valentina Paukner, Annika Suomi, Stephen J. Ferrari, Pier F. TI Imitation promotes affiliation in infant macaques at risk for impaired social behaviors SO DEVELOPMENTAL SCIENCE LA English DT Article ID TO-FACE INTERACTION; COMMUNICATIVE GAZE; NONHUMAN PRIMATE; EARLY EXPERIENCE; NEWBORN-INFANTS; RHESUS MACAQUES; AUTISM; CHILDREN; DEPRESSION; GESTURES AB Parental responsiveness and synchronization during early face-to-face interactions between mother and infant have been theorized to affect a broad spectrum of positive developmental outcomes in social and cognitive infant growth and to facilitate the development of a sense of self in the baby. Here we show that being imitated can significantly affect the behavior of nursery-reared infant monkeys, which are at an increased risk for developing aberrant social behaviors. Infants look longer and lipsmack more at an experimenter both during imitation and after being imitated. These results demonstrate that from early in life imitation might be used as a privileged form of communication by adults to enhance infants' visual engagement and their social communication. Imitation may therefore be useful to counteract the negative effects of early social adversities. C1 [Sclafani, Valentina; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Sclafani, Valentina; Paukner, Annika; Suomi, Stephen J.; Ferrari, Pier F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Anim Ctr, Bethesda, MD USA. RP Sclafani, V (reprint author), Dipartimento Neurosci, Via Volturno 39, I-43100 Parma, Italy. EM valentinasclafani@gmail.com FU Division of Intramural Research, NICHD; NIH [PO1HD064653] FX This research was supported by the Division of Intramural Research, NICHD, and by NIH PO1HD064653 grant. We thank E.A. Simpson and the nursery staff in the Laboratory of Comparative Ethology for assisting in data collection. NR 60 TC 4 Z9 4 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1363-755X EI 1467-7687 J9 DEVELOPMENTAL SCI JI Dev. Sci. PD JUL PY 2015 VL 18 IS 4 BP 614 EP 621 DI 10.1111/desc.12237 PG 8 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA CJ6TF UT WOS:000355625900008 PM 25227917 ER PT J AU Basavaraju, U Shebl, FM Palmer, AJ Berry, S Hold, GL El-Omar, EM Rabkin, CS AF Basavaraju, Umesh Shebl, Fatma M. Palmer, Andrew J. Berry, Susan Hold, Georgina L. El-Omar, Emad M. Rabkin, Charles S. TI Cytokine gene polymorphisms, cytokine levels and the risk of colorectal neoplasia in a screened population of Northeast Scotland SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article ID C-REACTIVE PROTEIN; GASTRIC-CANCER; INFLAMMATORY CYTOKINES; COMMON POLYMORPHISMS; COLON-CANCER; ASSOCIATION; ADENOMA; METAANALYSIS; INTERLEUKIN-6; PROMOTER AB Cytokine gene polymorphisms modify expression and their circulating protein levels reflect inflammatory response. Chronic inflammation plays a key role in the pathogenesis of colorectal neoplasia (CRN) associated with inflammatory bowel disease, but it is not clear whether inflammation is a cause or an effect of tumours in sporadic CRN. We therefore investigated the association of cytokine gene polymorphisms and circulating cytokine levels on the risk of CRN in Northeast Scotland, which has a high incidence of CRN. We recruited two groups of patients from a screening colonoscopy cohort, either preprocedure or 3-24 months postprocedure. Participants with CRN were compared with participants with no evidence of CRN (controls). Blood-derived DNA was used to genotype polymorphisms in IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes. Circulating levels of high-sensitivity C-reactive protein and six cytokines [interleukin-1 beta (IL-1 beta), IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha (TNF-alpha)] were measured. To examine the effect of CRN resection on marker levels, we used propensity score matching. A total of 884 patients were eligible for analysis, including 388 CRN cases and 496 controls. Cases were older (mean age 64 vs. 62 years, P < 0.01) and more likely to be men (67 vs. 55%, P < 0.001). Controls were more likely to be regular users of NSAID (P < 0.0001). Compared with homozygous carriage of respective common alleles, proinflammatory CC genotypes of IL1B-31C > T [odds ratio (OR) (95% confidence interval (CI) 1.68 (1.03-2.73)] and PTGS2-765 C > G [OR (95% CI) 2.97 (1.05-8.46)] were each associated with an increased risk of CRN. Conversely, carriage of the A allele of IL8-251A > T was associated with a lower risk of CRN compared with the TT genotype [ORs (95% CI) 0.60 (0.41-0.86) for heterozygous, 0.88 (0.57-1.37) for homozygous, and 0.68 (0.48-0.95) for heterozygous and homozygous combined]. Compared with postprocedure cases, IL8, TNF-alpha and C-reactive protein levels were significantly higher in preprocedure cases, but IL4 and IL10 protein levels were significantly lower. Proinflammatory cytokine gene polymorphisms in IL1B-31 and PTGS2-765 increase the risk of developing CRN. Levels of proinflammatory IL8, TNF-alpha and C-reactive protein markers are significantly higher while CRN is in situ. Along with the NSAID findings, these data point to inflammation as an underlying pathogenetic mechanism in CRN. C1 [Basavaraju, Umesh; Palmer, Andrew J.; Berry, Susan; Hold, Georgina L.; El-Omar, Emad M.] Univ Aberdeen, Div Appl Med, Gastrointestinal Res Grp, Aberdeen AB25 2ZD, Scotland. [Shebl, Fatma M.; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP El-Omar, EM (reprint author), Univ Aberdeen, Div Appl Med, Gastrointestinal Res Grp, Aberdeen AB25 2ZD, Scotland. EM e.el-omar@abdn.ac.uk FU charity CRANES (Cancer Research Aberdeen and Northeast Scotland); CRANES; Friends of Anchor FX Umesh Basavaraju was supported by a clinical fellowship awarded by the charity CRANES (Cancer Research Aberdeen and Northeast Scotland). This work was supported by funding CRANES and Friends of Anchor. NR 45 TC 8 Z9 8 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-8278 EI 1473-5709 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUL PY 2015 VL 24 IS 4 BP 296 EP 304 DI 10.1097/CEJ.0000000000000087 PG 9 WC Oncology SC Oncology GA CJ7EY UT WOS:000355658400004 PM 25350634 ER PT J AU Lee, H Kim, M Kim, N Macfarlan, T Pfaff, SL Mastick, GS Song, MR AF Lee, Hojae Kim, Minkyung Kim, Namhee Macfarlan, Todd Pfaff, Samuel L. Mastick, Grant S. Song, Mi-Ryoung TI Slit and Semaphorin signaling governed by Islet transcription factors positions motor neuron somata within the neural tube SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Islet1; Islet2; Neuropilinl; Slit2; Motor neuron somata ID LIM HOMEODOMAIN PROTEINS; AXON GUIDANCE; NERVOUS-SYSTEM; EXIT POINTS; INTERNEURON PROGRAMS; CREST CELLS; SPINAL-CORD; FACTOR HB9; IDENTITY; RECEPTOR AB Motor neurons send out axons to peripheral muscles while their cell bodies remain in the ventral spinal cord. The unique configuration of motor neurons spanning the border between the CNS and PNS has been explained by structural barriers such as boundary cap (BC) cells, basal lamina and radial glia. However, mechanisms in motor neurons that retain their position have not been addressed yet. Here we demonstrate that the Islet1 (Isl1) and Islet2 (Isl2) transcription factors, which are essential for acquisition of motor neuron identity, also contribute to restrict motor neurons within the neural tube. In mice that lack both Isl1 and Is12, large numbers of motor neurons exited the neural tube, even prior to the appearance of BC cells at the ventral exit points. Transcriptional profiling of motor neurons derived from Isl1 null embryonic stem cells revealed that transcripts of major genes involved in repulsive mechanisms were misregulated. Particularly, expression of Neuropilinl (Npr1) and Slit2 mRNA was diminished in Islet mutant mice, and these could be target genes of the Islet proteins. Consistent with this mechanism, Robo and Slit mutations in mice and knockdown of Npr1 and Slit2 in chick embryos caused motor neurons to migrate to the periphery. Together, our study suggests that Islet genes engage Robo-Slit and Neuropilin-Semaphorin signaling in motor neurons to retain motor somata within the CNS. (C) 2015 Elsevier Inc. All rights reserved. C1 [Lee, Hojae; Kim, Namhee; Song, Mi-Ryoung] Gwangju Inst Sci & Technol, Sch Life Sci, Cell Dynam Res Ctr, Gwangju 500712, South Korea. [Kim, Minkyung; Mastick, Grant S.] Univ Nevada, Dept Biol, Reno, NV 89557 USA. [Macfarlan, Todd] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Pfaff, Samuel L.] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. [Pfaff, Samuel L.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. RP Song, MR (reprint author), Gwangju Inst Sci & Technol, Sch Life Sci, Cell Dynam Res Ctr, Gwangju 500712, South Korea. EM msong@gist.ac.kr OI Macfarlan, Todd/0000-0003-2495-9809 FU NRF [2013R1A1A2058548, 2007-0056157]; Cell Dynamics Research Center; Intergrative Aging Research Center of Gwangju Institute of Science and Technology; KHIDI [HI14C3484]; NIH [RO1 NS054740, R21 NS077169] FX We thank the BioImaging Research Center and Systems Biology Research Center at GIST for use of the confocal imaging facility. Support for M-RS and this research was provided by grants from NRF (2013R1A1A2058548), the Cell Dynamics Research Center, NRF, (2007-0056157), Intergrative Aging Research Center of Gwangju Institute of Science and Technology and KHIDI HI14C3484. Support for GSM and MK include NIH RO1 NS054740 and R21 NS077169 to GSM, and use of tissue culture and imaging core facilities was supported by P20 RR-016464, P20 GM103440, P20 GM103554, and P20 GM103650. NR 54 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2015 VL 269 BP 17 EP 27 DI 10.1016/j.expneurol.2015.03.024 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CJ6YH UT WOS:000355640600003 PM 25843547 ER PT J AU Yang, LY Chu, YH Tweedie, D Yu, QS Pick, CG Hoffer, BJ Greig, NH Wang, JY AF Yang, L-Y. Chu, Y-H. Tweedie, D. Yu, Q-S. Pick, C. G. Hoffer, B. J. Greig, N. H. Wang, J-Y TI Post-trauma administration of the pifithrin-alpha oxygen analog improves histological and functional outcomes after experimental traumatic brain injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Traumatic brain injury (TBI); p53; Pifithrin-alpha (PFT-alpha); PFT-alpha oxygen analog; Apoptosis; Controlled cortical impact ID GLOBAL CEREBRAL-ISCHEMIA; HIPPOCAMPAL CA1 NEURONS; SEVERE HEAD-INJURY; INDUCED APOPTOSIS; CELL-DEATH; EXCITOTOXIC INSULTS; PROTEIN EXPRESSION; BH3-ONLY PROTEINS; DOPAMINE NEURONS; TRANSGENIC MICE AB Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Programmed death of neuronal cells plays a crucial role in acute and chronic neurodegeneration following TBI. The tumor suppressor protein p53, a transcription factor, has been recognized as an important regulator of apoptotic neuronal death. The p53 inactivator pifithrin-alpha (PET-alpha) has been shown to be neuroprotective against stroke. A previous cellular study indicated that PFT-alpha oxygen analog (PFT-alpha (O)) is more stable and active than PET-alpha. We aimed to investigate whether inhibition of p53 using PFT-alpha or PET-alpha (O) would be a potential neuroprotective strategy for TBI. To evaluate whether these drugs protect against excitotoxicity in vitro, primary rat cortical cultures were challenged with glutamate (50 mM) in the presence or absence of various concentrations of the p53 inhibitors PFT-alpha or PET-alpha (O). Cell viability was estimated by LDH assay. In vivo, adult Sprague Dawley rats were subjected to controlled cortical impact (CCI, with 4 m/s velocity, 2 mm deformation). Five hours after injury, PET-alpha or PET-alpha (O) (2 mg/kg, i.v.) was administered to animals. Sensory and motor functions were evaluated by behavioral tests at 24 h after TBI. The p53-positive neurons were identified by double staining with cell-specific markers. Levels of mRNA encoding for p53-regulated genes (BAX, PUMA, Bcl-2 and p21) were measured by reverse transcription followed by real time-PCR from TBI animals without or with PET-alpha/PET-alpha (O) treatment We found that PET-alpha(O) (10 mu M) enhanced neuronal survival against glutamate-induced cytotoxicity in vitro more effectively than PET-alpha (10 mu M). In vivo PET-alpha (O) treatment enhanced functional recovery and decreased contusion volume at 24 h post-injury. Neuroprotection by PET-alpha (O) treatment also reduced p53-positive neurons in the cortical contusion region. In addition, p53-regulated PUMA mRNA levels at 8 h were significantly reduced by PET-alpha (O) administration after TBI. PFT-alpha (O) treatment also decreased phospho-p53 positive neurons in the cortical contusion region. Our data suggest that PET-alpha (O) provided a significant reduction of cortical cell death and protected neurons from glutamate-induced excitotoxicity in vitro, as well as improved neurological functional outcome and reduced brain injury in vivo via anti-apoptotic mechanisms. The inhibition of p53-induced apoptosis by PFT-alpha (O) provides a useful tool to evaluate reversible apoptotic mechanisms and may develop into a novel therapeutic strategy for TBI. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yang, L-Y.; Chu, Y-H.; Wang, J-Y] Taipei Med Univ, Grad Inst Med Sci, Coll Med, Taipei 110, Taiwan. [Tweedie, D.; Yu, Q-S.; Greig, N. H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Pick, C. G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Pick, C. G.] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Hoffer, B. J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH USA. [Wang, J-Y] Taipei Med Univ, Dept Physiol, Coll Med, Sch Med, Taipei 110, Taiwan. RP Wang, JY (reprint author), Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Hsing St, Taipei 110, Taiwan. EM jywang2010@tmu.edu.tw RI Pick, Chaim/D-4789-2009 FU Ministry of Science and Technology, Taiwan [MOST103-2321-B-038-002]; Intramural Research Program, National Institute on Aging, NIH, USA FX This study was supported in part by a grant from the Ministry of Science and Technology (MOST103-2321-B-038-002 to JY Wang), Taiwan, and by the Intramural Research Program, National Institute on Aging, NIH, USA. NR 65 TC 7 Z9 8 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 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2015 VL 269 BP 56 EP 66 DI 10.1016/j.expneurol.2015.03.015 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CJ6YH UT WOS:000355640600006 PM 25819102 ER PT J AU Kwon, BK Streijger, F Hill, CE Anderson, AJ Bacon, M Beattie, MS Blesch, A Bradbury, EJ Brown, A Bresnahan, JC Case, CC Colburn, RW David, S Fawcett, JW Ferguson, AR Fischer, I Floyd, CL Gensel, JC Houle, JD Jakeman, LB Jeffery, ND Jones, LAT Kleitman, N Kocsis, J Lu, P Magnuson, DSK Marsala, M Moore, SW Mothe, AJ Oudega, M Plant, GW Rabchevsky, AS Schwab, JM Silver, J Steward, O Xu, XM Guest, JD Tetzlaff, W AF Kwon, Brian K. Streijger, Femke Hill, Caitlin E. Anderson, Aileen J. Bacon, Mark Beattie, Michael S. Blesch, Armin Bradbury, Elizabeth J. Brown, Arthur Bresnahan, Jacqueline C. Case, Casey C. Colburn, Raymond W. David, Samuel Fawcett, James W. Ferguson, Adam R. Fischer, Itzhak Floyd, Candace L. Gensel, John C. Houle, John D. Jakeman, Lyn B. Jeffery, Nick D. Jones, Linda Ann Truett Kleitman, Naomi Kocsis, Jeffery Lu, Paul Magnuson, David S. K. Marsala, Martin Moore, Simon W. Mothe, Andrea J. Oudega, Martin Plant, Giles W. Rabchevsky, Alexander Sasha Schwab, Jan M. Silver, Jerry Steward, Oswald Xu, Xiao-Ming Guest, James D. Tetzlaff, Wolfram TI Large animal and primate models of spinal cord injury for the testing of novel therapies SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Large animal models; Primate models; Questionnaire; Translation; Drug therapies; Cellular therapies ID PRECLINICAL EVALUATION; NONHUMAN PRIMATE; RECOMMENDATIONS; REGENERATION; TRIALS; STROKE AB Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose unique research questions prior to clinical trials, the role that such large animal and primate models should play in the translational pipeline is unclear. In this initiative we engaged members of the SCI research community in a questionnaire and round-table focus group discussion around the use of such models. Forty-one SCI researchers from academia, industry, and granting agencies were asked to complete a questionnaire about their opinion regarding the use of large animal and primate models in the context of testing novel therapeutics. The questions centered around how large animal and primate models of SCI would be best utilized in the spectrum of preclinical testing, and how much testing in rodent models was warranted before employing these models. Further questions were posed at a focus group meeting attended by the respondents. The group generally felt that large animal and primate models of SCI serve a potentially useful role in the translational pipeline for novel therapies, and that the rational use of these models would depend on the type of therapy and specific research question being addressed. While testing within these models should not be mandatory, the detection of beneficial effects using these models lends additional support for translating a therapy to humans. These models provides an opportunity to evaluate and refine surgical procedures prior to use in humans, and safety and bio-distribution in a spinal cord more similar in size and anatomy to that of humans. Our results reveal that while many feel that these models are valuable in the testing of novel therapies, important questions remain unanswered about how they should be used and how data derived from them should be interpreted. (C) 2015 Elsevier Inc. All rights reserved. C1 [Kwon, Brian K.; Streijger, Femke; Tetzlaff, Wolfram] Univ British Columbia, ICORD, Blusson Spinal Cord Ctr, Vancouver, BC V5Z 1M9, Canada. [Hill, Caitlin E.] Weill Cornell Med Coll, Burke Med Res Inst, White Plains, NY 10605 USA. [Anderson, Aileen J.] UC Irvine, Irvine, CA 92697 USA. [Bacon, Mark] Int Spinal Res Trust, Bramley Business Ctr, Guildford GU5 0AZ, Surrey, England. [Beattie, Michael S.; Bresnahan, Jacqueline C.] Univ Calif San Francisco, San Francisco, CA 94110 USA. [Blesch, Armin] Univ Heidelberg Hosp, Spinal Cord Injury Ctr, Heidelberg, Germany. [Bradbury, Elizabeth J.] Kings Coll London, Wolfson Ctr Age Related Dis, London SE1 1UL, England. [Brown, Arthur] Univ Western Ontario, Dept Anat & Cell Biol, Robarts Res Inst, London, ON N6A 5B7, Canada. [Case, Casey C.] Asterias Biotherapeut, Menlo Pk, CA 94025 USA. [Colburn, Raymond W.] Acorda Therapeut Inc, Ardsley, NY 10502 USA. [David, Samuel] McGill Univ, Ctr Hlth, Res Inst, Ctr Res Neurosci, Montreal, PQ H3G 1A4, Canada. [Fawcett, James W.] Univ Cambridge, John van Geest Ctr Brain Repair, Cambridge CB2 0PY, England. [Ferguson, Adam R.] Univ Calif San Francisco, Brain & Spinal Injury Ctr BASIC, Dept Neurol Surg, San Francisco, CA 94110 USA. [Fischer, Itzhak] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Floyd, Candace L.] Univ Alabama Birmingham, Birmingham, AL 35249 USA. [Gensel, John C.] Univ Kentucky, Spinal Cord & Brain Injury Res Ctr, Lexington, KY 40536 USA. [Houle, John D.] Drexel Univ, Coll Med, Spinal Cord Res Ctr, Philadelphia, PA 19129 USA. [Jakeman, Lyn B.] NINDS, NIH, Bethesda, MD 20852 USA. [Jeffery, Nick D.] Iowa State Univ, Coll Vet Med, Lloyd Vet Med Ctr, Ames, IA 50011 USA. [Jones, Linda Ann Truett; Kleitman, Naomi] Craig H Neilsen Fdn, Encino, CA 91436 USA. [Kocsis, Jeffery] Yale Univ, West Haven, CT 06516 USA. [Kocsis, Jeffery] VA CT Healthcare Ctr, Neurosci Ctr 127A, VA CT Healthcare Syst, West Haven, CT 06516 USA. [Lu, Paul] Univ Calif San Diego, VA San Diego Healthcare Syst, La Jolla, CA 92093 USA. [Magnuson, David S. K.] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Marsala, Martin] Univ Calif San Diego, Dept Anesthesiol SCRM, La Jolla, CA 92037 USA. [Moore, Simon W.] InVivo Therapeut Corp, Cambridge, MA 02139 USA. [Mothe, Andrea J.] Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. [Oudega, Martin] Univ Miami, Miller Sch Med, LPLC, Miami, FL 33136 USA. [Plant, Giles W.] Stanford Univ, Stanford, CA 94305 USA. [Rabchevsky, Alexander Sasha] Univ Kentucky, Lexington, KY 40536 USA. [Schwab, Jan M.] Ohio State Univ, Neurol, Columbus, OH 43210 USA. [Silver, Jerry] Case Western Reserve Univ, Dept Neurosci, Sch Med, Cleveland, OH 44106 USA. [Steward, Oswald] Univ Calif Irvine, Sch Med, Dept Anat & Neurobiol, Reeve Irvine Res Ctr, Irvine, CA 92697 USA. [Xu, Xiao-Ming] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Guest, James D.] Univ Miami, Neurol Surg, Miami, FL 33136 USA. RP Kwon, BK (reprint author), Univ British Columbia, Dept Orthopaed, ICORD Int Collaborat Repair Discoveries, Blusson Spinal Cord Ctr,VGH, 6th Floor,818 West 10th Ave, Vancouver, BC V5Z 1M9, Canada. EM brian.kwon@ubc.ca; femkestreijger@gmail.com; cah2024@med.cornell.edu; aja@uci.edu; mark@spinal-research.org; Michael.beattie@ucsf.edu; armin.blesch@med.uni-heidelberg.de; elizabeth.bradbury@kcl.ac.uk; abrown@robarts.ca; Jacqueline.bresnahan@ucsf.edu; ccase@asteriasbio.com; rcolburn@acorda.com; sam.david@mcgill.ca; jf108@cam.ac.uk; Adam.ferguson@ucsf.edu; Itzhak.Fischer@DrexelMed.edu; clfloyd@uab.edu; Gensel.1@uky.edu; jhoule@drexelmed.edu; lyn.jakeman@nih.gov; njeffery@iastate.edu; linda@chnfoundation.org; naomi@chnfoundation.org; jeffery.kocsis@yale.edu; plu@ucsd.edu; david.magnuson@louisville.edu; mmarsala@ucsd.edu; smoore@invivotherapeutics.com; amothe@uhnres.utoronto.ca; moudega@pitt.edu; gplant@stanford.edu; agrab@uky.edu; jan.schwab@osumc.edu; jxs10@case.edu; osteward@uci.edu; Xu26@iupui.edu; jguest@med.miami.edu; tetzlaff@icord.org RI Brown, Arthur/K-8328-2013; Fischer, Itzhak/D-1080-2012; OI Fischer, Itzhak/0000-0003-3187-8740; Xu, Xiao-ming/0000-0002-7229-0081; Blesch, Armin/0000-0003-1133-1174; Steward, Oswald/0000-0001-7069-8756; Jeffery, Nick/0000-0002-9812-1788; Kleitman, Naomi/0000-0003-1089-0257; Magnuson, David/0000-0003-3816-3676; , John/0000-0001-8980-108X; Fawcett, James/0000-0002-7990-4568 FU Rick Hansen Foundation [17S71110] FX Funding for this initiative was provided by a grant from the Rick Hansen Foundation (17S71110) to the Blusson Integrated Cure Partnership between ICORD and the Rick Hansen Institute. The sponsor had no role in the study design, data collection, interpretaion, and manuscript writing. The authors also gratefully acknowledge the assistance of Leilani Reichl and Andrew Pennington of the Vancouver Spine Research Program. BKK is the Canada Research Chair in Spinal Cord Injury. WT is the John and Penny Ryan BC Leadership Chair in Spinal Cord Research. NR 24 TC 12 Z9 13 U1 2 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2015 VL 269 BP 154 EP 168 DI 10.1016/j.expneurol.2015.04.008 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CJ6YH UT WOS:000355640600015 PM 25902036 ER PT J AU Deye, JA AF Deye, James A. TI Evidence-Based Quality Assurance for Radiation Therapy Clinical Trials In Regard to the Science Council and Therapy Physics Committee of AAPM SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 NCI, Radiat Res Program, Bethesda, MD 20892 USA. RP Deye, JA (reprint author), NCI, Radiat Res Program, Shady Grove Campus, Bethesda, MD 20892 USA. NR 2 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2015 VL 92 IS 3 BP 699 EP 699 DI 10.1016/j.ijrobp.2015.02.033 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CJ6WV UT WOS:000355636800034 PM 26068497 ER PT J AU Rizk, ML Du, LH Bennetto-Hood, C Wenning, L Teppler, H Homony, B Graham, B Fry, C Nachman, S Wiznia, A Worrell, C Smith, B Acosta, EP AF Rizk, Matthew L. Du, Lihong Bennetto-Hood, Chantelle Wenning, Larissa Teppler, Hedy Homony, Brenda Graham, Bobbie Fry, Carrie Nachman, Sharon Wiznia, Andrew Worrell, Carol Smith, Betsy Acosta, Edward P. TI Population pharmacokinetic analysis of raltegravir pediatric formulations in HIV-infected children 4 weeks to 18 years of age SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE raltegravir; pharmacokinetics; HIV; AIDS; pediatrics; IMPAACT study ID HUMAN PLASMA; SAFETY; EFFICACY; THERAPY; TRIAL AB P1066 is an open-label study of raltegravir in HIV positive youth, ages 4 weeks-18 years. Here we summarize P1066 pharmacokinetic (PK) data and a population PK model for the pediatric chewable tablet and oral granules. Raltegravir PK parameters were calculated using noncompartmental analysis. A 2-compartment model was developed using data from P1066 and an adult study of the pediatric formulations. Interindividual variability was described by an exponential error model, and residual variability was captured by an additive/proportional error model. Twelve-hour concentrations (C-12h) were calculated from the model-derived elimination rate constant and 8-hour observed concentration. Simulated steady-state concentrations were analyzed by noncompartmental analysis. Target area under the curve (AUC(0-12h)) and C-12h were achieved in each cohort. For the pediatric formulations, geometric mean AUC(0-12h) values were 18.0-22.6M-hr across cohorts, and C-12h values were 71-130nM, with lower coefficients of variation versus the film-coated tablet. A 2-compartment model with first-order absorption adequately described raltegravir plasma PK in pediatric and adult patients. Weight was a covariate on clearance and central volume and was incorporated using allometric scaling. Raltegravir chewable tablets and oral granules exhibited PK parameters consistent with those from prior adult studies and older children in P1066, as well as lower variability than the film-coated tablet. C1 [Rizk, Matthew L.; Du, Lihong; Wenning, Larissa; Teppler, Hedy; Homony, Brenda] Merck Sharp & Dohme Corp, Kenilworth, NJ USA. [Bennetto-Hood, Chantelle; Acosta, Edward P.] Univ Alabama Birmingham, Birmingham, AL USA. [Graham, Bobbie; Fry, Carrie] Frontier Sci Inc, Buffalo, NY USA. [Nachman, Sharon] SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA. [Wiznia, Andrew] Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10467 USA. [Worrell, Carol] NICHHD, Bethesda, MD 20892 USA. [Worrell, Carol; Smith, Betsy] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Rizk, ML (reprint author), Merck Res Labs, 351 North Sumneytown Pike, N Wales, PA 19454 USA. EM matthew.rizk@merck.com FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); NIAID, NIH, Department of Health and Human Services [HHSN272200800014C]; NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network - NICHD [N01-DK-9-001/HHSN267200800001C]; Merck Co. Inc.; NIAID 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) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACTLOC), UM1AI068616 (IMPAACTSDMC), and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). This project has been funded in whole or in part with federal funds from the NIAID, NIH, Department of Health and Human Services, under contract number HHSN272200800014C. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C), and by Merck & Co. Inc. Raltegravir supplies were provided by Merck & Co., Inc. NR 14 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUL PY 2015 VL 55 IS 7 BP 748 EP 756 DI 10.1002/jcph.493 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK0AJ UT WOS:000355865700006 PM 25753401 ER PT J AU Summersett-Ringgold, FC Li, KG Haynie, DL Iannotti, RJ AF Summersett-Ringgold, Faith C. Li, Kaigang Haynie, Denise L. Iannotti, Ronald J. TI Do School Resources Influence the Relationship Between Adolescent Financial Background and Their School Perceptions? SO JOURNAL OF SCHOOL HEALTH LA English DT Article DE school funding; school psychology; professional preparation of school health personnel ID EDUCATIONAL SUCCESS; CHILDREN; FAMILY; NEIGHBORHOOD; ACHIEVEMENT; PERSPECTIVE; ENVIRONMENT; ENGAGEMENT; ADJUSTMENT; MOTIVATION AB BACKGROUNDSocioeconomic status (SES) influences students' school perceptions and affects their performance, engagement, and personal beliefs. This study examined the effects of school population SES and school resources on the association between student SES and student perceptions. METHODSSchool liking, classmate social relationships, family affluence, and experience of hunger were assessed in a nationally representative sample of 12,642 students (grades 5-10) in the 2009-2010 Health Behavior in School-Aged Children study. School characteristics included school meal program, Title 1 dollars received per student, school resources, and urban/rural status. Multilevel analysis was used. RESULTSAt the individual level, both school liking and social relationships were negatively associated with student grade level. Boys liked school less and had more positive perceptions of social relationships than girls. Students in rural schools and who experienced hunger liked schools less and had poorer perceptions of social relationships than their respective counterparts. School-level percentage of students eligible for free/reduced meals accounted for 33% of the between-school variance in social relationships. CONCLUSIONSFamily and school economic characteristics and grade level influenced students' school perceptions. The associations between student SES, school population SES, and school perceptions suggests that school health professionals should recognize and address student economic issues at school. C1 [Summersett-Ringgold, Faith C.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Li, Kaigang; Haynie, Denise L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20852 USA. [Iannotti, Ronald J.] Univ Massachusetts, Dept Exercise & Hlth Sci, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Summersett-Ringgold, FC (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, 710N Lake Shore Dr, Chicago, IL 60611 USA. EM faithsummersett@u.northwestern.edu; kaigang.li@nih.gov; Denise_Haynie@nih.gov; Ronald.Iannotti@umb.edu OI Haynie, Denise/0000-0002-8270-6079 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Maternal and Child Health Bureau of the Health Resources and Services Administration [HHSN2672008000009C] FX This research was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Maternal and Child Health Bureau of the Health Resources and Services Administration, contract number HHSN2672008000009C. NR 45 TC 0 Z9 0 U1 5 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4391 EI 1746-1561 J9 J SCHOOL HEALTH JI J. Sch. Health PD JUL PY 2015 VL 85 IS 7 BP 413 EP 422 DI 10.1111/josh.12267 PG 10 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA CJ7MR UT WOS:000355680300001 PM 26032271 ER PT J AU Maawy, AA Hiroshima, Y Zhang, Y Garcia-Guzman, M Luiken, GA Kobayashi, H Hoffman, RM Bouvet, M AF Maawy, Ali A. Hiroshima, Yukihiko Zhang, Yong Garcia-Guzman, Miguel Luiken, George A. Kobayashi, Hisataka Hoffman, Robert M. Bouvet, Michael TI Photoimmunotherapy lowers recurrence after pancreatic cancer surgery in orthotopic nude mouse models SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Pancreatic cancer; Orthotopic mouse models; Photoimmunotherapy; CEA; Surgery ID FLUORESCENCE-GUIDED SURGERY; ANTI-CEA ANTIBODY; NEAR-INFRARED PHOTOIMMUNOTHERAPY; HUMAN COLON-CANCER; IMAGING-SYSTEM; PATIENT; TUMOR; RESECTION; MICE; SURVIVAL AB Background: Photoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti-carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted human pancreatic cancer in a nude mouse model to eliminate microscopic disease in the post-surgical tumor bed and prevent local as well as metastatic recurrence. Materials and methods: Athymic nude mice were orthotopically implanted with the human pancreatic cancer cell line BxPC3 expressing green fluorescent protein. After tumor engraftment, the mice were divided into two groups as follows: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT); and BLS only. Anti-CEA-IR700 (100 mu g) was administered to the treatment group via tail-vein injection 24 h before therapy. Tumors were resected, and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm(2) for 30 min. Mice were imaged noninvasively for 8 wk using an OV-100 small animal fluorescence imager. Results: BLS + PIT reduced local recurrence to 1/7 mice from 7/7 mice with BLS-only (P = 0.001) and metastatic recurrence to 2/7 mice compared with 6/7 mice with BLS-only (P = 0.03). Local tumor growth continued at a rapid rate after BLS-only compared with BLS + PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS + PIT (2.14 mm(2), 95% confidence interval [CI] [-2.06 to 6.34] and BLS-only groups (115.2 mm(2), 95% CI [88.8-141.6]) at 6 wk after surgery (P < 0.001). There was also a significant difference in tumor weight between the BLS + PIT group (6.65 mg, 95% CI [-6.35 to 19.65] and BLS-only group (1100 mg, 95% CI [794-1406] at 8 wk after surgery (P < 0.001). Conclusions: PIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that can lead to both local and metastatic recurrence. Further studies are warranted to investigate the potential toxicities of PIT, especially with regard to anastomoses, such as those involved in pancreaticoduodenectomy. (C) 2015 Elsevier Inc. All rights reserved. C1 [Maawy, Ali A.; Hiroshima, Yukihiko; Hoffman, Robert M.; Bouvet, Michael] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [Hiroshima, Yukihiko; Zhang, Yong; Hoffman, Robert M.] AntiCancer Inc, San Diego, CA USA. [Hiroshima, Yukihiko] Yokohama City Univ, Dept Surg, Yokohama, Kanagawa 232, Japan. [Garcia-Guzman, Miguel] Aspyrian Therapeut, San Diego, CA USA. [Luiken, George A.] OncoFluor Inc, San Diego, CA USA. [Kobayashi, Hisataka] NIH, Bethesda, MD USA. [Bouvet, Michael] VA Healthcare Syst, Dept Surg, San Diego, CA USA. RP Bouvet, M (reprint author), Moores UCSD Canc Ctr, Dept Surg, 3855 Hlth Sci,Dr 0987, La Jolla, CA 92093 USA. EM mbouvet@ucsd.edu FU National Cancer Institute [CA142669, CA132971] FX This work is supported in part by grants from the National Cancer Institute CA142669 and CA132971 (to M.B. and Anti-Cancer, Inc). NR 26 TC 6 Z9 6 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD JUL PY 2015 VL 197 IS 1 BP 5 EP 11 DI 10.1016/j.jss.2015.02.037 PG 7 WC Surgery SC Surgery GA CJ5UA UT WOS:000355554900002 PM 25799527 ER PT J AU Ogden, KM Hu, LY Jha, BK Sankaran, B Weiss, SR Silverman, RH Patton, JT Prasad, BVV AF Ogden, Kristen M. Hu, Liya Jha, Babal K. Sankaran, Banumathi Weiss, Susan R. Silverman, Robert H. Patton, John T. Prasad, B. V. Venkataram TI Structural Basis for 2 '-5 '-Oligoadenylate Binding and Enzyme Activity of a Viral RNase L Antagonist SO JOURNAL OF VIROLOGY LA English DT Article ID ANTIVIRAL INNATE IMMUNITY; DOUBLE-STRANDED-RNA; PROTEIN-KINASE PKR; MURINE CORONAVIRUS; L PATHWAY; INTERFERON; ROTAVIRUS; PHOSPHODIESTERASE; SYSTEM; 2-5A AB Synthesis of 2'-5'-oligoadenylates (2-5A) by oligoadenylate synthetase (OAS) is an important innate cellular response that limits viral replication by activating the latent cellular RNase, RNase L, to degrade single-stranded RNA. Some rotaviruses and corona-viruses antagonize the OAS/RNase L pathway through the activity of an encoded 2H phosphoesterase domain that cleaves 2-5A. These viral 2H phosphoesterases are phylogenetically related to the cellular A kinase anchoring protein 7 (AKAP7) and share a core structure and an active site that contains two well-defined H Phi(S/T)Phi (where Phi is a hydrophobic residue) motifs, but their mechanism of substrate binding is unknown. Here, we report the structures of a viral 2H phosphoesterase, the C-terminal domain (CTD) of the group A rotavirus (RVA) VP3 protein, both alone and in complex with 2-5A. The domain forms a compact fold, with a concave beta-sheet that contains the catalytic cleft, but it lacks two alpha-helical regions and two beta-strands observed in AKAP7 and other 2H phosphoesterases. The cocrystal structure shows significant conformational changes in the R loop upon ligand binding. Bioinformatics and biochemical analyses reveal that conserved residues and residues required for catalytic activity and substrate binding comprise the catalytic motifs and a region on one side of the binding cleft. We demonstrate that the VP3 CTD of group B rotavirus, but not that of group G, cleaves 2-5A. These findings suggest that the VP3 CTD is a streamlined version of a 2H phosphoesterase with a ligand-binding mechanism that is shared among 2H phosphodiesterases that cleave 2-5A. IMPORTANCE The C-terminal domain (CTD) of rotavirus VP3 is a 2H phosphoesterase that cleaves 2'-5'-oligoadenylates (2-5A), potent activators of an important innate cellular antiviral pathway. 2H phosphoesterase superfamily proteins contain two conserved catalytic motifs and a proposed core structure. Here, we present structures of a viral 2H phosphoesterase, the rotavirus VP3 CTD, alone and in complex with its substrate, 2-5A. The domain lacks two alpha-helical regions and beta-strands present in other 2H phosphoesterases. A loop of the protein undergoes significant structural changes upon substrate binding. Together with our bioinformatics and biochemical findings, the crystal structures suggest that the RVA VP3 CTD domain is a streamlined version of a cellular enzyme that shares a ligand-binding mechanism with other 2H phosphodiesterases that cleave 2-5A but differs from those of 2H phosphodiesterases that cleave other substrates. These findings may aid in the future design of antivirals targeting viral phosphodiesterases with cleavage specificity for 2-5A. C1 [Ogden, Kristen M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Hu, Liya; Prasad, B. V. Venkataram] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Jha, Babal K.; Silverman, Robert H.] Cleveland Clin, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44106 USA. [Sankaran, Banumathi] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley Ctr Struct Biol, Berkeley, CA 94720 USA. [Weiss, Susan R.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Prasad, BVV (reprint author), Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. EM vprasad@bcm.edu OI Weiss, Susan/0000-0002-8155-4528 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the NIH; NIH [R37 AI36040, RO1-AI104887]; Robert Welch Foundation [Q1279]; NIH; National Institute of General Medical Sciences; Howard Hughes Medical Institute; Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the NIH (to K.M.O. and J.T.P.), by NIH grants R37 AI36040 (to B.V.V.P.) and RO1-AI104887 (to S.R.W. and R.H.S.), and by Robert Welch Foundation grant Q1279 (to B.V.V.P.). The Berkeley Center for Structural Biology is supported in part by the NIH, National Institute of General Medical Sciences, and by the Howard Hughes Medical Institute. The Advanced LightSource is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under contract number DE-AC02-05CH11231. NR 46 TC 7 Z9 7 U1 2 U2 17 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 JUL PY 2015 VL 89 IS 13 BP 6633 EP 6645 DI 10.1128/JVI.00701-15 PG 13 WC Virology SC Virology GA CJ6GW UT WOS:000355593000011 PM 25878106 ER PT J AU Liu, L Patel, B Ghanem, MH Bundoc, V Zheng, ZL Morgan, RA Rosenberg, SA Dey, B Berger, EA AF Liu, Li Patel, Bhavik Ghanem, Mustafa H. Bundoc, Virgilio Zheng, Zhili Morgan, Richard A. Rosenberg, Steven A. Dey, Barna Berger, Edward A. TI Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MODIFIED T-CELLS; ENVELOPE GLYCOPROTEIN; CANCER-IMMUNOTHERAPY; ADOPTIVE THERAPY; SOLUBLE CD4; STEM-CELLS; IN-VIVO; GP120; INFECTION AB Adoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding. We compared a standard CD4 CAR with CD4-17b CARs where the polypeptide linker between the CD4 and 17b moieties is sufficiently long (CD4-35-17b CAR) versus too short (CD4-10-17b) to permit simultaneous binding of the two moieties to a single gp120 subunit. When transduced into a peripheral blood mononuclear cell (PBMC) or T cells thereof, all three CD4-based CARs displayed specific functional activities against HIV-1 Env-expressing target cells, including stimulation of gamma interferon (IFN-gamma) release, specific target cell killing, and suppression of HIV-1 pseudovirus production. In assays of spreading infection of PBMCs with genetically diverse HIV-1 primary isolates, the CD4-10-17b CAR displayed enhanced potency compared to the CD4 CAR whereas the CD4-35-17b CAR displayed diminished potency. Importantly, both CD4-17b CARs were devoid of a major undesired activity observed with the CD4 CAR, namely, rendering the transduced CD8(+) T cells susceptible to HIV-1 infection. Likely mechanisms for the superior potency of the CD4-10-17b CAR over the CD4-35-17b CAR include the greater potential of the former to engage in the serial antigen binding required for efficient T cell activation and the ability of two CD4-10-17b molecules to simultaneously bind a single gp120 subunit. IMPORTANCE HIV research has been energized by prospects for a cure for HIV infection or, at least, for a "functional cure" whereby antiretroviral therapy can be discontinued without virus rebound. This report describes a novel CD4-based "chimeric antigen receptor" (CAR) which, when genetically engineered into T cells, gives them the capability to selectively respond to and kill HIV-infected cells. This CAR displays enhanced features compared to previously described CD4-based CARs, namely, increased potency and avoidance of the undesired rendering of the genetically modified CD8 T cells susceptible to HIV infection. When adoptively transferred back to the individual, the genetically modified T cells will hopefully provide durable killing of infected cells and sustained virus suppression without continued antiretroviral therapy, i.e., a functional cure. C1 [Liu, Li; Patel, Bhavik; Ghanem, Mustafa H.; Bundoc, Virgilio; Dey, Barna; Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Zheng, Zhili; Morgan, Richard A.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM edward_berger@nih.gov FU Division of Intramural Research of NIAID and NCI; NIH Intramural AIDS Targeted Antiviral Program FX This research was funded in part by the Division of Intramural Research of NIAID and NCI and by the NIH Intramural AIDS Targeted Antiviral Program. NR 70 TC 13 Z9 13 U1 1 U2 16 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 JUL PY 2015 VL 89 IS 13 BP 6685 EP 6694 DI 10.1128/JVI.00474-15 PG 10 WC Virology SC Virology GA CJ6GW UT WOS:000355593000015 PM 25878112 ER PT J AU Yang, ZL Cao, S Martens, CA Porcella, SF Xie, Z Ma, M Shen, B Moss, B AF Yang, Zhilong Cao, Shuai Martens, Craig A. Porcella, Stephen F. Xie, Zhi Ma, Ming Shen, Ben Moss, Bernard TI Deciphering Poxvirus Gene Expression by RNA Sequencing and Ribosome Profiling SO JOURNAL OF VIROLOGY LA English DT Article ID GENOME-WIDE ANALYSIS; LATE MESSENGER-RNAS; HINDIII-D FRAGMENT; VACCINIA-VIRUS; NUCLEOTIDE RESOLUTION; EUKARYOTIC SYSTEMS; INITIATION SITES; SECRETED PROTEIN; DNA-SEQUENCE; IN-VIVO AB The more than 200 closely spaced annotated open reading frames, extensive transcriptional read-through, and numerous unpredicted RNA start sites have made the analysis of vaccinia virus gene expression challenging. Genome-wide ribosome profiling provided an unprecedented assessment of poxvirus gene expression. By 4 h after infection, approximately 80% of the ribosomeassociated mRNA was viral. Ribosome-associated mRNAs were detected for most annotated early genes at 2 h and for most intermediate and late genes at 4 and 8 h. Cluster analysis identified a subset of early mRNAs that continued to be translated at the later times. At 2 h, there was excellent correlation between the abundance of individual mRNAs and the numbers of associated ribosomes, indicating that expression was primarily transcriptionally regulated. However, extensive transcriptional readthrough invalidated similar correlations at later times. The mRNAs with the highest density of ribosomes had host response, DNA replication, and transcription roles at early times and were virion components at late times. Translation inhibitors were used to map initiation sites at single-nucleotide resolution at the start of most annotated open reading frames although in some cases a downstream methionine was used instead. Additional putative translational initiation sites with AUG or alternative codons occurred mostly within open reading frames, and fewer occurred in untranslated leader sequences, antisense strands, and intergenic regions. However, most open reading frames associated with these additional translation initiation sites were short, raising questions regarding their biological roles. The data were used to construct a high-resolution genome-wide map of the vaccinia virus translatome. IMPORTANCE This report contains the first genome-wide, high-resolution analysis of poxvirus gene expression at both transcriptional and translational levels. The study was made possible by recent methodological advances allowing examination of the translated regions of mRNAs including start sites at single-nucleotide resolution. Vaccinia virus ribosome-associated mRNA sequences were detected for most annotated early genes at 2 h and for most intermediate and late genes at 4 and 8 h after infection. The ribosome profiling approach was particularly valuable for poxviruses because of the close spacing of approximately 200 open reading frames and extensive transcriptional read-through resulting in overlapping mRNAs. The expression of intermediate and late genes, in particular, was visualized with unprecedented clarity and quantitation. We also identified novel putative translation initiation sites that were mostly associated with short protein coding sequences. The results provide a framework for further studies of poxvirus gene expression. C1 [Yang, Zhilong; Cao, Shuai] Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. [Martens, Craig A.; Porcella, Stephen F.] NIAID, Res Technol Sect, Genom Unit, Rocky Mt Labs,NIH, Hamilton, MT USA. [Xie, Zhi] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510275, Guangdong, Peoples R China. [Ma, Ming; Shen, Ben] Scripps Res Inst, Dept Chem, Jupiter, FL USA. [Shen, Ben] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL USA. [Shen, Ben] Scripps Res Inst, Nat Prod Lib Initiat, Jupiter, FL USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yang, ZL (reprint author), Kansas State Univ, Div Biol, Ackert Hall, Manhattan, KS 66506 USA. EM zyang@ksu.edu; bmoss@nih.gov FU National Institute of Allergy and Infectious Diseases [R00AI100919]; National Institute of General Medical Sciences [P20 GM103418]; National Cancer Institute grant [CA106150]; intramural research funds from the National Institute of Allergy and Infectious Diseases FX This project was supported in part by grants from the National Institute of Allergy and Infectious Diseases (R00AI100919) and National Institute of General Medical Sciences (a subaward of P20 GM103418) to Z.Y., by a National Cancer Institute grant (CA106150) to B.S., and by intramural research funds from the National Institute of Allergy and Infectious Diseases to B.M. NR 53 TC 12 Z9 12 U1 1 U2 11 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 JUL PY 2015 VL 89 IS 13 BP 6874 EP 6886 DI 10.1128/JVI.00528-15 PG 13 WC Virology SC Virology GA CJ6GW UT WOS:000355593000030 PM 25903347 ER PT J AU Baz, M Paskel, M Matsuoka, Y Zengel, JR Cheng, X Treanor, JJ Jin, H Subbarao, K AF Baz, Mariana Paskel, Myeisha Matsuoka, Yumiko Zengel, James R. Cheng, Xing Treanor, John J. Jin, Hong Subbarao, Kanta TI A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets SO JOURNAL OF VIROLOGY LA English DT Article ID PHASE-I TRIAL; A VIRUS; HEALTHY-ADULTS; PROTECTIVE IMMUNITY; ANTIBODY-RESPONSES; LIVE; TRANSMISSION; EQUINE; REPLICATION; CANDIDATE AB H3N8 influenza viruses are a commonly found subtype in wild birds, usually causing mild or no disease in infected birds. However, they have crossed the species barrier and have been associated with outbreaks in dogs, pigs, donkeys, and seals and therefore pose a threat to humans. A live attenuated, cold-adapted (ca) H3N8 vaccine virus was generated by reverse genetics using the wild-type (wt) hemagglutinin (HA) and neuraminidase (NA) genes from the A/blue-winged teal/Texas/Sg-00079/2007 (H3N8) (tl/TX/079/07) wt virus and the six internal protein gene segments from the ca influenza A virus vaccine donor strain, A/Ann Arbor/6/60 ca (H2N2), the backbone of the licensed seasonal live attenuated influenza vaccine. One dose of the tl/TX/079/07 ca vaccine induced a robust neutralizing antibody response against the homologous (tl/TX/079/07) and two heterologous influenza viruses, including the recently emerged A/harbor seal/New Hampshire/179629/2011 (H3N8) and A/northern pintail/Alaska/44228-129/2006 (H3N8) viruses, and conferred robust protection against the homologous and heterologous influenza viruses. We also analyzed human sera against the tl/TX/079/07 H3N8 avian influenza virus and observed low but detectable antibody reactivity in elderly subjects, suggesting that older H3N2 influenza viruses confer some cross-reactive antibody. The latter observation was confirmed in a ferret study. The safety, immunogenicity, and efficacy of the tl/TX/079/07 ca vaccine in mice and ferrets support further evaluation of this vaccine in humans for use in the event of transmission of an H3N8 avian influenza virus to humans. The human and ferret serology data suggest that a single dose of the vaccine may be sufficient in older subjects. IMPORTANCE Although natural infection of humans with an avian H3N8 influenza virus has not yet been reported, this influenza virus subtype has already crossed the species barrier and productively infected mammals. Pandemic preparedness is an important public health priority. Therefore, we generated a live attenuated avian H3N8 vaccine candidate and demonstrated that a single dose of the vaccine was highly immunogenic and protected mice and ferrets against homologous and heterologous H3N8 avian viruses. C1 [Baz, Mariana; Paskel, Myeisha; Matsuoka, Yumiko; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Zengel, James R.; Cheng, Xing; Jin, Hong] MedImmune LLC, Mountain View, CA USA. [Treanor, John J.] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural Research Program of the NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH, and was performed as part of a Cooperative Research and Development Agreement between the Laboratory of Infectious Diseases, NIAID, and MedImmune, LLC. NR 43 TC 2 Z9 2 U1 2 U2 10 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 JUL PY 2015 VL 89 IS 13 BP 6907 EP 6917 DI 10.1128/JVI.00280-15 PG 11 WC Virology SC Virology GA CJ6GW UT WOS:000355593000033 PM 25903333 ER PT J AU Ghosh, S Canugovi, C Yoon, JS Wilson, DM Croteau, DL Mattson, MP Bohr, VA AF Ghosh, Somnath Canugovi, Chandrika Yoon, Jeong Seon Wilson, David M., III Croteau, Deborah L. Mattson, Mark P. Bohr, Vilhelm A. TI Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice SO NEUROBIOLOGY OF AGING LA English DT Article DE Base excision repair; Stroke; Xrcc1; Oxidative stress ID BASE EXCISION-REPAIR; STRAND BREAK REPAIR; LIGASE-III; POLYMERASE-BETA; POLYNUCLEOTIDE KINASE; ALZHEIMERS-DISEASE; CEREBRAL-ISCHEMIA; OXIDATIVE STRESS; GLYCOSYLASE; DEATH AB Oxidative DNA damage is mainly repaired by base excision repair (BER). Previously, our laboratory showed that mice lacking the BER glycosylases 8-oxoguanine glycosylase 1 (Ogg1) or nei endonuclease VIII-like 1 (Neil1) recover more poorly from focal ischemic stroke than wild-type mice. Here, a mouse model was used to investigate whether loss of 1 of the 2 alleles of X-ray repair cross-complementing protein 1 (Xrcc1), which encodes a nonenzymatic scaffold protein required for BER, alters recovery from stroke. Ischemia and reperfusion caused higher brain damage and lower functional recovery in Xrcc1(+/-) mice than in wild-type mice. Additionally, a greater percentage of Xrcc1(+/-) mice died as a result of the stroke. Brain samples from human individuals who died of stroke and individuals who died of non-neurological causes were assayed for various steps of BER. Significant losses of thymine glycol incision, abasic endonuclease incision, and single nucleotide incorporation activities were identified, as well as lower expression of XRCC1 and NEIL1 proteins in stroke brains compared with controls. Together, these results suggest that impaired BER is a risk factor in ischemic brain injury and contributes to its recovery. Published by Elsevier Inc. C1 [Ghosh, Somnath; Canugovi, Chandrika; Wilson, David M., III; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA IRP, Lab Mol Gerontol, Biomed Res Ctr, Baltimore, MD 21224 USA. [Yoon, Jeong Seon; Mattson, Mark P.] NIA IRP, Lab Neurosci, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA IRP, Lab Mol Gerontol, Biomed Res Ctr, 251 Bayview Blvd,Ste 100, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural Research Program of the National Institutes of Health and National Institute on Aging [AG 000723-07]; NINDS/NIMH [CA 90073]; National Multiple Sclerosis Society; Department of Veterans Affairs FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health and National Institute on Aging (AG 000723-07). The authors would like to thank Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, Los Angeles, CA 90073 which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, and Department of Veterans Affairs for the human postmortem brain samples used in this study. Additionally, the authors would like to thank Drs. Beverly A. Baptiste and Raghavendra A. Shamanna for critically reading the manuscript. NR 46 TC 3 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2015 VL 36 IS 7 BP 2319 EP 2330 DI 10.1016/j.neurobiolaging.2015.04.004 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CJ3JH UT WOS:000355378700010 PM 25971543 ER PT J AU Szabo, S Mody, M Romero, R Xu, Y Karaszi, K Mihalik, N Xu, Z Bhatti, G Fule, T Hupuczi, P Krenacs, T Rigo, J Tarca, AL Hassan, SS Chaiworapongsa, T Kovalszky, I Papp, Z Than, NG AF Szabo, Szilvia Mody, Meera Romero, Roberto Xu, Yi Karaszi, Katalin Mihalik, Noemi Xu, Zhonghui Bhatti, Gaurav Fule, Tibor Hupuczi, Petronella Krenacs, Tibor Rigo, Janos, Jr. Tarca, Adi L. Hassan, Sonia S. Chaiworapongsa, Tinnakorn Kovalszky, Ilona Papp, Zoltan Than, Nandor Gabor TI Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome SO PATHOLOGY & ONCOLOGY RESEARCH LA English DT Article DE Anti-angiogenic factor; Hypertension; Mitogen activated protein kinase; Oxidative stress; Pregnancy; Signal transduction; Syncytiotrophoblast ID LATE-ONSET PREECLAMPSIA; GENE-EXPRESSION; PLACENTAL EXPRESSION; OXIDATIVE STRESS; MESSENGER-RNA; HUMAN TERM; KAPPA-B; APOPTOSIS; PREGNANCY; PROTEIN AB Preterm preeclampsia is associated with the failure of trophoblast invasion, placental hypoxic/ischemic injury and the release of toxic substances, which promote the terminal pathway of preeclampsia. In term preeclampsia, factors yet unknown trigger the placenta to induce the terminal pathway. The contribution of the villous trophoblast to these pathologic events has not been fully elucidated. Here we aimed to study how stress and signaling pathways influence trophoblastic functions in various subforms of preeclampsia. Tissue microarrays (TMAs) were constructed from placentas obtained from pregnant women in the following groups: 1-2) preterm preeclampsia with (n = 8) or without (n = 7) HELLP syndrome; 3) late-onset preeclampsia (n = 8); 4-5) preterm (n = 5) and term (n = 9) controls. TMA slides were stained for phosphorylated Akt-1, ERK1/2, JNK, and p38 kinases, and trophoblastic immunostainings were semi-quantitatively evaluated. BeWo cells were kept in various stress conditions, and the expression of FLT1, GCM1, LEP, and PGF was profiled by qRT-PCR, while Akt-1, ERK1/2, JNK, and p38 kinase activities were measured with phospho-kinase immunoassays. We found that: 1) Placental LEP and FLT1 expression was up-regulated in preterm preeclampsia with or without HELLP syndrome compared to controls; 2) Mean pp38 immunoscore was higher in preterm preeclampsia, especially in cases with HELLP syndrome, than in controls. 3) Mean pERK1/2 immunoscore was higher in preterm preeclampsia with HELLP syndrome than in controls. 4) In BeWo cells, ischemia up-regulated LEP expression, and it increased JNK and decreased ERK1/2 activity. 5) Hypoxia up-regulated FLT1 and down-regulated PGF expression, and it increased ERK1/2, JNK and p38 activity. 6) IL-1 beta treatment down-regulated PGF expression, and it increased JNK and p38 activity. 7) The p38 signaling pathway had the most impact on LEP, FLT1 and PGF expression. In conclusion, hypoxic and ischemic stress, along with unknown factors, activates trophoblastic p38 signaling, which has a key role in villous trophoblastic functional changes in preterm preeclampsia. The activation of ERK1/2 signaling may induce additional trophoblastic functional changes in HELLP syndrome, while distinct mechanisms may promote late-onset preeclampsia. C1 [Szabo, Szilvia] Semmelweis Univ, Fac Hlth Sci, Dept Morphol & Physiol, H-1085 Budapest, Hungary. [Szabo, Szilvia; Karaszi, Katalin; Mihalik, Noemi; Fule, Tibor; Krenacs, Tibor; Kovalszky, Ilona; Than, Nandor Gabor] Semmelweis Univ, Fac Med, Dept Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. [Mody, Meera; Romero, Roberto; Xu, Yi; Xu, Zhonghui; Bhatti, Gaurav; Tarca, Adi L.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Than, Nandor Gabor] Inst Child Hlth & Human Dev Eunice Kennedy Shrive, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI 48201 USA. [Mody, Meera] Univ Chicago, Chicago, IL 60637 USA. [Mihalik, Noemi] Semmelweis Univ, Fac Med, Dept Dermatol Dermatooncol & Venerol, H-1085 Budapest, Hungary. [Hupuczi, Petronella; Rigo, Janos, Jr.; Papp, Zoltan; Than, Nandor Gabor] Semmelweis Univ, Fac Med, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. [Hupuczi, Petronella; Papp, Zoltan; Than, Nandor Gabor] Semmelweis Univ, Fac Med, Matern Private Dept, H-1085 Budapest, Hungary. [Tarca, Adi L.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Than, Nandor Gabor] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Than, Nandor Gabor] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, Budapest, Hungary. RP Kovalszky, I (reprint author), Semmelweis Univ, Fac Med, Dept Pathol & Expt Canc Res 1, Ulloi St 26, H-1085 Budapest, Hungary. EM romeror@mail.nih.gov; koval@korb1.sote.hu; nthan@med.wayne.edu FU European Union [Pregenesys 037244]; Federal funds from the NICHD [HHSN275201300006C]; Hungarian Academy of Sciences Momentum grant [LP2014-7/2014] FX The experiments, analysis and interpretation of data and/or writing of the manuscript were supported, in part, by: the European Union FP6 grant "Pregenesys 037244" (to N.G.T.); the Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH, DHHS); Federal funds from the NICHD under Contract No. HHSN275201300006C; and the Hungarian Academy of Sciences Momentum grant (#LP2014-7/2014 to N.G.T.). The authors thank everyone who made this work possible, including patients, nurses, lab staff, and clinicians. The authors are grateful to Dr. Katalin Eder, Edit Parsch, Dr. Tibor Varkonyi (Semmelweis University), Po Jen Chiang, Jianhua Du and Dr. Theodore Price (Wayne State University) for their helpful technical assistance, and Sara Tipton (Wayne State University) for her critical reading of the manuscript. NR 51 TC 2 Z9 2 U1 4 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1219-4956 EI 1532-2807 J9 PATHOL ONCOL RES JI Pathol. Oncol. Res. PD JUL PY 2015 VL 21 IS 3 BP 659 EP 668 DI 10.1007/s12253-014-9872-9 PG 10 WC Oncology; Pathology SC Oncology; Pathology GA CJ6SU UT WOS:000355624700019 PM 25583406 ER PT J AU Cheung, CSF Zhu, ZY Lui, JCK Dimitrov, D Baron, J AF Cheung, Crystal Sao-Fong Zhu, Zhongyu Lui, Julian Chun-Kin Dimitrov, Dimiter Baron, Jeffrey TI Human Monoclonal Antibody Fragments Targeting Matrilin-3 in Growth Plate Cartilage SO PHARMACEUTICAL RESEARCH LA English DT Article DE childhood growth; drug targeting; scFv; skeletal diseases; yeast display ID CAPITAL FEMORAL EPIPHYSIS; NATRIURETIC-PEPTIDE; CHONDROCYTE DIFFERENTIATION; SALMON-CALCITONIN; GENE-EXPRESSION; MURINE HYPOPHOSPHATASIA; SKELETAL DEVELOPMENT; ENZYME REPLACEMENT; HORMONE TREATMENT; INDIAN HEDGEHOG AB Many genetic disorders, including chondrodysplasias, and acquired disorders impair growth plate function, resulting in short and sometimes malformed bones. There are multiple endocrine and paracrine factors that promote chondrogenesis at the growth plate, which could potentially be used to treat these disorders. Targeting these growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing undesirable effects on non-target tissues. Using yeast display technology, we selected single-chain variable antibody fragments that bound to human and mouse matrilin-3, an extracellular matrix protein specifically expressed in cartilage tissue. The ability of the selected antibody fragments to bind matrilin-3 and to bind cartilage tissue in vitro and in vivo was assessed by ELISA and immunohistochemistry. We identified antibody fragments that bound matrilin-3 with high affinity and also bound with high tissue specificity to cartilage homogenates and to cartilage structures in mouse embryo sections. When injected intravenously in mice, the antibody fragments specifically homed to cartilage. Yeast display successfully selected antibody fragments that are able to target cartilage tissue in vivo. Coupling these antibodies to chondrogenic endocrine and paracrine signaling molecules has the potential to open up new pharmacological approaches to treat childhood skeletal growth disorders. C1 [Cheung, Crystal Sao-Fong; Lui, Julian Chun-Kin; Baron, Jeffrey] NICHD, Sect Growth & Dev, NIH, Bethesda, MD 20892 USA. [Zhu, Zhongyu; Dimitrov, Dimiter] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Lui, JCK (reprint author), NICHD, Sect Growth & Dev, NIH, Bldg 10 CRC,Rm 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM luichunk@mail.nih.gov RI Lui, Chun Kin Julian/E-2253-2012 FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute, National Institutes of Health. C.S.C., Z.Z., J.C.L., D.D. and J.B are co-inventors in a provisional patent application (U.S. Patent Application No. 61/927,904) submitted by the National Institutes of Health. NR 46 TC 0 Z9 0 U1 1 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD JUL PY 2015 VL 32 IS 7 BP 2439 EP 2449 DI 10.1007/s11095-015-1636-z PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CJ1SH UT WOS:000355264100024 PM 25690340 ER PT J AU McGinty, EE Baller, J Azrin, ST Juliano-Bult, D Daumit, GL AF McGinty, Emma E. Baller, Julia Azrin, Susan T. Juliano-Bult, Denise Daumit, Gail L. TI Quality of medical care for persons with serious mental illness: A comprehensive review SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Bipolar disorder; Quality of care ID ACUTE MYOCARDIAL-INFARCTION; BEHAVIORAL-HEALTH-DISORDERS; 2013 ACCF/AHA GUIDELINE; ASSOCIATION TASK-FORCE; DIABETES CARE; OF-CARE; HEART-FAILURE; UNITED-STATES; CARDIOVASCULAR RISK; EXCESS MORTALITY AB Objectives: Prior studies suggest variation in the quality of medical care for somatic conditions such as cardiovascular disease and diabetes provided to persons with SMI, but to date no comprehensive review of the literature has been conducted. The goals of this review were to summarize the prior research on quality of medical care for the United States population with SMI; identify potential sources of variation in quality of care; and identify priorities for future research. Methods: Peer-reviewed studies were identified by searching four major research databases and subsequent reference searches of retrieved articles. All studies assessing quality of care for cardiovascular disease, diabetes, dyslipidemia, and HIV/AIDs among persons with schizophrenia and bipolar disorder published between January 2000 and December 2013 were included. Quality indicators and information about the study population and setting were abstracted by two trained reviewers. Results: Quality of medical care in the population with SMI varied by study population, time period, and setting. Rates of guideline-concordant care tended to be higher among veterans and lower among Medicaid beneficiaries. In many study samples with SMI, rates of guideline adherence were considerably lower than estimated rates for the overall US population. Conclusions: Future research should identify and address modifiable provider, insurer, and delivery system factors that contribute to poor quality of medical care among persons with SMI and examine whether adherence to clinical guidelines leads to improved health and disability outcomes in this vulnerable group. (C) 2015 Elsevier B.V. All rights reserved. C1 [McGinty, Emma E.; Baller, Julia] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Azrin, Susan T.] NIMH, New York, NY USA. [Juliano-Bult, Denise; Daumit, Gail L.] Johns Hopkins Med Inst, Div Gen Internal Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. RP McGinty, EE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 624 N Broadway,Room 359, Baltimore, MD 21205 USA. EM bmcginty@jhu.edu; jballer@jhu.edu; Susan.Azrin@nih.gov; Djuliano@mail.nih.gov; gdaumit@jhmi.edu FU National Institute of Mental Health (NIMH) FX This study was funded by the National Institute of Mental Health (NIMH). NR 84 TC 13 Z9 13 U1 8 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2015 VL 165 IS 2-3 BP 227 EP 235 DI 10.1016/j.schres.2015.04.010 PG 9 WC Psychiatry SC Psychiatry GA CJ5WE UT WOS:000355562400019 PM 25936686 ER PT J AU Person, RJ Ngalame, NNO Makia, NL Bell, MW Waalkes, MP Tokar, EJ AF Person, Rachel J. Ngalame, Ntube N. Olive Makia, Ngome L. Bell, Matthew W. Waalkes, Michael P. Tokar, Erik J. TI Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Inorganic arsenic; Human lung cells; Transformation; Adaptation; Lung cancer; KRAS ID INDUCED MALIGNANT-TRANSFORMATION; OXIDATIVE DNA-DAMAGE; RAS ONCOGENE ACTIVATION; STEM-CELLS; MONOMETHYLARSONOUS ACID; HUMAN METALLOTHIONEIN; SIGNAL-TRANSDUCTION; ADENOCARCINOMA; MICE; EXPRESSION AB Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 mu M; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3. (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphotylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and M12A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. Published by Elsevier Inc. C1 [Person, Rachel J.; Ngalame, Ntube N. Olive; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J.] NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Stem Cell Toxicol Grp, Res Triangle Pk, NC 27709 USA. RP Tokar, EJ (reprint author), NIEHS, POB 12233,Mail Drop E1-07,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM tokare@niehs.nih.gov FU National Institute of Environmental Health Sciences, Division of the National Toxicology Program [ES102925] FX The authors wish to thank Drs. Alex Merrick, Humphrey Yao, Michael DeVito, Darlene Dixon and John Bucher for their critical comments. This work was totally supported by Intramural Program funds from National Institute of Environmental Health Sciences, Division of the National Toxicology Program (ES102925). NR 65 TC 4 Z9 5 U1 2 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 1 PY 2015 VL 286 IS 1 BP 36 EP 43 DI 10.1016/j.taap.2015.03.014 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CJ6YL UT WOS:000355641000005 PM 25804888 ER PT J AU Hyun, SI Maruri-Avidal, L Moss, B AF Hyun, Seong-In Maruri-Avidal, Liliana Moss, Bernard TI Topology of Endoplasmic Reticulum-Associated Cellular and Viral Proteins Determined with Split-GFP SO TRAFFIC LA English DT Article DE calnexin; endoplasmic reticulum; green fluorescent protein; membrane topology; poxvirus; protein disulfide isomerase; tapasin; vaccinia virus ID GREEN FLUORESCENT PROTEIN; VACCINIA VIRUS; MEMBRANE-PROTEINS; LOCALIZATION; EXPRESSION; CELLS; ASSAY AB The split green fluorescent protein (GFP) system was adapted for investigation of the topology of ER-associated proteins. A 215-amino acid fragment of GFP (S1-10) was expressed in the cytoplasm as a free protein or fused to the N-terminus of calnexin and in the ER as an intraluminal protein or fused to the C-terminus of calnexin. A 16-amino acid fragment of GFP (S11) was fused to the N- or C-terminus of the target protein. Fluorescence occurred when both GFP fragments were in the same intracellular compartment. After validation with the cellular proteins PDI and tapasin, we investigated two vaccinia virus proteins (L2 and A30.5) of unknown topology that localize to the ER and are required for assembly of the viral membrane. Our results indicated that the N- and C-termini of L2 faced the cytoplasmic and luminal sides of the ER, respectively. In contrast both the N- and C-termini of A30.5 faced the cytoplasm. The system offers advantages for quickly determining the topology of intracellular proteins: the S11 tag is similar in length to commonly used epitope tags; multiple options are available for detecting fluorescence in live or fixed cells; transfection protocols are adaptable to numerous expression systems and can enable high throughput applications. C1 [Hyun, Seong-In; Maruri-Avidal, Liliana; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Hyun, Seong-In] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Catherine Cotter for maintaining cell lines. The study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. S. H. is a Ph.D. candidate in the Department of Cell Biology and Molecular Genetics at the University of Maryland, College Park, MD. The authors declare no conflict of interest. NR 26 TC 4 Z9 4 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 EI 1600-0854 J9 TRAFFIC JI Traffic PD JUL PY 2015 VL 16 IS 7 BP 787 EP 795 DI 10.1111/tra.12281 PG 9 WC Cell Biology SC Cell Biology GA CJ9QA UT WOS:000355836100008 PM 25761760 ER PT J AU Andrecka, J Arroyo, JO Takagi, Y de Wit, G Fineberg, A Mackinnon, L Young, G Sellers, JR Kukura, P AF Andrecka, J. Arroyo, J. Ortega Takagi, Y. de Wit, G. Fineberg, A. Mackinnon, L. Young, G. Sellers, J. R. Kukura, P. TI Structural dynamics of myosin 5 SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 10th European-Biophysical-Societies-Association (EBSA) European Biophysics Congress CY JUL 18-22, 2015 CL Dresden, GERMANY SP European Biophys Soc Assoc C1 [Andrecka, J.; Arroyo, J. Ortega; de Wit, G.; Fineberg, A.; Mackinnon, L.; Young, G.; Kukura, P.] Univ Oxford, Dept Chem, Oxford, England. [Takagi, Y.; Sellers, J. R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2015 VL 44 SU 1 MA P-193 BP S93 EP S93 PG 1 WC Biophysics SC Biophysics GA DR6GW UT WOS:000380001400194 ER PT J AU Konig, G Brooks, BR AF Konig, G. Brooks, B. R. TI Affordable and accurate QM/MM multi-scale free energy simulations SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 10th European-Biophysical-Societies-Association (EBSA) European Biophysics Congress CY JUL 18-22, 2015 CL Dresden, GERMANY SP European Biophys Soc Assoc C1 [Konig, G.; Brooks, B. R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2015 VL 44 SU 1 MA P-402 BP S148 EP S148 PG 1 WC Biophysics SC Biophysics GA DR6GW UT WOS:000380001400403 ER PT J AU Miller, BT Lee, J Damjanovic, A Brooks, BR AF Miller, B. T. Lee, J. Damjanovic, A. Brooks, B. R. TI Constant pH simulations in explicit solvent with the two dimensional EDS-HREM method SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 10th European-Biophysical-Societies-Association (EBSA) European Biophysics Congress CY JUL 18-22, 2015 CL Dresden, GERMANY SP European Biophys Soc Assoc C1 [Miller, B. T.; Lee, J.; Damjanovic, A.; Brooks, B. R.] NHLBI, Lab Computat Biol, Bethesda, MD 20892 USA. [Damjanovic, A.] Johns Hopkins Univ, Dept Biophys, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2015 VL 44 SU 1 MA P-406 BP S149 EP S149 PG 1 WC Biophysics SC Biophysics GA DR6GW UT WOS:000380001400407 ER PT J AU Anderson, BO Flanigan, J AF Anderson, Benjamin O. Flanigan, John TI Novel Methods for Measuring Global Cancer Burden Implications for Global Cancer Control SO JAMA ONCOLOGY LA English DT Editorial Material ID SYSTEMATIC ANALYSIS; CERVICAL-CANCER; 187 COUNTRIES; DISEASE; MORTALITY; INJURIES; BREAST C1 [Anderson, Benjamin O.] Univ Washington, Dept Surg, POB 356410, Seattle, WA 98195 USA. [Flanigan, John] NCI, Ctr Global Hlth, Rockville, MD USA. RP Anderson, BO (reprint author), Univ Washington, Dept Surg, POB 356410, Seattle, WA 98195 USA. EM banderso@uw.edu NR 11 TC 1 Z9 3 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUL PY 2015 VL 1 IS 4 BP 425 EP 427 DI 10.1001/jamaoncol.2015.1426 PG 3 WC Oncology SC Oncology GA DW5GS UT WOS:000383672100004 PM 26181245 ER PT J AU Chen, HX Abrams, JS AF Chen, Helen X. Abrams, Jeffrey S. TI Genomic Profiling Building a Continuum From Knowledge to Care SO JAMA ONCOLOGY LA English DT Editorial Material ID CANCER C1 [Chen, Helen X.; Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, Div Canc Therapy & Diag, 9609 Med Ctr Dr,Room 5436, Rockville, MD 20850 USA. RP Abrams, JS (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Therapy & Diag, 9609 Med Ctr Dr,Room 5436, Rockville, MD 20850 USA. EM abramsj@ctep.nci.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUL PY 2015 VL 1 IS 4 BP 474 EP 475 DI 10.1001/jamaoncol.2015.1333 PG 3 WC Oncology SC Oncology GA DW5GS UT WOS:000383672100015 PM 26181257 ER PT J AU Mailankody, S Prasad, V AF Mailankody, Sham Prasad, Vinay TI Five Years of Cancer Drug Approvals: Innovation, Efficacy, and Costs SO JAMA ONCOLOGY LA English DT Letter C1 [Mailankody, Sham; Prasad, Vinay] NCI, Med Oncol Serv, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Serv, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 6 TC 47 Z9 48 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUL PY 2015 VL 1 IS 4 BP 539 EP 540 DI 10.1001/jamaoncol.2015.0373 PG 2 WC Oncology SC Oncology GA DW5GS UT WOS:000383672100023 PM 26181265 ER PT J AU Steidl, S Cardiff, KM Wise, RA AF Steidl, Stephan Cardiff, Katherine M. Wise, Roy A. TI Increased latencies to initiate cocaine self-administration following laterodorsal tegmental nucleus lesions SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE ACh; Acetylcholine; Dopamine; Pedunculopontine tegmental nucleus; Reward; Ventral tegmental area ID REWARDING BRAIN-STIMULATION; MIDBRAIN DOPAMINE NEURONS; CHOLINERGIC NEURONS; INTRAVENOUS COCAINE; RAT; AREA; PEDUNCULOPONTINE; ACCUMBENS; RESPONSES; RELEASE AB Cholinergic input to the ventral tegmental area (VTA), origin of the mesocorticolimbic dopamine system that is critical for cocaine reward, is important for both cocaine seeking and cocaine taking. The laterodorsal tegmental nucleus (LDTg) provides one of the two major sources of excitatory cholinergic input to the VTA, but little is known of the role of the LDTg in cocaine reward. LDTg cholinergic cells express urotensin-II receptors and here we used local microinjections of a conjugate of the endogenous ligand for these receptors with diphtheria toxin (Dtx: :UII) to lesion the cholinergic cells of the LDTg in rats previously trained to self-administer cocaine (1 mg/kg/infusion, i.v.). Lesioned rats showed long latencies to initiate cocaine self-administration after treatment with the toxin, which resulted in a reduction in cocaine intake per session. Priming injections reduced latencies to initiate responding for cocaine in lesioned rats, and once they began to respond the rats regulated their moment-to-moment cocaine intake within normal limits. Thus we conclude that while LDTg cholinergic cell loss does not significantly alter the rewarding effects of cocaine, LDTg lesions can reduce the rat's responsiveness to cocaine-predictive stimuli. Published by Elsevier B.V. C1 [Steidl, Stephan; Cardiff, Katherine M.; Wise, Roy A.] NIDA, Intramural Res Program, NIH, DHHS, Baltimore, MD 21224 USA. RP Steidl, S (reprint author), Loyola Univ, Dept Psychol, 1032 West Sheridan Rd, Chicago, IL 60626 USA. EM ssteidl@luc.edu FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 34 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 1 PY 2015 VL 287 BP 82 EP 88 DI 10.1016/j.bbr.2015.02.049 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CI8QV UT WOS:000355037700010 PM 25746513 ER PT J AU Kiselycznyk, C Jury, NJ Halladay, LR Nakazawa, K Mishina, M Sprengel, R Grant, SGN Svenningsson, P Holmes, A AF Kiselycznyk, Carly Jury, Nicholas J. Halladay, Lindsay R. Nakazawa, Kazu Mishina, Masayoshi Sprengel, Rolf Grant, Seth G. N. Svenningsson, Per Holmes, Andrew TI NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Glutamate; PSD-95; Prefrontal cortex; GluN2B; GluA1; Depression ID FORCED SWIM TEST; MICE LACKING; ETHANOL INTOXICATION; STRESS-REACTIVITY; PREFRONTAL CORTEX; FEAR EXTINCTION; KNOCKOUT MICE; ANIMAL-MODELS; AMPA RECEPTOR; C57BL/6J MICE AB Drugs targeting the glutamate N-methyl-D-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressantrelated effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking G1uN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR. (C) 2015 Published by Elsevier B.V. C1 [Kiselycznyk, Carly; Jury, Nicholas J.; Halladay, Lindsay R.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, Bethesda, MD 20892 USA. [Nakazawa, Kazu] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. [Mishina, Masayoshi] Ritsumeikan Univ, Res Org Sci & Technol, Brain Sci Lab, Kusatsu, Shiga, Japan. [Sprengel, Rolf] Max Planck Inst Med Res, Dept Mol Neurobiol, D-69120 Heidelberg 1, Germany. [Grant, Seth G. N.] Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh, Midlothian, Scotland. [Svenningsson, Per] Karolinska Inst, Dept Clin Neurosci, Lab Translat Neuropharmacol, Stockholm, Sweden. RP Jury, NJ (reprint author), NIAAA, Lab Behav & Genom Neurosci, Bethesda, MD 20892 USA. EM nickjury@hotmail.com OI Nakazawa, Kazutoshi/0000-0001-5699-9093; Jury, Nicholas/0000-0002-4233-117X FU National Institute of Alcohol Abuse and Alcoholism Intramural Research Program [Z01-AA000411]; NIH [K22MH099164]; Deutsche Forschungsgemeinschaft [SFB636/A4] FX We are grateful to Guoxiang Luo for genotyping the GluA1 mutants. Research supported by the National Institute of Alcohol Abuse and Alcoholism Intramural Research Program (Z01-AA000411) and NIH grant K22MH099164 (K.N.). R.S. receives grant support from the Deutsche Forschungsgemeinschaft SFB636/A4. NR 58 TC 10 Z9 10 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 1 PY 2015 VL 287 BP 89 EP 95 DI 10.1016/j.bbr.2015.03.023 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CI8QV UT WOS:000355037700011 PM 25800971 ER PT J AU Blasio, A Valenza, M Lyer, MR Rice, KC Steardo, L Hayashi, T Cottone, P Sabino, V AF Blasio, Angelo Valenza, Marta Lyer, Malliga R. Rice, Kenner C. Steardo, Luca Hayashi, T. Cottone, Pietro Sabino, Valentina TI Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Ethanol; Addiction; Intake; Rat; Reinforcement; Reward ID CROSS-FOSTERING ANALYSIS; NUCLEUS-ACCUMBENS CORE; CENTRAL-NERVOUS-SYSTEM; KAPPA-OPIOID-RECEPTORS; BINGE-LIKE DRINKING; NMDA-INDUCED PAIN; ANIMAL-MODELS; 2ND-ORDER SCHEDULES; ETHANOL-CONSUMPTION; DOPAMINE RELEASE AB Sigma-1 receptor (Sig-1R) has been proposed as a novel therapeutic target for drug and alcohol addiction. We have shown previously that Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists on the other hand block excessive drinking in genetic and environmental models of alcoholism, without affecting intake in outbred non-dependent rats. Even though significant progress has been made in understanding the function of Sig-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. Administration of the selective Sig-1R antagonist BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats; the treatment had instead no effect on total fluid intake, food intake or body weight gain, proving selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction. (C) 2015 Elsevier B.V. All rights reserved. C1 [Blasio, Angelo; Valenza, Marta; Cottone, Pietro; Sabino, Valentina] Boston Univ, Sch Med, Lab Addict Disorders, Dept Pharmacol, Boston, MA 02118 USA. [Blasio, Angelo; Valenza, Marta; Cottone, Pietro; Sabino, Valentina] Boston Univ, Sch Med, Lab Addict Disorders, Dept Expt Therapeut, Boston, MA 02118 USA. [Blasio, Angelo; Valenza, Marta; Cottone, Pietro; Sabino, Valentina] Boston Univ, Sch Med, Lab Addict Disorders, Dept Psychiat, Boston, MA 02118 USA. [Lyer, Malliga R.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Lyer, Malliga R.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Steardo, Luca] Univ Roma La Sapienza, Dept Physiol & Pharmacol Vittorio Erspamer, I-00185 Rome, Italy. [Hayashi, T.] Nishikawa Hosp, Dept Med, Hamada, Shimane, Japan. RP Sabino, V (reprint author), Boston Univ, Sch Med, Lab Addict Disorders, Dept Pharmacol & Expt Therapeut, 72 E Concord St,R-612, Boston, MA 02118 USA. EM vsabino@bu.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5291-2012; OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279; Steardo, Luca/0000-0003-3570-2195 FU National Institute on Alcohol Abuse and Alcoholism [AA016731, MH093650, MH091945, DA030425]; National Institute of Mental Health; National Institute on Drug Abuse; Peter McManus Trust; Peter Paul Career Development Professorship; Boston University Undergraduate Research Opportunity Program; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX The authors thank Alyssa C. DiLeo and Stephen A. St. Cyr for technical assistance. We also thank The Scripps Research Institute and the University of Cagliari, CNR Neuroscience Institute for providing the Scr:sP and the original sP rats, respectively. This publication was made possible by grant numbers AA016731, MH093650, MH091945, and DA030425 from the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health and the National Institute on Drug Abuse, by the Peter McManus Trust, the Peter Paul Career Development Professorship (P.C.), and the Boston University Undergraduate Research Opportunity Program. A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 87 TC 1 Z9 1 U1 8 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 1 PY 2015 VL 287 BP 315 EP 322 DI 10.1016/j.bbr.2015.03.065 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CI8QV UT WOS:000355037700039 PM 25848705 ER PT J AU Aarestrup, J Gamborg, M Cook, MB Baker, JL AF Aarestrup, J. Gamborg, M. Cook, M. B. Baker, J. L. TI Childhood height increases the risk of prostate cancer mortality SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE (MeSH): body height; Body mass index; Child; Cohort studies; Growth; Mortality; Prostate neoplasms ID BODY-MASS INDEX; HEALTH RECORDS REGISTER; METAANALYSIS; COHORT; ADULTHOOD; DEATH; MEN AB Background: Adult body size is positively associated with aggressive and fatal prostate cancers. It is unknown whether these associations originate in early life. Therefore, we investigated if childhood height, body mass index (BMI; kg/m(2)) and growth are associated with prostate cancer-specific mortality and survival. Methods: Subjects were 125,208 men from the Copenhagen School Health Records Register, born 1930-1969 with height and weight measurements at ages 7-13 years. Linkage to the Danish Cancer Registry and the Register of Causes of Death enabled identification of incident and fatal prostate cancers. Cox proportional hazards regressions were performed. Results: 630 men had prostate cancer recorded as the underlying cause of death. Childhood height at age 13 years was positively associated with prostate cancer-specific mortality (hazard ratio [HR](per z-score) = 1.2, 95% confidence interval [CI]: 1.1-1.3). Associations were significant at all other childhood ages. Growth analyses showed that height at age 13 years had a stronger association with prostate cancer-specific mortality than height at age 7, suggesting the association at age 7 is largely mediated through later childhood height. The tallest boys at age 13 years had a significantly worse survival, but only when restricted to a diagnosis at <60 years of age (HRz-score (of 1) = 1.7, 95% CI: 1.3-2.4). These associations were significant at all other childhood ages. Childhood BMI was not associated with prostate cancer mortality or survival. Conclusion: Childhood height was positively associated with the hard end-point of prostate cancer-specific mortality, which strengthens prior epidemiologic observations of a positive association with prostate cancer incidence. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Aarestrup, J.; Gamborg, M.; Baker, J. L.] Bispebjerg Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [Aarestrup, J.; Gamborg, M.; Baker, J. L.] Frederiksberg Univ Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [Cook, M. B.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Baker, J. L.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, DK-2100 Copenhagen O, Denmark. RP Baker, JL (reprint author), Bispebjerg Hosp, Inst Prevent Med, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark. EM Julie.Aarestrup@regionh.dk; Michael.Orland.Gamborg@regionh.dk; cookmich@mail.nih.gov; Jennifer.Lyn.Baker@regionh.dk RI Cook, Michael/A-5641-2009; Baker, Jennifer/F-1917-2010 OI Cook, Michael/0000-0002-0533-7302; Baker, Jennifer/0000-0002-9649-6615 FU European Research Council Belgium, under the European Union [281419]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services, United States of America (USA) FX The research leading to these results has received funding from the European Research Council Belgium, under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 281419, childgrowth2cancer to JLB. MBC was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, United States of America (USA). The sponsors had no involvement in the conduct of this study and were not involved in the decision to submit the article for publication. NR 24 TC 4 Z9 4 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2015 VL 51 IS 10 BP 1340 EP 1345 DI 10.1016/j.ejca.2015.03.022 PG 6 WC Oncology SC Oncology GA CJ2RK UT WOS:000355332000015 PM 25899985 ER PT J AU Araki, T Nishino, M Zazueta, OE Gao, W Dupuis, J Okajima, Y Latourelle, JC Rosas, IO Murakami, T O'Connor, GT Washko, GR Hunninghake, GM Hatabu, H AF Araki, Tetsuro Nishino, Mizuki Zazueta, Oscar E. Gao, Wei Dupuis, Josee Okajima, Yuka Latourelle, Jeanne C. Rosas, Ivan O. Murakami, Takamichi O'Connor, George T. Washko, George R. Hunninghake, Gary M. Hatabu, Hiroto TI Paraseptal emphysema: Prevalence and distribution on CT and association with interstitial lung abnormalities SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Paraseptal emphysema; Interstitial lung abnormalities; CT ID HIGH-RESOLUTION CT; PATHOLOGICAL CORRELATION; COMPUTED-TOMOGRAPHY; PULMONARY-EMPHYSEMA; DIFFUSING-CAPACITY; REFERENCE VALUES; DEFINITION; DIAGNOSIS; DISEASE; QUANTIFICATION AB Objective: To investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities. Materials and methods: We assessed 2633 participants in the FHS for paraseptal emphysema on chest CT. Characteristics of the participants, including age, sex, smoking status, clinical symptoms, and results of pulmonary function tests, were compared between those with and without paraseptal emphysema. The association between paraseptal emphysema and interstitial lung abnormalities was investigated. Results: Of the 2633 participants, 86 (3%) had pure paraseptal emphysema (defined as paraseptal emphysema with no other subtypes of emphysema other than paraseptal emphysema or a very few centrilobular emphysema involved) in at least one lung zone. The upper zone of the lungs was almost always involved. Compared to the participants without paraseptal emphysema, those with pure paraseptal emphysema were significantly older, and were more frequently male and smokers (mean 64 years, 71% male, mean 36 pack-years, P < 0.001) and had significantly decreased FEV1/FVC% (P = 0.002), and diffusion capacity of carbon monoxide (DLCO) (P = 0.002). There was a significant association between pure paraseptal emphysema and interstitial lung abnormalities (P < 0.001). Conclusions: The prevalence of pure paraseptal emphysema was 3% in the FHS population, predominantly affects the upper lung zone, and contributes to decreased pulmonary function. Cigarette smoking, aging, and male gender were the factors associated with the presence of paraseptal emphysema. Significant association between paraseptal emphysema and interstitial lung abnormalities was observed. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Araki, Tetsuro; Nishino, Mizuki; Okajima, Yuka; Hatabu, Hiroto] Harvard Univ, Sch Med, Dept Radiol, Ctr Pulm Funct Imaging,Brigham & Womens Hosp, Boston, MA 02215 USA. [Araki, Tetsuro; Murakami, Takamichi] Kinki Univ, Fac Med, Dept Radiol, Osaka, Japan. [Zazueta, Oscar E.; Rosas, Ivan O.; Washko, George R.; Hunninghake, Gary M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Pulm & Crit Care Div, Boston, MA 02115 USA. [Gao, Wei; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Latourelle, Jeanne C.] Boston Univ, Sch Med, Dept Med & Neurol, Boston, MA 02118 USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Araki, T (reprint author), Harvard Univ, Sch Med, Dept Radiol, Ctr Pulm Funct Imaging,Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM taraki@partners.org FU NCI [1K23CA157631]; NIH [U01 HL105371, P01 HL114501, R01 HL116473, R01 HL107246, K08 HL092222, R01 HL111024, K25 HL104085]; NHLBI's Framingham Heart Study contract [R01 HL111024, N01-HC-25195] FX Dr. Nishino is supported by NCI Grant Number: 1K23CA157631. Dr. Rosas is supported by NIH Grant Number: U01 HL105371 and P01 HL114501. Dr. Washko is supported by NIH Grant Number: R01 HL116473, R01 HL107246 and P01 HL114501. Dr. Hunninghake is supported by NIH Grant Number: K08 HL092222, U01 HL105371, P01 HL114501, and R01 HL111024. Dr. Hatabu is supported by NIH Grant Number: K25 HL104085 and R01 HL116473. This work was partially supported by the NHLBI's Framingham Heart Study contract: N01-HC-25195 and R01 HL111024. NR 33 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD JUL PY 2015 VL 84 IS 7 BP 1413 EP 1418 DI 10.1016/j.ejrad.2015.03.010 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CJ1AA UT WOS:000355212100026 PM 25868675 ER PT J AU Auerbach, SS Phadke, DP Mav, D Holmgren, S Gao, Y Xie, B Shin, JH Shah, RR Merrick, BA Tice, RR AF Auerbach, Scott S. Phadke, Dhiral P. Mav, Deepak Holmgren, Stephanie Gao, Yuan Xie, Bin Shin, Joo Heon Shah, Ruchir R. Merrick, B. Alex Tice, Raymond R. TI RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE RNA-Seq; Toxicogenomics; Mechanism; FFPE; Aflatoxin B1 ID PARAFFIN-EMBEDDED TISSUE; GENOME GENE-EXPRESSION; MICROARRAY ANALYSIS; MESSENGER-RNA; BREAST-CANCER; STEM-CELLS; SAMPLES; AFLATOXIN-B1; CARCINOMA; PLATFORM AB Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE livers. The samples were derived from rats exposed to aflatoxin B-1 (AFB(1)) and a corresponding set of control animals. Principal components analysis indicated that samples were separated in the two groups representing presence or absence of chemical exposure, both in fresh frozen and FFPE sample types. Sixty-five percent of the differentially expressed transcripts (AFB(1) vs. controls) in fresh frozen samples were also differentially expressed in FFPE samples (overlap significance: P<0.0001). Genomic signature and gene set analysis of AFB(1) differentially expressed transcript lists indicated highly similar results between fresh frozen and FFPE at the level of chemogenomic signatures (i.e., single chemical/dose/duration elicited transcriptomic signatures), mechanistic and pathology signatures, biological processes, canonical pathways and transcription factor networks. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples. These results indicate that phenotypically anchored archival specimens represent a potentially informative resource for signature-based biomarker discovery and mechanistic characterization of toxicity. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Auerbach, Scott S.; Merrick, B. Alex; Tice, Raymond R.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Phadke, Dhiral P.; Mav, Deepak; Shah, Ruchir R.] SRA Int, Durham, NC USA. [Holmgren, Stephanie] NIEHS, Lib & Informat Serv Branch, Off Deputy Director, Res Triangle Pk, NC 27709 USA. [Gao, Yuan; Xie, Bin; Shin, Joo Heon] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21205 USA. RP Auerbach, SS (reprint author), POB 12233,MD K2-17, Res Triangle Pk, NC 27709 USA. EM auerbachs@niehs.nih.gov FU National Toxicology Program Division and Division of Intramural Research at the National Institute of Environmental Health Sciences of the NIH FX The authors would like to thank Drs. Richard S. Paules and Pierre Bushel for critical review of the manuscript. The research presented in this manuscript was supported by the Intramural Research Programs of the National Toxicology Program Division and Division of Intramural Research at the National Institute of Environmental Health Sciences of the NIH. The statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIH or the United States government. NR 68 TC 3 Z9 4 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD JUL PY 2015 VL 35 IS 7 BP 766 EP 780 DI 10.1002/jat.3068 PG 15 WC Toxicology SC Toxicology GA CJ2QT UT WOS:000355330300009 PM 25378103 ER PT J AU Greenberg, JA Burke, JF Haque, R Kahana, MJ Zaghloul, KA AF Greenberg, Jeffrey A. Burke, John F. Haque, Rafi Kahana, Michael J. Zaghloul, Kareem A. TI Decreases in theta and increases in high frequency activity underlie associative memory encoding SO NEUROIMAGE LA English DT Article DE Episodic memory; Associative memory encoding; Subsequent memory effect; iEEG ID COMPLEMENTARY-LEARNING-SYSTEMS; HUMAN EPISODIC MEMORY; MEDIAL TEMPORAL-LOBE; GAMMA OSCILLATIONS; BOLD SIGNAL; POWER; EEG; CONTEXT; CORTEX; HIPPOCAMPAL AB Episodic memory encoding refers to the cognitive process by which items and their associated contexts are stored in memory. To investigate changes directly attributed to the formation of explicit associations, we examined oscillatory power captured through intracranial electroencephalography (iEEG) as 27 neurosurgical patients receiving subdural and depth electrodes for seizure monitoring participated in a paired associates memory task. We examined low (3-8 Hz) and high (45-95 Hz) frequency activity, and found that the successful formation of new associations was accompanied by broad decreases in low frequency activity and a posterior to anterior progression of increases in high frequency activity in the left hemisphere. These data suggest that the observed patterns of activity may reflect the neural mechanisms underlying the formation of novel item-item associations. Published by Elsevier Inc. C1 [Greenberg, Jeffrey A.; Burke, John F.; Kahana, Michael J.] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. [Haque, Rafi; Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM kareem.zaghloul@nih.gov FU National Institutes of Health Intramural Research Program; NIH [MH055687, MH061975, NS067316, MH017168] FX This work was supported by the National Institutes of Health Intramural Research Program and by NIH grants MH055687, MH061975, NS067316, and MH017168. NR 50 TC 10 Z9 10 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 1 PY 2015 VL 114 BP 257 EP 263 DI 10.1016/j.neuroimage.2015.03.077 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CI8ES UT WOS:000355002900022 PM 25862266 ER PT J AU Day, PM Thompson, CD Lowy, DR Schiller, JT AF Day, Patricia M. Thompson, Cynthia D. Lowy, Douglas R. Schiller, John T. TI The HPV16 and MusPV1 papillomaviruses initially interact with distinct host components on the basement membrane SO VIROLOGY LA English DT Article DE MusPV1; MmuPV1; HPV16; Basement membrane (BM); Extracellular matrix (ECM); Cervicovaginal challenge model (CVC); Heparan sulfate proteoglycan (HSPG); Endocytosis; Heparin; Furin ID VIRUS-LIKE PARTICLES; SURFACE HEPARAN-SULFATE; MINOR CAPSID PROTEIN; CELL-SURFACE; HUMAN KERATINOCYTES; INFECTIOUS ENTRY; NEUTRALIZATION; TYPE-16; BINDING; L2 AB To understand and compare the mechanisms of murine and human PV infection, we examined pseudovirion binding and infection of the newly described MusPV1 using the murine cervicovaginal challenge model. These analyses revealed primary tissue interactions distinct from those previously described for HPV16. Unlike HPV16, MusPV1 bound basement membrane (BM) in an HSPG-independent manner. Nevertheless, subsequent HSPG interactions were critical. 12 antibodies or low doses of VLP antibodies, sufficient to prevent infection, did not lead to disassociation of the MusPV1 pseudovirions from the BM, in contrast to previous findings with HPV16. Similarly, furin inhibition did not lead to loss of MusPV1 from the BM. Therefore, phylogenetically distant PV types differ in their initial interactions with host attachment factors, but initiate their lifecycle on the acellular BM. Despite these differences, these distantly related PV types displayed similar intracellular trafficking patterns and susceptibilities to biochemical inhibition of infection. Published by Elsevier Inc. C1 [Day, Patricia M.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Day, PM (reprint author), NCI, Cellular Oncol Lab, NIH, Room 4112,Bldg 37, Bethesda, MD 20892 USA. EM pmd@nih.gov FU National Institutes of Health of the Center for Cancer Research, NCI, NIH [ZIA BC 009052] FX We gratefully acknowledge the gift of the rat anti-HPV16 L1 antiserum from Yawei Ni, DelSite Biotechnologies and Stuart Yuspa (NCI, NIH) for the murine keratinocyte cell lines. This research was supported by the Intramural Research Program of the National Institutes of Health, through project ZIA BC 009052 of the Center for Cancer Research, NCI, NIH. NR 55 TC 1 Z9 1 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL PY 2015 VL 481 BP 79 EP 94 DI 10.1016/j.virol.2015.02.021 PG 16 WC Virology SC Virology GA CI9CW UT WOS:000355069000009 PM 25771496 ER PT J AU Johnson, RE Hammoud, DA Lackemeyer, MG Yellayi, S Solomon, J Bohannon, JK Janosko, KB Jett, C Cooper, K Blaney, JE Jahrling, PB AF Johnson, Reed E. Hammoud, Dima A. Lackemeyer, Matthew G. Yellayi, Srikanth Solomon, Jeffrey Bohannon, Jordan K. Janosko, Krisztina B. Jett, Catherine Cooper, Kurt Blaney, Joseph E. Jahrling, Peter B. TI Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease SO VIROLOGY LA English DT Article DE Cowpox; Orthopoxvirus; Animal model; Computed tomography; CT; Pathogenesis; Aerosol inoculation ID MODIFIED VACCINIA VIRUS; CYNOMOLGUS MACAQUES; LETHAL MONKEYPOX; ORTHOPOXVIRUS INFECTION; NONHUMAN-PRIMATES; MODEL; PROTECTION; CHALLENGE; ST-246; VACCINATION AB Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CF) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 logio PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. Published by Elsevier Inc. C1 [Johnson, Reed E.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. [Hammoud, Dima A.; Solomon, Jeffrey] NIH, Ctr Clin, Ctr Infect Dis Imaging Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Lackemeyer, Matthew G.; Yellayi, Srikanth; Bohannon, Jordan K.; Janosko, Krisztina B.; Jett, Catherine; Cooper, Kurt; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Blaney, Joseph E.] NIAID, Off Sci Director, NIH, Frederick, MD 20892 USA. RP Johnson, RE (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. OI Solomon, Jeffrey/0000-0003-2711-1977 FU NIAID Division of Intramural Research; Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX This work was supported by the NIAID Division of Intramural Research. We are grateful to Marisa St. Claire, Russell Byrum, Dan Ragland, and the entire EVPS and IRF team for their contributions to these studies. We thank Jiro Wada for his contribution to the preparation of this manuscript. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract no. HHSN272200700016I. J.K.B. and K.B.J. performed this work as employees of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are: C.J., an employee of Tunnell Government Services, Inc.; M.G.L., an employee of Lovelace Respiratory Research Institute; and H.H. and I.I., both employees of MRI Global. NR 47 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL PY 2015 VL 481 BP 124 EP 135 DI 10.1016/j.virol.2015.02.044 PG 12 WC Virology SC Virology GA CI9CW UT WOS:000355069000013 PM 25776759 ER PT J AU Earl, PL Americo, JL Moss, B AF Earl, Patricia L. Americo, Jeffrey L. Moss, Bernard TI Genetic studies of the susceptibility of classical and wild-derived inbred mouse strains to monkeypox virus SO VIROLOGY LA English DT Article DE Poxvirus; Select agent; Virulence; Pathogenesis ID SMALL ANIMAL-MODELS; INFECTION; RESISTANCE; MICE AB Previously, we screened 38 inbred mouse strains for susceptibility to monkeypox virus (MPXV) and focused on wild-derived CAST mice because of their extreme vulnerability. Here, we provide further analysis of inbred mouse strains. NZW/Lac and C58 mice exhibited more weight loss than other classical inbred strains but all survived intranasal challenges with 10(4) to 10(6) PFU of MPXV. Mice from three wild derived strains, in addition to CAST, exhibited severe weight loss and died or were euthanized. LD50 values for CASA, MOLE and PERA were 100, 6800 and > 10(5) PFU, respectively. CASA was inbred independently from the same founders as CAST, whereas MOLE and PERA are genetically and geographically distinct. The MPXV susceptibility of the F1 progeny of CAST and either C57BL/6 or BALB/c indicated that resistance is dominant. Back-crossing the Fl progeny of C57BL/6 and CAST to CAST suggested more than one independent resistant locus. Published by Elsevier Inc. C1 [Earl, Patricia L.; Americo, Jeffrey L.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH [1 ZIA AI00097909] FX We thank Catherine Cotter for providing cells, the Comparative Medicine Branch, NIAID for care of animals and Thomas Kristie and Andrea Weisberg for assistance with the graphical abstract. The research (project 1 ZIA AI00097909) was supported by the Division of Intramural Research, NIAID, NIH. NR 15 TC 1 Z9 1 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 0042-6822 J9 VIROLOGY JI Virology PD JUL PY 2015 VL 481 BP 161 EP 165 DI 10.1016/j.virol.2015.02.048 PG 5 WC Virology SC Virology GA CI9CW UT WOS:000355069000017 PM 25791934 ER PT J AU Blehm, BH Jiang, N Kotobuki, Y Tanner, K AF Blehm, Benjamin H. Jiang, Nancy Kotobuki, Yorihisa Tanner, Kandice TI Deconstructing the role of the ECM microenvironment on drug efficacy targeting MAPK signaling in a pre-clinical platform for cutaneous melanoma SO BIOMATERIALS LA English DT Article DE 3D hydrogels; Hyaluronic acid; Metastasis; Microenvironment; Drug resistance; Brain ID BRAIN METASTASES; CELL-ADHESION; EXTRACELLULAR-MATRIX; THERAPEUTIC TARGETS; ACQUIRED-RESISTANCE; HYDROGEL PLATFORM; BASEMENT-MEMBRANE; HYALURONIC-ACID; CANCER; RGD AB Therapeutics targeting the BRAF kinase in cutaneous melanoma have significantly improved patient survival. However, durable responses in the face of metastatic disease are rarely realized where the problem of brain metastases is generally growing in magnitude. Tumor and stromal cells dynamically remodel the extracellular matrix (ECM) during the establishment of a metastatic lesion. We reasoned that ECM composition strongly determines drug efficacy on cell motility, adhesion and viability rendering one drug more potent and another less so. To test this hypothesis, we constructed platforms recreating the ECM composition due to the stroma and tumor cells, mimicking the brain's perivascular niche and hyaluronic acid (HA) rich parenchyma. Using human melanoma cell lines, we observed that cell adhesion was minimally affected by BRAF inhibition but ablated by ERK inhibition. Cell motility was impaired for both drugs. We determined that the composition and architecture of the ECM niche modulated drug efficacy. In one series, potency of BRAF inhibition was blunted in 3D Fibronectin-HA hydrogels whereas Laminin-HA hydrogels protected against ERK inhibition. In the other series, Laminin blunted drug efficacy, despite both series sharing the same BRAF mutation. These data reinforce the importance of contextual drug assessment in designing future therapeutics. Published by Elsevier Ltd. C1 [Blehm, Benjamin H.; Jiang, Nancy; Kotobuki, Yorihisa; Tanner, Kandice] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tanner, K (reprint author), 37 Convent Dr Bldg 37, Bethesda, MD 20852 USA. EM kandice.tanner@nih.gov FU National Institutes of Health, the National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. NR 61 TC 9 Z9 9 U1 3 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JUL PY 2015 VL 56 BP 129 EP 139 DI 10.1016/j.biomaterials.2015.03.041 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CI8SI UT WOS:000355041600014 PM 25934286 ER PT J AU Parapanov, R Lugrin, J Rosenblatt-Velin, N Feihl, F Waeber, B Milano, G Vergely, C Li, N Pacher, P Liaudet, L AF Parapanov, Roumen Lugrin, Jerome Rosenblatt-Velin, Nathalie Feihl, Francois Waeber, Bernard Milano, Giuseppina Vergely, Catherine Li, Na Pacher, Pal Liaudet, Lucas TI Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in the mouse SO CLINICAL SCIENCE LA English DT Article DE animal model; inflammation; innate immunity; myocardial infarction; oxidative stress; toll-like receptors ID ACTIVATED PROTEIN-KINASE; ISCHEMIA/REPERFUSION INJURY; IN-VIVO; INFARCTION; HEART; IDENTIFICATION; PEROXYNITRITE; CATALASE; MICE AB Myocardial ischaemia-reperfusion (MIR) triggers a sterile inflammatory response important for myocardial healing, but which may also contribute to adverse ventricular remodelling. Such inflammation is initiated by molecular danger signals released by damaged myocardium, which induce innate immune responses by activating toll-like receptors (TLRs). Detrimental roles have been recently reported for TLR2, TLR3 and TLR4. The role of other TLRs is unknown. We therefore evaluated the role of TLR5, expressed at high level in the heart, in the development of myocardial damage and inflammation acutely triggered by MIR. TLR5(-/-) and wild-type (WT) mice were exposed to MIR (30 min ischaemia, 2 h reperfusion). We measured infarct size, markers of cardiac oxidative stress, myocardial phosphorylation state of mitogen-activated protein (MAP) kinases and AKT, expression levels of chemokines and cytokines in the heart and plasma, as well as cardiac function by echography and conductance volumetry. TLR5-deficient mice had normal cardiac morphology and function under physiological conditions. After MIR, the absence of TLR5 promoted an increase in infarct size and myocardial oxidative stress. Lack of TLR5 fostered p38 phosphorylation, reduced AKT phosphorylation and markedly increased the expression of inflammatory cytokines, whereas it precipitated acute LV (left ventricle) dysfunction. Therefore, contrary to the detrimental roles of TLR2, TLR3 and TLR4 in the infarcted heart, TLR5 is important to limit myocardial damage, inflammation and functional compromise after MIR. C1 [Parapanov, Roumen; Lugrin, Jerome; Liaudet, Lucas] Univ Hosp Med Ctr, Dept Intens Care Med, CH-1011 Lausanne, Switzerland. [Parapanov, Roumen; Lugrin, Jerome; Milano, Giuseppina; Liaudet, Lucas] Fac Biol & Med, CH-1011 Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Feihl, Francois; Waeber, Bernard; Liaudet, Lucas] Univ Hosp Med Ctr, Div Clin Pathophysiol, CH-2011 Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Feihl, Francois; Waeber, Bernard; Liaudet, Lucas] Fac Biol & Med, CH-2011 Lausanne, Switzerland. [Milano, Giuseppina] Univ Hosp Med Ctr, Serv Cardiac Surg, CH-1011 Lausanne, Switzerland. [Vergely, Catherine; Li, Na] Univ Burgundy, Lab Cardiometab Pathophysiol & Pharmacol, Inserm UMR866, Fac Med & Pharm, F-21000 Dijon, France. [Pacher, Pal] NIAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Liaudet, L (reprint author), Univ Hosp Med Ctr, Dept Intens Care Med, CH-1011 Lausanne, Switzerland. EM lucas.liaudet@chuv.ch RI Lugrin, Jerome/F-8739-2011; Pacher, Pal/B-6378-2008; Vergely, Catherine/L-9534-2015; Liaudet, Lucas/E-1322-2017; OI Lugrin, Jerome/0000-0002-1178-2752; Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930; Milano, Giuseppina/0000-0002-5560-4667; VERGELY, CATHERINE/0000-0003-4009-776X FU Swiss National Foundation for Scientific Research [310030_135394/1, 310030_132491]; Emma Muschamp Foundation; Mahmoud Darvish Foundation; Intramural Program of National Institutes of Health/NIAAA FX This work was supported by the Swiss National Foundation for Scientific Research [grant numbers 310030_135394/1 (to L.L.) and 310030_132491 (to N.R.-V.)]; the Emma Muschamp Foundation; the Mahmoud Darvish Foundation; and the Intramural Program of National Institutes of Health/NIAAA (to P.P.). NR 38 TC 4 Z9 4 U1 2 U2 11 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0143-5221 EI 1470-8736 J9 CLIN SCI JI Clin. Sci. PD JUL PY 2015 VL 129 IS 2 BP 187 EP 198 DI 10.1042/CS20140444 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CI3NV UT WOS:000354655400009 PM 25757463 ER PT J AU Mach, J Huizer-Pajkos, A Kane, A Jones, B McKenzie, C Mitchell, SJ de Cabo, R Cogger, VC Le Couteur, DG Hilmer, SN AF Mach, John Huizer-Pajkos, Aniko Kane, Alice Jones, Brett McKenzie, Catriona Mitchell, Sarah J. de Cabo, Rafael Cogger, Victoria C. Le Couteur, David G. Hilmer, Sarah N. TI The effect of aging on mitochondrial and cytosolic hepatic intrinsic death pathway and apoptosis associated proteins in Fischer 344 rats SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Aging; Liver; Apoptosis; Mitochondria; Intrinsic death pathway ID FATTY LIVER-DISEASE; CELL-DEATH; OUTER-MEMBRANE; BCL-2 PROTEIN; CYTOCHROME-C; BAX; MICE; METABOLISM; MECHANISMS; BCL-X(L) AB Apoptosis is increased in the liver in old age and is a common pathological feature of liver disease. The mitochondria play a key role in regulating apoptosis via the intrinsic death pathway. As the effect of aging on this pathway is unclear, we aimed to characterize the impact of aging on the hepatic intrinsic death pathway and apoptosis. Livers from young adult (6.6 +/- 0.3 months, n = 9) and old (25.4 +/- 0.7 months, n = 9) male Fischer 344 rats were extracted for cellular fractionation and immunobloting. In old age there were lower mitochondrial protein levels of pro-apoptotic BAK, BID, tBID and VDAC1 (p < 0.05) and of anti-apoptotic Bcl-2. Compared to young, old rats had lower cytosolic protein levels of pro-apoptotic BAX, BAK, BID, tBID and anti-apoptotic Bcl-xL (p < 0.05). BAK, Bcl-2 and Bcl-xL were found in the cytosol. Furthermore with old age, cytosolic protein levels of cytochrome C, AIF and cleaved caspase-9 did not change but activation of caspase-3, -6 and -7 increased (p < 0.05) and DNA fragmentation trended to increase. Our results suggest an age-related decline in the levels of a number of proteins involved in the intrinsic death pathway, an uncoupling of intermediate apoptosis signaling and increased cellular apoptosis in the liver in old age. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mach, John; Huizer-Pajkos, Aniko; Kane, Alice; Jones, Brett; Hilmer, Sarah N.] Kolling Inst Med Res, Lab Ageing & Pharmacol, Sydney, NSW, Australia. [Mach, John; Huizer-Pajkos, Aniko; Kane, Alice; Hilmer, Sarah N.] Royal N Shore Hosp, Dept Clin Pharmacol, Sydney, NSW, Australia. [Mach, John; Huizer-Pajkos, Aniko; Kane, Alice; Hilmer, Sarah N.] Royal N Shore Hosp, Dept Aged Care, Sydney, NSW, Australia. [Mach, John; Kane, Alice; Jones, Brett; Cogger, Victoria C.; Le Couteur, David G.; Hilmer, Sarah N.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Jones, Brett] Royal N Shore Hosp, Dept Gastroenterol, Sydney, NSW, Australia. [McKenzie, Catriona] Royal Prince Alfred Hosp, Dept Pathol, Sydney, NSW, Australia. [Cogger, Victoria C.; Le Couteur, David G.] Concord Hosp, Ageing & Alzheimers Inst, Concord, NSW, Australia. [Cogger, Victoria C.; Le Couteur, David G.] Concord Hosp, Ctr Educ & Res Ageing, Concord, NSW, Australia. [Cogger, Victoria C.; Le Couteur, David G.] Univ Sydney, Sydney, NSW 2006, Australia. [Cogger, Victoria C.; Le Couteur, David G.] Concord Hosp, ANZAC Res Inst, Concord, NSW, Australia. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Hilmer, SN (reprint author), Royal N Shore Hosp, Kolling Inst Med Res, Lab Ageing & Pharmacol, Room 612027,Level 12, St Leonards, NSW 2065, Australia. EM sarah.hilmer@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Kane, Alice/0000-0002-4303-0491; , rafael/0000-0003-2830-5693 FU National Health and Medical Research Council of Australia [570968]; Geoff and Elaine Penney Ageing Research Unit; Royal North Shore Hospital, Australia; Intramural Research Program of the National Institute on Aging, National Institutes of Health FX The work was supported by the National Health and Medical Research Council of Australia (project grant number #570968), the Geoff and Elaine Penney Ageing Research Unit, Royal North Shore Hospital, Australia, and the Intramural Research Program of the National Institute on Aging. RdC and SJM are supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 44 TC 3 Z9 3 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL PY 2015 VL 67 BP 54 EP 61 DI 10.1016/j.exger.2015.04.009 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CI6MV UT WOS:000354874700007 PM 25910621 ER PT J AU Houghton, PJ Kurmasheva, RT Kolb, EA Gorlick, R Maris, JM Wu, JR Tong, ZE Arnold, MA Chatterjee, M Williams, TM Smith, MA AF Houghton, Peter J. Kurmasheva, Raushan T. Kolb, E. Anders Gorlick, Richard Maris, John M. Wu, Jianrong Tong, Zeen Arnold, Michael A. Chatterjee, Moumita Williams, Terence M. Smith, Malcolm A. TI Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane((R))) by the Pediatric Preclinical Testing Program (PPTP) SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Abraxane; developmental therapeutics; nab-paclitaxel; preclinical testing ID SOLVENT-BASED PACLITAXEL; REFRACTORY SOLID TUMORS; PHASE-III TRIAL; ONCOLOGY-GROUP; BREAST-CANCER; CREMOPHOR-EL; IN-VIVO; MODELS; FORMULATION; CHILDREN AB BackgroundNanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane((R))) is FDA approved for the treatment of several adult cancers. Antimitotic agents are essential components for curative therapy of pediatric solid tumors, although taxanes have shown limited activity. Because of the novel formulation, nab-paclitaxel was evaluated against a limited series of Pediatric Preclinical Testing Program (PPTP) solid tumors. ProceduresNab-paclitaxel was tested against a limited subset of PPTP solid tumor xenograft models at a dose of 50mg/kg using a q4dx3 schedule intravenously. ResultsNab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose. All 20 xenograft models tested were considered evaluable for efficacy. Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors. Objective responses were observed in 12 of 20 (60%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in 5 of 8 Ewing sarcoma models and 6 of 8 rhabdomyosarcomas. There were no objective regressions in either neuroblastoma (n=2) or osteosarcoma (n=2) xenograft panels. At the dose tested, systemic exposures of nab-paclitaxel in mice were somewhat greater than those tolerated in humans. ConclusionsThe high level of activity observed against the rhabdomyosarcoma and Ewing sarcoma PPTP preclinical models makes nab-paclitaxel an interesting agent to consider for pediatric evaluation. Pediatr Blood Cancer 2015;62:1214-1221. (c) 2015 Wiley Periodicals, Inc. C1 [Houghton, Peter J.; Kurmasheva, Raushan T.] Nationwide Childrens Hosp, Columbus, OH 43205 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Tong, Zeen] Celgene Corp, Los Angeles, CA USA. [Arnold, Michael A.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43205 USA. [Arnold, Michael A.] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Chatterjee, Moumita; Williams, Terence M.] James Canc Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Houghton, PJ (reprint author), Nationwide Childrens Hosp, Ctr Childhood Canc, Res Inst, 700 Childrens Dr, Columbus, OH 43205 USA. EM Peter.Houghton@nationwidechildrens.org FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216; CA21765; CA108786 NR 26 TC 7 Z9 7 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2015 VL 62 IS 7 BP 1214 EP 1221 DI 10.1002/pbc.25474 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CI1YQ UT WOS:000354541600021 PM 25809532 ER PT J AU Schlogl, M Piaggi, P Votruba, SB Walter, M Krakoff, J Thearle, MS AF Schloegl, Mathias Piaggi, Paolo Votruba, Susanne B. Walter, Mary Krakoff, Jonathan Thearle, Marie S. TI Increased 24-hour ad libitum food intake is associated with lower plasma irisin concentrations the following morning in adult humans SO APPETITE LA English DT Article DE Irisin; Ad libitum food intake ID SKELETAL-MUSCLE; RESISTANCE EXERCISE; CIRCULATING IRISIN; BODY-COMPOSITION; OBESE MEN; ENERGY-EXPENDITURE; PHYSICAL-ACTIVITY; ADIPOSE-TISSUE; WHITE FAT; PROTEIN AB Background: The relationship between food intake and irisin concentrations in humans is unclear. Objectives: To determine whether the previous day's intake impacts fasting plasma irisin concentrations, or whether fasting irisin concentrations associate with subsequent ad libitum food intake. Methods: Sixty-six nondiabetic adults (42 men) were admitted for a study of the determinants of energy intake. After 6 days of a weight maintaining diet, ad libitum energy intake over 3 days was assessed using a vending machine paradigm. Fasting plasma irisin concentrations were measured on the morning of the second day of the vending period. Results: There were no correlations between irisin and demographic or anthropometric parameters. On day 1, subjects consumed 144 +/- 52% of weight maintaining energy needs. Every additional 500 kcal consumed on day 1 associated with a 3.4% lower irisin concentration the following morning (95% CI -6.2, -0.4%, p = 0.01; adjusted for age, sex and race). If energy intake was expressed as a percentage of weight maintaining energy needs, every 10% increase associated with a 1.9% lower irisin concentration (95% CI -3.7, -0.1%; adjusted p = 0.02). A 100 kcal increase in carbohydrate or fat consumption associated with a 1.3% (95% CI -2.5, -0.1%, p = 0.01) and a 0.6% (95% CI -1.1, -0.0%, p = 0.02) lower irisin concentration, respectively. There was no association between fasting irisin concentrations and subsequent energy intake on day 2 (r = 0.19, p = 0.1). Conclusions: Higher ad libitum 24 h energy intake was associated with lower fasting irisin concentrations the following morning, but fasting irisin concentrations did not predict subsequent energy intake. The decrease in irisin concentrations with increased energy intake is consistent with the detrimental metabolic effects of overeating. Published by Elsevier Ltd. C1 [Schloegl, Mathias; Piaggi, Paolo; Votruba, Susanne B.; Krakoff, Jonathan; Thearle, Marie S.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. [Walter, Mary] NIDDK, Clin Core Lab, Phoenix, AZ USA. RP Schlogl, M (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. EM mathias.schlogl@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX MS and PP were supported by a visiting fellowship award of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 51 TC 4 Z9 4 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD JUL 1 PY 2015 VL 90 BP 154 EP 159 DI 10.1016/j.appet.2015.03.003 PG 6 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA CI2NK UT WOS:000354584100020 PM 25765248 ER PT J AU Song, MY Gong, J Giovannucci, EL Berndt, SI Brenner, H Chang-Claude, J Curtis, KR Harrison, TA Hoffmeister, M Hsu, L Jiao, S Le Marchand, L Potter, JD Schoen, RE Seminara, D Slattery, ML White, E Wu, KN Ogino, S Fuchs, CS Hunter, DJ Tworoger, SS Hu, FB Rimm, E Jensen, M Peters, U Chan, AT AF Song, Mingyang Gong, Jian Giovannucci, Edward L. Berndt, Sonja I. Brenner, Hermann Chang-Claude, Jenny Curtis, Keith R. Harrison, Tabitha A. Hoffmeister, Michael Hsu, Li Jiao, Shuo Le Marchand, Loic Potter, John D. Schoen, Robert E. Seminara, Daniela Slattery, Martha L. White, Emily Wu, Kana Ogino, Shuji Fuchs, Charles S. Hunter, David J. Tworoger, Shelley S. Hu, Frank B. Rimm, Eric Jensen, Majken Peters, Ulrike Chan, Andrew T. TI Genetic variants of adiponectin and risk of colorectal cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE adiponectin; single-nucleotide polymorphism; Mendelian randomization; colorectal cancer; lifestyle factors ID MOLECULAR-WEIGHT ADIPONECTIN; GENOME-WIDE ASSOCIATION; SOLUBLE LEPTIN RECEPTOR; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; MENDELIAN RANDOMIZATION; CIRCULATING ADIPONECTIN; SUSCEPTIBILITY LOCI; METABOLIC SYNDROME; SERUM ADIPONECTIN AB Circulating adiponectin has been associated with lower risk of colorectal cancer (CRC). Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with adiponectin levels. However, it is unclear whether these SNPs are associated with CRC risk. In addition, previous data on SNPs in the adiponectin pathway and their associations with CRC are inconsistent. Therefore, we examined 19 SNPs in genes related to adiponectin or its receptors and their associations with CRC using logistic regression among 7,020 cases and 7,631 controls drawn from ten studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium. Using data from a subset of two large cohort studies, we also assessed the contribution of individual SNPs and an adiponectin genetic score to plasma adiponectin after accounting for lifestyle factors among 2,217 women and 619 men. We did not find any statistically significant association between the 19 adiponectin-associated SNPs and CRC risk (multivariable-adjusted odds ratios ranged from 0.89 to 1.05, all p>0.05). Each SNP explained less than 2.50% of the variance of plasma adiponectin, and the genetic score collectively accounted for 2.95 and 1.42% of the variability of adiponectin in women and men, respectively, after adjustment for age, body mass index, physical activity, smoking, alcohol consumption, regular use of aspirin or nonsteroidal anti-inflammatory drug and postmenopausal hormone use. In conclusion, our findings do not support an association between known adiponectin-related common SNPs and CRC incidence. However, known common SNPs account for only a limited proportion of the interindividual variance in circulating adiponectin. Further work is warranted to investigate the relationship between adiponectin and CRC while accounting for other components in the pathway. What's new? Obesity is a well-established risk factor for colorectal cancer, and mounting evidence suggests that the adipocyte-derived hormone adiponectin is behind that link. In the present investigation, common genetic variants in the adiponectin (ADIPOQ) gene were analyzed for potential relationships with colorectal cancer risk. However, no statistically significant associations were identified. Because common genetic determinants account for only a limited proportion of the variance in circulating adiponectin concentrations, factors that influence adiponectin receptors and other components of the adiponectin pathway should be investigated. C1 [Song, Mingyang; Giovannucci, Edward L.; Wu, Kana; Hunter, David J.; Hu, Frank B.; Rimm, Eric; Jensen, Majken] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Song, Mingyang; Giovannucci, Edward L.; Ogino, Shuji; Hunter, David J.; Tworoger, Shelley S.; Hu, Frank B.; Rimm, Eric] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gong, Jian; Curtis, Keith R.; Harrison, Tabitha A.; Hsu, Li; Jiao, Shuo; Potter, John D.; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Giovannucci, Edward L.; Ogino, Shuji; Fuchs, Charles S.; Hunter, David J.; Tworoger, Shelley S.; Hu, Frank B.; Rimm, Eric; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Ogino, Shuji; Fuchs, Charles S.; Hunter, David J.; Tworoger, Shelley S.; Hu, Frank B.; Rimm, Eric; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Heidelberg, Germany. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Hsu, Li] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Potter, John D.; White, Emily; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM achan@partners.org RI Hoffmeister, Michael/B-5745-2012; Song, Mingyang/M-6701-2013; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Song, Mingyang/0000-0002-1324-0316; Brenner, Hermann/0000-0002-6129-1572; Tworoger, Shelley/0000-0002-6986-7046; Potter, John/0000-0001-5439-1500 FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, R01 CA60987, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, K05 CA154337, K24 DK098311]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Harvard Transdisciplinary Research Center on Energetics and Cancer (TREC) [1U54CA155626] FX Grant sponsor: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services; Grant numbers: U01 CA137088, R01 CA059045, R01 CA60987, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, K05 CA154337, K24 DK098311; Grant sponsor: German Research Council (Deutsche Forschungsgemeinschaft); Grant numbers: BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1; Grant sponsor: German Federal Ministry of Education and Research; Grant numbers: 01KH0404, 01ER0814; Grant sponsor: Harvard Transdisciplinary Research Center on Energetics and Cancer (TREC); Grant number: 1U54CA155626 NR 50 TC 2 Z9 2 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2015 VL 137 IS 1 BP 154 EP 164 DI 10.1002/ijc.29360 PG 11 WC Oncology SC Oncology GA CG4ZH UT WOS:000353297600015 PM 25431318 ER PT J AU Inoue-Choi, M Jones, RR Anderson, KE Cantor, KP Cerhan, JR Krasner, S Robien, K Weyer, PJ Ward, MH AF Inoue-Choi, Maki Jones, Rena R. Anderson, Kristin E. Cantor, Kenneth P. Cerhan, James R. Krasner, Stuart Robien, Kim Weyer, Peter J. Ward, Mary H. TI Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE nitrate; nitrite; ovarian cancer; diet; drinking water; disinfection byproducts ID DRINKING-WATER NITRATE; OLDER WOMEN; DIETARY NITRATE; NO ASSOCIATION; BLADDER-CANCER; UNITED-STATES; HEALTH; MEAT; CONSUMPTION; RED AB Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3-N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI=1.22-3.38, p(trend)=0.003) in the highest quartile (2.98 mg/L) compared with the lowest quartile (0.47 mg/L; reference) of NO3-N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR=1.53, CI=0.93-2.54) compared with the same reference group. Associations were stronger when vitamin C intake was 9.75 g day(-1): HR, 0.67; 95%CI, 0.50 to 0.89; p trend=0.002). We observed similar patterns of association for men and women as well as by alcohol beverage type. In analyses stratified by smoking status, the inverse association with consumption was apparent for ever smokers (HR, 0.51; 95%CI, 0.36 to 0.73; p trend<0.0001) but not among never smokers (HR, 1.08; 95%CI, 0.66 to 1.76; P trend=0.78; p interaction=0.01). Our study findings offer further support that alcohol consumption is associated with reduced RCC risk, regardless of sex or alcoholic beverage type. The finding of interaction with smoking is novel and requires confirmation. C1 [Karami, Sara; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Daugherty, Sarah E.] Patient Ctr Outcome Res Inst, Washington, DC USA. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,6E624, Rockville, MD 20850 USA. EM karamis@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural Research Program of the NCI; Division of Cancer Epidemiology and Genetics; National Institutes of Health; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS FX Grant sponsors: Intramural Research Program of the NCI; Division of Cancer Epidemiology and Genetics; National Institutes of Health; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS NR 26 TC 5 Z9 5 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2015 VL 137 IS 1 BP 238 EP 242 DI 10.1002/ijc.29359 PG 5 WC Oncology SC Oncology GA CG4ZH UT WOS:000353297600024 PM 25431248 ER PT J AU Kraemer, MUG Sinka, ME Duda, KA Mylne, AQN Shearer, FM Barker, CM Moore, CG Carvalho, RG Coelho, GE Van Bortel, W Hendrickx, G Schaffner, F Elyazar, IRF Teng, HJ Brady, OJ Messina, JP Pigott, DM Scott, TW Smith, DL Wint, GRW Golding, N Hay, SI AF Kraemer, Moritz U. G. Sinka, Marianne E. Duda, Kirsten A. Mylne, Adrian Q. N. Shearer, Freya M. Barker, Christopher M. Moore, Chester G. Carvalho, Roberta G. Coelho, Giovanini E. Van Bortel, Wim Hendrickx, Guy Schaffner, Francis Elyazar, Iqbal R. F. Teng, Hwa-Jen Brady, Oliver J. Messina, Jane P. Pigott, David M. Scott, Thomas W. Smith, David L. Wint, G. R. William Golding, Nick Hay, Simon I. TI The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus SO ELIFE LA English DT Article ID DOMINANT ANOPHELES VECTORS; DENGUE VIRUS TRANSMISSION; ASIAN TIGER MOSQUITO; BOOSTED REGRESSION TREES; CHIKUNGUNYA VIRUS; DISTRIBUTION MODELS; DISTRIBUTION MAPS; BIONOMIC PRECIS; CLIMATE-CHANGE; HUMAN MALARIA AB Dengue and chikungunya are increasing global public health concerns due to their rapid geographical spread and increasing disease burden. Knowledge of the contemporary distribution of their shared vectors, Aedes aegypti and Aedes albopictus remains incomplete and is complicated by an ongoing range expansion fuelled by increased global trade and travel. Mapping the global distribution of these vectors and the geographical determinants of their ranges is essential for public health planning. Here we compile the largest contemporary database for both species and pair it with relevant environmental variables predicting their global distribution. We show Aedes distributions to be the widest ever recorded; now extensive in all continents, including North America and Europe. These maps will help define the spatial limits of current autochthonous transmission of dengue and chikungunya viruses. It is only with this kind of rigorous entomological baseline that we can hope to project future health impacts of these viruses. C1 [Kraemer, Moritz U. G.; Sinka, Marianne E.; Duda, Kirsten A.; Messina, Jane P.; Pigott, David M.; Smith, David L.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford, England. [Mylne, Adrian Q. N.; Shearer, Freya M.; Brady, Oliver J.; Pigott, David M.; Golding, Nick; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Barker, Christopher M.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Moore, Chester G.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Carvalho, Roberta G.; Coelho, Giovanini E.] Minist Hlth, Natl Dengue Control Program, Brasilia, DF, Brazil. [Van Bortel, Wim] European Ctr Dis Prevent & Control, Stockholm, Sweden. [Hendrickx, Guy; Schaffner, Francis] Avia GIS, Zoersel, Belgium. [Elyazar, Iqbal R. F.] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Teng, Hwa-Jen] Ctr Dis Control, Ctr Res Diagnost & Vaccine Dev, Taipei, Taiwan. [Scott, Thomas W.; Smith, David L.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD USA. [Wint, G. R. William] Univ Oxford, Dept Zool, Environm Res Grp Oxford, Oxford, England. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. RP Kraemer, MUG (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford, England. EM moritz.kraemer@zoo.ox.ac.uk; simon.hay@well.ox.ac.uk OI Pigott, David/0000-0002-6731-4034; Golding, Nick/0000-0001-8916-5570; Brady, Oliver/0000-0002-3235-2129; Hay, Simon/0000-0002-0611-7272 FU Studienstiftung des Deutschen Volkes; Bill and Melinda Gates Foundation [OPP1053338]; Wellcome Trust [095066]; European Centre for Disease Prevention and Control [ECDC/09/018]; European Commission Directorate-General for Research and Innovation [21803]; Biotechnology and Biological Sciences Research Council (BBSRC; National Aeronautics and Space Administration (NASA) [NNX15AF36G]; National Institutes of Health (NIH) RAPIDD program; National Institutes of Health (NIH) [R01-AI069341, R01-AI091980] FX Studienstiftung des Deutschen Volkes Moritz UG Kraemer; Bill and Melinda Gates Foundation #OPP1053338 Nick Golding; Wellcome Trust #095066 Kirsten A Duda, Adrian QN Mylne, Simon I Hay; European Centre for Disease Prevention and Control ECDC/09/018 Wim Van Bortel, Guy Hendrickx, Francis Schaffner; European Commission Directorate-General for Research and Innovation #21803 Oliver J Brady, Jane P Messina; Biotechnology and Biological Sciences Research Council (BBSRC) Oliver J Brady; National Aeronautics and Space Administration (NASA) #NNX15AF36G Christopher M Barker; National Institutes of Health (NIH) RAPIDD program Christopher M Barker, Thomas W Scott, David L Smith, Simon I Hay; National Institutes of Health (NIH) R01-AI069341 Thomas W Scott; National Institutes of Health (NIH) R01-AI091980 Thomas W Scott NR 125 TC 119 Z9 123 U1 24 U2 62 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 30 PY 2015 VL 4 AR e08347 DI 10.7554/eLife.08347 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DG6JY UT WOS:000372191700001 PM 26126267 ER PT J AU Christy, B Demaria, M Campisi, J Huang, J Jones, D Dodds, SG Williams, C Hubbard, G Livi, CB Gao, XL Weintraub, S Curiel, T Sharp, ZD Hasty, P AF Christy, Barbara Demaria, Marco Campisi, Judith Huang, Jing Jones, Diane Dodds, Sherry G. Williams, Charnae Hubbard, Gene Livi, Carolina B. Gao, Xiaoli Weintraub, Susan Curiel, Tyler Sharp, Z. Dave Hasty, Paul TI p53 and rapamycin are additive SO ONCOTARGET LA English DT Article DE mTOR; p53; rapamycin; longevity; SASP ID EXTENDS LIFE-SPAN; CELL-CYCLE ARREST; GENETICALLY HETEROGENEOUS MICE; EMBRYONIC STEM-CELLS; DNA-DAMAGE RESPONSE; TUMOR SUPPRESSION; DIETARY-RESTRICTION; TRANSPLANT RECIPIENTS; MAINTENANCE PATHWAYS; SECRETORY PHENOTYPE AB Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic. C1 [Christy, Barbara; Jones, Diane; Dodds, Sherry G.; Williams, Charnae; Livi, Carolina B.; Sharp, Z. Dave; Hasty, Paul] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Christy, Barbara; Jones, Diane; Dodds, Sherry G.; Williams, Charnae; Livi, Carolina B.; Sharp, Z. Dave; Hasty, Paul] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, San Antonio, TX 78229 USA. [Hubbard, Gene] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Gao, Xiaoli; Weintraub, Susan] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Curiel, Tyler] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Christy, Barbara; Curiel, Tyler; Sharp, Z. Dave; Hasty, Paul] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Christy, Barbara; Sharp, Z. Dave; Hasty, Paul] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Demaria, Marco; Campisi, Judith] Buck Inst Res Aging, Novato, CA USA. [Huang, Jing] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hasty, P (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. EM hastye@uthscsa.edu RI Huang, Jing/A-2566-2009 OI Huang, Jing/0000-0002-7163-5156 FU NIH [RC2AG036613]; [P01AG017242]; [1S10RR031586-01]; [P30 CA054174] FX This work was supported by NIH grants (RC2AG036613, Project 1, ZDS and PH, and P01AG017242, Core B and Project 3, PH and JC and 1S10RR031586-01 to STW and P30 CA054174 to STW. NR 77 TC 3 Z9 3 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 30 PY 2015 VL 6 IS 18 BP 15802 EP 15813 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2UL UT WOS:000359012000028 PM 26158292 ER PT J AU Gooskens, SL Gadd, S Auvil, JMG Gerhard, DS Khan, J Patidar, R Meerzaman, D Chen, QR Hsu, CH Yan, CH Nguyen, C Hu, Y Mullighan, CG Ma, J Jennings, LJ de Krijger, RR van den Heuvel-Eibrink, MM Smith, MA Ross, N Gastier-Foster, JM Perlman, EJ AF Gooskens, Saskia L. Gadd, Samantha Auvil, Jaime M. Guidry Gerhard, Daniela S. Khan, Javed Patidar, Rajesh Meerzaman, Daoud Chen, Qing-Rong Hsu, Chih Hao Yan, Chunhua Cu Nguyen Hu, Ying Mullighan, Charles G. Ma, Jing Jennings, Lawrence J. de Krijger, Ronald R. van den Heuvel-Eibrink, Marry M. Smith, Malcolm A. Ross, Nicole Gastier-Foster, Julie M. Perlman, Elizabeth J. TI TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney SO ONCOTARGET LA English DT Article DE clear cell sarcoma of the kidney; whole genome sequencing; methylation; TCF21; TARID ID TUMOR STUDY-GROUP; PROGENITOR CELLS; RECURRING TRANSLOCATION; CHILDHOOD-CANCER; LUNG-CANCER; WILMS-TUMOR; GENE; METHYLATION; POD1; DIFFERENTIATION AB Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood tumor whose molecular pathogenesis remains poorly understood. We analyzed a discovery set of 13 CCSKs for changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation. No recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified. One tumor with t(10; 17)(q22; p13) involving fusion of YHWAE with NUTM2B was identified. Integrated analysis of expression and methylation data identified promoter hypermethylation and low expression of the tumor suppressor gene TCF21 (Pod-1/capsulin/epicardin) in all CCSKs except the case with t(10; 17) (q22; p13). TARID, the long noncoding RNA responsible for demethylating TCF21, was virtually undetectable in most CCSKs. TCF21 hypermethylation and decreased TARID expression were validated in an independent set of CCSK tumor samples. The presence of significant hypermethylation of TCF21, a transcription factor known to be active early in renal development, supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. Future studies are needed to functionally verify a tumorigenic role of TCF21 down-regulation and to tie this to the unique gene expression pattern of CCSK. C1 [Gooskens, Saskia L.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Hematol & Oncol, Rotterdam, Netherlands. [Gooskens, Saskia L.; van den Heuvel-Eibrink, Marry M.] Princess Maxima Ctr Pediat Oncol, Dept Pediat Oncol, Utrecht, Netherlands. [Gadd, Samantha; Jennings, Lawrence J.; Perlman, Elizabeth J.] Northwestern Univ, Dept Pathol, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. [Gadd, Samantha; Jennings, Lawrence J.; Perlman, Elizabeth J.] Northwestern Univ, Robert H Lurie Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Auvil, Jaime M. Guidry; Gerhard, Daniela S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Khan, Javed; Patidar, Rajesh] NCI, Genet Branch, Oncogen Sect, Bethesda, MD 20892 USA. [Meerzaman, Daoud; Chen, Qing-Rong; Hsu, Chih Hao; Yan, Chunhua; Cu Nguyen; Hu, Ying] NCI, Computat Genom Res Grp, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Mullighan, Charles G.; Ma, Jing] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [de Krijger, Ronald R.] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. [de Krijger, Ronald R.] Reinier de Graaf Hosp, Dept Pathol, Delft, Netherlands. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Ross, Nicole; Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Dept Pathol & Lab Med, Nationwide Childrens Hosp, Columbus, OH 43210 USA. RP Perlman, EJ (reprint author), Northwestern Univ, Dept Pathol, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. EM Eperlman@luriechildrens.org OI Mullighan, Charles/0000-0002-1871-1850 FU NCI [U10 CA98543]; National Cancer Institute, US National Institutes of Health [HHSN261200800001E]; NIH [U10CA42326, U10CA98543, U24CA114766, U10CA88131]; American and Lebanese Syrian Associated Charities of St Jude; Pediatric Oncology Center Society for Research; DaDa foundation; Dutch Cancer Foundation FX The TARGET initiative is supported by NCI Grant U10 CA98543. Work performed under contracts from the National Cancer Institute, US National Institutes of Health within HHSN261200800001E include specimen processing (the Children's Oncology Group Biopathology Center (BPC)), whole genomic sequencing (Complete Genomics, Inc.). The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.; This work is also supported by NIH U10CA42326 (EJP); U10CA98543 (JSD, EJP); U24CA114766; U10CA88131 (EJP), and the American and Lebanese Syrian Associated Charities of St Jude (JM, CM). In addition, this work was supported by the Pediatric Oncology Center Society for Research (KOCR, Rotterdam, The Netherlands), the DaDa foundation (Nieuwerkerk a/d Ijssel, The Netherlands) and the Dutch Cancer Foundation (KWF, Amsterdam, The Netherlands). NR 54 TC 7 Z9 7 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 30 PY 2015 VL 6 IS 18 BP 15828 EP 15841 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2UL UT WOS:000359012000030 PM 26158413 ER PT J AU Thomas, A Chen, YB Yu, TH Gill, A Prasad, V AF Thomas, Anish Chen, Yuanbin Yu, Tinghui Gill, Ammara Prasad, Vinay TI Distinctive clinical characteristics of malignant mesothelioma in young patients SO ONCOTARGET LA English DT Article DE mesothelioma; SEER analysis; incidence among the young; asbestos ID EXPANDED ACCESS PROGRAM; GERMLINE BAP1 MUTATIONS; PERITONEAL MESOTHELIOMA; PLEURAL MESOTHELIOMA; ASBESTOS; COMBINATION; SURVIVAL; CANCER; CARCINOGENESIS; CISPLATIN AB Although considered a disease of the elderly, a subset of patients with mesothelioma are young (<40 years). The goal of this study was to understand their characteristics and outcomes. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract mesothelioma cases (1990-2010). We modeled Kaplan-Meyer survival curves stratified by site of disease, and age of presentation. 2% (207 of 12345) of mesothelioma patients are young. Sex distribution is comparable among the young (51% males, 49% females); males predominated (78%, 22%) in the older cohort. Frequency of pleural and peritoneal mesothelioma are similar in the young (47%, 48% respectively); pleural disease predominated in the old (90%, 9%). Cancer-directed surgeries are more frequent in the young. Regardless of histologic subtype, young patients with pleural (11 vs. 8 months) and peritoneal (not reached vs. 10 months) mesothelioma had significantly improved overall survival. In multivariate analysis, younger age was an independent prognostic factor. Although rare, mesothelioma do occur in the young; their characteristics are distinct from those of older patients. Further studies are needed to understand the interplay between genetic susceptibility and mineral fiber carcinogenesis in the pathogenesis of mesothelioma in the young. C1 [Thomas, Anish; Chen, Yuanbin] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yu, Tinghui] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gill, Ammara] Meyer Orthoped & Rehabil Hosp, Springfield, MO USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 27 TC 2 Z9 2 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 30 PY 2015 VL 6 IS 18 BP 16766 EP 16773 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2UL UT WOS:000359012000097 PM 26202904 ER PT J AU Chen, F He, J Zhang, JQ Chen, GK Thomas, V Ambrosone, CB Bandera, EV Berndt, SI Bernstein, L Blot, WJ Cai, QY Carpten, J Casey, G Chanock, SJ Cheng, I Chu, LS Deming, SL Driver, WR Goodman, P Hayes, RB Hennis, AJM Hsing, AW Hu, JJ Ingles, SA John, EM Kittles, RA Kolb, S Leske, MC Millikan, RC Monroe, KR Murphy, A Nemesure, B Neslund-Dudas, C Nyante, S Ostrander, EA Press, MF Rodriguez-Gil, JL Rybicki, BA Schumacher, F Stanford, JL Signorello, LB Strom, SS Stevens, V Van Den Berg, D Wang, ZM Witte, JS Wu, SY Yamamura, Y Zheng, W Ziegler, RG Stram, AH Kolonel, LN Le Marchand, L Henderson, BE Haiman, CA Stram, DO AF Chen, Fang He, Jing Zhang, Jianqi Chen, Gary K. Thomas, Venetta Ambrosone, Christine B. Bandera, Elisa V. Berndt, Sonja I. Bernstein, Leslie Blot, William J. Cai, Qiuyin Carpten, John Casey, Graham Chanock, Stephen J. Cheng, Iona Chu, Lisa Deming, Sandra L. Driver, W. Ryan Goodman, Phyllis Hayes, Richard B. Hennis, Anselm J. M. Hsing, Ann W. Hu, Jennifer J. Ingles, Sue A. John, Esther M. Kittles, Rick A. Kolb, Suzanne Leske, M. Cristina Millikan, Robert C. Monroe, Kristine R. Murphy, Adam Nemesure, Barbara Neslund-Dudas, Christine Nyante, Sarah Ostrander, Elaine A. Press, Michael F. Rodriguez-Gil, Jorge L. Rybicki, Ben A. Schumacher, Fredrick Stanford, Janet L. Signorello, Lisa B. Strom, Sara S. Stevens, Victoria Van Den Berg, David Wang, Zhaoming Witte, John S. Wu, Suh-Yuh Yamamura, Yuko Zheng, Wei Ziegler, Regina G. Stram, Alexander H. Kolonel, Laurence N. Le Marchand, Loic Henderson, Brian E. Haiman, Christopher A. Stram, Daniel O. TI Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults SO PLOS ONE LA English DT Article ID POPULATION-STRUCTURE; GENETIC PATHWAY; MIXED MODELS; ASSOCIATION; SIMILARITY; REGRESSION AB Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R-2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious. C1 [Chen, Fang; He, Jing; Zhang, Jianqi; Chen, Gary K.; Casey, Graham; Ingles, Sue A.; Monroe, Kristine R.; Schumacher, Fredrick; Van Den Berg, David; Stram, Alexander H.; Henderson, Brian E.; Haiman, Christopher A.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Chen, Fang; He, Jing; Zhang, Jianqi; Chen, Gary K.; Casey, Graham; Ingles, Sue A.; Monroe, Kristine R.; Press, Michael F.; Schumacher, Fredrick; Van Den Berg, David; Stram, Alexander H.; Henderson, Brian E.; Haiman, Christopher A.; Stram, Daniel O.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Thomas, Venetta; Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Thomas, Venetta; Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [Berndt, Sonja I.; Chanock, Stephen J.; Hsing, Ann W.; Nyante, Sarah; Wang, Zhaoming; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bernstein, Leslie] Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, City Of Hope, CA USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.; Cai, Qiuyin; Deming, Sandra L.; Zheng, Wei] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Blot, William J.; Cai, Qiuyin; Deming, Sandra L.; Zheng, Wei] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA. [Cheng, Iona; Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Chu, Lisa; John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Driver, W. Ryan; Stevens, Victoria] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Goodman, Phyllis; Kolb, Suzanne; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Hayes, Richard B.] NYU, Dept Environm Med, Div Epidemiol, Langone Med Ctr, New York, NY 10016 USA. [Hennis, Anselm J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Hennis, Anselm J. M.; Leske, M. Cristina; Nemesure, Barbara; Wu, Suh-Yuh] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [John, Esther M.] Stanford Univ, Div Epidemiol, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Inst, Stanford, CA USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. [Millikan, Robert C.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Millikan, Robert C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Murphy, Adam] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Neslund-Dudas, Christine; Rybicki, Ben A.] Henry Ford Hosp, Dept Biostat & Res Epidemiol, Detroit, MI 48202 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Witte, John S.; Yamamura, Yuko] Univ Calif San Francisco, Dept Epidemiol & Biostat, Inst Human Genet, San Francisco, CA 94143 USA. RP Stram, DO (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM stram@usc.edu OI Hayes, Richard/0000-0002-0918-661X; Ostrander, Elaine/0000-0001-6075-9738 FU African American Prostate Cancer (AAPC) GWAS study, NCI [5R01CA165862]; Era of Hope Scholar Award, Department of Defense Breast Cancer Research Program [5U19CA148537]; Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), NCI [U01HG004802-04, 1U01HG007397-01]; Population Architecture using Genomics and Epidemiology (PAGE), NHGRI [15UB8402]; New Methods for Genomic Studies in African American Women, California Breast Cancer Research Program [RC2CA148085] FX 5R01CA165862 African American Prostate Cancer (AAPC) GWAS study, NCI; Era of Hope Scholar Award (to CAH), Department of Defense Breast Cancer Research Program; 5U19CA148537 Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), NCI; U01HG004802-04 and 1U01HG007397-01, Population Architecture using Genomics and Epidemiology (PAGE), NHGRI; 15UB8402, New Methods for Genomic Studies in African American Women, California Breast Cancer Research Program; RC2CA148085, Expanding resources for understanding the genetic basis for prostate cancer in African Americans. NR 26 TC 0 Z9 0 U1 4 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2015 VL 10 IS 6 AR e0131106 DI 10.1371/journal.pone.0131106 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BR UT WOS:000358151300033 PM 26125186 ER PT J AU Edefonti, V Hashibe, M Parpinel, M Ferraroni, M Turati, F Serraino, D Matsuo, K Olshan, AF Zevallos, JP Winn, DM Moysich, K Zhang, ZF Morgenstern, H Levi, F Kelsey, K McClean, M Bosetti, C Schantz, S Yu, GP Boffetta, P Chuang, SC Lee, YCA La Vecchia, C Decarli, A AF Edefonti, V. Hashibe, M. Parpinel, M. Ferraroni, M. Turati, F. Serraino, D. Matsuo, K. Olshan, A. F. Zevallos, J. P. Winn, D. M. Moysich, K. Zhang, Z-F Morgenstern, H. Levi, F. Kelsey, K. McClean, M. Bosetti, C. Schantz, S. Yu, G-P Boffetta, P. Chuang, S-C Lee, Y-C A. La Vecchia, C. Decarli, A. TI Vitamin E intake from natural sources and head and neck cancer risk: a pooled analysis in the International Head and Neck Cancer Epidemiology consortium SO BRITISH JOURNAL OF CANCER LA English DT Article DE head and neck cancer; INHANCE; laryngeal cancer; oral and pharyngeal cancer; vitamin E ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; PHARYNGEAL CANCER; ORAL-CANCER; ANTIOXIDANT VITAMINS; LARYNGEAL-CANCER; DIETARY PATTERNS; SERUM MICRONUTRIENTS; ESOPHAGEAL CANCER; ALPHA-TOCOPHEROL AB Background: Evidence for the possible effect of vitamin E on head and neck cancers (HNCs) is limited. Methods: We used individual-level pooled data from 10 case-control studies (5959 cases and 12 248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium to assess the association between vitamin E intake from natural sources and cancer of the oral cavity/pharynx and larynx. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models applied to quintile categories of nonalcohol energy-adjusted vitamin E intake. Results: Intake of vitamin E was inversely related to oral/pharyngeal cancer (OR for the fifth vs the first quintile category = 0.59, 95% CI: 0.49-0.71; P for trend <0.001) and to laryngeal cancer (OR = 0.67, 95% CI: 0.54-0.83, P for trend <0.001). There was, however, appreciable heterogeneity of the estimated effect across studies for oral/pharyngeal cancer. Inverse associations were generally observed for the anatomical subsites of oral and pharyngeal cancer and within covariate strata for both sites. Conclusion: Our findings suggest that greater vitamin E intake from foods may lower HNC risk, although we were not able to explain the heterogeneity observed across studies or rule out certain sources of bias. C1 [Edefonti, V.; Ferraroni, M.; La Vecchia, C.; Decarli, A.] Univ Milan, Lab Stat Med Biometria Epidemiol GA Maccacaro, Dipartimento Sci Clin & Comunita, I-20133 Milan, Italy. [Hashibe, M.] Univ Utah, Sch Med, Div Publ Hlth, Dept Family & Prevent Med, Salt Lake City, UT 84108 USA. [Hashibe, M.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84108 USA. [Parpinel, M.] Univ Udine, Dept Med & Biol Sci, I-33100 Udine, Italy. [Turati, F.] Fdn IRCSS Ist Nazl Tumori Milano, SC Stat Med Biometria & Bioinformat, I-20133 Milan, Italy. [Serraino, D.] IRCCS, CRO Aviano Natl Canc Inst, Epidemiol & Biostat Unit, I-33081 Aviano, PN, Italy. [Matsuo, K.] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Higashi Ku, Fukuoka 8128582, Japan. [Olshan, A. F.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Zevallos, J. P.] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC 27599 USA. [Winn, D. M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Moysich, K.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Zhang, Z-F] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. [Morgenstern, H.] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI USA. [Morgenstern, H.] Univ Michigan, Dept Environm Hlth Sci, Sch Publ Hlth, Ann Arbor, MI USA. [Morgenstern, H.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI USA. [Levi, F.] Lausanne Univ Hosp CHUV, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland. [Kelsey, K.] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. [McClean, M.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. [Bosetti, C.] IRCCS Ist Ric Farmacol Mario Negri, Dept Epidemiol, I-20156 Milan, Italy. [Schantz, S.] New York Eye & Ear Infirm, Dept Otolaryngol, New York, NY 10003 USA. [Yu, G-P] Peking Univ, Med Informat Ctr, Beijing, Peoples R China. [Boffetta, P.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, P.] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Chuang, S-C] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan, Miaoli County, Taiwan. [Lee, Y-C A.] Univ Utah, Sch Med, Dept Family & Prevent Med, Divis Publ Hlth, Salt Lake City, UT 84108 USA. RP Edefonti, V (reprint author), Univ Milan, Lab Stat Med Biometria Epidemiol GA Maccacaro, Dipartimento Sci Clin & Comunita, Via A Vanzetti 5, I-20133 Milan, Italy. EM valeria.edefonti@unimi.it RI McClean, Michael/J-2934-2015; U-ID, Kyushu/C-5291-2016; Turati, Federica/K-3841-2016; Parpinel, Maria/B-1605-2012; Decarli, Adriano/C-3129-2017; Ferraroni, Monica/D-6548-2017; OI Turati, Federica/0000-0002-5841-5773; Parpinel, Maria/0000-0003-1309-4467; Decarli, Adriano/0000-0003-1451-8292; Ferraroni, Monica/0000-0002-4542-4996; Serraino, Diego/0000-0003-0565-8920; La Vecchia, Carlo/0000-0003-1441-897X; EDEFONTI, VALERIA CARLA/0000-0002-1995-1477 FU National Institutes of Health (NIH), National Cancer Institute, (NCI) [R03CA113157]; NIDCR [R03DE016611]; Italy Multicenter study: Italian Association for Research on Cancer (AIRC); Italy Multicenter study: Italian League Against Cancer; Italy Multicenter study: Italian Ministry of Research; Swiss study: Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633]; Los Angeles study: NIH [P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667]; Los Angeles study: Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Boston study: NIH [R01CA078609, R01CA100679]; US multicenter study: Intramural Program of the NCI, NIH, USA; MSKCC study: NIH [R01CA051845]; Japan study: Scientific Research grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan [20012005, 17015052]; North Carolina study; Buffalo study; Milan study: Italian Association for Cancer Research (AIRC) [10068]; Milan study: Italian Foundation for Cancer Research (FIRC); Milan study: Italian Ministry of Education [PRIN 2009 X8YCBN]; FIRC; Japan study: Ministry of Health, Labor and Welfare of Japan FX The INHANCE Pooled Data Project was supported by grants from the National Institutes of Health (NIH), National Cancer Institute, (NCI) R03CA113157 and NIDCR R03DE016611. Individual studies were funded by the following grants: (1) Italy Multicenter study: Italian Association for Research on Cancer (AIRC), Italian League Against Cancer, and Italian Ministry of Research; (2) Swiss study: the Swiss Research against Cancer/Oncosuisse (KFS-700 and OCS-1633); (3) Los Angeles study: NIH (P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667) and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; (4) Boston study: NIH (R01CA078609, R01CA100679); (5) US multicenter study: The Intramural Program of the NCI, NIH, USA; (6) MSKCC study: NIH (R01CA051845); (7) Japan study (20012005): Scientific Research grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan (17015052) and grant for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan (H20-002); (8) North Carolina (2002-2006) study; (9) Buffalo study; (10) Milan study (2006-2009): Italian Association for Cancer Research (AIRC Grant Number 10068), Italian Foundation for Cancer Research (FIRC), and Italian Ministry of Education (PRIN 2009 X8YCBN). FT was supported by a fellowship from FIRC. NR 82 TC 3 Z9 3 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 30 PY 2015 VL 113 IS 1 BP 182 EP 192 DI 10.1038/bjc.2015.149 PG 11 WC Oncology SC Oncology GA CL7YJ UT WOS:000357188500026 PM 25989276 ER PT J AU Steeves, JA Tudor-Locke, C Murphy, RA King, GA Fitzhugh, EC Harris, TB AF Steeves, Jeremy A. Tudor-Locke, Catrine Murphy, Rachel A. King, George A. Fitzhugh, Eugene C. Harris, Tamara B. TI Classification of occupational activity categories using accelerometry: NHANES 2003-2004 SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Occupational activity; Accelerometer; Work; Employment; Classification; Cross-sectional ID TIME PHYSICAL-ACTIVITY; ISCHEMIC-HEART-DISEASE; ALL-CAUSE MORTALITY; LEISURE-TIME; SEDENTARY BEHAVIOR; UNITED-STATES; CARDIOVASCULAR-DISEASE; WORKING POPULATION; ENERGY-EXPENDITURE; SITTING TIME AB Background: An individual's occupational activity (OA) may contribute significantly to daily physical activity (PA) and sedentary behavior (SB). However, there is little consensus about which occupational categories involve high OA or low OA, and the majority of categories are unclassifiable with current methods. The purpose of this study was to present population estimates of accelerometer-derived PA and SB variables for adults (n = 1112, 20-60 years) working the 40 occupational categories collected during the 2003-2004 National Health and Nutrition Examination Survey (NHANES). Methods: ActiGraph accelerometer-derived total activity counts/day (TAC), activity counts/minute, and proportion of wear time spent in moderate-to-vigorous PA [MVPA], lifestyle, and light PA organized by occupational category were ranked in ascending order and SB was ranked in descending order. Summing the ranks of the six accelerometer-derived variables generated a summary score for each occupational category, which was re-ranked in ascending order. Higher rankings indicated higher levels of OA, lower rankings indicated lower levels of OA. Tertiles of the summary score were used to establish three mutually exclusive accelerometer-determined OA groupings: high OA, intermediate OA, and low OA. Results: According to their summary score, 'farm and nursery workers' were classified as high OA and 'secretaries, stenographers, and typists' were classified as low OA. Consistent with previous research, some low OA occupational categories (e.g., 'engineers, architects, and scientists', 'technicians and related support occupations', 'management related occupations', 'executives, administrators, and managers', 'protective services', and 'writers, artists, entertainers, and athletes') associated with higher education and income had relatively greater amounts of MVPA compared to other low OA occupational categories, likely due to the greater percentage of men in those occupations and/or the influence of higher levels of leisure time PA. Men had more TAC, activity counts/minute and time in MVPA, but similar proportions of SB compared to women in all three OA groupings. Conclusions: Objectively measured PA allowed for a more precise estimate of the amount of PA and SB associated with different occupations and facilitated systematic classification of the 40 different occupational categories into three distinct OA groupings. This information provides new opportunities to explore the relationship between OA and health outcomes. C1 [Steeves, Jeremy A.] Univ Wisconsin, Dept Kinesiol, Milwaukee, WI 53201 USA. [Tudor-Locke, Catrine] Pennington Biomed Res Ctr, Walking Behav Lab, Baton Rouge, LA 70808 USA. [Murphy, Rachel A.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [King, George A.] Univ Texas El Paso, Dept Kinesiol, El Paso, TX 79968 USA. [Fitzhugh, Eugene C.] Univ Tennessee, Dept Kinesiol Recreat & Sports Studies, Knoxville, TN USA. RP Steeves, JA (reprint author), Univ Wisconsin, Dept Kinesiol, 2400 E Hartford Ave, Milwaukee, WI 53201 USA. EM steevesj@uwm.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. The authors acknowledge the editorial assistance of the NIH Fellows Editorial Board, National Institutes of Health. NR 68 TC 2 Z9 2 U1 5 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD JUN 30 PY 2015 VL 12 AR 89 DI 10.1186/s12966-015-0235-z PG 20 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA CM5FC UT WOS:000357711200001 PM 26122724 ER PT J AU Moore, N Andresen, J Lofgren, B Pijanowski, B Kim, DY AF Moore, Nathan Andresen, Jeffrey Lofgren, Brent Pijanowski, Bryan Kim, Dong-Yun TI Projected land-cover change effects on East African rainfall under climate change SO INTERNATIONAL JOURNAL OF CLIMATOLOGY LA English DT Article DE climate change; land-use change; hydrology ID SURFACE-TEMPERATURE; REGIONAL CLIMATE; INTERANNUAL VARIABILITY; INDIAN-OCEAN; GREATER HORN; SHORT RAINS; IMPACTS; SYSTEM; MANAGEMENT; DYNAMICS AB Both land-cover/land-use change (LCLUC) and greenhouse gas (GHG) concentrations have been shown to influence regional climate, albeit at different spatial scales. In East Africa, climate changes due to changing GHG concentrations are broadly projected to be warmer and wetter. LCLUC projections include trends towards both agricultural intensification and agricultural expansion into savannas, which may result in complex climate interactions and impacts. The primary objective of this study was to examine the regional responses to future GHG, LCLUC, and their combined effects in East Africa, and to better understand how hydrometeorological mechanisms might be altered by LCLUC in future scenarios. In this study, we present high-resolution decadal simulations from a regional climate model that compare the relative and combined effects of projected LCLUC and GHG. This research suggests that taken separately, these two climate forcings may significantly alter regional precipitation patterns both temporally and spatially but in potentially different and independent ways. In combination, some portions of the region exhibit responses dominated by either LCLUC or GHG effects, but certain areas show complex effects resulting from the combined influence of these two forcings. Perhaps most importantly, the results suggest that projected precipitation changes around major population areas may be as strongly influenced by LCLUC as by GHG effects. C1 [Moore, Nathan; Andresen, Jeffrey] Michigan State Univ, Dept Geog, E Lansing, MI 48824 USA. [Lofgren, Brent] NOAA, Great Lakes Environm Res Lab, Ann Arbor, MI 48105 USA. [Pijanowski, Bryan] Purdue Univ, Dept Forestry & Nat Resources, W Lafayette, IN 47907 USA. [Kim, Dong-Yun] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Moore, N (reprint author), Michigan State Univ, Dept Geog, 673 Auditorium Rd, E Lansing, MI 48824 USA. EM andresen@msu.edu OI Lofgren, Brent/0000-0003-2189-0914 FU NSF Biocomplexity of Coupled Human and Natural Systems Program [BCS 0308420, BCS/CNH 0709671]; Rockefeller Foundation [2009 CLI 324]; Directorate for Geosciences of the National Science Foundation (NSF); Office of Biological and Environmental Research of the U.S. Department of Energy FX This work was funded by NSF Biocomplexity of Coupled Human and Natural Systems Program awards BCS 0308420 and BCS/CNH 0709671 and award 2009 CLI 324 from the Rockefeller Foundation. This research used data provided by the Community Climate System Model project (www.ccsm.ucar.edu), supported by the Directorate for Geosciences of the National Science Foundation (NSF) and the Office of Biological and Environmental Research of the U.S. Department of Energy. The NCAR GIS Initiative provided CCSM data in a GIS format through GIS Climate Change Scenarios portal (http://www.gisclimatechange.org). We would like to acknowledge the support of our late colleague and friend Dr David Campbell, without whom this study would not have been possible. NR 69 TC 0 Z9 0 U1 3 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-8418 EI 1097-0088 J9 INT J CLIMATOL JI Int. J. Climatol. PD JUN 30 PY 2015 VL 35 IS 8 BP 1772 EP 1783 DI 10.1002/joc.4117 PG 12 WC Meteorology & Atmospheric Sciences SC Meteorology & Atmospheric Sciences GA CM5OG UT WOS:000357737000006 ER PT J AU Kishi, S Teixido-Tura, G Ning, HY Venkatesh, BA Wu, CL Almeida, A Choi, EY Gjesdal, O Jacobs, DR Schreiner, PJ Gidding, SS Liu, K Lima, JAC AF Kishi, Satoru Teixido-Tura, Gisela Ning, Hongyan Venkatesh, Bharath Ambale Wu, Colin Almeida, Andre Choi, Eui-Young Gjesdal, Ola Jacobs, David R., Jr. Schreiner, Pamela J. Gidding, Samuel S. Liu, Kiang Lima, Joao A. C. TI Cumulative Blood Pressure in Early Adulthood and Cardiac Dysfunction in Middle Age The CARDIA Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE echocardiography; hypertension; left ventricular function; speckle tracking ID LEFT-VENTRICULAR HYPERTROPHY; AMERICAN-HEART-ASSOCIATION; ASYMPTOMATIC INDIVIDUALS; YOUNG-ADULTS; ARTERIAL-HYPERTENSION; MYOCARDIAL FIBROSIS; MAGNETIC-RESONANCE; LIFETIME RISK; DASH DIET; FAILURE AB BACKGROUND Cumulative blood pressure (BP) exposure may adversely influence myocardial function, predisposing individuals to heart failure later in life. OBJECTIVES This study sought to investigate how cumulative exposure to higher BP influences left ventricular (LV) function during young to middle adulthood. METHODS The CARDIA (Coronary Artery Risk Development in Young Adults) study prospectively enrolled 5,115 healthy African Americans and whites in 1985 and 1986 (baseline). At the year 25 examination, LV function was measured by 2-dimensional echocardiography; cardiac deformation was assessed in detail by speckle-tracking echocardiography. We used cumulative exposure of BP through baseline and up to the year 25 examination (millimeters of mercury x year) to represent long-term exposure to BP levels. Linear regression and logistic regression were used to quantify the association of BP measured repeatedly through early adulthood (18 to 30 years of age) up to middle age (43 to 55 years). RESULTS Among 2,479 participants, cumulative BP measures were not related to LV ejection fraction; however, high cumulative exposure to systolic blood pressure (SBP) and diastolic blood pressure (DBP) were associated with lower longitudinal strain rate (both p < 0.001). For diastolic function, higher cumulative exposures to SBP and DBP were associated with low early diastolic longitudinal peak strain rate. Of note, higher DBP (per SD increment) had a stronger association with diastolic dysfunction compared with SBP. CONCLUSIONS Higher cumulative exposure to BP over 25 years from young adulthood to middle age is associated with incipient LV systolic and diastolic dysfunction in middle age. (C) 2015 by the American College of Cardiology Foundation. C1 [Kishi, Satoru; Venkatesh, Bharath Ambale; Almeida, Andre; Choi, Eui-Young; Gjesdal, Ola; Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21287 USA. [Teixido-Tura, Gisela] Hosp Valle De Hebron, Dept Cardiol, Barcelona, Spain. [Ning, Hongyan; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Wu, Colin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.; Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Gidding, Samuel S.] Alfred I duPont Hosp Children, Nemours Cardiac Ctr, Wilmington, DE USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, 600 North Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Teixido-Tura, Gisela/0000-0003-4714-2420 FU National Heart, Lung, and Blood Institute [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C, AG0005]; Intramural Research Program of the National Institute on Aging; National Institute on Aging FX The CARDIA Study is supported by Contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute, the Intramural Research Program of the National Institute on Aging, and an intra-agency agreement between the National Institute on Aging and the National Heart, Lung, and Blood Institute (AG0005). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 43 TC 18 Z9 19 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 30 PY 2015 VL 65 IS 25 BP 2679 EP 2687 DI 10.1016/j.jacc.2015.04.042 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL2LJ UT WOS:000356775100001 PM 26112189 ER PT J AU Chen, HM Chen, J Muir, LA Ronquist, S Meixner, W Ljungman, M Ried, T Smale, S Rajapakse, I AF Chen, Haiming Chen, Jie Muir, Lindsey A. Ronquist, Scott Meixner, Walter Ljungman, Mats Ried, Thomas Smale, Stephen Rajapakse, Indika TI Functional organization of the human 4D Nucleome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 4D Nucleome; networks; Laplacian; interphase nucleus; phase plane ID LONG-RANGE INTERACTIONS; HUMAN GENOME; TOPOLOGICAL DOMAINS; RNA-SEQ; CHROMATIN; PRINCIPLES; CELLS; MAP AB The 4D organization of the interphase nucleus, or the 4D Nucleome (4DN), reflects a dynamical interaction between 3D genome structure and function and its relationship to phenotype. We present initial analyses of the human 4DN, capturing genome-wide structure using chromosome conformation capture and 3D imaging, and function using RNA-sequencing. We introduce a quantitative index that measures underlying topological stability of a genomic region. Our results show that structural features of genomic regions correlate with function with surprising persistence over time. Furthermore, constructing genome-wide gene-level contact maps aided in identifying gene pairs with high potential for coregulation and colocalization in a manner consistent with expression via transcription factories. We additionally use 2D phase planes to visualize patterns in 4DN data. Finally, we evaluated gene pairs within a circadian gene module using 3D imaging, and found periodicity in the movement of clock circadian regulator and period circadian clock 2 relative to each other that followed a circadian rhythm and entrained with their expression. C1 [Chen, Haiming; Chen, Jie; Ronquist, Scott; Meixner, Walter; Rajapakse, Indika] Univ Michigan, Sch Med, Dept Computat Med Bioinformat, Ann Arbor, MI 48109 USA. [Chen, Jie] Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA. [Muir, Lindsey A.] Univ Michigan, Sch Med, Dept Pediat Pulm Med, Ann Arbor, MI 48109 USA. [Ljungman, Mats] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Ljungman, Mats; Rajapakse, Indika] Univ Michigan, Sch Med, Translat Oncol Program, Ann Arbor, MI 48109 USA. [Ried, Thomas] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Smale, Stephen] City Univ Hong Kong, Dept Math, Hong Kong 999077, Hong Kong, Peoples R China. [Smale, Stephen] Univ Calif Berkeley, Dept Math, Berkeley, CA 94720 USA. [Rajapakse, Indika] Univ Michigan, Dept Math, Coll Literature Sci & Arts, Ann Arbor, MI 48109 USA. RP Rajapakse, I (reprint author), Univ Michigan, Sch Med, Dept Computat Med Bioinformat, Ann Arbor, MI 48109 USA. EM indikar@umich.edu OI Muir, Lindsey/0000-0002-1756-0325 FU DARPA Biochronicity Program; NIH Grant [K25DK082791-01A109] FX We thank the University of Michigan Sequencing Core, and especially Jeanne Geskes, for assistance. We thank Richard McEachin and Nicholas Comment for support in processing Illumina sequence data with a standardized pipeline. We also thank Laura Seaman, Ravi Allada, Alfred Hero, Daniel Burns, and Vyrn Muir for critical reading of the manuscript and helpful discussions. We extend special thanks to James Gimlett and Fariba Fahroo at Defense Advanced Research Projects Agency (DARPA) and Christian Macedonia for support and encouragement. We are grateful to Job Dekker for providing the Hi-C protocol. This work is supported, in part, by the DARPA Biochronicity Program and NIH Grant K25DK082791-01A109 (to I.R.). NR 35 TC 16 Z9 16 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2015 VL 112 IS 26 BP 8002 EP 8007 DI 10.1073/pnas.1505822112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL6LU UT WOS:000357079400045 PM 26080430 ER PT J AU Jones, K Wei, C Schoser, B Meola, G Timchenko, N Timchenko, L AF Jones, Karlie Wei, Christina Schoser, Benedikt Meola, Giovanni Timchenko, Nikolai Timchenko, Lubov TI Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE myotonic dystrophy; RNA foci; p68 RNA helicase; CUG repeats ID EXPANDED CUG REPEATS; BINDING PROTEIN; MESSENGER-RNA; MUSCLE; EXPANSION; ZNF9 AB Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are neuromuscular diseases, caused by accumulation of CUG and CCUG RNAs in toxic aggregates. Here we report that the increased stability of the mutant RNAs in both types of DMis caused by deficiency of RNA helicase p68. We have identified p68 by studying CCUG-binding proteins associated with degradation of the mutant CCUG repeats. Protein levels of p68 are reduced in DM1 and DM2 biopsied skeletal muscle. Delivery of p68 in DM1/2 cells causes degradation of the mutant RNAs, whereas delivery of p68 in skeletal muscle of DM1 mouse model reduces skeletal muscle myopathy and atrophy. Our study shows that correction of p68 may reduce toxicity of the mutant RNAs in DM1 and in DM2. C1 [Jones, Karlie] NIAID, NIH, Bethesda, MD 20892 USA. [Wei, Christina; Timchenko, Lubov] Cincinnati Childrens Hosp, Div Neurol, Cincinnati, OH 45219 USA. [Wei, Christina; Timchenko, Nikolai; Timchenko, Lubov] Univ Cincinnati, Med Ctr, Cincinnati, OH 45219 USA. [Schoser, Benedikt] Univ Munich, Friedrich Baur Inst, Dept Neurol, D-80336 Munich, Germany. [Meola, Giovanni] Univ Milan, IRCCS Policlin San Donato, Dept Neurol, I-20097 Milan, Italy. [Timchenko, Nikolai] Cincinnati Childrens Hosp, Dept Surg, Cincinnati, OH 45219 USA. RP Timchenko, L (reprint author), Cincinnati Childrens Hosp, Div Neurol, Cincinnati, OH 45219 USA. EM Lubov.Timchenko@cchmc.org OI meola, giovanni/0000-0001-6396-717X; Schoser, Benedikt/0000-0002-2757-8131 FU National Institutes of Health [AR044387, AR052791, AR064488, CA159942, DK102597, GM551888]; Fondazione Malattie Miotoniche; Cincinnati Children's Hospital Medical Center FX We thank Bingwen Jin for the cloning of p68 plasmid. This research is supported by National Institutes of Health Grants AR044387, AR052791, AR064488 (to L.T.) and CA159942, DK102597, GM551888 (to N.T.); by a grant from Fondazione Malattie Miotoniche (to G.M.); and by internal development funds from Cincinnati Children's Hospital Medical Center (to L.T. and N.T.). NR 21 TC 4 Z9 4 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2015 VL 112 IS 26 BP 8041 EP 8045 DI 10.1073/pnas.1422273112 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL6LU UT WOS:000357079400052 PM 26080402 ER PT J AU Shin, JH Adrover, MF Wess, J Alvarez, VA AF Shin, Jung Hoon Adrover, Martin F. Wess, Juergen Alvarez, Veronica A. TI Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dopamine neurons; synaptic transmission; muscarinic receptors; nicotinic receptors; dopamine release ID NEOSTRIATAL CHOLINERGIC INTERNEURONS; RECEPTOR KNOCKOUT MICE; RAT-BRAIN; IN-VITRO; ACETYLCHOLINE; RELEASE; STRIATUM; NEURONS; MODULATION; ACTIVATION AB Cholinergic transmission in the striatum functions as a key modulator of dopamine (DA) transmission and synaptic plasticity, both of which are required for reward and motor learning. Acetylcholine (ACh) can elicit striatal DA release through activation of nicotinic ACh receptors (nAChRs) on DA axonal projections. However, it remains controversial how muscarinic ACh receptors (mAChRs) modulate striatal DA release, with studies reporting both potentiation and depression of striatal DA transmission by mAChR agonists. This study investigates the mAChR-mediated regulation of release from three types of midbrain neurons that project to striatum: DA, DA/glutamate, and glutamate neurons. We found that M-5 mAChRs potentiate DA and glutamate release only from DA and DA/glutamate projections from the midbrain. We also show that M-2/M-4 mAChRs depress the nAChR-dependent mechanism of DA release in the striatum. These results suggest that M-5 receptors on DA neuron terminals enhance DA release, whereas M-2/M-4 autoreceptors on cholinergic terminals inhibit ACh release and subsequent nAChR-dependent DA release. Our findings clarify the mechanisms of mAChR-dependent modulation of DA and glutamate transmission in the striatum. C1 [Shin, Jung Hoon; Adrover, Martin F.; Alvarez, Veronica A.] NIAAA, NIH, Bethesda, MD 20892 USA. [Wess, Juergen] NIDDK, NIH, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015 OI Alvarez, Veronica /0000-0003-2611-8675 FU Intramural Programs of National Institute on Alcohol Abuse and Alcoholism; National Institute of Neurological Disorders and Stroke [ZIA-AA000421] FX This study was funded by the Intramural Programs of the National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (ZIA-AA000421). We are grateful to Roland Bock (National Institute on Alcohol Abuse and Alcoholism, NIH) for developing the analysis software, Dr. Michael Krashes (National Institute of Diabetes and Digestive and Kidney Diseases, NIH) for providing vGluT2-cre mice, and Dr. Karl Deisseroth (Stanford University) for providing the channelrhodopsin-2 constructs. We also thank Dr. David Lovinger, Dr. Yolanda Mateo, and Dr. Armando Salinas and the members of the V.A.A. laboratory for their valuable comments on the manuscript. NR 36 TC 11 Z9 12 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2015 VL 112 IS 26 BP 8124 EP 8129 DI 10.1073/pnas.1508846112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL6LU UT WOS:000357079400066 PM 26080439 ER PT J AU Smith, RC Barillas-Mury, C Jacobs-Lorena, M AF Smith, Ryan C. Barillas-Mury, Carolina Jacobs-Lorena, Marcelo TI Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mosquito; malaria; innate immune response; hemocytes; late-phase immunity ID COMPLEMENT-LIKE PROTEIN; ANTIPLASMODIAL IMMUNITY; MALARIA PARASITES; NITRIC-OXIDE; DROSOPHILA; INFECTION; PATHWAY; BERGHEI; CELLS; INVASION AB Plasmodium parasites must complete development in the mosquito vector for transmission to occur. The mosquito innate immune response is remarkably efficient in limiting parasite numbers. Previous work has identified a LPS-induced TNF alpha transcription factor (LITAF)-like transcription factor, LITAF-like 3 (LL3), which significantly influences parasite numbers. Here, we demonstrate that LL3 does not influence invasion of the mosquito midgut epithelium or ookinete- to-oocyst differentiation but mediates a late-phase immune response that decreases oocyst survival. LL3 expression in the midgut and hemocytes is activated by ookinete midgut invasion and is independent of the mosquito microbiota, suggesting that LL3 may be a component of a wound-healing response. LL3 silencing abrogates the ability of mosquito hemocytes to differentiate and respond to parasite infection, implicating hemocytes as critical modulators of the late-phase immune response. C1 [Smith, Ryan C.; Jacobs-Lorena, Marcelo] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Jacobs-Lorena, M (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM mlorena@jhsph.edu OI Smith, Ryan/0000-0003-0245-2265 FU National Research Service Award [F32AI088835]; Johns Hopkins Malaria Research Institute postdoctoral fellowship; National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01AI031478] FX The authors thank Lindsey Garver for her helpful training regarding hemocyte perfusion and counting techniques as well as Jonas King for valuable discussions regarding hemocyte biology. This work would not have been possible without assistance from Christopher Kizito and the Johns Hopkins Malaria Research Institute parasite and insectary facility support staff. We thank Sarah Short for critical reading of the manuscript and members of the M.J.-L. laboratory for helpful discussions during its preparation. This research was supported by National Research Service Award F32AI088835 (to R.C.S.), a Johns Hopkins Malaria Research Institute postdoctoral fellowship (to R.C.S.), and Grant R01AI031478 (to M.J.-L.) from the National Institutes of Health/National Institute of Allergy and Infectious Diseases. NR 43 TC 6 Z9 6 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2015 VL 112 IS 26 BP E3412 EP E3420 DI 10.1073/pnas.1420078112 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL6LU UT WOS:000357079400014 PM 26080400 ER PT J AU Alvarez, LM Rivera, JJ Stockdale, L Saini, S Lee, RT Griffith, LG AF Alvarez, Luis M. Rivera, Jaime J. Stockdale, Linda Saini, Sunil Lee, Richard T. Griffith, Linda G. TI Tethering of Epidermal Growth Factor (EGF) to Beta Tricalcium Phosphate (beta TCP) via Fusion to a High Affinity, Multimeric beta TCP-Binding Peptide: Effects on Human Multipotent Stromal Cells/Connective Tissue Progenitors SO PLOS ONE LA English DT Article ID MESENCHYMAL STEM-CELLS; HUMAN BONE-MARROW; ACID-RICH SEQUENCES; IN-VIVO; FACTOR RECEPTOR; FILAMENTOUS BACTERIOPHAGE; HYDROXYAPATITE CRYSTALS; ADSORPTION PROTEIN; TITANIUM SURFACES; COLONY FORMATION AB Transplantation of freshly-aspirated autologous bone marrow, together with a scaffold, is a promising clinical alternative to harvest and transplantation of autologous bone for treatment of large defects. However, survival proliferation, and osteogenic differentiation of the marrow-resident stem and progenitor cells with osteogenic potential can be limited in large defects by the inflammatory microenvironment. Previous studies using EGF tethered to synthetic polymer substrates have demonstrated that surface-tethered EGF can protect human bone marrow-derived osteogenic stem and progenitor cells from pro-death inflammatory cues and enhance their proliferation without detriment to subsequent osteogenic differentiation. The objective of this study was to identify a facile means of tethering EGF to clinically-relevant beta TCP scaffolds and to demonstrate the bioactivity of EGF tethered to beta TCP using stimulation of the proliferative response of human bone-marrow derived mesenchymal stem cells (hBMSC) as a phenotypic metric. We used a phage display library and panned against beta TCP and composites of beta TCP with a degradable polyester biomaterial, together with orthogonal blocking schemes, to identify a 12-amino acid consensus binding peptide sequence, LLADTTHHRPWT, with high affinity for beta TCP. When a single copy of this beta TCP-binding peptide sequence was fused to EGF via a flexible peptide tether domain and expressed recombinantly in E. coli together with a maltose-binding domain to aid purification, the resulting fusion protein exhibited modest affinity for beta TCP. However, a fusion protein containing a linear concatamer containing 10 repeats of the binding motif the resulting fusion protein showed high affinity stable binding to beta TCP, with only 25% of the protein released after 7 days at 37 degrees C. The fusion protein was bioactive, as assessed by its abilities to activate kinase signaling pathways downstream of the EGF receptor when presented in soluble form, and to enhance the proliferation of hBMSC when presented in tethered form on commercial beta TCP bone regeneration scaffolds. C1 [Alvarez, Luis M.; Rivera, Jaime J.; Stockdale, Linda; Griffith, Linda G.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Saini, Sunil] Integra Life Sci, Plainsboro, NJ USA. [Lee, Richard T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Alvarez, Luis M.] US Mil Acad, Dept Chem & Life Sci, West Point, NY 10996 USA. [Alvarez, Luis M.] NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. RP Griffith, LG (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM griff@mit.edu FU NIH [R01DE019523, 1R01HL117986]; Armed Forces Institute for Regenerative Medicine (AFIRM); NIH Biotechnology Training Program [T32 GM008334]; Hertz Foundation FX Funding: Funding for this work was provided by NIH R01DE019523 (LGG), the Armed Forces Institute for Regenerative Medicine (AFIRM) (LGG), NIH Biotechnology Training Program T32 GM008334 fellowship (JR), NIH 1R01HL117986 (RTL), and a Hertz Foundation Pre-doctoral Fellowship (LMA). NR 94 TC 2 Z9 2 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2015 VL 10 IS 6 AR e0129600 DI 10.1371/journal.pone.0129600 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BL UT WOS:000358150400023 PM 26121597 ER PT J AU Nilsson, C Hejdeman, B Godoy-Ramirez, K Tecleab, T Scarlatti, G Brave, A Earl, PL Stout, RR Robb, ML Shattock, RJ Biberfeld, G Sandstrom, E Wahren, B AF Nilsson, Charlotta Hejdeman, Bo Godoy-Ramirez, Karina Tecleab, Teghesti Scarlatti, Gabriella Brove, Andreas Earl, Patricia L. Stout, Richard R. Robb, Merlin L. Shattock, Robin J. Biberfeld, Gunnel Sandstrom, Eric Wahren, Britta TI HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; HUMORAL IMMUNE-RESPONSES; BOOST VACCINE; VIRUS ANKARA; VIVO ELECTROPORATION; RHESUS MACAQUES; BROAD; IMMUNIZATION; EXPRESSION; DELIVERY AB Background We compared safety and immunogenicity of intradermal (ID) vaccination with and without electroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers. Methods HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet) with (n= 16) or without (n= 9) ID EP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVACMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA. Results The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-. ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p= 0.6158). The first HIV-MVA or HIV-MVA+ gp140 vaccination increased the IFN-. ELISpot response rate to 18/19 (95%). CD4(+) and/or CD8(+) T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4(+) and CD8(+) T cell response was noted, with 78% and 71% responders, respectively. IFN-. and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8(+) response to Gag was broader with expression of IFN-gamma, IL-2, MIP-1 beta and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients. Conclusion Intradermal electroporation of HIV-DNA was well tolerated. Strong cell-and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use. C1 [Nilsson, Charlotta; Godoy-Ramirez, Karina; Tecleab, Teghesti; Brove, Andreas; Biberfeld, Gunnel] Publ Hlth Agcy Sweden, Dept Microbiol, Solna, Sweden. [Nilsson, Charlotta; Biberfeld, Gunnel; Wahren, Britta] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Nilsson, Charlotta] Karolinska Inst, Dept Lab Med, Huddinge, Sweden. [Hejdeman, Bo] Karolinska Inst, Dept Educ & Clin Res, Venhalsan, Stockholm, Sweden. [Scarlatti, Gabriella] IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Viral Evolut & Transmiss Unit, Milan, Italy. [Earl, Patricia L.] NIAID, NIH, Bethesda, MD 20892 USA. [Stout, Richard R.] Bioject Inc, Tigard, OR USA. [Robb, Merlin L.] Walter Reed Army Inst Res, Mil HIV Res Program, Rockville, MD USA. [Shattock, Robin J.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis, Div Med, London, England. RP Nilsson, C (reprint author), Publ Hlth Agcy Sweden, Dept Microbiol, Solna, Sweden. EM charlotta.nilsson@folkhalsomyndigheten.se FU Regional HIV/AIDS Team for Africa; Embassy of Sweden, Lusaka; Sweden and Norway [2150012801]; US Military HIV Research program; Walter Reed Army Institute of Research (WRAIR); Division of Intramural Research; NIAID; NIH FX This study was supported by The Regional HIV/AIDS Team for Africa, Embassy of Sweden, Lusaka, jointly funded by Sweden and Norway (Sida contribution number 2150012801). Additional support was provided by the US Military HIV Research program, Walter Reed Army Institute of Research (WRAIR) and the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views and opinions expressed herein do not necessarily reflect those of the U.S. Army or the department of Defense. NR 40 TC 4 Z9 4 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2015 VL 10 IS 6 AR e0131748 DI 10.1371/journal.pone.0131748 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BL UT WOS:000358150400151 PM 26121679 ER PT J AU Rouquette-Jazdanian, AK Kortum, RL Li, WM Merrill, RK Nguyen, PH Samelson, LE Sommers, CL AF Rouquette-Jazdanian, Alexandre K. Kortum, Robert L. Li, Wenmei Merrill, Robert K. Nguyen, Phan H. Samelson, Lawrence E. Sommers, Connie L. TI miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways SO PLOS ONE LA English DT Article ID FAMILY-MEMBER BIM; FOXO TRANSCRIPTION FACTORS; P21-ACTIVATED PROTEIN-KINASES; INDUCE APOPTOSIS; GENETIC-EVIDENCE; PROSTATE-CANCER; ERK ACTIVATION; BREAST-CANCER; MOUSE MODEL; BCL-2 AB Linker for Activation of T cells (LAT) is an adapter protein that is essential for T cell function. Knock-in mice with a LAT mutation impairing calcium flux develop a fatal CD4(+) lymphoproliferative disease. miR-155 is a microRNA that is correlated with hyperproliferation in a number of cancers including lymphomas and leukemias and is overexpressed in mutant LAT T cells. To test whether miR-155 was merely indicative of T cell activation or whether it contributes to lymphoproliferative disease in mutant LAT mice, we interbred LAT mutant and miR-155-deficient mice. miR-155 deficiency markedly inhibited lymphoproliferative disease by stimulating BIM-dependent CD4+ T cell apoptosis, even though ERK activation and T cell proliferation were increased in double mutant CD4(+) T cells. Bim/Bcl2l11 expression is activated by the forkhead transcription factor FOXO3. Using miR-155-deficient, LAT mutant T cells as a discovery tool, we found two connected pathways that impact the nuclear translocation and activation of FOXO3 in T cells. One pathway is mediated by the inositide phosphatase SHIP-1 and the serine/threonine kinases AKT and PDK1. The other pathway involves PAK1 and JNK kinase activation. We define crosstalk between the two pathways via the kinase mTOR, which stabilizes PAK1. This study establishes a role for PAK1 in T cell apoptosis, which contrasts to its previously identified role in T cell proliferation. Furthermore, miR-155 regulates the delicate balance between PAK1-mediated proliferation and apoptosis in T cells impacting lymphoid organ size and function. C1 [Rouquette-Jazdanian, Alexandre K.; Kortum, Robert L.; Li, Wenmei; Merrill, Robert K.; Nguyen, Phan H.; Samelson, Lawrence E.; Sommers, Connie L.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sommers, CL (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM sommersc@mail.nih.gov FU Intramural Research Program of the National Cancer Institute Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Cancer Institute Center for Cancer Research (to LES). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 8 Z9 8 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2015 VL 10 IS 6 AR e0131823 DI 10.1371/journal.pone.0131823 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BL UT WOS:000358150400162 PM 26121028 ER PT J AU Pfeiffer, CM Sternberg, MR Fazili, Z Lacher, DA Zhang, M Johnson, CL Hamner, HC Bailey, RL Rader, JI Yamini, S Berry, RJ Yetley, EA AF Pfeiffer, Christine M. Sternberg, Maya R. Fazili, Zia Lacher, David A. Zhang, Mindy Johnson, Clifford L. Hamner, Heather C. Bailey, Regan L. Rader, Jeanne I. Yamini, Sedigheh Berry, R. J. Yetley, Elizabeth A. TI Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2 SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE National Health and Nutrition Examination Survey; Folate vitamers; 5-Methyltetrahydrofolate; Unmetabolised folic acid; Non-methyl folate; Folate oxidation products; Liquid chromatography-MS/MS ID TANDEM MASS-SPECTROMETRY; UNMETABOLIZED FOLIC-ACID; LIFE-STYLE VARIABLES; NEURAL-TUBE DEFECTS; MICROBIOLOGIC ASSAY; NHANES 1988-2010; RBC FOLATE; LC-MS/MS; BIOMARKERS; RADIOASSAY AB Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population >= 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37.5 nmol/l; 100 %), UMFA (1.21 nmol/l; 99.9 %), MeFox (1.53 nmol/l; 98.8 %), and THF (1.01 nmol/l; 85.2 %) were mostly detectable. 5-FormylTHF (3.6 %) and 5,10-methenylTHF (4.4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86.7 %); UMFA (4.0 %), non-methyl folate (4.7 %) and MeFox (4.5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r < 0.4) but significant (P < 0.05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics. C1 [Pfeiffer, Christine M.; Sternberg, Maya R.; Fazili, Zia; Zhang, Mindy] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Lacher, David A.; Johnson, Clifford L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Hamner, Heather C.; Berry, R. J.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Bailey, Regan L.; Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Rader, Jeanne I.; Yamini, Sedigheh] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Pfeiffer, CM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. EM cpfeiffer@cdc.gov OI Berry, Robert/0000-0002-7162-5046 FU Office of Dietary Supplements, NIH FX Data collection and laboratory analyses of folate supported by funding from the Office of Dietary Supplements, NIH. None of the authors has reported a conflict of interest. NR 45 TC 13 Z9 13 U1 2 U2 13 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD JUN 28 PY 2015 VL 113 IS 12 BP 1965 EP 1977 DI 10.1017/S0007114515001142 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM7PR UT WOS:000357887800014 PM 25917925 ER PT J AU Ranjan, A Wang, F Mizuguchi, G Wei, D Huang, YZ Wu, C AF Ranjan, Anand Wang, Feng Mizuguchi, Gaku Wei, Debbie Huang, Yingzi Wu, Carl TI H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast SO ELIFE LA English DT Article ID CHROMATIN REMODELING COMPLEX; CATALYTIC SUBUNIT; IN-VIVO; SWR1; CHAPERONE; GENOME; TRANSCRIPTION; EXCHANGE; OCTAMER; BINDING AB The histone variant H2A.Z is a universal mark of gene promoters, enhancers, and regulatory elements in eukaryotic chromatin. The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer. Binding of both substrates, the canonical nucleosome and the H2A.Z-H2B dimer, is essential for activation of SWR1. We found that SWR1 primarily recognizes key residues within the alpha 2 helix in the histone-fold of nucleosomal histone H2A, a region not previously known to influence remodeler activity. Moreover, SWR1 interacts preferentially with nucleosomal DNA at superhelix location 2 on the nucleosome face distal to its linker-binding site. Our findings provide new molecular insights on recognition of the canonical nucleosome by a chromatin remodeler and have implications for ATP-driven mechanisms of histone eviction and deposition. C1 [Ranjan, Anand; Mizuguchi, Gaku; Wu, Carl] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Wang, Feng; Wei, Debbie; Huang, Yingzi; Wu, Carl] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ranjan, A (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. EM ranjana@janelia.hhmi.org; wuc@janelia.hhmi.org FU Howard Hughes Medical Institute (HHMI); National Cancer Institute (NCI) FX Howard Hughes Medical Institute (HHMI) Janelia Research Campus Anand Ranjan, Carl Wu; National Cancer Institute (NCI) Intramural funding Anand Ranjan, Debbie Wei, Carl Wu NR 33 TC 5 Z9 5 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 27 PY 2015 VL 4 AR e06845 DI 10.7554/eLife.06845 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ5ND UT WOS:000374254500001 PM 26116819 ER PT J AU Kuang, RX Perruche, S Chen, WJ AF Kuang, Ruixia Perruche, Sylvain Chen, WanJun TI Apoptotic cell-linked immunoregulation: implications for promoting immune tolerance in transplantation SO CELL AND BIOSCIENCE LA English DT Review ID REGULATORY T-CELLS; GROWTH-FACTOR-BETA; TGF-BETA; DENDRITIC CELLS; INFECTIOUS TOLERANCE; MONOCLONAL-ANTIBODY; DEPENDENT MANNER; RETINOIC-ACID; CUTTING EDGE; INDUCTION AB The induction of alloantigen-specific immune tolerance is the "Holy-Grail" in transplantation. Although it had been previously demonstrated that transient depletion of T cells through apoptosis could lead to long-term immune tolerance, the underlying mechanism responsible for this tolerance induction and maintenance was unknown. In this short article, a novel mechanism for long-term immune tolerance via transient T cell apoptosis will be discussed, based on our recent findings in a CD3-specific antibody treatment-induced immune tolerance mouse model. Transforming growth factor-beta, which is produced by immature dendritic cells whilst they phagocytose apoptotic T cells and by macrophages, plays an important role in initiating long-term immune tolerance. A possible model of how allospecific-immune tolerance can be induced in order to prevent allograft rejection in transplantation will be also proposed. C1 [Kuang, Ruixia] Qingdao Univ, Dept Plast Surg, Affiliated Hosp, Qingdao, Peoples R China. [Perruche, Sylvain] INSERM, UMR1098, Besancon, France. [Chen, WanJun] NIDCR, Mucosal Immunol Sect, OPCB, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), NIDCR, Mucosal Immunol Sect, OPCB, NIH, Bethesda, MD 20892 USA. EM wchen@dir.nidcr.nih.gov FU NIH, NIDCR FX We would like to thank Prof. Philippe Saas, Inserm, UMR1098, Besancon, France for critically reading the manuscript. We apologize to those whose work was not cited because of space limitations. W.J.C. is supported by the Intramural Research program of NIH, NIDCR. NR 45 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JUN 27 PY 2015 VL 5 AR 27 DI 10.1186/s13578-015-0019-9 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CL2GW UT WOS:000356762600001 PM 26110047 ER PT J AU Gershburg, S Geltz, J Peterson, KE Halford, WP Gershburg, E AF Gershburg, Svetlana Geltz, Joshua Peterson, Karin E. Halford, William P. Gershburg, Edward TI The UL13 and US3 Protein Kinases of Herpes Simplex Virus 1 Cooperate to Promote the Assembly and Release of Mature, Infectious Virions SO PLOS ONE LA English DT Article ID OPEN READING FRAME; OPEN-READING-FRAME-47 ORF47 PROTEIN; INNER NUCLEAR-MEMBRANE; PROGRAMMED CELL-DEATH; DNA-DAMAGE RESPONSE; RNA-POLYMERASE-II; HUMAN T-CELLS; HUMAN CYTOMEGALOVIRUS; POSTTRANSLATIONAL MODIFICATION; VIRAL REPLICATION AB Herpes simplex virus type 1 (HSV-1) encodes two bona fide serine/threonine protein kinases, the US3 and UL13 gene products. HSV-1 Delta US3 mutants replicate with wild-type efficiency in cultured cells, and HSV-1 Delta UL13 mutants exhibit < 10-fold reduction in infectious viral titers. Given these modest phenotypes, it remains unclear how the US3 and UL13 protein kinases contribute to HSV-1 replication. In the current study, we designed a panel of HSV-1 mutants, in which portions of UL13 and US3 genes were replaced by expression cassettes encoding mCherry protein or green fluorescent protein (GFP), respectively, and analyzed DNA replication, protein expression, and spread of these mutants in several cell types. Loss of US3 function alone had largely negligible effect on viral DNA accumulation, gene expression, virion release, and spread. Loss of UL13 function alone also had no appreciable effects on viral DNA levels. However, loss of UL13 function did result in a measurable decrease in the steady-state levels of two viral glycoproteins (gC and gD), release of total and infectious virions, and viral spread. Disruption of both genes did not affect the accumulation of viral DNA, but resulted in further reduction in gC and gD steady-state levels, and attenuation of viral spread and infectious virion release. These data show that the UL13 kinase plays an important role in the late phase of HSV-1 infection, likely by affecting virion assembly and/or release. Moreover, the data suggest that the combined activities of the US3 and UL13 protein kinases are critical to the efficient assembly and release of infectious virions from HSV-1-infected cells. C1 [Gershburg, Svetlana; Geltz, Joshua; Halford, William P.; Gershburg, Edward] So Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Springfield, IL 62794 USA. [Peterson, Karin E.] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Gershburg, E (reprint author), So Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Springfield, IL 62794 USA. EM egershburg@siumed.edu RI Peterson, Karin/D-1492-2016; OI Peterson, Karin/0000-0003-4177-7249; Gershburg, Edward/0000-0003-3584-9947 FU Southern Illinois University School of Medicine FX This work was supported by start-up funds and by the Research Seed Grant from Southern Illinois University School of Medicine (EG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 106 TC 0 Z9 0 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2015 VL 10 IS 6 AR e0131420 DI 10.1371/journal.pone.0131420 PG 27 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1AM UT WOS:000358147500157 PM 26115119 ER PT J AU Yoshimura, T Liu, MY Chen, X Li, LZ Wang, JM AF Yoshimura, Teizo Liu, Mingyong Chen, Xin Li, Liangzhu Wang, Ji Ming TI Crosstalk between tumor cells and macrophages in stroma renders tumor cells as the primary source of MCP-1/CCL2 in Lewis lung carcinoma SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE monocytes/macrophages; chemokines; inflammation; tumor microenvironment; lung cancer ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; LIGAND 2; IN-VIVO; CANCER; GENE; EXPRESSION; GROWTH; MICE; INFILTRATION; METASTASIS AB The chemokine MCP-1/CCL2 is produced by a variety of tumors and plays an important role in cancer progression. We and others previously demonstrated that the primary source of MCP-1 in several mouse tumors, including 4T1 breast cancer, M5076 sarcoma, and B16 melanoma, was stromal cells. In the present study, we identified that tumor cells were the primary source of MCP-1 in Lewis lung carcinoma (LLC), because MCP-1 mRNA was highly expressed in tumors grown in both wild type (WT) and MCP-1-/mice with elevated serum MCP-1 levels. Since LLC cells isolated from tumors expressed low levels of MCP-1 in vitro, it appeared that the tumor-stromal cell interaction in a tumor microenvironment increased MCP-1 expression in LLC cells. In fact, co-culture of LLC cells with normal mouse peritoneal macrophages or normal lung cells containing macrophages increased MCP-1 expression by LLC cells. Macrophages from TNFa-/mice failed to activate LLC cells and anti-TNFa neutralizing antibody abolished the effect of WT macrophages on LLC cells. When LLC cells were transplanted into TNFa-/- mice, the levels of MCP-1 mRNA in tumors and serum MCP-1 levels were markedly lower as compared to WT mice, and importantly, tumors grew more slowly. Taken together, our results indicate that TNFa released by tumor cell-activated macrophages is critical for increased MCP-1 production by tumors cells. Thus, disruption of tumor-stromal cell interaction may inhibit tumor progression by reducing the production of tumor-promoting proinflammatory mediators, such as MCP-1. C1 [Yoshimura, Teizo; Liu, Mingyong; Li, Liangzhu; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Liu, Mingyong] Third Mil Med Univ, Daping Hosp, Dept Spine Surg, Chongqing, Peoples R China. [Chen, Xin] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Macao, Peoples R China. [Chen, Xin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD USA. [Li, Liangzhu] Shanghai Jiao Tong Univ, Sch Pharm, Minist Educ, Engn Res Ctr Cell & Therapeut Antibody, Shanghai 200030, Peoples R China. RP Yoshimura, T (reprint author), NCI, Bldg 559,Room 2,POB B, Frederick, MD 21702 USA. EM yoshimut@mail.nih.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU NIH, NCI; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Natural Science Foundation of China [81470073] FX We are grateful to Dr. O. M. Zack Howard, Ms. Kelli Czarra, Mr. Timothy Back, and staff of LASP, Leidos Biomedical Research, Inc., for their assistance in animal studies. We are also grateful to Dr. Joost J. Oppenheim for his critical comments. This research was supported by the Intramural Research Program of the NIH, NCI, and National Cancer Institute, National Institutes of Health Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. LL was supported by National Natural Science Foundation of China (81470073). NR 39 TC 3 Z9 4 U1 0 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JUN 26 PY 2015 VL 6 AR 332 DI 10.3389/fimmu.2015.00332 PG 10 WC Immunology SC Immunology GA CL9EX UT WOS:000357279500001 PM 26167165 ER PT J AU Vo, PT Pantin, J Ramos, C Cook, L Cho, E Kurlander, R Khuu, H Barrett, J Leitman, S Childs, RW AF Vo, P. T. Pantin, J. Ramos, C. Cook, L. Cho, E. Kurlander, R. Khuu, H. Barrett, J. Leitman, S. Childs, R. W. TI Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE Severe aplastic anemia; Rabbit versus horse ATG conditioning; Allogeneic bone marrow transplant; Identical twins ID BONE-MARROW-TRANSPLANTATION; HEMATOPOIETIC-CELL TRANSPLANTATION; GRAFT-REJECTION; ANTITHYMOCYTE GLOBULIN; FAILURE SYNDROMES; RISK-FACTORS AB Severe aplastic anemia (SAA) is a rare disorder leading to bone marrow failure, which if left untreated, is invariably fatal. Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective. HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor. Recent studies showing the addition of antithymocyte globulin (ATG) to the conditioning regimen improves engraftment and reduces the risk of graft-versus-host disease (GVHD). There are currently two ATG preparations in the USA, equine (or horse) and rabbit ATG. These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011]. Here, we report a case of two monozygotic twins with constitutional SAA that evolved to myelodysplastic syndrome (MDS) who both underwent allogeneic peripheral blood stem cell transplantation (PBSC) from the same single HLA antigen mismatched sibling donor with the only difference in the transplant regimen being the type of ATG used in the preparative regimen; one twin received horse ATG and the other received rabbit ATG during conditioning. This report emphasizes that dramatic differences in donor T cell chimerism and clinical outcomes including GVHD can occur as a consequence of the type of ATG that is utilized in the transplant conditioning regimen. These differences highlight that these agents should not be considered interchangeable drugs when used in this setting. C1 [Vo, P. T.; Ramos, C.; Cook, L.; Cho, E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Pantin, J.] Georgia Regents Univ, Dept Hematol & Oncol, Augusta, GA USA. [Kurlander, R.] NHLBI, Dept Clin Pathol, Hematol Serv, NIH, Bethesda, MD 20892 USA. [Khuu, H.] NIH, Cell Lab Proc Sect, Dept Transfus Med, Blood Bank, Bethesda, MD 20892 USA. [Barrett, J.] NHLBI, Stem Cell Allogen Transplantat, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Leitman, S.] NHLBI, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. [Childs, R. W.] NHLBI, Transplantat Immunotherapy, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Vo, PT (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM uyenphuong18@yahoo.com OI Pantin, Jeremy/0000-0001-7536-0623 NR 18 TC 3 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD JUN 26 PY 2015 VL 8 AR 78 DI 10.1186/s13045-015-0173-x PG 8 WC Oncology; Hematology SC Oncology; Hematology GA CL8UP UT WOS:000357249900001 PM 26113077 ER PT J AU Wilkinson, AV Koehly, LM Vandewater, EA Yu, RK Fisher-Hoch, SP Prokhorov, AV Kohl, HW Spitz, MR Shete, S AF Wilkinson, Anna V. Koehly, Laura M. Vandewater, Elizabeth A. Yu, Robert K. Fisher-Hoch, Susan P. Prokhorov, Alexander V. Kohl, Harold W. Spitz, Margaret R. Shete, Sanjay TI Demographic, psychosocial, and genetic risk associated with smokeless tobacco use among Mexican heritage youth SO BMC MEDICAL GENETICS LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; ORIGIN YOUTH; CIGARETTE-SMOKING; SOCIAL-STATUS; ADOLESCENT SMOKING; SENSATION SEEKING; COLLEGE-STUDENTS; WEIGHT CONCERNS; UNITED-STATES; ANXIETY AB Background: Despite well-established negative health consequences of smokeless tobacco use (STU), the number and variety of alternative non-combustible tobacco products on the market have increased tremendously over the last 10 years, as has the market share of these products relative to cigarettes. While STU among non-Hispanic white youth has decreased over the last 10 years, the prevalence has remained constant among Hispanic youth. Here we examine demographic, psychosocial, and genetic risk associated with STU among Mexican heritage youth. Methods: Participants (50.5 % girls) reported on psychosocial risk factors in 2008-09 (n = 1,087, mean age = 14.3 years), and smokeless tobacco use in 2010-11 (mean age = 16.7 years). Participants provided a saliva sample that was genotyped for genes in the dopamine, serotonin and opioid pathways. Results: Overall 62 (5.7 %) participants reported lifetime STU. We identified five single nucleotide polymorphisms that increased the risk for lifetime use. Specifically, rs2023902 on SERGEF (OR = 1.93; 95 % CI: 1.05-3.53), rs16941667 on ALDH2 (OR = 3.14; 95 % CI: 1.65-5.94), and rs17721739 on TPH1 (OR = 1.71; 95 % CI: 1.00-2.91) in the dopamine pathway, rs514912 on TRH-DE (OR = 1.84; 95 % CI: 1.25-2.71) in the serotonin pathway, and rs42451417 on the serotonin transporter gene, SLC6A4 (OR = 3.53; 95 % CI: 1.56-7.97). After controlling for genetic risk, being male (OR = 1.86; 95 % CI: 1.02-3.41), obesity status (OR = 2.22; 95 % CI: 1.21-4.09), and both higher levels of anxiety (OR = 1.04; 95 % CI: 1.01-1.08) and social disinhibition (OR = 1.26; 95 % CI: 1.07-1.48) were associated with increased use. High subjective social status (OR = 0.78; 95 % CI: 0.64-0.93) was protective against use, while higher parental education (OR = 2.01; 95 % CI: 1.03-3.93) was associated with increased use. Conclusions: These data suggest that use of genetic risk, along with psychosocial, demographic, and behavioral risk factors may increase our ability to identify youth at increased risk for STU, which in turn may improve our ability to effectively target prevention messages to Mexican heritage youth. C1 [Wilkinson, Anna V.; Vandewater, Elizabeth A.; Kohl, Harold W.] Michael & Susan Dell Ctr Hlth Living, Austin, TX 78701 USA. [Wilkinson, Anna V.; Vandewater, Elizabeth A.; Kohl, Harold W.] Univ Texas Austin, Sch Publ Hlth, Austin, TX 78701 USA. [Koehly, Laura M.] NHGRI, Social & Behav Div, Bethesda, MD 20892 USA. [Yu, Robert K.; Prokhorov, Alexander V.; Shete, Sanjay] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Fisher-Hoch, Susan P.] Univ Texas Brownsville, Sch Publ Hlth, Brownsville, TX 78520 USA. [Kohl, Harold W.] Univ Texas Austin, Dept Kinesiol & Hlth Educ, Austin, TX 78701 USA. [Spitz, Margaret R.] Baylor Coll Med, Houston, TX 77030 USA. RP Wilkinson, AV (reprint author), Michael & Susan Dell Ctr Hlth Living, Austin Reg Campus,1616 Guadalupe St,Suite 6300, Austin, TX 78701 USA. EM anna.v.wilkinson@uth.tmc.edu FU National Cancer Institute [CA105203, CA126988]; Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health [Z01HG200335]; Caroline W. Law Fund for Cancer Prevention; Duncan Family Institute for Cancer Prevention and Risk Assessment FX We thank the cohort staff for conducting all field interviews and maintaining the high participation rates. We thank the participants for providing the data and their parents for permitting their children to join the study. Without their support this research would not be possible. This research is supported by the National Cancer Institute grants [CA105203 to MRS, and CA126988 to AVW] and partially supported by the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health [Z01HG200335 to LMK]. The Mexican American Cohort Study receives funds collected pursuant to the Comprehensive Tobacco Settlement of 1998, and appropriated by the 76th legislature to The University of Texas M. D. Anderson Cancer Center, from the Caroline W. Law Fund for Cancer Prevention, and by the Duncan Family Institute for Cancer Prevention and Risk Assessment. The funders did not contribute to the design and conduct of the study, the data collection, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript. NR 53 TC 1 Z9 1 U1 3 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUN 26 PY 2015 VL 16 AR 43 DI 10.1186/s12881-015-0188-8 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CL5NL UT WOS:000357006500001 PM 26111525 ER PT J AU Emanuel, EJ Bedarida, G Macci, K Gabler, NB Rid, A Wendler, D AF Emanuel, Ezekiel J. Bedarida, Gabriella Macci, Kristy Gabler, Nicole B. Rid, Annette Wendler, David TI Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CLINICAL-TRIALS; ADVERSE EVENTS; BENEFITS AB Objective To quantify the frequency and seriousness of adverse events in non-oncology phase I studies with healthy participants. Design Meta-analysis of individual, healthy volunteer level data. Setting Phase I studies with healthy volunteers conducted between September 2004 and March 2011 at Pfizer's three dedicated phase I testing sites in Belgium, Singapore, and the United States. These included studies in which drug development was terminated. Participants 11 028 participants who received the study drug in 394 distinct non-oncology phase I studies, which involved 4620 unique individuals. A total of 2460 (53.2%) participants were involved in only one study, whereas others participated in two or more studies. Main outcome measures Adverse events classified as mild, moderate, and severe as well as serious adverse events-defined by the Food and Drug Administration as events that result in death, a life threatening event, admission to hospital, prolongation of existing hospital stay, a persistent or major disability, or a congenital anomaly or birth defect. Pfizer researchers of phase I trials determined adverse events, and serious adverse events were those filed with the FDA. Results Overall, 4000 (36.3%) participants who received the study drug experienced no adverse events and 7028 (63.7%) experienced 24 643 adverse events. Overall, 84.6% (n=20 840) of adverse events were mild and 1.0% (n=255) were severe. 34 (0.31%) serious adverse events occurred among the 11 028 participants who received the study agent, with no deaths or life threatening events. Of the 34 serious adverse events, 11 were related to the study drug and seven to study procedures, whereas 16 were unrelated to a study drug or procedure, including four that occurred when the participant was receiving a placebo. Overall, 24.1% (n=5947) of adverse events were deemed to be unrelated to the study drug. With a total of 143 (36%) studies involving placebo, 10.3% (n=2528) of all adverse events occurred among participants receiving placebo. The most common adverse events were headache (12.2%, n=3017), drowsiness (9.8%, n=2410), and diarrhea (6.9%, n=1698). Research on drugs for neuropsychiatric indications had the highest frequency of adverse events (3015 per 1000 participants). Conclusion Among 11 028 healthy participants who received study drug in non-oncology phase I studies, the majority (85%) of adverse events were mild. 34 (0.31%) serious adverse events occurred, with no life threatening events or deaths. Half of all adverse events were related to the study drug or to procedures. Extrapolation of these data to other types of phase I studies, especially with biological agents, may not be warranted. C1 [Emanuel, Ezekiel J.] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Emanuel, Ezekiel J.] Univ Penn, Off Provost, Philadelphia, PA 19104 USA. [Bedarida, Gabriella; Macci, Kristy] Pfizer, New Haven Clin Res Unit, New Haven, CT USA. [Gabler, Nicole B.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Rid, Annette] Kings Coll London, Dept Social Sci Hlth & Med, London WC2R 2LS, England. [Wendler, David] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. EM vp-global@upenn.edu FU NIH intramural research funds; Department of Medical Ethics and Health Policy of the Perelman School of Medicine, University of Pennsylvania; Pfizer; Swiss National Science Foundation [PA00B-117505/1, PA0033-117502/2] FX This study was funded, in part by NIH intramural research funds and in part by funds from the Department of Medical Ethics and Health Policy of the Perelman School of Medicine, University of Pennsylvania. The researchers from NIH, University of Pennsylvania, and King's College London were independent of Pfizer and had no financial compensation from Pfizer. NBG was awarded a Pfizer grant that ended in 2009. The two Pfizer employees were paid by Pfizer. AR received funding from the Swiss National Science Foundation (PA00B-117505/1 and PA0033-117502/2). Pfizer provided no specific financial support for this study. NR 20 TC 7 Z9 7 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUN 26 PY 2015 VL 350 AR h3271 DI 10.1136/bmj.h3271 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CL7OD UT WOS:000357160700002 PM 26115663 ER PT J AU Wei, JJ Gibbs, JS Hickman, HD Cush, SS Bennink, JR Yewdell, JW AF Wei, Jiajie Gibbs, James S. Hickman, Heather D. Cush, Stephanie S. Bennink, Jack R. Yewdell, Jonathan W. TI Ubiquitous Autofragmentation of Fluorescent Proteins Creates Abundant Defective Ribosomal Products (DRiPs) for Immunosurveillance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE antigen processing; immunology; protein misfolding; protein processing; protein synthesis; DRiPs; fluorescent protein; fragmentation; immunosurveillance ID NEWLY SYNTHESIZED PROTEINS; CLASS-I MOLECULES; QUALITY-CONTROL; ANTIGENIC PEPTIDES; MAMMALIAN-CELLS; MAJOR SOURCE; DEGRADATION; TRANSLATION; CHROMOPHORE; VIRUS AB Background: Fragments are rapidly generated from GFP. Results: Fragmentation occurs in all fluorescent proteins examined, requires chromophore rearrangement, and is a major source of MHC-I ligands. Conclusion: Fragmentation, a by-product of chromophore rearrangement, creates DRiPs. Significance: Fluorescent protein fragments are generated at high levels, likely influencing experimental outcomes. GFP fragments are the first natural DRiPs biochemically characterized relevant for immunosurveillance. Green fluorescent protein (GFP) and other fluorescent proteins are essential tools for biological research. When fused to peptides or proteins as a reporter, GFP enables localization and quantitation of gene products in otherwise unmanipulated live cells or organisms. We previously reported that a sizable fraction of nascent GFP is post-translationally converted into a 20-kDa Triton X-100-insoluble proteasome substrate (Qian, S. B., Princiotta, M. F., Bennink, J. R., and Yewdell, J. W. (2006) J. Biol. Chem. 281, 392-400; Dolan, B. P., Li, L., Veltri, C. A., Ireland, C. M., Bennink, J. R., and Yewdell, J. W. (2011) J. Immunol. 186, 2065-2072). Here, we show that a similarly sized fragment is generated by all GFP and red fluorescent protein family members we examined. We demonstrate that fragmentation is a by-product of GFP chromophore rearrangement. A non-rearranging GFP mutant fails to fragment and generates diminished levels of K-b-SIINFEKL complexes when SIINFEKL is genetically fused to either the C- or N-terminal domains of GFP fusion proteins. Instructively, another fragmenting GFP mutant that cannot create the functional chromophore but still generates fragments also demonstrates diminished K-b-SIINFEKL generation. However, the mutant and wild-type fragments differ fundamentally in that wild-type fragments are rapidly liberated from the intact molecule and degraded quickly, accounting for increased K-b-SIINFEKL generation. In the fragmenting mutant, the fragments are generated slowly and remain associated, likely in a native conformation based on their original structural description (Barondeau, D. P., Kassmann, C. J., Tainer, J. A., and Getzoff, E. D. (2006) J. Am. Chem. Soc. 128, 4685-4693). The wild-type GFP fragments represent the first biochemically defined natural defective ribosomal products to contribute peptides for immunosurveillance, enabling quantitation of peptide generation efficiency from this source of defective ribosomal products. More broadly, given the wide use of fluorescent proteins, their ubiquitous and abundant fragmentation must be considered when interpreting experiments using these extremely useful probes. C1 [Wei, Jiajie; Gibbs, James S.; Hickman, Heather D.; Cush, Stephanie S.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, 33 North Dr, Bethesda, MD 20892 USA. EM JYEWDELL@niaid.nih.gov FU National Institutes of Health grants from NIAID, Division of Intramural Research FX This work was supported, in whole or in part, by National Institutes of Health grants from NIAID, Division of Intramural Research. The authors declare that they have no conflicts of interest with the contents of this article. NR 40 TC 1 Z9 1 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 26 PY 2015 VL 290 IS 26 BP 16431 EP 16439 DI 10.1074/jbc.M115.658062 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CL4NR UT WOS:000356930100043 PM 25971973 ER PT J AU Liu, YT Tian, AL Wang, X Qi, J Wang, FK Ma, Y Ito, Y Wei, Y AF Liu, Yating Tian, Ailin Wang, Xiong Qi, Jing Wang, Fengkang Ma, Ying Ito, Yoichiro Wei, Yun TI Fabrication of chiral amino acid ionic liquid modified magnetic multifunctional nanospheres for centrifugal chiral chromatography separation of racemates SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Fabrication; Chiral amino acid ionic liquid; Magnetic nanospheres; Centrifugal chiral chromatography; D- and L-Tryptophan ID NANOPARTICLES; TRYPTOPHAN; SELECTOR AB As the rapid development of nanotechnology, the magnetic nanospheres modified with special chiral selective ligands show a great potentiality in enantiomeric separation. In this study, magnetic nanospheres modified with task-specific chiral ionic liquid were designed for the separation of chiral amino acids. These modified magnetic nanospheres were effective in a direct chiral separation of five racemic amino acids (D- and L-cysteine, D- and L-arginine, D- and L-leucine, D- and L-glutamine and D- and L-tryptophan). Furthermore, a new online method for complete separation of the enantiomers via the magnetic nanospheres was established with centrifugal chiral chromatography using a spiral tube assembly mounted on a type-J coil planet centrifuge. One kind of chiral compounds, D- and L-tryptophan was resolved well using this method. These results demonstrated that the modified nanospheres display a good chiral recognition ability, and can be used as a potential material for chiral separation of various racemates. (C) 2015 Elsevier B.V. All rights reserved. C1 [Liu, Yating; Tian, Ailin; Wang, Xiong; Qi, Jing; Wang, Fengkang; Wei, Yun] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Ma, Ying; Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wei, Y (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, 15 North 3th Ring East Rd, Beijing 100029, Peoples R China. EM weiyun@mail.buct.edu.cn FU National Natural Science Foundation of China (NSFC) [21075007]; Program for New Century Excellent Talents in University [NCET-11-0563]; Beijing Nova program interdisciplinary [Z141107001814114]; Fundamental Research Funds for the Central Universities [YS1406]; Special Fund for Agro-scientific Research in the Public Interest [200803022, 201103027] FX This work was supported by National Natural Science Foundation of China (NSFC, Grant No. 21075007), Program for New Century Excellent Talents in University (NCET-11-0563), Beijing Nova program interdisciplinary (Z141107001814114), the Fundamental Research Funds for the Central Universities (YS1406) and Special Fund for Agro-scientific Research in the Public Interest (project 200803022 and 201103027). NR 29 TC 7 Z9 9 U1 7 U2 54 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 26 PY 2015 VL 1400 BP 40 EP 46 DI 10.1016/j.chroma.2015.04.045 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CL1ZD UT WOS:000356742500005 PM 25976126 ER PT J AU Mason-Osann, E Hollevoet, K Niederfellner, G Pastan, I AF Mason-Osann, Emily Hollevoet, Kevin Niederfellner, Gerhard Pastan, Ira TI Quantification of recombinant immunotoxin delivery to solid tumors allows for direct comparison of in vivo and in vitro results SO SCIENTIFIC REPORTS LA English DT Article ID TRANSFERRIN RECEPTOR; MONOCLONAL-ANTIBODY; CANCER; PENETRATION; MESOTHELIN; CARCINOMA; BIODISTRIBUTION; IMMUNOTHERAPY; ANTIGENICITY; PANCREAS AB Solid tumors present challenges for delivery of protein therapeutics; current methods cannot quantify the functional effects of these agents. RG7787 (anti-mesothelin recombinant immunotoxin) is highly cytotoxic to pancreatic cancer cell lines, but with limited activity in vivo. To investigate this discrepancy, we developed a flow cytometry method to quantify the amount of RG7787 internalized per cell in tumors and used it to analyze tumor responses by determining the number of molecules of RG7787 internalized per cell in vivo and comparing it to that needed to kill cells in vitro. At a maximum tolerated dose of 7.5 mg/kg, tumor cells in vivo internalized a wide range of RG7787 with the average amount equivalent to the amount that induced growth arrest in vitro. However, 20% of cells accumulated 20,300 ITs per cell, sufficient to kill cells in vitro. At 2.5 mg/kg the top 20% of cells internalized enough RG7787 to only induce growth arrest. These data are in agreement with tumor responses; 22% regression following a 7.5 mg/kg dose and growth stabilization following 2.5 mg/kg. Comparing amounts of RIT delivered in vivo and in vitro can explain tumor responses and should facilitate the development of more active immunotoxins and other antibody based agents. C1 [Mason-Osann, Emily; Hollevoet, Kevin; Pastan, Ira] NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Niederfellner, Gerhard] Roche Diagnost GmbH, Innovat Ctr Penzberg, Roche Pharmaceut Res & Early Dev, Discovery Oncol, D-82377 Penzberg, Germany. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov OI Mason-Osann, Emily/0000-0003-0890-6440 FU Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research; NCI [2791]; Hoffmann-La Roche Inc. [2791]; F. Hoffmann-La Roche Ltd. [2791] FX The authors would like to thank Hoffmann-La Roche Inc. for supplying RG7787; K. Wolcott, L. Xiang, Dr. Y. Zhang and Dr. F. Mueller for technical guidance and support; and Dr. C. Alewine, Dr. D. FitzGerald, Dr. M. Onda, Dr. B. Lee and D. R. Walker for reading and editing the manuscript. Funding: This research was supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research and by a Cooperative Research and Development Agreement (#2791) between the NCI, Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd. NR 31 TC 6 Z9 6 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 26 PY 2015 VL 5 AR 10832 DI 10.1038/srep10832 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4IH UT WOS:000356915300001 PM 26111884 ER PT J AU Mital, J Lutter, EI Barger, AC Dooley, CA Hackstadt, T AF Mital, Jeffrey Lutter, Erika I. Barger, Alexandra C. Dooley, Cheryl A. Hackstadt, Ted TI Chlamydia trachomatis inclusion membrane protein CT850 interacts with the dynein light chain DYNLT1 (Tctex1) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Chlamydia; Microtubules; Dynein; Vesicle trafficking ID HOST-CELL DYNEIN; CYTOPLASMIC DYNEIN; SUPERFAMILY PROTEINS; ORGANELLE TRANSPORT; MICROTUBULE NETWORK; VIRAL INTERACTIONS; VIRUS-INFECTION; DYNACTIN; ADENOVIRUS; SUBUNIT AB Chlamydia trachomatis actively subverts the minus-end directed microtubule motor, dynein, to traffic along microtubule tracks to the Microtubule Organizing Center (MTOC) where it remains within a membrane bound replicative vacuole for the duration of its intracellular development. Unlike most substrates of the dynein motor, disruption of the dynactin cargo-linking complex by over-expression of the p50 dynamitin subunit does not inhibit C. trachomatis transport. A requirement for chlamydial protein synthesis to initiate this process suggests that a chlamydial product supersedes a requirement for p50 dynamitin. A yeast 2-hybrid system was used to screen the chlamydia inclusion membrane protein CT850 against a HeLa cell cDNA library and identified an interaction with the dynein light chain DYNLT1 (Tctexl). This interaction was at least partially dependent upon an (R/K-R/K-X-X-R/K) motif that is characteristic of DYNLT1 binding domains. CT850 expressed ectopically in HeLa cells localized at the MTOC and this localization is similarly dependent upon the predicted DYNLT1 binding domain. Furthermore, DYNLT1 is enriched at focal concentrations of CT850 on the chlamydial inclusion membrane that are known to interact with dynein and microtubules. Depletion of DYNLT1 disrupts the characteristic association of the inclusion membrane with centrosomes. Collectively, the results suggest that CT850 interacts with DYNLT1 to promote appropriate positioning of the inclusion at the MTOC. Published by Elsevier Inc. C1 [Mital, Jeffrey; Lutter, Erika I.; Barger, Alexandra C.; Dooley, Cheryl A.; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Mital, Jeffrey] Quinnipiac Univ, Hamden, CT 06518 USA. RP Hackstadt, T (reprint author), NIAID, Rocky Mt Lab, Intracellular Parasites Lab, 903 S Fourth St, Hamilton, MT 59840 USA. EM Ted_Hackstadt@NIH.Gov FU Intramural Research Program of the NIAID/NIH FX This work was supported by the Intramural Research Program of the NIAID/NIH. We thank Janet Sager for technical assistance and Drs. D. Bublitz and A. Omsland for critical review of the manuscript. NR 38 TC 7 Z9 7 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 26 PY 2015 VL 462 IS 2 BP 165 EP 170 DI 10.1016/j.bbrc.2015.04.116 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CK3LS UT WOS:000356118200013 PM 25944661 ER PT J AU Mitchell, JC Constable, R So, E Vance, C Scotter, E Glover, L Hortobagyi, T Arnold, ES Ling, SC McAlonis, M Da Cruz, S Polymenidou, M Tessarolo, L Cleveland, DW Shaw, CE AF Mitchell, Jacqueline C. Constable, Remy So, Eva Vance, Caroline Scotter, Emma Glover, Leanne Hortobagyi, Tibor Arnold, Eveline S. Ling, Shuo-Chien McAlonis, Melissa Da Cruz, Sandrine Polymenidou, Magda Tessarolo, Lino Cleveland, Don W. Shaw, Christopher E. TI Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE TDP-43; Amyotrophic lateral sclerosis; Mouse ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; TRANSGENIC MICE; BINDING PROTEIN; SPINAL-CORD; FUNCTIONAL IMPLICATIONS; HEXANUCLEOTIDE REPEAT; TARDBP MUTATIONS; GENE; EXPRESSION AB Introduction: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in similar to 90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS. Results: Expression of human wild-type TDP-43 (TDP-43(WT)) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43(Q331K)) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43(WTxQ331K)) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8-10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex, with TDP-43, ubiquitin and p62 cytoplasmic inclusions and an increase in insoluble TDP-43. Nuclear clearance of TDP-43 was not observed in TDP-43(Q331K) mice but was seen in 65 % of aggregate containing spinal cord motor neurons in TDP-43(WTxQ331K) mice. Conclusions: We hypothesise that cytoplasmic TDP-43(Q331K) aggregates facilitate the recruitment of WT protein in compound animals, which dramatically accelerates neurodegeneration and disease progression. The exploration of disease mechanisms in slow and rapid disease models of TDP-43 proteinopathy will help elucidate novel drug targets and provide a more informative platform for preclinical trials. C1 [Mitchell, Jacqueline C.; Constable, Remy; So, Eva; Vance, Caroline; Scotter, Emma; Hortobagyi, Tibor; Shaw, Christopher E.] Kings Coll London, Kings Ctr Neurodegenerat Res, Dept Basic & Clin Neurosci, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England. [Glover, Leanne] Kings Coll London, Ctr Ultrastruct Imaging, London SE1 1UL, England. [Arnold, Eveline S.; Ling, Shuo-Chien; McAlonis, Melissa; Da Cruz, Sandrine; Polymenidou, Magda; Cleveland, Don W.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Arnold, Eveline S.; Ling, Shuo-Chien; McAlonis, Melissa; Da Cruz, Sandrine; Polymenidou, Magda; Cleveland, Don W.] Univ Calif San Diego, Dept Mol Med, La Jolla, CA 92093 USA. [Tessarolo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Shaw, CE (reprint author), Kings Coll London, Kings Ctr Neurodegenerat Res, Dept Basic & Clin Neurosci, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England. EM christopher.shaw@kcl.ac.uk RI Mitchell, Jacqueline/C-7953-2012; Scotter, Emma/C-4833-2012 OI Mitchell, Jacqueline/0000-0002-2677-398X; Scotter, Emma/0000-0003-4064-3599 FU Medical Research Council [, G0500289, G0900635, G1100695, MC_G1000733]; Wellcome Trust [089701, 089701/Z/09/2] NR 53 TC 6 Z9 6 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD JUN 25 PY 2015 VL 3 AR 36 DI 10.1186/s40478-015-0212-4 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CP9WO UT WOS:000360246300001 PM 26108367 ER PT J AU Selfridge, BR Wang, XH Zhang, YN Yin, H Grace, PM Watkins, LR Jacobson, AE Rice, KC AF Selfridge, Brandon R. Wang, Xiaohui Zhang, Yingning Yin, Hang Grace, Peter M. Watkins, Linda R. Jacobson, Arthur E. Rice, Kenner C. TI Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NEUROPATHIC PAIN; NITRIC-OXIDE; NALTREXONE; NALOXONE; NEUROIMMUNOPHARMACOLOGY; NEUROINFLAMMATION; INFLAMMATION; RECOGNITION; ACTIVATION; MECHANISMS AB Activation of Toll-like receptors has been linked to neuropathic pain aria opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compound's based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N-phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 1j) showed,75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 mu M/1.4 mu M) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia. C1 [Selfridge, Brandon R.; Jacobson, Arthur E.; Rice, Kenner C.] Natl Inst Drug Abuse, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Selfridge, Brandon R.; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wang, Xiaohui; Zhang, Yingning; Grace, Peter M.; Watkins, Linda R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Wang, Xiaohui; Yin, Hang] Univ Colorado, Dept Chem & Biochem, BioFrontiers Inst, Boulder, CO 80309 USA. RP Rice, KC (reprint author), Natl Inst Drug Abuse, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM kr21f@nih.gov RI Wang, Xiaohui/B-8126-2011; OI Wang, Xiaohui/0000-0002-3415-5612; Grace, Peter/0000-0002-8999-1220 FU NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism; Bioscience Discovery Evaluation Program of the state of Colorado; NIH [GM101279]; NHMRC CJ Martin Fellowship [IDD 1054091] FX The work of the Drug Design and Synthesis Section was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism. The work on in vitro characterization was supported by a grant from the Bioscience Discovery Evaluation Program of the state of Colorado and Grant NIH GM101279, and a NHMRC CJ Martin Fellowship [Grant IDD 1054091] to P.M.G. The authors express their gratitude to Noel Whittaker, Mass Spectrometry Facility NIDDK, for mass spectral data. We also thank Dr. John Forsayeth, University of California, San Francisco, for helpful discussions. NR 40 TC 5 Z9 6 U1 3 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 25 PY 2015 VL 58 IS 12 BP 5038 EP 5052 DI 10.1021/acs.jmedchem.5b00426 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CL7FX UT WOS:000357139000016 PM 26010811 ER PT J AU Agniswamy, J Louis, JM Shen, CH Yashchuk, S Ghosh, AK Weber, IT AF Agniswamy, Johnson Louis, John M. Shen, Chen-Hsiang Yashchuk, Sofiya Ghosh, Arun K. Weber, Irene T. TI Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL DRUG-RESISTANCE; X-RAY; BIOLOGICAL EVALUATION; MEDICINAL CHEMISTRY; CLINICAL INHIBITORS; CRYSTAL-STRUCTURE; 20 MUTATIONS; DESIGN; LIGAND AB An extremely drug resistant Mutant of HIV-1 protease (PR):bearing 20 mutations (PR20), has been studied With two potent antiviral investigational inhibitors. GRL-5010A and GRL-4410A were designed, to introduce hydrogen bond interactions with the flexible flaps of the PR by incorporating gem-difluorines and alkoxy, respectively) at the C4 position of the bis-THF of darunavir. PR20 provides an excellent model for high level resistance, since clinical inhibitors are >1000-fold less active on PR20 than On Wild-type enzyme. GRL-5010A and GRL-4410A show inhibition constants of 4.3 +/- 7.0 and 1.7 +/- 1.8 nM, respectively, for PR20, compared to the binding affinity of 41 +/- 1 nM measured for darunavir. Crystal structures of PR20 in complexes with the two inhibitors confirmed the new hydrogen bond interactions with Gly 48 in the flap of the enzyme. The two new compounds are more effective than darunavir in inhibiting mature PR20 and show promise for further development of antiviral agents targeting highly resistant PR mutants. C1 [Agniswamy, Johnson; Shen, Chen-Hsiang; Weber, Irene T.] Georgia State Univ, Mol Basis Dis Program, Dept Biol, Atlanta, GA 30303 USA. [Louis, John M.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Chem Phys Lab, DHHS, Bethesda, MD 20892 USA. [Yashchuk, Sofiya; Ghosh, Arun K.] Purdue Univ, Dept Chem & Med Chem, W Lafayette, IN 47907 USA. RP Weber, IT (reprint author), Georgia State Univ, Mol Basis Dis Program, Dept Biol, Atlanta, GA 30303 USA. EM iweber@gsu.edu RI shen, chen-hsiang/D-7309-2016 FU National Institutes of Health [GM062920, GM053386]; NIDDK, National Institutes of Health FX The research was supported in part by the National Institutes of Health Grants GM062920 (I.T.W.), GM053386 (A.K.G.) and Intramural Research Program of the NIDDK, National Institutes of Health. We thank Annie Aniana for technical assistance. This research was authored, in whole or in part, by National Institutes of Health staff. Data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22ID at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at www.ser-cat.org/members.html. NR 40 TC 1 Z9 1 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 25 PY 2015 VL 58 IS 12 BP 5088 EP 5095 DI 10.1021/acs.jmedchem.5b00474 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CL7FX UT WOS:000357139000019 PM 26010498 ER PT J AU Caceres, M Ortiz, L Recabarren, T Romero, A Colombo, A Leiva-Salcedo, E Varela, D Rivas, J Silva, I Morales, D Campusano, C Almarza, O Simon, F Toledo, H Park, KS Trimmer, JS Cerda, O AF Caceres, Monica Ortiz, Liliana Recabarren, Tatiana Romero, Anibal Colombo, Alicia Leiva-Salcedo, Elias Varela, Diego Rivas, Jose Silva, Ian Morales, Diego Campusano, Camilo Almarza, Oscar Simon, Felipe Toledo, Hector Park, Kang-Sik Trimmer, James S. Cerda, Oscar TI TRPM4 Is a Novel Component of the Adhesome Required for Focal Adhesion Disassembly, Migration and Contractility SO PLOS ONE LA English DT Article ID CATION CHANNEL TRPM4; CELL-MIGRATION; CALCIUM OSCILLATIONS; SIGNALING COMPLEXES; MICROARRAY ANALYSIS; BETA-PIX; ACTIVATION; EXPRESSION; ZEBRAFISH; MOTILITY AB Cellular migration and contractility are fundamental processes that are regulated by a variety of concerted mechanisms such as cytoskeleton rearrangements, focal adhesion turnover, and Ca2+ oscillations. TRPM4 is a Ca2+-activated non-selective cationic channel (Ca2+-NSCC) that conducts monovalent but not divalent cations. Here, we used a mass spectrometry-based proteomics approach to identify putative TRPM4-associated proteins. Interestingly, the largest group of these proteins has actin cytoskeleton-related functions, and among these nine are specifically annotated as focal adhesion-related proteins. Consistent with these results, we found that TRPM4 localizes to focal adhesions in cells from different cellular lineages. We show that suppression of TRPM4 in MEFs impacts turnover of focal adhesions, serum-induced Ca2+ influx, focal adhesion kinase (FAK) and Rac activities, and results in reduced cellular spreading, migration and contractile behavior. Finally, we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. Together, these findings provide the first evidence, to our knowledge, for a TRP channel specifically localized to focal adhesions, where it performs a central role in modulating cellular migration and contractility. C1 [Caceres, Monica; Ortiz, Liliana; Recabarren, Tatiana; Romero, Anibal; Rivas, Jose; Silva, Ian; Morales, Diego; Campusano, Camilo; Almarza, Oscar; Toledo, Hector; Cerda, Oscar] Univ Chile, Fac Med, Inst Ciencias Biomed ICBM, Programa Biol Celular & Mol, Santiago, Chile. [Caceres, Monica; Park, Kang-Sik; Trimmer, James S.; Cerda, Oscar] Univ Calif Davis, Coll Biol Sci, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA. [Recabarren, Tatiana; Colombo, Alicia] Univ Chile, Fac Med, Inst Ciencias Biomed ICBM, Programa Anat & Biol Desarrollo, Santiago, Chile. [Leiva-Salcedo, Elias] NICHD, Sect Cellular Signaling, Program Dev Biol, NIH, Bethesda, MD USA. [Varela, Diego] Univ Chile, Fac Med, Inst Ciencias Biomed ICBM, Programa Fisiopatol, Santiago, Chile. [Simon, Felipe] Univ Andres Bello, Fac Ciencias Biol, Dept Ciencias Biol, Santiago, Chile. [Simon, Felipe] Univ Andres Bello, Fac Med, Santiago, Chile. [Simon, Felipe] Millennium Inst Immunol & Immunotherapy, Santiago, Chile. [Park, Kang-Sik] Kyung Hee Univ, Sch Med, Dept Physiol, Seoul, South Korea. [Trimmer, James S.] Univ Calif Davis, Sch Med, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. RP Cerda, O (reprint author), Univ Chile, Fac Med, Inst Ciencias Biomed ICBM, Programa Biol Celular & Mol, Santiago, Chile. EM oscarcerda@med.uchile.cl RI Colombo , Alicia /I-3329-2013; OI Almarza, Oscar/0000-0003-0460-3143 FU Fondecyt [11121239, 11140064, 1120240, 1121078, 1120126]; NIH [R01 NS042225]; Conicyt; Millennium Institute on Immunology and Immunotherapy [P09-016-F] FX This research was funded by Fondecyt 11121239 to OC, Fondecyt 11140064 to MC, and NIH R01 NS042225 to JST. A doctoral Fellowship from Conicyt supports AR. Fondecyt 1120240 funded DV. Fondecyt 1121078 and Millennium Institute on Immunology and Immunotherapy P09-016-F supported FS. Fondecyt 1120126 funded HT. NR 78 TC 2 Z9 2 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 25 PY 2015 VL 10 IS 6 AR e0130540 DI 10.1371/journal.pone.0130540 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4OY UT WOS:000356933800061 PM 26110647 ER PT J AU Taylor-Burds, C Cheng, P Wray, S AF Taylor-Burds, Carol Cheng, Paul Wray, Susan TI Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABA(A) Mediated Excitation SO PLOS ONE LA English DT Article ID HORMONE-RELEASING HORMONE; GAMMA-AMINOBUTYRIC-ACID; ROOT GANGLION NEURONS; CL-/HCO3-EXCHANGER; NA-K-2CL COTRANSPORTER; ANION-EXCHANGER; INTRACELLULAR CHLORIDE; TARGETED DISRUPTION; CALCIUM OSCILLATOR; LHRH NEURONS AB A developmental "switch" in chloride transporters occurs in most neurons resulting in GABA(A) mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABA(A) receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH) neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABA(A) receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABA(A) receptor activation. Anion exchangers (AEs) are also potential modulators of responses to GABA(A) activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s) underlying GABA(A) mediated depolarization, GnRH neurons were analyzed for 1) expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2) responses to GABA(A) receptor activation in NKCC1(-/-) mice and 3) function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1(-/-) mice retained relatively normal responses to the GABA(A) agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO3- mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABA(A) mediated transmission in GnRH neurons. C1 [Taylor-Burds, Carol; Cheng, Paul; Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov OI Cheng-Hathaway, Paul/0000-0002-3240-9316 FU Intramural Research Program of National Institutes of Health, National Institute of Neurological Disorder and Stroke Grant award [NS002824-23] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorder and Stroke Grant NS002824-23 awarded to SW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 2 Z9 2 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 25 PY 2015 VL 10 IS 6 AR e0131076 DI 10.1371/journal.pone.0131076 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4OY UT WOS:000356933800115 PM 26110920 ER PT J AU Caskey, M Klein, F Lorenzi, JCC Seaman, MS West, AP Buckley, N Kremer, G Nogueira, L Braunschweig, M Scheid, JF Horwitz, JA Shimeliovich, I Ben-Avraham, S Witmer-Pack, M Platten, M Lehmann, C Burke, LA Hawthorne, T Gorelick, RJ Walker, BD Keler, T Gulick, RM Fatkenheuer, G Schlesinger, SJ Nussenzweig, MC AF Caskey, Marina Klein, Florian Lorenzi, Julio C. C. Seaman, Michael S. West, Anthony P., Jr. Buckley, Noreen Kremer, Gisela Nogueira, Lilian Braunschweig, Malte Scheid, Johannes F. Horwitz, Joshua A. Shimeliovich, Irina Ben-Avraham, Sivan Witmer-Pack, Maggi Platten, Martin Lehmann, Clara Burke, Leah A. Hawthorne, Thomas Gorelick, Robert J. Walker, Bruce D. Keler, Tibor Gulick, Roy M. Faetkenheuer, Gerd Schlesinger, Sarah J. Nussenzweig, Michel C. TI Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117 SO NATURE LA English DT Article ID MONOCLONAL-ANTIBODIES; HIV-1 NEUTRALIZATION; GENETIC-DETERMINANTS; PASSIVE TRANSFER; IN-VIVO; THERAPY; VIRUS; IMMUNOTHERAPY; VACCINE; MICE AB HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned(1-3). However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated(6-10). Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody(11), in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log(10) and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure. C1 [Caskey, Marina; Klein, Florian; Lorenzi, Julio C. C.; Buckley, Noreen; Nogueira, Lilian; Braunschweig, Malte; Scheid, Johannes F.; Horwitz, Joshua A.; Shimeliovich, Irina; Ben-Avraham, Sivan; Witmer-Pack, Maggi; Burke, Leah A.; Schlesinger, Sarah J.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Seaman, Michael S.] Harvard Univ, Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [West, Anthony P., Jr.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Kremer, Gisela; Platten, Martin; Lehmann, Clara; Faetkenheuer, Gerd] Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany. [Kremer, Gisela] Univ Cologne, Clin Trials Ctr Cologne, ZKS Koln, D-50931 Cologne, Germany. [Braunschweig, Malte] Univ Freiburg, D-79085 Freiburg, Germany. [Platten, Martin; Lehmann, Clara; Faetkenheuer, Gerd] Partner Site Bonn Cologne, German Ctr Infect Res DZIF, Cologne, Germany. [Burke, Leah A.; Gulick, Roy M.] Cornell Univ, Div Infect Dis, Weill Med Coll, New York, NY 10065 USA. [Hawthorne, Thomas; Keler, Tibor] Celldex Therapeut Inc, Hampton, NJ 08827 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Walker, Bruce D.] Massachusetts Gen Hosp, Radon Inst MGH MIT & Harvard, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Walker, Bruce D.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu RI Cetrulo Lorenzi, Julio Cesar/B-5264-2008; OI Cetrulo Lorenzi, Julio Cesar/0000-0003-2492-3961; Ben-Avraham, Sivan/0000-0002-9130-0062 FU CNPq "Ciencia sem Fronteiras" Brazil [248676/2013-0]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) [OPP1033115, OPP1092074, OPP1040753, OPP1032144]; Cooperative Centers on Human Immunology from NIH [U19A1111825-01]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000043]; Robertson Foundation; NCI/NIH [HHSN261200800001E]; German Center for Infection Research (DZIF) [3BNC117]; Mark and Lisa Schwartz Foundation; CAVD [43307] FX We thank all individuals who participated in this study. We thank the Rockefeller University Hospital Clinical Research Support Office and nursing staff, as well as T. Kummerle, C. Wyen, and L. Siegel for help with recruitment; S. Kiss for ophthalmologic assessments; F. Maldarelli and J. Lifson for single-copy analysis and B. Freemire for technical assistance; J. Pring, A. Almaktari, C. Unsen, S. Hadrigan, E. Thomas, H. Gruell, D. Gillor, and U. Sandaradura de Silva for sample processing and study coordination, and N. Rodziewicz for help with HIV-1 culturing. We thank A. Louie and C. Conrad for help with regulatory submissions; L. Thomas for IND-enabling studies, L Vitale for cell line and anti-idiotype antibody development, B. Riordan, A. Rayo and J. Andreozzi for anti-idiotype ELISA method development and sample analysis, R. Hammond for process development, and S. DiSciullo for 3BNC117 manufacturing; J. Perry for performing neutralization assays. We thank M. Suarez-Farinas for support with statistical analysis; P. Fast and H. Park for clinical monitoring; and E. Gotschlich and B. Caller for input on study design. J.C.C.L. is supported by an award from CNPq "Ciencia sem Fronteiras" Brazil (248676/2013-0). This work was supported in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grants OPP1033115 (M.C.N.), OPP1092074 (M.C.N.), OPP1040753 (A.P.W.) and OPP1032144 (M.S.S.), and U19A1111825-01 Cooperative Centers on Human Immunology from NIH to M.C.N., by grant #UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), by a grant from the Robertson Foundation to M.C.N., in part with Federal funds from the NCI/NIH, under Contract No. HHSN261200800001E, and a grant from the German Center for Infection Research (DZIF) to G.F. 3BNC117 was generated from a subject in the International HIV Controller Study, supported by the Mark and Lisa Schwartz Foundation and CAVD Grant 43307. M.C.N. and B.D.W. are Howard Hughes Medical Institute Investigators. The authors declare no competing financial interests. NR 40 TC 142 Z9 144 U1 9 U2 53 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 25 PY 2015 VL 522 IS 7557 BP 487 EP + DI 10.1038/nature14411 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL2OC UT WOS:000356782900052 PM 25855300 ER PT J AU Henriques, C Miller, MP Catanho, M de Carvalho, TMU Krieger, MA Probst, CM de Souza, W Degrave, W Amara, SG AF Henriques, Cristina Miller, Megan P. Catanho, Marcos Ulisses de Carvalho, Tecia Maria Krieger, Marco Aurelio Probst, Christian M. de Souza, Wanderley Degrave, Wim Amara, Susan Gaye TI Identification and functional characterization of a novel arginine/ornithine transporter, a member of a cationic amino acid transporter subfamily in the Trypanosoma cruzi genome SO PARASITES & VECTORS LA English DT Article DE Arginine; Ornithine; Transporter; Protozoan; Trypanosomatids; T. cruzi; Parasite ID ARGININE DECARBOXYLASE; METACYCLIC TRYPOMASTIGOTES; PROTOZOAN PARASITES; LEISHMANIA-DONOVANI; KINETIC-PROPERTIES; FAMILY; GENE; EPIMASTIGOTES; AFFINITY; DATABASE AB Background: Trypanosoma cruzi, the etiological agent of Chagas disease, is auxotrophic for arginine. It obtains this amino acid from the host through transporters expressed on the plasma membrane and on the membranes of intracellular compartments. A few cationic amino acid transporters have been characterized at the molecular level, such as the novel intracellular arginine/ornithine transporter, TcCAT1.1, a member of the TcCAT subfamily that is composed of four almost identical open reading frames in the T. cruzi genome. Methods: The functional characterization of the TcCAT1.1 isoform was performed in two heterologous expression systems. TcCAT subfamily expression was evaluated by real-time PCR in polysomal RNA fractions, and the cellular localization of TcCAT1.1 fused to EGFP was performed by confocal and immunoelectron microscopy. Results: In the S. cerevisiae expression system, TcCAT1.1 showed high affinity for arginine (K-m = 0.085 +/- 0.04 mM) and low affinity for ornithine (K-m = 1.7 +/- 0.2 mM). Xenopus laevis oocytes expressing TcCAT1.1 showed a 7-fold increase in arginine uptake when they were pre-loaded with arginine, indicating that transport is enhanced by substrates on the trans side of the membrane (trans-stimulation). Oocytes that were pre-loaded with [H-3]-arginine displayed a 16-fold higher efflux of [H-3]-arginine compared with that of the control. Analysis of polysomal RNA fractions demonstrated that the expression of members of the arginine transporter TcCAT subfamily is upregulated under nutritional stress and that this upregulation precedes metacyclogenesis. To investigate the cellular localization of the transporter, EGFP was fused to TcCAT1.1, and fluorescence microscopy and immunocytochemistry revealed the intracellular labeling of vesicles in the anterior region, in a network of tubules and vesicles. Conclusions: TcCAT1.1 is a novel arginine/ornithine transporter, an exchanger expressed in intracellular compartments that is physiologically involved in arginine homeostasis throughout the T. cruzi life cycle. The properties and estimated kinetic parameters of TcCAT1.1 can be extended to other members of the TcCAT subfamily. C1 [Henriques, Cristina] Fiocruz Mato Grosso do Sul, Fundacao Oswaldo Cruz, BR-89081746 Campo Grande, MS, Brazil. [Amara, Susan Gaye] NIMH, NIH, Bethesda, MD 20892 USA. [Miller, Megan P.; Amara, Susan Gaye] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15260 USA. [Catanho, Marcos; Degrave, Wim] Inst Oswaldo Cruz, FIOCRUZ, Lab Genom Func & Bioinformat, BR-21040900 Rio De Janeiro, RJ, Brazil. [Henriques, Cristina; Ulisses de Carvalho, Tecia Maria; de Souza, Wanderley] Filho UFRJ, Inst Biofis Carlos Chagas, Labo Ultraestrutura Celular Hertha Meyer, BR-21949900 Rio De Janeiro, RJ, Brazil. [Henriques, Cristina; de Souza, Wanderley] Univ Fed Rio de Janeiro CENABIO, Nucleo Biol Estrutural & Biomagens, Rio De Janeiro, RJ, Brazil. [de Souza, Wanderley] Inst Nacl Ciencia & Tecnol Biol Estrutural & Biom, Rio De Janeiro, Brazil. [Krieger, Marco Aurelio; Probst, Christian M.] Fiocruz MS, Inst Carlos Chagas, BR-81350010 Curitiba, Parana, Brazil. RP Henriques, C (reprint author), Fiocruz Mato Grosso do Sul, Fundacao Oswaldo Cruz, Rua Gabriel Abrao 92 Jardim Nacoes, BR-89081746 Campo Grande, MS, Brazil. EM henriques@fiocruz.br RI Probst, Christian/B-8678-2009 OI Probst, Christian/0000-0001-9993-6375 FU University of Pittsburgh; CNPq; FAPERJ-APQ1 [E-26/171.172.2006] FX Supported by: University of Pittsburgh, CNPq and FAPERJ-APQ1 E-26/171.172.2006. NR 69 TC 1 Z9 1 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JUN 25 PY 2015 VL 8 AR 346 DI 10.1186/s13071-015-0950-y PG 18 WC Parasitology SC Parasitology GA CL6LP UT WOS:000357078900001 PM 26109388 ER PT J AU Lindskog, C Linne, J Fagerberg, L Hallstrom, BM Sundberg, CJ Lindholm, M Huss, M Kampf, C Choi, H Liem, DA Ping, PP Varemo, L Mardinoglu, A Nielsen, J Larsson, E Ponten, F Uhlen, M AF Lindskog, Cecilia Linne, Jerker Fagerberg, Linn Hallstrom, Bjorn M. Sundberg, Carl Johan Lindholm, Malene Huss, Mikael Kampf, Caroline Choi, Howard Liem, David A. Ping, Peipei Varemo, Leif Mardinoglu, Adil Nielsen, Jens Larsson, Erik Ponten, Fredrik Uhlen, Mathias TI The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling SO BMC GENOMICS LA English DT Article DE Transcriptome; Proteome; Cardiac and skeletal muscle ID HUMAN PROTEIN ATLAS; MYOCARDIAL-INFARCTION; MUSCULAR-DYSTROPHY; BETA-ENOLASE; EXPRESSION; MUTATIONS; CELLS; INTEGRATION; REGENERATION; CYTOSKELETON AB Background: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. Results: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. Conclusions: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease. C1 [Lindskog, Cecilia; Linne, Jerker; Kampf, Caroline; Ponten, Fredrik] Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, SE-75185 Uppsala, Sweden. [Fagerberg, Linn; Hallstrom, Bjorn M.; Uhlen, Mathias] AlbaNova Univ Ctr, KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden. [Sundberg, Carl Johan; Lindholm, Malene] Karolinska Inst, Dept Physiol & Pharmacol, SE-17177 Stockholm, Sweden. [Huss, Mikael] Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, SE-17121 Solna, Sweden. [Choi, Howard; Liem, David A.; Ping, Peipei; Uhlen, Mathias] Univ Calif Los Angeles, David Geffen Sch Med, NHLBI Prote Ctr, Dept Physiol, Los Angeles, CA 90095 USA. [Choi, Howard; Liem, David A.; Ping, Peipei; Uhlen, Mathias] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA. [Varemo, Leif; Mardinoglu, Adil; Nielsen, Jens] Chalmers, Dept Chem & Biol Engn, SE-41258 Gothenburg, Sweden. [Larsson, Erik] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, SE-75185 Uppsala, Sweden. RP Uhlen, M (reprint author), AlbaNova Univ Ctr, KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden. EM mathias.uhlen@scilifelab.se RI Lindholm, Malene/E-5125-2017; OI Nielsen, Jens/0000-0002-9955-6003; Fagerberg, Linn/0000-0003-0198-7137; Huss, Mikael/0000-0003-0839-2451 FU Knut and Alice Wallenberg Foundation; Wallenberg Advanced Bioinformatics Infrastructure; NHLBI Proteomics Centers Award [HHSN268201000035C]; Swedish National Centre for Research in Sports FX The entire staff of the Human Protein Atlas program and the Science for Life Laboratory are acknowledged for valuable contributions. We thank Uppsala Biobank and the Department of Pathology at Uppsala Akademiska hospital, Uppsala, Sweden for kindly providing clinical specimens used in this study. This work was supported by the Knut and Alice Wallenberg Foundation, the Wallenberg Advanced Bioinformatics Infrastructure and the NHLBI Proteomics Centers Award (HHSN268201000035C). The skeletal muscle sampling was supported by the Swedish National Centre for Research in Sports. NR 43 TC 8 Z9 8 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 25 PY 2015 VL 16 AR 475 DI 10.1186/s12864-015-1686-y PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CL2GK UT WOS:000356761400001 PM 26109061 ER PT J AU Carrillo, JA He, YH Luo, J Menendez, KR Tablante, NL Zhao, K Paulson, JN Li, BC Song, JZ AF Carrillo, Jose A. He, Yanghua Luo, Juan Menendez, Kimberly R. Tablante, Nathaniel L. Zhao, Keji Paulson, Joseph N. Li, Bichun Song, Jiuzhou TI Methylome Analysis in Chickens Immunized with Infectious Laryngotracheitis Vaccine SO PLOS ONE LA English DT Article ID DNA METHYLATION; BIOCONDUCTOR PACKAGE; GENE-EXPRESSION; VIRUS-VACCINE; HUMAN GENOME; IN-VITRO; CHIP-SEQ; CANCER; INITIATION; PROMOTERS AB In this study we investigated the methylome of chickens immunized with Infectious laryngotracheitis (ILT) vaccine derived from chicken embryos. Methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) method was employed in the detection of the 1,155 differentially methylated regions (DMRs) across the entire genome. After validation, we ascertained the genomic DMRs distribution and annotated them regarding genes, transcription start sites (TSS) and CpG islands. We found that global DNA methylation decreased in vaccinated birds, presenting 704 hypomethylated and 451 hypermethylated DMRs, respectively. Additionally, we performed an enrichment analysis detecting gene networks, in which cancer and RNA post-transcriptional modification appeared in the first place, followed by humoral immune response, immunological disease and inflammatory disease. The top four identified canonical pathways were EIF2 signaling, regulation of EIF4 and p70S6K signaling, axonal guidance signaling and mTOR signaling, providing new insight regarding the mechanisms of ILT etiology. Lastly, the association between DNA methylation and differentially expressed genes was examined, and detected negative correlation in seventeen of the eighteen genes. C1 [Carrillo, Jose A.; He, Yanghua; Luo, Juan; Song, Jiuzhou] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Menendez, Kimberly R.; Tablante, Nathaniel L.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Zhao, Keji] NHLBI, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. [Paulson, Joseph N.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Li, Bichun] Yangzhou Univ, Coll Anim Sci & Technol, Yangzhou City, Jiangsu, Peoples R China. RP Song, JZ (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM songj88@umd.edu FU United States Department of Agriculture (USDA)-Natural Resources Institute/National Institute of Food and Agriculture from the USDA National Institute of Food and Agriculture [2010-65205-20588] FX This project was supported by United States Department of Agriculture (USDA)-Natural Resources Institute/National Institute of Food and Agriculture 2010-65205-20588 from the USDA National Institute of Food and Agriculture. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 2 Z9 2 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2015 VL 10 IS 6 AR e0100476 DI 10.1371/journal.pone.0100476 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4OM UT WOS:000356932500001 PM 26107953 ER PT J AU Federer, LM Lu, YL Joubert, DJ Welsh, J Brandys, B AF Federer, Lisa M. Lu, Ya-Ling Joubert, Douglas J. Welsh, Judith Brandys, Barbara TI Biomedical Data Sharing and Reuse: Attitudes and Practices of Clinical and Scientific Research Staff SO PLOS ONE LA English DT Article ID TRIAL DATA; SCIENCE; ACCESS AB Background Significant efforts are underway within the biomedical research community to encourage sharing and reuse of research data in order to enhance research reproducibility and enable scientific discovery. While some technological challenges do exist, many of the barriers to sharing and reuse are social in nature, arising from researchers' concerns about and attitudes toward sharing their data. In addition, clinical and basic science researchers face their own unique sets of challenges to sharing data within their communities. This study investigates these differences in experiences with and perceptions about sharing data, as well as barriers to sharing among clinical and basic science researchers. Methods Clinical and basic science researchers in the Intramural Research Program at the National Institutes of Health were surveyed about their attitudes toward and experiences with sharing and reusing research data. Of 190 respondents to the survey, the 135 respondents who identified themselves as clinical or basic science researchers were included in this analysis. Odds ratio and Fisher's exact tests were the primary methods to examine potential relationships between variables. Worst-case scenario sensitivity tests were conducted when necessary. Results and Discussion While most respondents considered data sharing and reuse important to their work, they generally rated their expertise as low. Sharing data directly with other researchers was common, but most respondents did not have experience with uploading data to a repository. A number of significant differences exist between the attitudes and practices of clinical and basic science researchers, including their motivations for sharing, their reasons for not sharing, and the amount of work required to prepare their data. Conclusions Even within the scope of biomedical research, addressing the unique concerns of diverse research communities is important to encouraging researchers to share and reuse data. Efforts at promoting data sharing and reuse should be aimed at solving not only technological problems, but also addressing researchers' concerns about sharing their data. Given the varied practices of individual researchers and research communities, standardizing data practices like data citation and repository upload could make sharing and reuse easier. C1 [Federer, Lisa M.; Lu, Ya-Ling; Joubert, Douglas J.; Welsh, Judith; Brandys, Barbara] NIH, NIH Lib, Div Lib Serv, Off Res Serv, Bethesda, MD 20892 USA. RP Federer, LM (reprint author), NIH, NIH Lib, Div Lib Serv, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. EM lisa.federer@nih.gov OI Joubert, Douglas/0000-0003-4090-5587 NR 44 TC 2 Z9 2 U1 0 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2015 VL 10 IS 6 AR e0129506 DI 10.1371/journal.pone.0129506 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4OM UT WOS:000356932500059 PM 26107811 ER PT J AU Tian, HY Zhou, S Dong, L Van Boeckel, TP Pei, Y Wu, QZ Yuan, WP Guo, Y Huang, SQ Chen, WH Lu, XL Liu, Z Bai, YQ Yue, TX Grenfell, B Xu, B AF Tian, Huaiyu Zhou, Sen Dong, Lu Van Boeckel, Thomas P. Pei, Yao Wu, Qizhong Yuan, Wenping Guo, Yan Huang, Shanqian Chen, Wenhuan Lu, Xueliang Liu, Zhen Bai, Yuqi Yue, Tianxiang Grenfell, Bryan Xu, Bing TI Climate change suggests a shift of H5N1 risk in migratory birds SO ECOLOGICAL MODELLING LA English DT Article; Proceedings Paper CT 19th Biennial Conference of the International-Society-for-Ecological-Modelling (ISEM) CY OCT 28-31, 2013 CL Toulouse, FRANCE SP Int Soc Ecol Modelling, Univ Toulouse, INRA, INP, CNRS, METEO France, Elsevier, Air France, Federat Rech Agrobiosciences, Interact & Biodiversites, MAD Environnement, SO Toulouse, Galleries Lafayette DE Climate change; Avian influenza; H5N1; Migratory birds ID AVIAN INFLUENZA-VIRUS; LONG-DISTANCE MIGRANT; WILD BIRDS; DUCKS; TRANSMISSION; PERSISTENCE; NORTH; WATER; DISTRIBUTIONS; TEMPERATURE AB Migratory birds are considered to have played an important role in the spread of highly pathogenic avian influenza H5N1. However, how bird species are expected to modify their wintering sites in response to climate change, and in turn affect the geographic distribution of the risk associated with H5N1 outbreaks, is unknown. We explored the association between past climate variability and H5N1 outbreaks that were attributed to migratory birds from 2005 to 2009. We then predicted the distribution of risk associated with H5N1 outbreaks based on future climate change scenarios. Overlapping the probabilities of bird distribution and H5N1 outbreaks produced final emergence risk. Our results suggest that minimum daily temperature in the winter (-15 to -11 degrees C, 15 to 17 degrees C) and maximum daily temperature in the summer (12 to 15 degrees C, 30 to 35 degrees C) governed wild bird migratory routes, while high mean air pressure and low mean specific humidity in the winter impacted the outbreaks of H5N1 among migratory birds. By the end of 2030, Europe may be at higher risk for H5N1 outbreaks in January and February. Northern Africa and Southern and Western Asia will likely be a higher risk for H5N1 outbreaks from April to June. Our findings suggest a potential shift in H5N1 risk from Southeast Asia to the western part of the world due to climate change. The results of this study could be used to inform policy in the area of H5N1 outbreak detection and preparedness. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tian, Huaiyu; Wu, Qizhong; Yuan, Wenping; Guo, Yan; Huang, Shanqian; Xu, Bing] Beijing Normal Univ, Coll Global Change & Earth Syst Sci, State Key Lab Remote Sensing Sci, Beijing 100875, Peoples R China. [Zhou, Sen; Pei, Yao; Chen, Wenhuan; Bai, Yuqi; Xu, Bing] Tsinghua Univ, Ctr Earth Syst Sci, Key Lab Earth Syst Modelling, Minist Educ, Beijing 100084, Peoples R China. [Zhou, Sen; Pei, Yao; Chen, Wenhuan; Bai, Yuqi; Xu, Bing] Tsinghua Univ, Sch Environm, Beijing 100084, Peoples R China. [Dong, Lu] Beijing Normal Univ, Coll Life Sci, Key Lab Biodivers & Ecol Engn, Minist Educ, Beijing 100875, Peoples R China. [Van Boeckel, Thomas P.; Grenfell, Bryan] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Lu, Xueliang; Liu, Zhen] Beijing Normal Univ, Ctr Informat & Network Technol, Beijing 100875, Peoples R China. [Yue, Tianxiang] Chinese Acad Sci, Inst Geog Sci & Nat Resources Res, Beijing 100101, Peoples R China. [Grenfell, Bryan] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Xu, Bing] Univ Utah, Dept Geog, Salt Lake City, UT 84112 USA. RP Xu, B (reprint author), Tsinghua Univ, Ctr Earth Syst Sci, Beijing 100084, Peoples R China. EM bingxu@tsinghua.edu.cn RI robot, alpha/B-8656-2008; Tian, Huaiyu/G-1934-2016 OI robot, alpha/0000-0001-6308-3083; NR 60 TC 5 Z9 6 U1 9 U2 58 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3800 EI 1872-7026 J9 ECOL MODEL JI Ecol. Model. PD JUN 24 PY 2015 VL 306 SI SI BP 6 EP 15 DI 10.1016/j.ecolmodel.2014.08.005 PG 10 WC Ecology SC Environmental Sciences & Ecology GA CJ7VI UT WOS:000355708000002 ER PT J AU Iqbal, B Shah, IA Bhat, GA Bhat, AB Rafiq, R Nabi, S Malekhzadeh, R Abnet, CC Boffetta, P Jenab, M Dar, NA AF Iqbal, Beenish Shah, Idrees Ayoub Bhat, Gulzar Ahmad Bhat, Arshid Bashir Rafiq, Rumaisa Nabi, Sumaiya Malekhzadeh, Reza Abnet, Christian C. Boffetta, Paolo Jenab, Mazda Dar, Nazir Ahmad TI Impediments in foreign collaboration and conducting a high throughput molecular epidemiology research in India, an assessment from a feasibility study SO SPRINGERPLUS LA English DT Article DE Feasibility study; Research limitations; Collaboration; ESCC; Kashmir; India ID SQUAMOUS-CELL CARCINOMA; ESOPHAGEAL CANCER; KASHMIR; RISK; POPULATION; VALIDITY; COHORT AB Background: Esophageal cancer is one of the world's top ten cancers. Its incidence, especially in the form of squamous cell carcinoma, is very high in some Asian regions including Kashmir. Jammu Kashmir and Ladakh are three provinces of Jammu and Kashmir, the northern most state of India. The three regions represent ethnically diverse socio-cultural populations with different incidences of esophageal squamous cell carcinoma (ESCC), a suitable setting for epidemiological studies. Hence, comparing the lifestyle, dietary habits and gene pools between the three regions will help in elucidation of ESCC etiology further. Therefore, to assess the possibility of conducting a larger case control study, we carried out a feasibility study to identify the collaborators as well as to explore patient referral systems and available research facilities in the state. Findings: We found conducting good cancer molecular epidemiology studies is difficult due to lack of proper research facilities and favourable administrative guidelines. The appropriate storage, transportation and analyses facilities of biological specimens for genome-wide association study and assessment of nutrition and exposure markers are unavailable or not sufficiently developed. Guidelines that can encourage scientific collaborations within the country seem unavailable. However, the administrative guidelines available under which the export of biological specimens out of India for analysis seems impossible. Consequently, Indian researchers are unable to collaborate with foreign scientists and render state of art research facilities inaccessible to them. Scientists in other parts of India may also confront with most of these impediments. Conclusion: The study found that for conducting conclusive molecular epidemiological studies in India, referral system in hospitals is not systematic, scientific research facilities are inadequate as well as the guidelines for foreign collaboration are not favourable. C1 [Iqbal, Beenish; Shah, Idrees Ayoub; Bhat, Gulzar Ahmad; Bhat, Arshid Bashir; Rafiq, Rumaisa; Nabi, Sumaiya; Dar, Nazir Ahmad] Univ Kashmir, Dept Biochem, Srinagar 190006, Jammu & Kashmir, India. [Malekhzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY USA. [Jenab, Mazda] WHO, IARC, Sect Nutr & Metab, Lyon, France. RP Dar, NA (reprint author), Univ Kashmir, Dept Biochem, Srinagar 190006, Jammu & Kashmir, India. EM nazirramzan@uok.edu.in RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU World Health Organization [001] NR 12 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD JUN 23 PY 2015 VL 4 AR 287 DI 10.1186/s40064-015-1046-z PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO6IX UT WOS:000359261500001 PM 26120504 ER PT J AU Dillon, LW Kumar, P Shibata, Y Wang, YH Willcox, S Griffith, JD Pommier, Y Takeda, S Dutta, A AF Dillon, Laura W. Kumar, Pankaj Shibata, Yoshiyuki Wang, Yuh-Hwa Willcox, Smaranda Griffith, Jack D. Pommier, Yves Takeda, Shunichi Dutta, Anindya TI Production of Extrachromosomal MicroDNAs Is Linked to Mismatch Repair Pathways and Transcriptional Activity SO CELL REPORTS LA English DT Article ID STRAND BREAK REPAIR; HOMOLOGOUS RECOMBINATION; VERTEBRATE CELLS; HUMAN GENOME; R-LOOPS; DNA; INSTABILITY; TERMINATION; EXPRESSION; INTEGRITY AB MicroDNAs are <400-base extrachromosomal circles found in mammalian cells. Tens of thousands of microDNAs have been found in all tissue types, including sperm. MicroDNAs arise preferentially from areas with high gene density, GC content, and exon density from promoters with activating chromatin modifications and in sperm from the 5'-UTR of full-length LINE-1 elements, but are depleted from lamin-associated heterochromatin. Analysis of microDNAs from a set of human cancer cell lines revealed lineage-specific patterns of microDNA origins. A survey of microDNAs from chicken cells defective in various DNA repair proteins reveals that homologous recombination and non-homologous end joining repair pathways are not required for microDNA production. Deletion of the MSH3 DNA mismatch repair protein results in a significant decrease in microDNA abundance, specifically from non-CpG genomic regions. Thus, microDNAs arise as part of normal cellular physiology-either from DNA breaks associated with RNA metabolism or from replication slippage followed by mismatch repair. C1 [Dillon, Laura W.; Kumar, Pankaj; Shibata, Yoshiyuki; Wang, Yuh-Hwa; Dutta, Anindya] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Willcox, Smaranda; Griffith, Jack D.] Univ N Carolina, Dept Microbiol & Immunol, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. [Pommier, Yves] NCI, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Takeda, Shunichi] Kyoto Univ, Japan Sci & Technol Corp, CREST Res Project, Radiat Genet,Fac Med,Sakyo Ku, Yoshida, Kyoto 6068501, Japan. RP Dutta, A (reprint author), Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. EM ad8q@virginia.edu RI Dutta, Anindya/P-3203-2016; OI Dutta, Anindya/0000-0002-4319-0073 FU NIH [RO1CA60499, PO1CA104160, T32CA009109, GM31819, EM13773, RO1GM101192]; Department of Defense [W81XWH-13-1-0088]; Center for Cancer Research [Z01-BC-006150]; Ovarian Cancer Research Fund [290250]; Kaleidoscope of Hope Foundation FX We thank E. Rissman from the University of Virginia for providing mouse sperm samples, A. Jazaeri from MD Anderson Cancer Center for providing the human ovarian cancer cell lines OVCAR8 and ES-2, and all members of the A. D. lab for helpful discussions. This work was supported by grants from the NIH (RO1CA60499 and PO1CA104160 to A. D., T32CA009109 to L. W. D., GM31819 and EM13773 to J. D. G., and RO1GM101192 to Y.-H.W.), Department of Defense (W81XWH-13-1-0088 to P.K.), NCI Intramural Program, Center for Cancer Research (Z01-BC-006150 to Y.P.), Ovarian Cancer Research Fund (290250 to L.W.D.), and Kaleidoscope of Hope Foundation (to L.W.D.). NR 26 TC 6 Z9 6 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 23 PY 2015 VL 11 IS 11 BP 1749 EP 1759 DI 10.1016/j.celrep.2015.05.020 PG 11 WC Cell Biology SC Cell Biology GA CL3PW UT WOS:000356863600008 PM 26051933 ER PT J AU Falgairolle, M O'Donovan, MJ AF Falgairolle, Melanie O'Donovan, Michael J. TI Pharmacological Investigation of Fluoro-Gold Entry into Spinal Neurons SO PLOS ONE LA English DT Article ID AMPA RECEPTOR TRAFFICKING; DORSAL-HORN NEURONS; EXCITATORY AMINO-ACIDS; LONG-TERM DEPRESSION; GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY; MEDIATED ENDOCYTOSIS; HIPPOCAMPAL-NEURONS; COBALT ACCUMULATION; CAPSAICIN RECEPTOR AB The fluorescent tracer Fluoro-Gold has been widely used to label neurons retrogradely. Here we show that Fluoro-Gold can also enter neurons through AMPA receptor endocytosis. We found that a 30 minute application of Fluoro-Gold to the isolated spinal cord labeled neurons under control conditions and in the presence of glutamatergic agonists including NMDA and AMPA. The labeling was abolished or greatly reduced by glutamatergic antagonists and the endocytic inhibitors Dynasore and dynamin inhibitory peptide. Whole cell recordings from spinal neurons exposed to extracellular AMPA revealed large inward currents that spontaneously decayed in the presence of the agonist but were maintained when a dynamin inhibitory peptide was included in the electrode. These findings suggest that Fluoro-Gold enters spinal neurons through AMPA-mediated receptor internalization. Drugs used to induce locomotor-like activity in the spinal cord also increased and decreased Fluoro-Gold labeling in a drug and lamina specific manner, indicating that AMPAR endocytosis is altered in the presence of the locomotor cocktail. Our findings suggest that endocytosis of Fluoro-Gold could potentially complicate the interpretation of experiments in which the tracer is used to label neurons retrogradely. Moreover, they also demonstrate that many drugs, including the locomotor cocktail, can modulate the number and/or the composition of AMPA receptors on spinal neurons and thereby affect network excitability. C1 [Falgairolle, Melanie; O'Donovan, Michael J.] NINDS, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP O'Donovan, MJ (reprint author), NINDS, Sect Dev Neurobiol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov FU intramural program of National Institutes of Neurological Disorders and Stroke FX This work was supported by the intramural program of National Institutes of Neurological Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2015 VL 10 IS 6 AR UNSP e0131430 DI 10.1371/journal.pone.0131430 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4DD UT WOS:000356901900078 PM 26102354 ER PT J AU McMurray, RG Butte, NF Crouter, SE Trost, SG Pfeiffer, KA Bassett, DR Puyau, MR Berrigan, D Watson, KB Fulton, JE AF McMurray, Robert G. Butte, Nancy F. Crouter, Scott E. Trost, Stewart G. Pfeiffer, Karin A. Bassett, David R. Puyau, Maurice R. Berrigan, David Watson, Kathleen B. Fulton, Janet E. CA CDC NCI NCCOR Res Grp Energy Expen TI Exploring Metrics to Express Energy Expenditure of Physical Activity in Youth SO PLOS ONE LA English DT Article ID BODY-SIZE; SUBSTRATE UTILIZATION; AEROBIC POWER; CHILDREN; ADOLESCENTS; EXPLANATION; COMPENDIUM; VARIABLES; EXERCISE; ECONOMY AB Background Several approaches have been used to express energy expenditure in youth, but no consensus exists as to which best normalizes data for the wide range of ages and body sizes across a range of physical activities. This study examined several common metrics for expressing energy expenditure to determine whether one metric can be used for all healthy children. Such a metric could improve our ability to further advance the Compendium of Physical Activities for Youth. Methods A secondary analysis of oxygen uptake (VO2) data obtained from five sites was completed, that included 947 children ages 5 to 18 years, who engaged in 14 different activities. Resting metabolic rate (RMR) was computed based on Schofield Equations [Hum Nutr Clin Nut. 39 (Suppl 1), 1985]. Absolute oxygen uptake (ml.min(-1)), oxygen uptake per kilogram body mass (VO2 in ml. kg(-1).min(-1)), net oxygen uptake (VO2 - resting metabolic rate), allometric scaled oxygen uptake (VO2 in ml. kg(-0.75).min(-1)) and YOUTH-MET (VO2.[resting VO2](-1)) were calculated. These metrics were regressed with age, sex, height, and body mass. Results Net and allometric-scaled VO2, and YOUTH-MET were least associated with age, sex and physical characteristics. For moderate-to-vigorous intensity activities, allometric scaling was least related to age and sex. For sedentary and low-intensity activities, YOUTH-MET was least related to age and sex. Conclusions No energy expenditure metric completely eliminated the influence of age, physical characteristics, and sex. The Adult MET consistently overestimated EE. YOUTH-MET was better for expressing energy expenditure for sedentary and light activities, whereas allometric scaling was better for moderate and vigorous intensity activities. From a practical perspective, The YOUTH-MET may be the more feasible metric for improving of the Compendium of Physical Activities for Youth. C1 [McMurray, Robert G.] Univ N Carolina, Exercise & Sport Sci & Nutr, Chapel Hill, NC 27599 USA. [Butte, Nancy F.; Puyau, Maurice R.] Baylor Coll Med, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Crouter, Scott E.; Bassett, David R.] Univ Tennessee, Dept Kinesiol Recreat & Sport Studies, Knoxville, TN USA. [Trost, Stewart G.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Exercise & Nutr Sci, Brisbane, Qld 4001, Australia. [Pfeiffer, Karin A.] Michigan State Univ, Dept Kinesiol, E Lansing, MI 48824 USA. [Berrigan, David] NCI, Ctr Dis Control & Prevent, Natl Collaborat Childhood Obes Res, Washington, DC USA. [Watson, Kathleen B.; Fulton, Janet E.] CDC, Div Nutr Phys Act & Obes, Atlanta, GA 30333 USA. RP McMurray, RG (reprint author), Univ N Carolina, Exercise & Sport Sci & Nutr, Chapel Hill, NC 27599 USA. EM exphys@live.unc.edu RI Crouter, Scott/H-4852-2011; OI Crouter, Scott/0000-0003-1297-9538; Trost, Stewart/0000-0001-9587-3944 FU NHLBI NIH HHS [R21 HL093407]; NICHD NIH HHS [L30 HD066736] NR 32 TC 2 Z9 2 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2015 VL 10 IS 6 AR e0130869 DI 10.1371/journal.pone.0130869 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL4DD UT WOS:000356901900064 PM 26102204 ER PT J AU den Boon, JA Pyeon, D Wang, SS Horswill, M Schiffman, M Sherman, M Zuna, RE Wang, Z Hewitt, SM Pearson, R Schott, M Chung, L He, QL Lambert, P Walker, J Newton, MA Wentzensen, N Ahlquist, P AF den Boon, Johan A. Pyeon, Dohun Wang, Sophia S. Horswill, Mark Schiffman, Mark Sherman, Mark Zuna, Rosemary E. Wang, Zhishi Hewitt, Stephen M. Pearson, Rachel Schott, Meghan Chung, Lisa He, Qiuling Lambert, Paul Walker, Joan Newton, Michael A. Wentzensen, Nicolas Ahlquist, Paul TI Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cervical cancer; HPV; estrogen; tumor microenvironment; stroma ID EPITHELIAL-MESENCHYMAL TRANSITION; SQUAMOUS-CELL CARCINOMAS; GENE-EXPRESSION; FANCONI-ANEMIA; BREAST-CANCER; MONOCLONAL-ANTIBODY; E7 ONCOPROTEIN; ALPHA; PROTEIN; DNA AB To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1-CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ER alpha) to CxCa, ER alpha expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ER alpha in CIN and tumor cells was confirmed at the protein level. However, ER alpha expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ER alpha to FSP1+, CD34+, SMA- precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1-, CD34-, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERa mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ER alpha-induced stroma-tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ER alpha+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ER alpha in tumor-associated stromal fibroblasts. C1 [den Boon, Johan A.; Horswill, Mark; Ahlquist, Paul] Univ Wisconsin, Morgridge Inst Res, Madison, WI 53715 USA. [den Boon, Johan A.; Schott, Meghan; Lambert, Paul; Ahlquist, Paul] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53792 USA. [den Boon, Johan A.; Horswill, Mark; Pearson, Rachel; Schott, Meghan; Ahlquist, Paul] Univ Wisconsin, Inst Mol Virol, Madison, WI 53706 USA. [Pyeon, Dohun] Univ Colorado Denver, Sch Med, Dept Immunol & Microbiol, Aurora, CO 80045 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Schiffman, Mark; Sherman, Mark; Hewitt, Stephen M.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zuna, Rosemary E.; Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Wang, Zhishi; Chung, Lisa; He, Qiuling; Newton, Michael A.] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. [Pearson, Rachel; Ahlquist, Paul] Univ Wisconsin, Howard Hughes Med Inst, Madison, WI 53706 USA. [Newton, Michael A.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53792 USA. RP Ahlquist, P (reprint author), Univ Wisconsin, Morgridge Inst Res, Madison, WI 53715 USA. EM wentzenn@mail.nih.gov; ahlquist@wisc.edu OI Hewitt, Stephen/0000-0001-8283-1788 FU NIH [CA22443]; Morgridge Institute for Research FX We are extremely grateful for the participation of the many women enrolled in our studies. We thank Jane Weeks for cryosectioning, George Flentke and Jamie Ahrens for assistance with LCM, and Denis Lee and Ginger Pocock for assistance with IHC and IFA, as well as many other colleagues and students for assistance and helpful expertise in interpretation of results. The research was funded in part by NIH Grant CA22443 and by support provided by the Morgridge Institute for Research. P.A. is an Investigator of the Howard Hughes Medical Institute. NR 84 TC 19 Z9 20 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 2015 VL 112 IS 25 BP E3255 EP E3264 DI 10.1073/pnas.1509322112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL1UV UT WOS:000356731300017 PM 26056290 ER PT J AU Stewart-Jones, GBE Thomas, PV Chen, M Druz, A Joyce, MG Kong, WP Sastry, M Soto, C Yang, YP Zhang, BS Chen, L Chuang, GY Georgiev, IS McLellan, JS Srivatsan, S Zhou, TQ Baxa, U Mascola, JR Graham, BS Kwong, PD AF Stewart-Jones, Guillaume B. E. Thomas, Paul V. Chen, Man Druz, Aliaksandr Joyce, M. Gordon Kong, Wing-Pui Sastry, Mallika Soto, Cinque Yang, Yongping Zhang, Baoshan Chen, Lei Chuang, Gwo-Yu Georgiev, Ivelin S. McLellan, Jason S. Srivatsan, Sanjay Zhou, Tongqing Baxa, Ulrich Mascola, John R. Graham, Barney S. Kwong, Peter D. TI A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus SO PLOS ONE LA English DT Article ID COILED-COIL; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; BACTERIOPHAGE-T4 FIBRITIN; MONOCLONAL-ANTIBODY; PROTEIN; DOMAIN; TRIMERS; INFECTION; PRIMATES AB Recombinant subunit vaccines should contain minimal non-pathogen motifs to reduce potential off-target reactivity. We recently developed a vaccine antigen against respiratory syncytial virus (RSV), which comprised the fusion (F) glycoprotein stabilized in its pre-fusion trimeric conformation by "DS-Cav1" mutations and by an appended C-terminal trimerization motif or "foldon" from T4-bacteriophage fibritin. Here we investigate the creation of a cysteine zipper to allow for the removal of the phage foldon, while maintaining the immunogenicity of the parent DS-Cav1+foldon antigen. Constructs without foldon yielded RSV F monomers, and enzymatic removal of the phage foldon from pre-fusion F trimers resulted in their dissociation into monomers. Because the native C terminus of the pre-fusion RSV F ectodomain encompasses a viral trimeric coiled-coil, we explored whether introduction of cysteine residues capable of forming inter-protomer disulfides might allow for stable trimers. Structural modeling indicated the introduced cysteines to form disulfide "rings", with each ring comprising a different set of inward facing residues of the coiled-coil. Three sets of rings could be placed within the native RSV F coiled-coil, and additional rings could be added by duplicating portions of the coiled-coil. High levels of neutralizing activity in mice, equivalent to that of the parent DS-Cav1+foldon antigen, were elicited by a 4-ring stabilized RSV F trimer with no foldon. Structure-based alteration of a viral coiled-coil to create a cysteine zipper thus allows a phage trimerization motif to be removed from a candidate vaccine antigen. C1 [Stewart-Jones, Guillaume B. E.; Thomas, Paul V.; Chen, Man; Druz, Aliaksandr; Joyce, M. Gordon; Kong, Wing-Pui; Sastry, Mallika; Soto, Cinque; Yang, Yongping; Zhang, Baoshan; Chen, Lei; Chuang, Gwo-Yu; Georgiev, Ivelin S.; McLellan, Jason S.; Srivatsan, Sanjay; Zhou, Tongqing; Mascola, John R.; Graham, Barney S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA. [Baxa, Ulrich] Leidos Biomed Res Inc, Electron Microscopy Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases [ZIA AI005024-13]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, ZIA AI005024-13. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Leidos Biomedical Research, Inc., provided support in the form of a salary for author UB. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 7 Z9 7 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 22 PY 2015 VL 10 IS 6 AR e0128779 DI 10.1371/journal.pone.0128779 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3FM UT WOS:000356835800019 PM 26098893 ER PT J AU Tan, DD Yang, HP Yuan, Y Bonnemann, C Chang, XZ Wang, S Wu, YC Wu, XR Xiong, H AF Tan, Dandan Yang, Haipo Yuan, Yun Bonnemann, Carsten Chang, Xingzhi Wang, Shuang Wu, Yuchen Wu, Xiru Xiong, Hui TI Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy SO PLOS ONE LA English DT Article ID LAMIN A/C MUTATIONS; GENE-MUTATIONS; DROPPED HEAD; TISSUE; INVOLVEMENT; DEFECTS; DEATH AB This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD. C1 [Tan, Dandan; Yang, Haipo; Chang, Xingzhi; Wang, Shuang; Wu, Xiru; Xiong, Hui] Peking Univ, Hosp 1, Dept Pediat, Beijing 100871, Peoples R China. [Tan, Dandan; Wu, Yuchen] Nanchang Univ, Affiliated Hosp 1, Dept Neurol, Nanchang, Peoples R China. [Yuan, Yun] Peking Univ, Hosp 1, Dept Neurol, Beijing 100871, Peoples R China. [Bonnemann, Carsten] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. RP Xiong, H (reprint author), Peking Univ, Hosp 1, Dept Pediat, Beijing 100871, Peoples R China. EM xh_bjbj@163.com FU National Natural Science Foundation of China [81271400]; National Basic Research Program of China [2012CB944602] FX This work was supported by grants from the National Natural Science Foundation of China (81271400), and the National Basic Research Program of China (2012CB944602). NR 24 TC 4 Z9 5 U1 4 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 22 PY 2015 VL 10 IS 6 AR e0129699 DI 10.1371/journal.pone.0129699 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3FM UT WOS:000356835800036 PM 26098624 ER PT J AU House, CD Wang, BD Ceniccola, K Williams, R Simaan, M Olender, J Patel, V Baptista-Hon, DT Annunziata, CM Gutkind, JS Hales, TG Lee, NH AF House, Carrie D. Wang, Bi-Dar Ceniccola, Kristin Williams, Russell Simaan, May Olender, Jacqueline Patel, Vyomesh Baptista-Hon, Daniel T. Annunziata, Christina M. Gutkind, J. Silvio Hales, Tim G. Lee, Norman H. TI Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-KINASE-A; PROSTATE-CANCER; BREAST-CANCER; MEMBRANE DEPOLARIZATION; INDEPENDENT MECHANISM; MEDIATED ACTIVATION; NEURONAL CELLS; SODIUM; EXPRESSION; RAP1 AB Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes. C1 [House, Carrie D.; Wang, Bi-Dar; Ceniccola, Kristin; Williams, Russell; Olender, Jacqueline; Lee, Norman H.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC 20052 USA. [Simaan, May; Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Baptista-Hon, Daniel T.; Hales, Tim G.] Univ Dundee, Ninewells Hosp, Inst Acad Anaesthesia, Div Neurosci, Dundee DD1 9SY, Scotland. [House, Carrie D.; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Bethesda, MD 20892 USA. RP Lee, NH (reprint author), George Washington Univ, Dept Physiol & Pharmacol, Washington, DC 20052 USA. EM nhlee@gwu.edu RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU NIH grant [R01 CA120316]; PhRMA Foundation Award FX NIH grant R01 CA120316 (N.H. Lee), PhRMA Foundation Award (C.D. House) NR 51 TC 6 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 22 PY 2015 VL 5 AR 11541 DI 10.1038/srep11541 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9ZK UT WOS:000356597900002 PM 26096612 ER PT J AU Zou, DH McSweeney, C Sebastian, A Reynolds, DJ Dong, FP Zhou, YJ Deng, DZ Wang, YG Liu, L Zhu, J Zou, JZ Shi, YS Albert, I Mao, YW AF Zou, Donghua McSweeney, Colleen Sebastian, Aswathy Reynolds, Derrick James Dong, Fengping Zhou, Yijing Deng, Dazhi Wang, Yonggang Liu, Long Zhu, Jun Zou, Jizhong Shi, Yongsheng Albert, Istvan Mao, Yingwei TI A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors SO NEURAL DEVELOPMENT LA English DT Article DE RBM8a; Exon junction complex; Neurodevelopment; Neural progenitor cells; Psychiatric disorders; Nonsense mediated mRNA decay ID MESSENGER-RNA DECAY; EXON-JUNCTION COMPLEX; NONSENSE-MEDIATED DECAY; ABSENT RADIUS SYNDROME; STEM-CELL; UPF1 PHOSPHORYLATION; OXIDATIVE STRESS; TAR SYNDROME; NMD FACTORS; GENE AB Background: Nonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear. Result: We found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment. Conclusions: Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses. C1 [Zou, Donghua; Mao, Yingwei] Guangxi Med Univ, Affiliated Hosp 1, Dept Neurol, Nanning 530021, Guangxi Provinc, Peoples R China. [Zou, Donghua] Chinese Peoples Liberat Army, Hosp 303, Dept Geriatr, Nanning 530021, Guangxi Provinc, Peoples R China. [Zou, Donghua; McSweeney, Colleen; Dong, Fengping; Zhou, Yijing; Deng, Dazhi; Liu, Long; Mao, Yingwei] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Sebastian, Aswathy; Albert, Istvan] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Reynolds, Derrick James; Shi, Yongsheng] Univ Calif Irvine, Sch Med, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. [Deng, Dazhi] Guangxi Zhuang Autonomous Reg Peoples Hosp, Dept Emergency, Nanning 530021, Guangxi Provinc, Peoples R China. [Wang, Yonggang] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Neurol, Shanghai 200127, Peoples R China. [Liu, Long] Natl Univ Def Technol, Coll Sci, Dept Biol & Chem, Changsha 410073, Peoples R China. [Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Zou, Jizhong] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Mao, YW (reprint author), Guangxi Med Univ, Affiliated Hosp 1, Dept Neurol, Nanning 530021, Guangxi Provinc, Peoples R China. EM yzm1@psu.edu OI zou, dong hua/0000-0002-3891-9472 FU Intramural NIH HHS; NCI NIH HHS [R01 CA177651]; NIGMS NIH HHS [R01 GM090056] NR 90 TC 5 Z9 5 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8104 J9 NEURAL DEV JI Neural Dev. PD JUN 21 PY 2015 VL 10 AR 18 DI 10.1186/s13064-015-0045-7 PG 16 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA CL0UB UT WOS:000356657500001 PM 26094033 ER PT J AU Dagdug, L Berezhkovskii, AM Skvortsov, AT AF Dagdug, Leonardo Berezhkovskii, Alexander M. Skvortsov, Alexei T. TI Trapping of diffusing particles by striped cylindrical surfaces. Boundary homogenization approach SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONTROLLED LIGAND-BINDING; NO-SHEAR CONDITIONS; EFFECTIVE SLIP; RECEPTORS; PERMEABILITY; AUTOCRINE; MEMBRANE; ARRAYS; FLOW AB We study trapping of diffusing particles by a cylindrical surface formed by rolling a flat surface, containing alternating absorbing and reflecting stripes, into a tube. For an arbitrary stripe orientation with respect to the tube axis, this problem is intractable analytically because it requires dealing with non-uniform boundary conditions. To bypass this difficulty, we use a boundary homogenization approach which replaces non-uniform boundary conditions on the tube wall by an effective uniform partially absorbing boundary condition with properly chosen effective trapping rate. We demonstrate that the exact solution for the effective trapping rate, known for a flat, striped surface, works very well when this surface is rolled into a cylindrical tube. This is shown for both internal and external problems, where the particles diffuse inside and outside the striped tube, at three orientations of the stripe direction with respect to the tube axis: (a) perpendicular to the axis, (b) parallel to the axis, and (c) at the angle of pi/4 to the axis. (C) 2015 AIP Publishing LLC. C1 [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Skvortsov, Alexei T.] Def Sci & Technol Org, Maritime Div, Fishermans Bend, Vic 3207, Australia. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. FU Consejo Nacional de Ciencia y Tecnologia (CONACyT) [176452]; Intramural Research Program of the NIH, Center for Information Technology FX We are grateful to Raphael Voituriez for sending us a formal proof29 that, in the case of only one absorbing stripe parallel to the tube axis, the boundary homogenization approach leads to the exact result for the mean particle lifetime in the internal problem, prior to its publication in Ref. 31. We are also grateful to Jean-Francois Rupprecht for drawing our attention to Eq. (29) from Ref. 31, which provides an exact solution for the mean particle lifetime in the internal problem with several identical, evenly spaced stripes, parallel to the tube axis. L.D. thanks Consejo Nacional de Ciencia y Tecnologia (CONACyT) for partial support under Grant No. 176452. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 39 TC 3 Z9 3 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 21 PY 2015 VL 142 IS 23 AR 234902 DI 10.1063/1.4922444 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CL0HU UT WOS:000356623000032 PM 26093574 ER PT J AU Brinton, LA Key, TJ Kolonel, LN Michels, KB Sesso, HD Ursin, G Van Den Eeden, SK Wood, SN Falk, RT Parisi, D Guillemette, C Caron, P Turcotte, V Habel, LA Isaacs, CJ Riboli, E Weiderpass, E Cook, MB AF Brinton, Louise A. Key, Tim J. Kolonel, Laurence N. Michels, Karin B. Sesso, Howard D. Ursin, Giske Van Den Eeden, Stephen K. Wood, Shannon N. Falk, Roni T. Parisi, Dominick Guillemette, Chantal Caron, Patrick Turcotte, Veronique Habel, Laurel A. Isaacs, Claudine J. Riboli, Elio Weiderpass, Elisabete Cook, Michael B. TI Prediagnostic Sex Steroid Hormones in Relation to Male Breast Cancer Risk SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BASE-LINE CHARACTERISTICS; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; KLINEFELTER-SYNDROME; COLLABORATIVE REANALYSIS; ESTROGEN METABOLISM; REPLACEMENT THERAPY; EPIC COHORT; MEN; PREMENOPAUSAL AB Purpose Although previous studies have implicated a variety of hormone-related risk factors in the etiology of male breast cancers, no previous studies have examined the effects of endogenous hormones. Patients and Methods Within the Male Breast Cancer Pooling Project, an international consortium comprising 21 case-control and cohort investigations, a subset of seven prospective cohort studies were able to contribute prediagnostic serum or plasma samples for hormone quantitation. Using a nested case-control design, multivariable unconditional logistic regression analyses estimated odds ratios and 95% CIs for associations between male breast cancer risk and 11 individual estrogens and androgens, as well as selected ratios of these analytes. Results Data from 101 cases and 217 matched controls were analyzed. After adjustment for age and date of blood draw, race, and body mass index, androgens were found to be largely unrelated to risk, but circulating estradiol levels showed a significant association. Men in the highest quartile had an odds ratio of 2.47 (95% CI, 1.10 to 5.58) compared with those in the lowest quartile (trend P = .06). Assessment of estradiol as a ratio to various individual androgens or sum of androgens showed no further enhancement of risk. These relations were not significantly modified by either age or body mass index, although estradiol was slightly more strongly related to breast cancers occurring among younger (age < 67 years) than older men. Conclusion Our results support the notion of an important role for estradiol in the etiology of male breast cancers, similar to female breast cancers. (C) 2015 by American Society of Clinical Oncology C1 [Brinton, Louise A.; Wood, Shannon N.; Falk, Roni T.; Cook, Michael B.] NCI, Bethesda, MD 20892 USA. [Parisi, Dominick] Informat Management Serv Inc, Rockville, MD USA. [Key, Tim J.] Univ Oxford, Oxford OX1 2JD, England. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London SW7 2AZ, England. [Kolonel, Laurence N.] Univ Hawaii, Honolulu, HI 96822 USA. [Michels, Karin B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Michels, Karin B.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Michels, Karin B.; Sesso, Howard D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ursin, Giske] Univ Oslo, N-0316 Oslo, Norway. [Ursin, Giske; Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Ursin, Giske; Weiderpass, Elisabete] Univ Tromso, Arctic Univ Norway, Tromso, Norway. [Ursin, Giske; Weiderpass, Elisabete] Karolinska Inst, Stockholm, Sweden. [Ursin, Giske; Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Ursin, Giske] Univ So Calif, Los Angeles, CA USA. [Van Den Eeden, Stephen K.; Habel, Laurel A.] Kaiser Permanente No Calif, Oakland, CA USA. [Guillemette, Chantal; Caron, Patrick; Turcotte, Veronique] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada. [Guillemette, Chantal; Caron, Patrick; Turcotte, Veronique] Univ Laval, Quebec City, PQ, Canada. [Isaacs, Claudine J.] Georgetown Univ, Washington, DC USA. RP Brinton, LA (reprint author), 9609 Med Ctr Dr,Rm 7-E102, Bethesda, MD 20892 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Cook, Michael/A-5641-2009; Weiderpass, Elisabete/M-4029-2016 OI Brinton, Louise/0000-0003-3853-8562; Cook, Michael/0000-0002-0533-7302; Weiderpass, Elisabete/0000-0003-2237-0128 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI); NCI Research Grant [CA167552]; NCI [CA097193, CA34944, CA40360, HL26490, HL34595]; Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; Federal Ministry of Education and Research (Germany); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane (Sweden); Regional Government of Vasterbotten (Sweden); Cancer Research United Kingdom (United Kingdom); UK Medical Research Council (United Kingdom); Danish Cancer Society (Denmark); Italian Association for Research on Cancer (Italy); National Research Council Italy (Italy); HuGeF Foundation (Italy); Instituto de Salud Carlos III Red Tematica de Investigacion Cooperativa en Cancer (Spain); Hellenic Health Foundation (Greece); Stavros Niarchos Foundation (Greece); Hellenic Ministry of Health and Social Solidarity (Greece) FX Supported in part by intramural funds from the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI); by NCI Research Grant No. CA167552 (for the Health Professionals Follow-Up Study); and by NCI Grants No. CA097193, CA34944, CA40360, HL26490, and HL34595 (for the Physicians' Health Study). The EPIC (European Prospective Investigation Into Cancer and Nutrition) study was supported in part by the Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Skane and Vasterbotten (Sweden); Cancer Research United Kingdom and UK Medical Research Council (United Kingdom); Danish Cancer Society (Denmark); Italian Association for Research on Cancer, National Research Council Italy, and HuGeF Foundation (Italy); Instituto de Salud Carlos III Red Tematica de Investigacion Cooperativa en Cancer (Spain); and the Hellenic Health Foundation, Stavros Niarchos Foundation, and Hellenic Ministry of Health and Social Solidarity (Greece). NR 56 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 BP 2041 EP 2050 DI 10.1200/JCO.2014.59.1602 PG 10 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800011 PM 25964249 ER PT J AU Weber, JS Yang, JC Atkins, MB Disis, ML AF Weber, Jeffrey S. Yang, James C. Atkins, Michael B. Disis, Mary L. TI Toxicities of Immunotherapy for the Practitioner SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID NECROSIS-FACTOR RECEPTOR; IPILIMUMAB-INDUCED HYPOPHYSITIS; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; RESISTANT PROSTATE-CANCER; HIGH-DOSE INTERLEUKIN-2; PEPTIDE-BASED VACCINES; RENAL-CELL CARCINOMA; METASTATIC MELANOMA; T-CELLS; CLINICAL-TRIAL AB The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell-mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities. (C) 2015 by American Society of Clinical Oncology C1 [Weber, Jeffrey S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Yang, James C.] Natl Canc Inst, Bethesda, MD USA. [Atkins, Michael B.] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Disis, Mary L.] Univ Washington, Fred Hutchinson Canc Ctr, Seattle, WA 98195 USA. RP Weber, JS (reprint author), H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr,SRB 2, Tampa, FL 33612 USA. EM jeffrey.weber@moffitt.org NR 105 TC 66 Z9 69 U1 11 U2 20 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 BP 2092 EP U154 DI 10.1200/JCO.2014.60.0379 PG 9 WC Oncology SC Oncology GA CR9DG UT WOS:000361652800016 PM 25918278 ER PT J AU Mohammed, A Janakiram, NB Madka, V Brewer, M Ritchie, RL Lightfoot, S Kumar, G Sadeghi, M Patlolla, JMR Yamada, HY Cruz-Monserrate, Z May, R Houchen, CW Steele, VE Rao, CV AF Mohammed, Altaf Janakiram, Naveena B. Madka, Venkateshwar Brewer, Misty Ritchie, Rebekah L. Lightfoot, Stan Kumar, Gaurav Sadeghi, Michael Patlolla, Jagan Mohan R. Yamada, Hiroshi Y. Cruz-Monserrate, Zobeida May, Randal Houchen, Courtney W. Steele, Vernon E. Rao, Chinthalapally V. TI Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression SO ONCOTARGET LA English DT Article DE pancreatic cancer; inflammation; dual COX-5-LOX inhibition; cancer stem cells; p48(Cre/+)-LSL-Kras(G12D/+) mice ID ENGINEERED MOUSE MODELS; INTRAEPITHELIAL NEOPLASIA; DUCTAL ADENOCARCINOMA; PREVENTS PROGRESSION; ARACHIDONIC-ACID; INHIBITOR; MICE; LICOFELONE; CARCINOMA; 5-LIPOXYGENASE AB Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. C1 [Mohammed, Altaf; Janakiram, Naveena B.; Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L.; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R.; Yamada, Hiroshi Y.; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, PC Stephenson Canc Ctr, Ctr Canc Prevent & Drug Dev,Dept Med,Hemonc Sect, Oklahoma City, OK 73106 USA. [Cruz-Monserrate, Zobeida] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [May, Randal; Houchen, Courtney W.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Digest Dis Sect, Oklahoma City, OK USA. [Steele, Vernon E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Mohammed, A (reprint author), Univ Oklahoma, Hlth Sci Ctr, PC Stephenson Canc Ctr, Ctr Canc Prevent & Drug Dev,Dept Med,Hemonc Sect, Oklahoma City, OK 73106 USA. EM amohamme@ouhsc.edu; cv-rao@ouhsc.edu FU National Cancer Institute [N01-CN-53300] FX This work was supported in part by the National Cancer Institute N01-CN-53300 and Kerley-Cade Endowed Chair Fund to C.V. Rao. NR 50 TC 10 Z9 10 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 20 PY 2015 VL 6 IS 17 BP 15524 EP 15539 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2TY UT WOS:000359010700065 PM 25906749 ER PT J AU Chen, GS de las Fuentes, L Gu, CC He, J Gu, DF Kelly, T Hixson, J Jacquish, C Rao, DC Rice, TK AF Chen, Gengsheng de las Fuentes, Lisa Gu, Chi C. He, Jiang Gu, Dongfeng Kelly, Tanika Hixson, James Jacquish, Cashell Rao, D. C. Rice, Treva K. TI Aggregate blood pressure responses to serial dietary sodium and potassium intervention: defining responses using independent component analysis SO BMC GENETICS LA English DT Article DE Blood pressure; Cardiovascular diseases; Hypertension; Independent component analysis ID SALT-SENSITIVITY; SYSTOLIC HYPERTENSION; HERITABILITY; METAANALYSIS; FAMILIES; DISEASE; HEART; ASSOCIATION; POPULATION; RATIONALE AB Background: Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies. Results: In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A "heat map" protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64 %) and general hypertension (56 %) components. There is a pattern of higher heritability for the component response to intervention (40-42 %) as compared to those for the traditional intervention responses computed as delta scores (24 %-40 %). Conclusions: In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications. C1 [Chen, Gengsheng; de las Fuentes, Lisa; Gu, Chi C.; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [He, Jiang; Kelly, Tanika] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Gu, Dongfeng] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Hixson, James] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Jacquish, Cashell] NHLBI, Bethesda, MD 20892 USA. RP Rice, TK (reprint author), Washington Univ, Sch Med, St Louis, MO 63130 USA. EM treva@wubios.wustl.edu FU National Heart, Lung and Blood Institute [U01HL072507, R01HL087263, R01HL090682]; National Institutes of Health [T32HL091823] FX This work was supported by the National Heart, Lung and Blood Institute (grants U01HL072507, R01HL087263 and R01HL090682), and National Institutes of Health (grant T32HL091823 to G.C.). Upsher-Smith Laboratories Inc. provided Klor-Con M20 potassium tables for the GenSalt study. NR 39 TC 0 Z9 0 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD JUN 20 PY 2015 VL 16 AR 64 DI 10.1186/s12863-015-0226-8 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CK8GU UT WOS:000356477300001 PM 26088064 ER PT J AU Heindel, JJ Saal, FSV Blumberg, B Bovolin, P Calamandrei, G Ceresini, G Cohn, BA Fabbri, E Gioiosa, L Kassotis, C Legler, J La Merrill, M Rizzir, L Machtinger, R Mantovani, A Mendez, MA Montanini, L Molteni, L Nagel, SC Parmigiani, S Panzica, G Paterlini, S Pomatto, V Ruzzin, J Sartor, G Schug, TT Street, ME Suvorov, A Volpi, R Zoeller, RT Palanza, P AF Heindel, Jerrold J. Saal, Frederick S. vom Blumberg, Bruce Bovolin, Patrizia Calamandrei, Gemma Ceresini, Graziano Cohn, Barbara A. Fabbri, Elena Gioiosa, Laura Kassotis, Christopher Legler, Juliette La Merrill, Michele Rizzir, Laura Machtinger, Ronit Mantovani, Alberto Mendez, Michelle A. Montanini, Luisa Molteni, Laura Nagel, Susan C. Parmigiani, Stefano Panzica, Giancarlo Paterlini, Silvia Pomatto, Valentina Ruzzin, Jerome Sartor, Giorgio Schug, Thaddeus T. Street, Maria E. Suvorov, Alexander Volpi, Riccardo Zoeller, R. Thomas Palanza, Paola TI Parma consensus statement on metabolic disruptors SO ENVIRONMENTAL HEALTH LA English DT Editorial Material DE Metabolic disruptor; Obesogen; Obesity; Diabetes; Metabolic syndrome; Developmental Programming ID EPIGENETIC TRANSGENERATIONAL INHERITANCE; BISPHENOL-A CONCENTRATION; ENVIRONMENTAL CHEMICALS; WAIST CIRCUMFERENCE; PERINATAL EXPOSURE; INSULIN-RESISTANCE; PRENATAL EXPOSURE; FOOD-INTAKE; OBESITY; ENDOCRINE AB A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome. C1 [Heindel, Jerrold J.; Schug, Thaddeus T.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Saal, Frederick S. vom; Kassotis, Christopher; Suvorov, Alexander] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Blumberg, Bruce] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA. [Bovolin, Patrizia; Pomatto, Valentina] Univ Turin, Dept Life Sci & Syst Biol, Turin, Italy. [Calamandrei, Gemma] Inst Super Sanita, Dept Cell Biol & Neurosci, Rome, Italy. [Ceresini, Graziano] Univ Parma, Dept Clin & Expt Med, I-43100 Parma, Italy. [Cohn, Barbara A.] Inst Publ Hlth, Berkeley, CA USA. [Fabbri, Elena] Univ Bologna, Interdepartment Ctr Environm Sci Res, Ravenna, Italy. [Gioiosa, Laura; Palanza, Paola] Univ Parma, Dept Neurosci, I-43100 Parma, Italy. [Legler, Juliette] Vrije Univ Amsterdam, Dept Toxicol & Environm Hlth, Amsterdam, Netherlands. [La Merrill, Michele] Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. [Rizzir, Laura] Univ Milan, Dept Hlth Sci, Monza, Italy. [Machtinger, Ronit] Sheba Med Ctr, Tel Aviv, Israel. [Machtinger, Ronit] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Mantovani, Alberto] Inst Super Sanita, Rome, Italy. [Mendez, Michelle A.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Montanini, Luisa] Univ Parma, Dept Pediat, I-43100 Parma, Italy. [Molteni, Laura] Univ Milan, Monza, Italy. [Nagel, Susan C.] Univ Missouri, Dept Obstet Gynecol & Womens Hlth, Columbia, MO USA. [Parmigiani, Stefano] Univ Parma, Fac Med, I-43100 Parma, Italy. [Panzica, Giancarlo; Paterlini, Silvia] Univ Turin, Dept Neurosci & Neurosci Inst Cavalieri Ottolengh, Turin, Italy. [Ruzzin, Jerome] Univ Bergen, Dept Biol, Bergen, Norway. [Sartor, Giorgio] Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy. [Street, Maria E.] Univ Hosp, Dept Pediat, Parma, Italy. [Volpi, Riccardo] Univ Parma, Dept Internal Med, I-43100 Parma, Italy. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov OI PARMIGIANI, STEFANO/0000-0002-6658-2029; Nagel, Susan C./0000-0003-4703-7604; Legler, Juliette/0000-0001-6321-1567; Suvorov, Alexander/0000-0002-2757-5897; Street, Maria Elisabeth/0000-0001-8427-8971; Panzica, Giancarlo/0000-0002-9302-4647 NR 49 TC 20 Z9 20 U1 2 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JUN 20 PY 2015 VL 14 AR 54 DI 10.1186/s12940-015-0042-7 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CL0SB UT WOS:000356652300001 PM 26092037 ER PT J AU Lobstein, T Jackson-Leach, R Moodie, ML Hall, KD Gortmaker, SL Swinburn, BA James, WPT Wang, YF McPherson, K AF Lobstein, Tim Jackson-Leach, Rachel Moodie, Marjory L. Hall, Kevin D. Gortmaker, Steven L. Swinburn, Boyd A. James, W. Philip T. Wang, Youfa McPherson, Klim TI Child and adolescent obesity: part of a bigger picture SO LANCET LA English DT Article ID ASSESSING COST-EFFECTIVENESS; PRIMARY-SCHOOL CHILDREN; BODY-MASS INDEX; QUALITY-OF-LIFE; PREVENTION PROGRAM; ACTIVE-TRANSPORT; OVERWEIGHT; FOOD; INTERVENTIONS; HEALTH AB The prevalence of childhood overweight and obesity has risen substantially worldwide in less than one generation. In the USA, the average weight of a child has risen by more than 5 kg within three decades, to a point where a third of the country's children are overweight or obese. Some low-income and middle-income countries have reported similar or more rapid rises in child obesity, despite continuing high levels of undernutrition. Nutrition policies to tackle child obesity need to promote healthy growth and household nutrition security and protect children from inducements to be inactive or to overconsume foods of poor nutritional quality. The promotion of energy-rich and nutrient-poor products will encourage rapid weight gain in early childhood and exacerbate risk factors for chronic disease in all children, especially those showing poor linear growth. Whereas much public health effort has been expended to restrict the adverse marketing of breastmilk substitutes, similar effort now needs to be expanded and strengthened to protect older children from increasingly sophisticated marketing of sedentary activities and energy-dense, nutrient-poor foods and beverages. To meet this challenge, the governance of food supply and food markets should be improved and commercial activities subordinated to protect and promote children's health. C1 [Lobstein, Tim; Jackson-Leach, Rachel; James, W. Philip T.] World Obes Federat, London WC1N 2JU, England. [Moodie, Marjory L.] Deakin Univ, Deakin Hlth Econ, Melbourne, Vic, Australia. [Swinburn, Boyd A.] Deakin Univ, WHO Collaborating Ctr Obes Prevent, Melbourne, Vic, Australia. [Swinburn, Boyd A.] Univ Auckland, Sch Populat Hlth, Auckland 1, New Zealand. [Hall, Kevin D.] NIDDK, NIH, Bethesda, MD 20892 USA. [Gortmaker, Steven L.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Wang, Youfa] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [McPherson, Klim] Univ Oxford, New Coll, Oxford, England. RP Lobstein, T (reprint author), World Obes Federat, Charles Darwin House, London WC1N 2JU, England. EM tlobstein@worldobesity.org FU World Obesity Federation; US National Collaborative on Childhood Obesity Research; RWJF [260639]; CDC [U48/DP00064]; NIH [1R01HD064685-01A1, U54HD070725]; Nutrition and Obesity Policy, Research and Evaluation Network; Office of Behavioural and Social Sciences Research of NIH FX The work for this paper was supported by the World Obesity Federation, formerly the International Association for the Study of Obesity (IASO). Additional work was done in part for the Envision Project, supported by the US National Collaborative on Childhood Obesity Research, which coordinates childhood obesity research across the National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), US Department of Agriculture, and the Robert Wood Johnson Foundation (RWJF). The work was also supported in part by grants from RWJF (grant 260639), CDC (U48/DP00064) and NIH (1R01HD064685-01A1, U54HD070725), including the Nutrition and Obesity Policy, Research and Evaluation Network, and the Office of Behavioural and Social Sciences Research of NIH. We thank Faten Ben Abdelaziz of WHO Regional Office for the Eastern Mediterranean for comments and advice on the manuscript and for regional media advertising data. We thank Caroline Hancock for sharing her MSc in Public Health dissertation. We thank Jaap Seidell and Carolyn Summerbell for their comments on an earlier version of the manuscript, and to the anonymous reviewers of the submitted drafts. NR 89 TC 90 Z9 94 U1 38 U2 103 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 20 PY 2015 VL 385 IS 9986 BP 2510 EP 2520 DI 10.1016/S0140-6736(14)61746-3 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CK9AR UT WOS:000356532500026 PM 25703114 ER PT J AU Dietz, WH Baur, LA Hall, K Puhl, RM Taveras, EM Uauy, R Kopelman, P AF Dietz, William H. Baur, Louise A. Hall, Kevin Puhl, Rebecca M. Taveras, Elsie M. Uauy, Ricardo Kopelman, Peter TI Management of obesity: improvement of health-care training and systems for prevention and care SO LANCET LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; SUSTAINED WEIGHT-LOSS; CHILDHOOD OBESITY; PHYSICAL-ACTIVITY; BARIATRIC SURGERY; NATIONAL-SURVEY; ADAPTIVE THERMOGENESIS; ADOLESCENT OVERWEIGHT; TREATMENT OUTCOMES AB Although the caloric deficits achieved by increased awareness, policy, and environmental approaches have begun to achieve reductions in the prevalence of obesity in some countries, these approaches are insufficient to achieve weight loss in patients with severe obesity. Because the prevalence of obesity poses an enormous clinical burden, innovative treatment and care-delivery strategies are needed. Nonetheless, health professionals are poorly prepared to address obesity. In addition to biases and unfounded assumptions about patients with obesity, absence of training in behaviour-change strategies and scarce experience working within interprofessional teams impairs care of patients with obesity. Modalities available for the treatment of adult obesity include clinical counselling focused on diet, physical activity, and behaviour change, pharmacotherapy, and bariatric surgery. Few options, few published reports of treatment, and no large randomised trials are available for paediatric patients. Improved care for patients with obesity will need alignment of the intensity of therapy with the severity of disease and integration of therapy with environmental changes that reinforce clinical strategies. New treatment strategies, such as the use of technology and innovative means of health-care delivery that rely on health professionals other than physicians, represent promising options, particularly for patients with overweight and patients with mild to moderate obesity. The co-occurrence of undernutrition and obesity in low-income and middle-income countries poses unique challenges that might not be amenable to the same strategies as those that can be used in high-income countries. C1 [Dietz, William H.] George Washington Univ, Sumner M Redstone Global Ctr Prevent & Wellness, Washington, DC 20052 USA. [Baur, Louise A.] Childrens Hosp Westmead, Sch Clin, Weight Management Serv, Westmead, NSW, Australia. [Hall, Kevin] NIDDK, Lab Biol Modeling, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Puhl, Rebecca M.] Yale Univ, Ctr Food Policy & Obes, New Haven, CT USA. [Taveras, Elsie M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp Children, Div Gen Acad Pediat, Boston, MA USA. [Uauy, Ricardo] Univ Catolica Chile, Div Pediat, Escuela Med, Santiago, Chile. [Kopelman, Peter] St Georges Univ London, London, England. RP Dietz, WH (reprint author), George Washington Univ, Sumner M Redstone Global Ctr Prevent & Wellness, Washington, DC 20052 USA. EM dietzwcd4@gmail.com FU JPB Foundation; Institute of Medicine; Cardinal Health Foundation; State of Kansas FX WHD declares consulting fees and travel reimbursement from the JPB Foundation, the Institute of Medicine, the Cardinal Health Foundation, and the State of Kansas: and honoraria and travel support from the Kansas Health Foundation, Case Western Reserve University, Cleveland Town Hall, and the National Institute for Health Care Management. KH has a patent pending for the personalised dynamic feedback control of body weight. LAB, RMP, EMT, RU, and PK declare no competing interests. NR 114 TC 38 Z9 38 U1 12 U2 46 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 20 PY 2015 VL 385 IS 9986 BP 2521 EP 2533 DI 10.1016/S0140-6736(14)61748-7 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA CK9AR UT WOS:000356532500027 PM 25703112 ER PT J AU Margolese, RG Cecchini, RS Julian, TB Ganz, PA Costantino, JP Vallow, L Albain, KS Whitworth, PW Cianfrocca, ME Brufsky, A Gross, HM Soori, GS Hopkins, JO Fehrenbacher, L Sturtz, K Wozniak, TF Seay, TE Mamounas, EP Wolmark, N AF Margolese, Richard G. Cecchini, Reena S. Julian, Thomas B. Ganz, Patricia A. Costantino, Joseph P. Vallow, Laura Albain, Kathy S. Whitworth, Pat W. Cianfrocca, Mary E. Brufsky, Adam Gross, Howard M. Soori, Gamini S. Hopkins, Judith O. Fehrenbacher, Louis Sturtz, Keren Wozniak, Timothy F. Seay, Thomas E. Mamounas, Eleftherios P. Wolmark, Norman TI Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NRG Oncol, NSABP, Montreal, PQ, Canada. McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. NRG Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. NRG Oncol, NSABP, Pittsburgh, PA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NRG Oncol, NSABP, Los Angeles, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. NRG Oncol, NSABP, ALLIANCE, NCCRT, Jacksonville, FL USA. Mayo Clin, Jacksonville, FL 32224 USA. NRG Oncol, NSABP, SWOG, Maywood, IL USA. Loyola Univ Chicago, Stritch Sch Med, Maywood, IL USA. NRG Oncol, NSABP, ALLIANCE, ACOSOG, Nashville, TN USA. Nashville Breast Ctr, Nashville, TN USA. SWOG, ECOG, ACRIN, Gilbert, AZ USA. Banner MD Anderson Canc Ctr, Gilbert, AZ USA. NRG Oncol, NSABP, Pittsburgh, PA USA. Magee Womens Hosp, Pittsburgh, PA USA. NRG Oncol, NSABP, Dayton, OH USA. Dayton Phys LLC, Hem & Onc Div, Dayton, OH USA. NRG Oncol, NSABP, Omaha, NE USA. Nebraska Canc Specialists, Omaha, NE USA. NRG Oncol, NSABP, Winston Salem, NC USA. SCOR NCORP, Winston Salem, NC USA. Forsyth Reg Canc Ctr, Winston Salem, NC USA. NRG Oncol, NSABP, Novato, CA USA. Kaiser Permanente No Calif, Novato, CA USA. Colorado Canc Res Program, Denver, CO USA. NRG Oncol, NSABP, Newark, DE USA. Christiana Care Hlth Syst, CCOP, Newark, DE USA. NRG Oncol, NSABP, Atlanta, GA USA. Atlanta Reg Community Clin Oncol Program, Atlanta, GA USA. NRG Oncol, NSABP, Orlando, FL USA. UF Canc Ctr Orlando Hlth, Orlando, FL USA. NRG Oncol, NSABP, Pittsburgh, PA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2015 VL 33 IS 18 SU S MA LBA500 PG 1 WC Oncology SC Oncology GA DO9HQ UT WOS:000378096500009 ER PT J AU Labo, N Miley, W Benson, CA Campbell, TB Whitby, D AF Labo, Nazzarena Miley, Wendell Benson, Constance A. Campbell, Thomas B. Whitby, Denise TI Epidemiology of Kaposi's sarcoma-associated herpesvirus in HIV-1-infected US persons in the era of combination antiretroviral therapy SO AIDS LA English DT Article DE antiretroviral therapy; epidemiology; herpesvirus 8; highly active; HIV-1; human; Kaposi's sarcoma ID HUMAN-IMMUNODEFICIENCY-VIRUS; SWISS HIV COHORT; LOW VIRAL LOAD; HOMOSEXUAL-MEN; UNITED-STATES; RISK-FACTORS; CELL COUNT; HUMAN-HERPESVIRUS-8; ANTIBODIES; PREVALENCE AB Objective:To determine the effect of the introduction of combination antiretroviral treatment (cART) in the HIV-1-infected US population on the epidemiology of Kaposi's sarcoma-associated herpesvirus (KSHV).Design, setting and participants:We investigated the epidemiology of KSHV in 5022 HIV-1-infected, antiretroviral-naive US persons participating in six AIDS Clinical Trials Group (ACTG)-randomized clinical trials, and followed in a long-term cohort study. We tested the first and last available sera of each participant for antibodies to KSHV K8.1 and ORF73.Main outcome measures:We studied prevalence and incidence of KSHV infection, incidence of Kaposi's sarcoma, and overall survival.Results:KSHV prevalence was 38.1% [95% confidence interval (CI) 36.8-39.5%]. Male sex, Caucasian race, age between 30 and 49 years, residence in north-eastern or western United States, and enrolment after 2001 were independently associated with prevalent infection. KSHV incidence was 4.07/100person-years (95% CI 3.70-4.47). Male sex, Caucasian race, age below 30, and enrolment after 2001 were associated with incident infection. CD4(+) cell count increase following cART was associated with lower risk. Kaposi's sarcoma incidence was 104.05/100000person-years (95% CI 71.17-146.89). Higher baseline CD4(+) cell count, but not increase in CD4(+) cell count after cART, was associated with lower hazard of Kaposi's sarcoma. Randomized assignment of protease inhibitors was not associated with better KSHV outcomes.Conclusions:HIV-1-infected individuals, in particular Caucasian men, remain at a significant risk for KSHV co-infection and Kaposi's sarcoma. Thus, optimal management of HIV-1 infection should continue to include vigilance for manifestations of KSHV co-infection, including Kaposi's sarcoma.Video abstract:https://vimeo.com/126172348 C1 [Labo, Nazzarena; Miley, Wendell; Whitby, Denise] Leidos Biomed Inc, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Labo, Nazzarena] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Benson, Constance A.] Univ Calif San Diego, Div Infect Dis, San Diego, CA 92103 USA. [Campbell, Thomas B.] Univ Colorado Denver, Div Infect Dis, Dept Med, Aurora, CO USA. RP Labo, N (reprint author), Leidos Biomed Inc, Viral Oncol Sect, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, POB B, Frederick, MD 21702 USA. EM whitbyd@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program; AIDS Clinical Trials Group (ACTG) - National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI68636, AI69450] FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and the Intramural Research Program, as well as the AIDS Clinical Trials Group (ACTG), funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants AI68636, AI69450). NR 38 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN 19 PY 2015 VL 29 IS 10 BP 1217 EP 1225 DI 10.1097/QAD.0000000000000682 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DB4KM UT WOS:000368481900001 PM 26035321 ER PT J AU Chornokur, G Lin, HY Tyrer, JP Lawrenson, K Dennis, J Amankwah, EK Qu, XT Tsai, YY Jim, HSL Chen, ZH Chen, AY Permuth-Wey, J Aben, KKH Anton-Culver, H Antonenkova, N Bruinsma, F Bandera, EV Bean, YT Beckmann, MW Bisogna, M Bjorge, L Bogdanova, N Brinton, LA Brooks-Wilson, A Bunker, CH Butzow, R Campbell, IG Carty, K Chang-Claude, J Cook, LS Cramer, DW Cunningham, JM Cybulski, C Dansonka-Mieszkowska, A du Bois, A Despierre, E Dicks, E Doherty, JA Dork, T Durst, M Easton, DF Eccles, DM Edwards, RP Ekici, AB Fasching, PA Fridley, BL Gao, YT Gentry-Maharaj, A Giles, GG Glasspool, R Goodman, MT Gronwald, J Harrington, P Harter, P Hein, A Heitz, F Hildebrandt, MAT Hillemanns, P Hogdall, CK Hogdall, E Hosono, S Jakubowska, A Jensen, A Ji, BT Karlan, BY Kelemen, LE Kellar, M Kiemeney, LA Krakstad, C Kjaer, SK Kupryjanczyk, J Lambrechts, D Lambrechts, S Le, ND Lee, AW Lele, S Leminen, A Lester, J Levine, DA Liang, D Lim, BK Lissowska, J Lu, K Lubinski, J Lundvall, L Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR McNeish, I Menon, U Milne, RL Modugno, F Moysich, KB Ness, RB Nevanlinna, H Eilber, U Odunsi, K Olson, SH Orlow, I Orsulic, S Weber, RP Paul, J Pearce, CL Pejovic, T Pelttari, LM Pike, MC Poole, EM Risch, HA Rosen, B Rossing, MA Rothstein, JH Rudolph, A Runnebaum, IB Rzepecka, IK Salvesen, HB Schernhammer, E Schwaab, I Shu, XO Shvetsov, YB Siddiqui, N Sieh, W Song, H Southey, MC Spiewankiewicz, B Sucheston, L Teo, SH Terry, KL Thompson, PJ Thomsen, L Tangen, IL Tworoger, SS van Altena, AM Vierkant, RA Vergote, I Walsh, CS Wang-Gohrke, S Wentzensen, N Whittemore, AS Wicklund, KG Wilkens, LR Wu, AH Wu, XF Woo, YL Yang, HN Zheng, W Ziogas, A Hasmad, HN Berchuck, A Iversen, ES Schildkraut, JM Ramus, SJ Goode, EL Monteiro, ANA Gayther, SA Narod, SA Pharoah, PP Sellers, TA Phelan, CM AF Chornokur, Ganna Lin, Hui-Yi Tyrer, Jonathan P. Lawrenson, Kate Dennis, Joe Amankwah, Ernest K. Qu, Xiaotao Tsai, Ya-Yu Jim, Heather S. L. Chen, Zhihua Chen, Ann Y. Permuth-Wey, Jennifer Aben, Katja K. H. Anton-Culver, Hoda Antonenkova, Natalia Bruinsma, Fiona Bandera, Elisa V. Bean, Yukie T. Beckmann, Matthias W. Bisogna, Maria Bjorge, Line Bogdanova, Natalia Brinton, Louise A. Brooks-Wilson, Angela Bunker, Clareann H. Butzow, Ralf Campbell, Ian G. Carty, Karen Chang-Claude, Jenny Cook, Linda S. Cramer, Daniel W. Cunningham, Julie M. Cybulski, Cezary Dansonka-Mieszkowska, Agnieszka du Bois, Andreas Despierre, Evelyn Dicks, Ed Doherty, Jennifer A. Dork, Thilo Durst, Matthias Easton, Douglas F. Eccles, Diana M. Edwards, Robert P. Ekici, Arif B. Fasching, Peter A. Fridley, Brooke L. Gao, Yu-Tang Gentry-Maharaj, Aleksandra Giles, Graham G. Glasspool, Rosalind Goodman, Marc T. Gronwald, Jacek Harrington, Patricia Harter, Philipp Hein, Alexander Heitz, Florian Hildebrandt, Michelle A. T. Hillemanns, Peter Hogdall, Claus K. Hogdall, Estrid Hosono, Satoyo Jakubowska, Anna Jensen, Allan Ji, Bu-Tian Karlan, Beth Y. Kelemen, Linda E. Kellar, Mellissa Kiemeney, Lambertus A. Krakstad, Camilla Kjaer, Susanne K. Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Alice W. Lele, Shashi Leminen, Arto Lester, Jenny Levine, Douglas A. Liang, Dong Lim, Boon Kiong Lissowska, Jolanta Lu, Karen Lubinski, Jan Lundvall, Lene Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. McNeish, Iain Menon, Usha Milne, Roger L. Modugno, Francesmary Moysich, Kirsten B. Ness, Roberta B. Nevanlinna, Heli Eilber, Ursula Odunsi, Kunle Olson, Sara H. Orlow, Irene Orsulic, Sandra Weber, Rachel Palmieri Paul, James Pearce, Celeste L. Pejovic, Tanja Pelttari, Liisa M. Pike, Malcolm C. Poole, Elizabeth M. Risch, Harvey A. Rosen, Barry Rossing, Mary Anne Rothstein, Joseph H. Rudolph, Anja Runnebaum, Ingo B. Rzepecka, Iwona K. Salvesen, Helga B. Schernhammer, Eva Schwaab, Ira Shu, Xiao-Ou Shvetsov, Yurii B. Siddiqui, Nadeem Sieh, Weiva Song, Honglin Southey, Melissa C. Spiewankiewicz, Beata Sucheston, Lara Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Thomsen, Lotte Tangen, Ingvild L. Tworoger, Shelley S. van Altena, Anne M. Vierkant, Robert A. Vergote, Ignace Walsh, Christine S. Wang-Gohrke, Shan Wentzensen, Nicolas Whittemore, Alice S. Wicklund, Kristine G. Wilkens, Lynne R. Wu, Anna H. Wu, Xifeng Woo, Yin-Ling Yang, Hannah Zheng, Wei Ziogas, Argyrios Hasmad, Hanis N. Berchuck, Andrew Iversen, Edwin S. Schildkraut, Joellen M. Ramus, Susan J. Goode, Ellen L. Monteiro, Alvaro N. A. Gayther, Simon A. Narod, Steven A. Pharoah, Pauld. P. Sellers, Thomas A. Phelan, Catherine M. CA Georgia Chenevix-Trench AOCS Ma TI Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; UDP-GLUCURONOSYLTRANSFERASES; IRON TRANSPORT; FAMILY SLC25; COLON-CANCER; EXPRESSION; POLYMORPHISM; HEPHAESTIN; CARCINOMA AB Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10(-4)). Conclusion These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes. C1 [Chornokur, Ganna; Amankwah, Ernest K.; Tsai, Ya-Yu; Permuth-Wey, Jennifer; Monteiro, Alvaro N. A.; Sellers, Thomas A.; Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Lin, Hui-Yi; Qu, Xiaotao; Chen, Zhihua; Chen, Ann Y.] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Tyrer, Jonathan P.; Dicks, Ed; Song, Honglin; Pharoah, Pauld. P.] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Lawrenson, Kate; Dennis, Joe; Easton, Douglas F.; Lee, Alice W.; Pearce, Celeste L.; Pike, Malcolm C.; Wu, Anna H.; Ramus, Susan J.; Gayther, Simon A.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Amankwah, Ernest K.] All Childrens Hosp Johns Hopkins Med, Clin & Translat Res Org, St Petersburg, FL USA. [Jim, Heather S. L.] H Lee Moffitt Canc Ctr & Res Inst, Dept Hlth Outcomes & Behav, Tampa, FL USA. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Aben, Katja K. H.] Comprehens Canc Ctr Netherlands, Nijmegen, Netherlands. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Genet Epidemiol Res Inst, Ctr Canc Genet Res & Prevent, Irvine, CA USA. [Antonenkova, Natalia] NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus. [Bruinsma, Fiona; Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Australia. [Bandera, Elisa V.; Bean, Yukie T.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Kellar, Mellissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Bean, Yukie T.; Kellar, Mellissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen Nuremberg Comprehens Canc Ctr,Erlangen E, D-91054 Erlangen, Germany. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Gynecol Serv, Dept Surg, New York, NY 10021 USA. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Univ Bergen, Dept Clin Med, Ctr Canc Biomarkers, Bergen, Norway. [Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany. [Brinton, Louise A.; Ji, Bu-Tian; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Bunker, Clareann H.; Modugno, Francesmary] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Campbell, Ian G.] Peter MacCallum Canc Ctr, Canc Genet Lab, Div Res, St Andrews, Australia. [Campbell, Ian G.; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Campbell, Ian G.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Carty, Karen; Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Carty, Karen; Glasspool, Rosalind; Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja; Wang-Gohrke, Shan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Dept Internal Med, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Tworoger, Shelley S.] Brigham & Womens Hosp, Obstet & Gynecol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Inst Oncol, Warsaw, Poland. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Knappschaft GmbH, Dept Gynaecol & Gynaecol Oncol, Kliniken Essen Mitte Evang Huyssens Stiftung, Essen, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynaecol & Gynaecol Oncol, Wiesbaden, Germany. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Div Gynecol Oncol, Dept Obstet & Gynaecol, Leuven, Belgium. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Harrington, Patricia] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Ctr Canc Epidemiol, Cambridge, England. [Doherty, Jennifer A.] Geisel Sch Med, Dept Epidemiol, Hanover, NH USA. [Doherty, Jennifer A.; Rossing, Mary Anne; Wicklund, Kristine G.] Univ Washington, Program Epidemiol, Div Publ Hlth Sci, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Dork, Thilo; Hillemanns, Peter] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Durst, Matthias; Runnebaum, Ingo B.] Univ Jena, Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Eccles, Diana M.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Edwards, Robert P.] Magee Womens Res Inst, Ovarian Canc Ctr Excellence, Womens Canc Res Program, Pittsburgh, PA USA. [Edwards, Robert P.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Comprehens Canc Ctr Erlangen Nuremberg, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Biostat & Informat Shared Resource, Kansas City, KS 66103 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Womens Canc, London, England. [Giles, Graham G.] Univ Melbourne, Ctr Epidemiol & Biostat, Sch Populat & Global Hlth, Melbourne, Australia. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Canc Prevent & Control Samuel Oschin Comprehens C, Los Angeles, CA 90048 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Community & Populat Hlth Res Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hogdall, Estrid] Univ Copenhagen, Mol Unit, Dept Pathol, Herlev Hosp, Copenhagen, Denmark. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hosono, Satoyo; Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med Sci, Nagoya, Aichi, Japan. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine S.] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Kelemen, Linda E.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Kjaer, Susanne K.] Univ Copenhagen, Dept Gynaecol, Rigshosp, Copenhagen, Denmark. [Hogdall, Claus K.; Lundvall, Lene] Univ Copenhagen, Dept Gynaecol, Juliane Marie Ctr, Righosp, Copenhagen, Denmark. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Louvain, Belgium. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Lele, Shashi; Moysich, Kirsten B.; Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lim, Boon Kiong; Woo, Yin-Ling] Univ Malaya, Dept Obstet & Gynaecol, Med Ctr, Kuala Lumpur, Malaysia. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, Nijmegen, Netherlands. [McGuire, Valerie] Stanford Univ, Dept Hlth Res & Policy Epidemiol, Sch Med, Stanford, CA 94305 USA. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [McNeish, Iain] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Glasgow, Lanark, Scotland. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Sch Med, Pittsburgh, PA USA. [Thomsen, Lotte] Univ Copenhagen, Dept Pathol, Rigshosp, Copenhagen, Denmark. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Weber, Rachel Palmieri] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Pearce, Celeste L.] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Poole, Elizabeth M.; Schernhammer, Eva] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Schernhammer, Eva; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rosen, Barry] Univ Toronto, Fac Med, Dept Gynecol Oncol, Princess Margaret Hosp, Toronto, ON, Canada. [Rosen, Barry] Univ Toronto, Fac Med, Dept Obstet & Gynecol, Toronto, ON, Canada. [Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Dept Hlth Res & Policy Epidemiol, Sch Med, Stanford, CA 94305 USA. [Schwaab, Ira] Inst Human Genet & Anthropol, Wiesbaden, Germany. [Shu, Xiao-Ou] Vanderbilt Univ, Epidemiol Ctr & Vanderbilt, Ingram Canc Ctr, Sch Med, Nashville, TN 37235 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Canc Epidemiol Program, Ctr Canc, Honolulu, HI 96822 USA. [Spiewankiewicz, Beata] Maria Sklodowska Curie Mem Canc Ctr, Dept Gynecol Oncol, Warsaw, Poland. [Spiewankiewicz, Beata] Inst Oncol, Warsaw, Poland. [Teo, Soo-Hwang; Hasmad, Hanis N.] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Med Ctr, Canc Res Inst, Kuala Lumpur, Malaysia. [Vierkant, Robert A.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Zheng, Wei] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Sch Med, Nashville, TN 37235 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. QIMR, Berghofer Med Res Inst, Brisbane, Qld, Australia. [Georgia Chenevix-Trench AOCS Ma] Peter MacCallum Canc Ctr, East Melbourne, Australia. [Iversen, Edwin S.] Duke Univ, Dept Stat, Durham, NC USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Pharoah, Pauld. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. RP Phelan, CM (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Dept Canc Epidemiol, Tampa, FL 33612 USA. EM catherine.phelan@moffitt.org RI Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; Dork, Thilo/J-8620-2012; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Gronwald, Jacek/A-4576-2017; Teo, Soo-hwang/H-2353-2014; Bandera, Elisa/M-4169-2014; Hein, Alexander/F-6999-2010; Woo, Yin Ling/B-5198-2010; Massuger, Leon/H-8072-2014; Kiemeney, Lambertus/D-3357-2009; Brooks-Wilson, Angela/E-9399-2012; van Altena, Anne/B-9824-2016 OI Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Glasspool, Rosalind/0000-0002-5000-1680; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; McNeish, Iain/0000-0002-9387-7586; Orlow, Irene/0000-0001-6234-6961; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871; Bandera, Elisa/0000-0002-8789-2755; Hein, Alexander/0000-0003-2601-3398; Woo, Yin Ling/0000-0003-1742-1066; Kiemeney, Lambertus/0000-0002-2368-1326; Brooks-Wilson, Angela/0000-0003-1009-6408; FU NIH [R01 CA-1491429]; European Commission [223175 HEALTH F2 2009-223175]; Genetic Associations and Mechanisms in Oncology (GAME-ON); NCI Cancer Post-GWAS Initiative [U19-CA148112]; Ovarian Cancer Research Fund [PPD/RPCI.07]; National Health and Medical Research Council; Canadian Institute of Health Research New Investigator Award [MSH-87734]; NIEHS T32 training grant [T32ES013678]; California Cancer Research Program [00-01389V- 20170, N01-CN25403, 2II0200]; Canadian Institutes of Health Research [MOP-86727]; Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124]; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Helse Vest; Norwegian Cancer Society; Norwegian Research Council; Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Ministry of Health Labour and Welfare of Japan; L & S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute [K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598]; US Public Health Service [PSA-042205]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01GB 9401]; State of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme"; Royal Marsden Hospital; Mermaid I project; WorkSafeBC 14; [R01-CA080978]; [R01-CA083918]; [R01-CA087538]; [R01-CA092044]; [R01-095023]; [R01-CA122443]; [R01-CA112523]; [R01-CA114343]; [R01-CA126841]; [R01-CA136924]; [R03-CA113148]; [R03-CA115195]; [U01-CA069417]; [U01-CA071966]; [R01-CA076016]; [R01-CA061132]; [R01-CA067262]; [R01-CA071766]; [R01-CA074850]; [R01-CA080742]; [R01-CA058860]; [R01-CA061107] FX The scientific development and funding for this project were funded by the following: NIH R01 CA-1491429 (Phelan PI); the US National Cancer Institute (R01-CA076016); the COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 HEALTH F2 2009-223175); the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112); the Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Investigator-specific funding: GCT is supported by the National Health and Medical Research Council; BK holds an ACS Early Detection Professorship (SIOP-06-258-01-COUN); LEK is supported by a Canadian Institute of Health Research New Investigator Award (MSH-87734). AWL is supported by NIEHS T32 training grant (T32ES013678). Funding of included studies: Funding of the constituent studies was provided by the California Cancer Research Program (00-01389V- 20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy For Cancer Control from the Ministry of Health Labour and Welfare of Japan; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the US Public Health Service (PSA-042205); The National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V.; Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme" and the Royal Marsden Hospital; WorkSafeBC 14. NR 65 TC 3 Z9 3 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2015 VL 10 IS 6 AR e0128106 DI 10.1371/journal.pone.0128106 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3FE UT WOS:000356835000013 PM 26091520 ER PT J AU Paoloni, M Mazcko, C Selting, K Lana, S Barber, L Phillips, J Skorupski, K Vail, D Wilson, H Biller, B Avery, A Kiupel, M LeBlanc, A Bernhardt, A Brunkhorst, B Tighe, R Khanna, C AF Paoloni, Melissa Mazcko, Christina Selting, Kimberly Lana, Susan Barber, Lisa Phillips, Jeffrey Skorupski, Katherine Vail, David Wilson, Heather Biller, Barbara Avery, Anne Kiupel, Matti LeBlanc, Amy Bernhardt, Anna Brunkhorst, Beatrice Tighe, Robert Khanna, Chand TI Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma SO PLOS ONE LA English DT Article ID METASTATIC MELANOMA; MURAMYL TRIPEPTIDE; CLINICAL-TRIALS; TNF-ALPHA; CANCER; INTERLEUKIN-2; VACCINE; IMMUNOTHERAPY; OSTEOSARCOMA; CISPLATIN AB Background Interleukin (IL)-12 is a pro-inflammatory cytokine that mediates T-helper type 1 responses and cytotoxic T-cell activation, contributing to its utility as anti-cancer agent. Systemic administration of IL-12 often results in unacceptable toxicity; therefore, strategies to direct delivery of IL-12 to tumors are under investigation. The objective of this study was to assist the preclinical development of NHS-IL12, an immunocytokine consisting of an antibody, which targets necrotic tumor regions, linked to IL-12. Specifically this study sought to evaluate the safety, serum pharmacokinetics, anti-tumor activity, and immune modulation of NHS-IL12 in dogs with naturally occurring cancers. Methodology/Principal Findings A rapid dose-escalation study of NHS-IL12 administered subcutaneously to dogs with melanoma was conducted through the Comparative Oncology Trials Consortium (COTC). Eleven dogs were enrolled in four dose-escalation cohorts; thereafter, an additional seven dogs were treated at the defined tolerable dose of 0.8 mg/m(2). The expanded cohort at this fixed dose (ten dogs in total) was accrued for further pharmacokinetics and pharmacodynamics assessment. NHS-IL12 levels, serum cytokine concentrations, and peripheral blood mononuclear cell characterization (post-treatment) and draining lymph node immune profiling, and tumor biopsies (pre- and post-treatment) were collected. Adverse events included thrombocytopenia, liver enzymopathies, fever, and vasculitis. Correlation between interferon (IFN)-gamma induction, adverse events, and NHS-IL12 exposure (maximum concentration and area under the concentration-time curve) were dose-dependent. Serum IL-10 levels and intratumoral CD8(+) populations increased after treatment. Partial responses, according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, were observed in two dogs treated with NHS-IL12 0.8 mg/m(2) and 1.6 mg/m(2). Conclusions/Significance NHS-IL12 was administered safely to dogs with melanoma and both immunologic and clinical activity was observed. This study successfully defined a narrow therapeutic window for systemic delivery of NHS-IL12 via the subcutaneous route. Results will inform the design and implementation of first-in-human clinical trials of NHS-IL12 in cancer patients. C1 [Paoloni, Melissa; Mazcko, Christina; LeBlanc, Amy; Khanna, Chand] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Selting, Kimberly] Univ Missouri, Coll Vet Med, Columbia, MO USA. [Lana, Susan; Biller, Barbara; Avery, Anne] Colorado State Univ, Coll Vet Med & Biol Sci, Ft Collins, CO 80523 USA. [Barber, Lisa] Tufts Univ, Sch Vet Med, North Grafton, MA 01536 USA. [Phillips, Jeffrey] Univ Tennessee, Coll Vet Med, Knoxville, TN USA. [Skorupski, Katherine] Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA. [Vail, David] Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. [Wilson, Heather] Texas A&M Univ, Coll Vet Med, College Stn, TX 77843 USA. [Kiupel, Matti] Michigan State Univ, Coll Vet Med, E Lansing, MI 48824 USA. [Bernhardt, Anna; Brunkhorst, Beatrice; Tighe, Robert] EMD Serono Res & Dev Inst, Billerica, MA USA. RP Khanna, C (reprint author), NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); Merck KGaA, Darmstadt, Germany; National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and by Merck KGaA, Darmstadt, Germany. NHS-IL12 was provided by EMD Serono, Billerica, MA. Editorial assistance was provided by Marianne Jenal-Eyholzer, PhD CMPP, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany. AB, BB, and RT are employees of EMD Serono, Billerica, MA, USA (a subsidiary of Merck KGaA, Darmstadt, Germany). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 3 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2015 VL 10 IS 6 AR e0129954 DI 10.1371/journal.pone.0129954 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3FE UT WOS:000356835000076 PM 26091536 ER PT J AU Yang, XP Jiang, K Hirahara, K Vahedi, G Afzali, B Sciume, G Bonelli, M Sun, HW Jankovic, D Kanno, Y Sartorelli, V O'Shea, JJ Laurence, A AF Yang, Xiang-Ping Jiang, Kan Hirahara, Kiyoshi Vahedi, Golnaz Afzali, Behdad Sciume, Giuseppe Bonelli, Michael Sun, Hong-Wei Jankovic, Dragana Kanno, Yuka Sartorelli, Vittorio O'Shea, John J. Laurence, Arian TI EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion SO SCIENTIFIC REPORTS LA English DT Article ID PLASTICITY; PROTEIN; HOMEOSTASIS; CYTOKINE; LINEAGE; GENES; MAINTENANCE; METHYLATION; COMMITMENT; SENESCENCE AB The roles of EZH2 in various subsets of CD4(+) T cells are controversial and its mechanisms of action are incompletely understood. FOXP3-positive Treg cells are a critical helper T cell subset, and dysregulation of Treg generation or function results in systemic autoimmunity. FOXP3 associates with EZH2 to mediate gene repression and suppressive function. Herein, we demonstrate that deletion of Ezh2 in CD4(+) T cells resulted in reduced numbers of Treg cells in vivo and differentiation in vitro and an increased proportion of memory CD4(+) T cells in part due to exaggerated production of effector cytokines. Furthermore, we found that both Ezh2-deficient Treg cells and T effector cells were functionally impaired in vivo: Tregs failed to constrain autoimmune colitis and T effector cells neither provided a protective response to T. gondii infection nor mediated autoimmune colitis. The dichotomous function of EZH2 in regulating differentiation and senescence in effector and regulatory T cells helps to explain the apparent existing contradictions in literature. C1 [Yang, Xiang-Ping] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Basic Med, Dept Immunol, Wuhan 430030, Peoples R China. [Yang, Xiang-Ping; Jiang, Kan; Hirahara, Kiyoshi; Vahedi, Golnaz; Afzali, Behdad; Sciume, Giuseppe; Bonelli, Michael; Kanno, Yuka; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Afzali, Behdad] Kings Coll London, MRC Ctr Transplantat, London, England. [Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Laurence, Arian] Freeman Rd Hosp, Northern Ctr Canc Care, Newcastle Upon Tyne, Tyne & Wear, England. [Laurence, Arian] John Radcliffe Hosp, NDM Expt Med, Oxford OX3 9DU, England. RP Yang, XP (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Basic Med, Dept Immunol, Wuhan 430030, Peoples R China. EM yangxp@hust.edu.cn; arian.laurence@ndm.ox.ac.uk RI Afzali, Behdad/H-8565-2013; Laurence, Arian/A-8770-2009; Sciume, Giuseppe/K-8985-2016; Hirahara, Kiyoshi/E-2460-2017 OI Kanno, Yuka/0000-0001-5668-9319; Afzali, Behdad/0000-0003-2968-1156; Laurence, Arian/0000-0003-0942-8292; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449 FU welcome trust; NIAMS FX We thank J. Simone and J. Lay (Flow Cytometry Section, NIAMS) and the NIAMS LACU staff for their excellent technical support. B.A is supported by a welcome trust fellowship. The Intramural Research programs of NIAMS have supported this work. NR 33 TC 9 Z9 9 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 19 PY 2015 VL 5 AR 10643 DI 10.1038/srep10643 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9AY UT WOS:000356533500001 PM 26090605 ER PT J AU Scruggs, BS Gilchrist, DA Nechaev, S Muse, GW Burkholder, A Fargo, DC Adelman, K AF Scruggs, Benjamin S. Gilchrist, Daniel A. Nechaev, Sergei Muse, Ginger W. Burkholder, Adam Fargo, David C. Adelman, Karen TI Bidirectional Transcription Arises from Two Distinct Hubs of Transcription Factor Binding and Active Chromatin SO MOLECULAR CELL LA English DT Article ID GENE-EXPRESSION; HUMAN PROMOTERS; DIVERGENT TRANSCRIPTION; INFLAMMATORY RESPONSE; MAMMALIAN PROMOTERS; RNA EXOSOME; U1 SNRNP; KAPPA-B; ENHANCERS; MACROPHAGE AB Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNA genes. We find that coupled sense and anti-sense TSSs precisely define the boundaries of a nucleo-some-depleted region (NDR) that is highly enriched in transcription factor (TF) motifs. Notably, as the distance between sense and anti-sense TSSs increases, so does the size of the NDR, the level of signal-dependent TF binding, and gene activation. We further discover a group of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Interestingly, this signature identifies divergent promoters that are activated during immune challenge. We propose that anti-sense promoters serve as platforms for TF binding and establishment of active chromatin to further regulate or enhance sense-strand mRNA expression. C1 [Scruggs, Benjamin S.; Gilchrist, Daniel A.; Nechaev, Sergei; Muse, Ginger W.; Adelman, Karen] NIEHS, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC 27709 USA. [Burkholder, Adam; Fargo, David C.] NIEHS, Ctr Integrat Bioinformat, Res Triangle Pk, NC 27709 USA. RP Adelman, K (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov OI Scruggs, Benjamin/0000-0002-0990-9478; Gilchrist, Daniel/0000-0003-1668-2790 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101987] FX We thank Paul Wade, Torben Jensen, and Chris Burge for helpful comments on this project and manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to K.A. (Z01 ES101987). NR 40 TC 31 Z9 33 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 18 PY 2015 VL 58 IS 6 BP 1101 EP 1112 DI 10.1016/j.molcel.2015.04.006 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CR0CV UT WOS:000360986700021 PM 26028540 ER PT J AU Arimbasseri, AG Maraia, RJ AF Arimbasseri, Aneeshkumar G. Maraia, Richard J. TI Mechanism of Transcription Termination by RNA Polymerase III Utilizes a Non-template Strand Sequence-Specific Signal Element SO MOLECULAR CELL LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CLEAVAGE ACTIVITY; DNA HYBRID; MUTATIONS; COMPLEXES; ELONGATION; SUBUNIT; YEAST; PROCESSIVITY; SUBCOMPLEX AB Understanding the mechanism of transcription termination by a eukaryotic RNA polymerase (RNAP) has been limited by lack of a characterizable intermediate that reflects transition from an elongation complex to a true termination event. While other multisubunit RNAPs require multipartite cis-signals and/or ancillary factors to mediate pausing and release of the nascent transcript from the clutches of these enzymes, RNAP III does so with precision and efficiency on a simple oligo(dT) tract, independent of other cis-elements or trans-factors. We report an RNAP III pre-termination complex that reveals termination mechanisms controlled by sequence-specific elements in the non-template strand. Furthermore, the TFIIF-like RNAP III subunit C37 is required for this function of the non-template strand signal. The results reveal the RNAP III terminator as an information-rich control element. While the template strand promotes destabilization via a weak oligo(rU:dA) hybrid, the non-template strand provides distinct sequence-specific destabilizing information through interactions with the C37 subunit. C1 [Arimbasseri, Aneeshkumar G.; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov OI Arimbasseri, Gopalakrishnan Aneeshkumar/0000-0001-5266-2688 FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HD000412-24 PGD] FX We thank J. Iben (NICHD) for terminator LOGOs; M. Kashlev, M. Kireeva (NCI), D. Luse (Cleveland Clinic, Cleveland), and members of The Friday Seminar for discussion; and I. Artsimovitch (Ohio State University, Columbus) for comments. This work was supported by the Intramural Research Program (HD000412-24 PGD) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 40 TC 13 Z9 13 U1 3 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 18 PY 2015 VL 58 IS 6 BP 1124 EP 1132 DI 10.1016/j.molcel.2015.04.002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CR0CV UT WOS:000360986700023 PM 25959395 ER PT J AU Handelman, SK Seweryn, M Smith, RM Hartmann, K Wang, DX Pietrzak, M Johnson, AD Kloczkowski, A Sadee, W AF Handelman, Samuel K. Seweryn, Michal Smith, Ryan M. Hartmann, Katherine Wang, Danxin Pietrzak, Maciej Johnson, Andrew D. Kloczkowski, Andrzej Sadee, Wolfgang TI Conditional entropy in variation-adjusted windows detects selection signatures associated with expression quantitative trait loci (eQTLs) SO BMC GENOMICS LA English DT Article ID TRANSCRIPTIONAL REGULATION; GENETIC-VARIATION; SEQUENCING DATA; DRUG TARGETS; LIFE-STYLE; GENOME; POPULATION; MODELS; VARIANTS; DATABASE AB Background: Over the past 50,000 years, shifts in human-environmental or human-human interactions shaped genetic differences within and among human populations, including variants under positive selection. Shaped by environmental factors, such variants influence the genetics of modern health, disease, and treatment outcome. Because evolutionary processes tend to act on gene regulation, we test whether regulatory variants are under positive selection. We introduce a new approach to enhance detection of genetic markers undergoing positive selection, using conditional entropy to capture recent local selection signals. Results We use conditional logistic regression to compare our Adjusted Haplotype Conditional Entropy (H vertical bar H) measure of positive selection to existing positive selection measures. H vertical bar H and existing measures were applied to published regulatory variants acting in cis (cis-eQTLs), with conditional logistic regression testing whether regulatory variants undergo stronger positive selection than the surrounding gene. These cis-eQTLs were drawn from six independent studies of genotype and RNA expression. The conditional logistic regression shows that, overall, H vertical bar H is substantially more powerful than existing positive-selection methods in identifying cis-eQTLs against other Single Nucleotide Polymorphisms (SNPs) in the same genes. When broken down by Gene Ontology, H vertical bar H predictions are particularly strong in some biological process categories, where regulatory variants are under strong positive selection compared to the bulk of the gene, distinct from those GO categories under overall positive selection.. However, cis-eQTLs in a second group of genes lack positive selection signatures detectable by H vertical bar H, consistent with ancient short haplotypes compared to the surrounding gene (for example, in innate immunity GO: 0042742); under such other modes of selection, H vertical bar H would not be expected to be a strong predictor.. These conditional logistic regression models are adjusted for Minor allele frequency(MAF); otherwise, ascertainment bias is a huge factor in all eQTL data sets. Relationships between Gene Ontology categories, positive selection and eQTL specificity were replicated with H vertical bar H in a single larger data set. Our measure, Adjusted Haplotype Conditional Entropy (H vertical bar H), was essential in generating all of the results above because it: 1) is a stronger overall predictor for eQTLs than comparable existing approaches, and 2) shows low sequential auto-correlation, overcoming problems with convergence of these conditional regression statistical models. Conclusions: Our new method, H vertical bar H, provides a consistently more robust signal associated with cis-eQTLs compared to existing methods. We interpret this to indicate that some cis-eQTLs are under positive selection compared to their surrounding genes. Conditional entropy indicative of a selective sweep is an especially strong predictor of eQTLs for genes in several biological processes of medical interest. Where conditional entropy is a weak or negative predictor of eQTLs, such as innate immune genes, this would be consistent with balancing selection acting on such eQTLs over long time periods. Different measures of selection may be needed for variant prioritization under other modes of evolutionary selection. C1 [Handelman, Samuel K.; Smith, Ryan M.; Hartmann, Katherine; Wang, Danxin; Pietrzak, Maciej; Sadee, Wolfgang] Ohio State Univ, Coll Med, Ctr Pharmacogen, Columbus, OH 43210 USA. [Seweryn, Michal] Math Biosci Inst, Columbus, OH 43210 USA. [Seweryn, Michal] Univ Lodz, Fac Math & Comp Sci, PL-90131 Lodz, Poland. [Seweryn, Michal; Pietrzak, Maciej] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. [Johnson, Andrew D.] NHLBI, Div Intramural Res, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA USA. [Kloczkowski, Andrzej] Nationwide Childrens Hosp, Battelle Ctr Math Med, Columbus, OH 43205 USA. [Kloczkowski, Andrzej] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43205 USA. [Kloczkowski, Andrzej] Chinese Acad Sci, Kavli Inst Theoret Phys China, Beijing 100190, Peoples R China. RP Handelman, SK (reprint author), Ohio State Univ, Coll Med, Ctr Pharmacogen, Graves Hall,330 W 10th Ave, Columbus, OH 43210 USA. EM handelman.9@osu.edu RI Johnson, Andrew/G-6520-2013 FU NIGMS grant [U01 092655]; NSF [0931642] FX The authors acknowledge that this material is based upon work supported by or in part by NIGMS grant U01 092655 to the XGEN consortium, and by NSF agreement no. 0931642 to the Mathematical Biosciences Institute. Publication of this work was supported in part by an allocation of computing time from the Ohio Supercomputer Center. None of these funding agencies had any part in the research presented here, or in the preparation thereof. NR 52 TC 1 Z9 1 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 18 PY 2015 VL 16 SU 8 AR S8 DI 10.1186/1471-2164-16-S8-S8 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CN1GA UT WOS:000358165000009 PM 26111110 ER PT J AU Gao, M Paul, S Schwieters, CD You, ZQ Shao, H Herbert, JM Parquette, JR Jaroniec, CP AF Gao, Min Paul, Subhradip Schwieters, Charles D. You, Zhi-Qiang Shao, Hui Herbert, John M. Parquette, Jon R. Jaroniec, Christopher P. TI A Structural Model for a Self-Assembled Nanotube Provides Insight into Its Exciton Dynamics SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID SOLID-STATE NMR; EXCITATION-ENERGY TRANSFER; LIGHT-HARVESTING COMPLEX; AMYLOID FIBRILS; RHODOPSEUDOMONAS-ACIDOPHILA; LH2 BACTERIOCHLOROPHYLL; CONJUGATED POLYMERS; MOLECULAR-STRUCTURE; PROTEIN; SPECTROSCOPY AB The design and synthesis of functional self-assembled nanostructures is frequently an empirical process fraught with critical knowledge gaps about atomic-level structure in these noncovalent systems. Here, we report a structural model for a semiconductor nanotube formed via the self-assembly of naphthalenediimide-lysine (NDI-Lys) building blocks determined using experimental C-13-C-13 and C-13-N-15 distance restraints from solid-state nuclear magnetic resonance supplemented by electron microscopy and X-ray powder diffraction data. The structural model reveals a two-dimensional-crystal-like architecture of stacked monolayer rings each containing similar to 50 NDI-Lys molecules, with significant pi-stacking interactions occurring both within the confines of the ring and along the long axis of the tube. Excited-state delocalization and energy transfer are simulated for the nanotube based on time-dependent density functional theory and an incoherent hopping model. Remarkably, these calculations reveal efficient energy migration from the excitonic bright state, which is in agreement with the rapid energy transfer within NDI-Lys nanotubes observed previously using fluorescence spectroscopy. C1 [Gao, Min; Paul, Subhradip; You, Zhi-Qiang; Shao, Hui; Herbert, John M.; Parquette, Jon R.; Jaroniec, Christopher P.] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Herbert, JM (reprint author), Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. EM herbert@chemistry.ohio-state.edu; parquett@chemistry.ohio-state.edu; jaroniec@chemistry.ohio-state.edu RI Herbert, John/A-9573-2008; Gao, Min/H-9266-2015; Jaroniec, Christopher/A-4948-2008; OI Herbert, John/0000-0002-1663-2278; Jaroniec, Christopher/0000-0003-0364-2888 FU National Science Foundation [MCB-1243461, CHE-0748448, CHE-1412295]; National Institutes of Health [R01GM094357]; Camille and Henry Dreyfus Foundation (Camille Dreyfus Teacher-Scholar Award); Alfred P. Sloan Foundation; NIH Intramural Research Program of the Center for Information Technology FX This research was supported by grants from the National Science Foundation (MCB-1243461 to C.P.J., CHE-0748448 to J.M.H., and CHE-1412295 to J.R.P.), the National Institutes of Health (R01GM094357 to C.P.J.), the Camille and Henry Dreyfus Foundation (Camille Dreyfus Teacher-Scholar Award to C.P.J. and J.M.H), and the Alfred P. Sloan Foundation (Research Fellowship to J.M.H.). C.D.S. was supported by the NIH Intramural Research Program of the Center for Information Technology. NR 57 TC 5 Z9 5 U1 2 U2 33 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD JUN 18 PY 2015 VL 119 IS 24 BP 13948 EP 13956 DI 10.1021/acs.jpcc.5b03398 PG 9 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA CL2DX UT WOS:000356754900067 PM 26120375 ER PT J AU Szalay, CI Erdelyi, K Kokeny, G Lajtar, E Godo, M Revesz, C Kaucsar, T Kiss, N Sarkozy, M Csont, T Krenacs, T Szenasi, G Pacher, P Hamar, P AF Szalay, Csaba Imre Erdelyi, Katalin Koekeny, Gabor Lajtar, Eniko Godo, Maria Revesz, Csaba Kaucsar, Tamas Kiss, Norbert Sarkoezy, Marta Csont, Tamas Krenacs, Tibor Szenasi, Gabor Pacher, Pal Hamar, Peter TI Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain SO PLOS ONE LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GELATINASE-ASSOCIATED LIPOCALIN; ADRIAMYCIN-INDUCED GLOMERULOSCLEROSIS; CHRONIC KIDNEY-DISEASE; INDUCED NEPHROPATHY; OXIDATIVE STRESS; PODOCYTE INJURY; GENE-EXPRESSION; MODEL; SUSCEPTIBILITY AB Chronic renal fibrosis is the final common pathway of end stage renal disease caused by glomerular or tubular pathologies. Genetic background has a strong influence on the progression of chronic renal fibrosis. We recently found that Rowett black hooded rats were resistant to renal fibrosis. We aimed to investigate the role of sustained inflammation and oxidative/nitrative stress in renal fibrosis progression using this new model. Our previous data suggested the involvement of podocytes, thus we investigated renal fibrosis initiated by doxorubicin-induced (5 mg/kg) podocyte damage. Doxorubicin induced progressive glomerular sclerosis followed by increasing proteinuria and reduced bodyweight gain in fibrosis-sensitive, Charles Dawley rats during an 8-week long observation period. In comparison, the fibrosis-resistant, Rowett black hooded rats had longer survival, milder proteinuria and reduced tubular damage as assessed by neutrophil gelatinase-associated lipocalin (NGAL) excretion, reduced loss of the slit diaphragm protein, nephrin, less glomerulosclerosis, tubulointerstitial fibrosis and matrix deposition assessed by periodic acid-Schiff, Picro-Sirius-red staining and fibronectin immunostaining. Less fibrosis was associated with reduced profibrotic transforming growth factor-beta, (TGF-beta 1) connective tissue growth factor (CTGF), and collagen type I alpha 1 (COL-1a1) mRNA levels. Milder inflammation demonstrated by histology was confirmed by less monocyte chemotactic protein 1 (MCP-1) mRNA. As a consequence of less inflammation, less oxidative and nitrative stress was obvious by less neutrophil cytosolic factor 1 (p47(phox)) and NADPH oxidase-2 (p91(phox)) mRNA. Reduced oxidative enzyme expression was accompanied by less lipid peroxidation as demonstrated by 4-hydroxynonenal (HNE) and less protein nitrosylation demonstrated by nitrotyrosine (NT) immunohistochemistry and quantified by Western blot. Our results demonstrate that mediators of fibrosis, inflammation and oxidative/nitrative stress were suppressed in doxorubicin nephropathy in fibrosis-resistant Rowett black hooded rats underlying the importance of these pathomechanisms in the progression of renal fibrosis initiated by glomerular podocyte damage. C1 [Szalay, Csaba Imre; Koekeny, Gabor; Lajtar, Eniko; Godo, Maria; Revesz, Csaba; Kaucsar, Tamas; Kiss, Norbert; Szenasi, Gabor; Hamar, Peter] Semmelweis Univ, Inst Pathophysiol, H-1085 Budapest, Hungary. [Erdelyi, Katalin; Pacher, Pal] NIAAA, NIH, DICBR, Lab Physiol Studies,Sect Oxidat Stress & Tissue I, Bethesda, MD USA. [Sarkoezy, Marta; Csont, Tamas] Univ Szeged, Fac Med, Dept Biochem, Szeged, Hungary. [Krenacs, Tibor] 1st Semmelweis Univ, Dept Pathol & Expt Canc Rese, MTA SE Tumor Progress Res Grp, Budapest, Hungary. RP Hamar, P (reprint author), Semmelweis Univ, Inst Pathophysiol, H-1085 Budapest, Hungary. EM hamar.peter@med.semmelweis-univ.hu RI Pacher, Pal/B-6378-2008; Kaucsar, Tamas/H-4904-2016 OI Pacher, Pal/0000-0001-7036-8108; Kaucsar, Tamas/0000-0003-4460-1265 FU Hungarian Research Fund [OTKA-ANN(FWF) 110810, OTKA-SNN 114619]; Intramural Research Program of NIAAA/NIH; Bolyai Research Scholarship of the Hungarian Academy of Sciences FX Support was provided to P. Hamar from the Hungarian Research Fund: OTKA-ANN(FWF) 110810 and OTKA-SNN 114619, and to P. Pacher from the Intramural Research Program of NIAAA/NIH. P Hamar acknowledges support from the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the Merit Prize of the Semmelweis University. NR 61 TC 3 Z9 4 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2015 VL 10 IS 6 AR e0127090 DI 10.1371/journal.pone.0127090 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9NT UT WOS:000356567500007 PM 26086199 ER PT J AU Zhao, CP Carrillo, JA Tian, F Zan, LS Updike, SM Zhao, K Zhan, F Song, JZ AF Zhao, Chunping Carrillo, Jose A. Tian, Fei Zan, Linsen Updike, Scott M. Zhao, Keji Zhan, Fei Song, Jiuzhou TI Genome-Wide H3K4me3 Analysis in Angus Cattle with Divergent Tenderness SO PLOS ONE LA English DT Article ID SKELETAL-MUSCLE; MEAT QUALITY; HISTONE DEACETYLASES; REGULATORY FACTORS; GENE-EXPRESSION; BEEF TENDERNESS; METHYLATION; METHYLTRANSFERASE; DIFFERENTIATION; POSTMORTEM AB Tenderness is one of the most important properties of meat quality, which is influenced by genetic and environmental factors. As an intensively studied epigenetic marker, histone methylation, occurring on arginine and lysine residues, has pivotal regulatory functions on gene expression. To examine whether histone methylation involves in beef tenderness variation, we analyzed the transcriptome and H3K4me3 enrichment profiles of muscle strips obtained from the longissimus dorsi (LD) of Angus steers previously classify to the tender or tough group. We first plotted a global bovine H3K4me3 map on chromosomes and called peak-enriched regions and genes. We found that majorities of H3K4me3 on genes were occupying the first intron and intergenic regions and its maps displayed similar patterns in tender and tough groups, with high H3K4me3 enrichment surrounding the transcription start site (TSS). We also explored the relationship of H3K4me3 and gene expression. The results showed that H3K4me3 enrichment is highly positively correlated with gene expression across the whole genome. Cluster analysis results confirmed the relationship of H3K4me3 enrichment and gene expression. By using a pathway-based approach in genes with H3K4me3 enrichment in promoter regions from the tender cluster, we revealed that those genes involved in the development of different tissues-connective tissue, skeletal and muscular system and functional tissues-; while in tough group those genes engaged in cell death, lipid metabolism and small molecule biochemistry. The results from this study provide a deep insight into understanding of the mechanisms of epigenetic regulations in meat quality and beef tenderness. C1 [Zhao, Chunping; Zan, Linsen] Northwest A&F Univ, Coll Anim Sci & Technol, Yangling, Shaanxi, Peoples R China. [Zhao, Chunping; Carrillo, Jose A.; Tian, Fei; Updike, Scott M.; Zhan, Fei; Song, Jiuzhou] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Song, JZ (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM songj88@umd.edu FU Maryland Agricultural Experiment Station (MAES); Jorgensen Endowment Funds FX The work was supported by Maryland Agricultural Experiment Station (MAES) and Jorgensen Endowment Funds. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 0 Z9 0 U1 3 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2015 VL 10 IS 6 AR e0115358 DI 10.1371/journal.pone.0115358 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9NT UT WOS:000356567500001 PM 26086782 ER PT J AU Yong, ST Nguyen, HN Choi, JH Bortner, CD Williams, J Pulloor, NK Krishnan, MN Shears, SB AF Yong, Sheila T. Nguyen, Hoai-Nghia Choi, Jae H. Bortner, Carl D. Williams, Jason Pulloor, Niyas K. Krishnan, Manoj N. Shears, Stephen B. TI Identification of a functional nuclear translocation sequence in hPPIP5K2 SO BMC CELL BIOLOGY LA English DT Article DE Cell-signaling; Nuclear translocation; Inositol phosphate kinase; Trafficking ID INOSITOL HEXAKISPHOSPHATE KINASE; DIPHOSPHOINOSITOL PENTAKISPHOSPHATE; PHOSPHORYLATION ADJACENT; LOCALIZATION SIGNALS; PYROPHOSPHATES; IMPORT; DOMAINS; PROTEIN; FAMILY; POLYPHOSPHATES AB Background: Cells contain several inositol pyrophosphates (PP-InsPs; also known as diphosphoinositol polyphosphates), which play pivotal roles in cellular and organismic homeostasis. It has been proposed that determining mechanisms of compartmentation of the synthesis of a particular PP-InsP is key to understanding how each of them may exert a specific function. Human PPIP5K2 (hPPIP5K2), one of the key enzymes that synthesizes PP-InsPs, contains a putative consensus sequence for a nuclear localization signal (NLS). However, such in silico analysis has limited predictive power, and may be complicated by phosphorylation events that can dynamically modulate NLS function. We investigated if this candidate NLS is functional and regulated, using the techniques of cell biology, mutagenesis and mass spectrometry. Results: Multiple sequence alignments revealed that the metazoan PPIP5K2 family contains a candidate NLS within a strikingly well-conserved 63 amino-acid domain. By analyzing the distribution of hPPIP5K2-GFP in HEK293T cells with the techniques of confocal microscopy and imaging flow cytometry, we found that a distinct pool of hPPIP5K2 is present in the nucleus. Imaging flow cytometry yielded particular insight into the characteristics of the nuclear hPPIP5K2 sub-pool, through a high-throughput, statistically-robust analysis of many hundreds of cells. Mutagenic disruption of the candidate NLS in hPPIP5K2 reduced its degree of nuclear localization. Proximal to the NLS is a Ser residue (S1006) that mass spectrometry data indicate is phosphorylated inside cells. The degree of nuclear localization of hPPIP5K2 was increased when S1006 was rendered non-phosphorylatable by its mutation to Ala. Conversely, a S1006D phosphomimetic mutant of hPPIP5K2 exhibited a lower degree of nuclear localization. Conclusions: The current study describes for the first time the functional significance of an NLS in the conserved PPIP5K2 family. We have further demonstrated that there is phosphorylation of a Ser residue that is proximal to the NLS of hPPIP5K2. These conclusions draw attention to nuclear compartmentation of PPIP5K2 as being a physiologically relevant and covalently-regulated event. Our study also increases general insight into the consensus sequences of other NLSs, the functions of which might be similarly regulated. C1 [Yong, Sheila T.; Nguyen, Hoai-Nghia; Choi, Jae H.; Bortner, Carl D.; Shears, Stephen B.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Williams, Jason] NIEHS, Prot Microcharacterizat Core Facil, Mass Spectrometry Grp, NIH, Res Triangle Pk, NC 27709 USA. [Pulloor, Niyas K.; Krishnan, Manoj N.] DUKE NUS Grad Med Sch, Program Emerging Infect Dis, Singapore 169857, Singapore. RP Shears, SB (reprint author), NIEHS, Lab Signal Transduct, NIH, 101 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences; Singapore MoE grant [MOE2012-T2-1-137] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. MNK was funded by Singapore MoE grant MOE2012-T2-1-137. We thank Agnes Janoshazi for assistance with confocal microscopy, and Shobana Vaidyanathan at Amnis Corporation for advice concerning ImageStreamX. NR 42 TC 1 Z9 1 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD JUN 18 PY 2015 VL 16 AR 17 DI 10.1186/s12860-015-0063-7 PG 11 WC Cell Biology SC Cell Biology GA CK7KO UT WOS:000356411500001 PM 26084399 ER PT J AU Germain, RN AF Germain, Ronald N. TI Healing the NIH-Funded Biomedical Research Enterprise SO CELL LA English DT Editorial Material AB Many feel that the R01 grant system supporting biomedical research in the U.S. is broken, discouraging entry of young investigators into the system and inadequately supporting more established investigators. Here, I argue for a "person-not-project"-based scheme that would permit creative, unfettered research by new investigators, better tie ongoing research contributions to continued funding, and help match the number of investigators seeking support with available funds. C1 NIAID, Lab Syst Biol, NIH, Bethesda, MD 20817 USA. RP Germain, RN (reprint author), NIAID, Lab Syst Biol, NIH, Bethesda, MD 20817 USA. EM rgermain@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 14 TC 6 Z9 6 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 18 PY 2015 VL 161 IS 7 BP 1485 EP 1491 DI 10.1016/j.cell.2015.05.052 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL0GG UT WOS:000356618200002 PM 26091028 ER PT J AU Park, DJ Dudas, G Wohl, S Goba, A Whitmer, SLM Andersen, KG Sealfon, RS Ladner, JT Kugelman, JR Matranga, CB Winnicki, SM Qu, J Gire, SK Gladden-Young, A Jalloh, S Nosamiefan, D Yozwiak, NL Moses, LM Jiang, PP Lin, AE Schaffner, SF Bird, B Towner, J Mamoh, M Gbakie, M Kanneh, L Kargbo, D Massally, JLB Kamara, FK Konuwa, E Sellu, J Jalloh, AA Mustapha, I Foday, M Yillah, M Erickson, BR Sealy, T Blau, D Paddock, C Brault, A Amman, B Basile, J Bearden, S Belser, J Bergeron, E Campbell, S Chakrabarti, A Dodd, K Flint, M Gibbons, A Goodman, C Klena, J McMullan, L Morgan, L Russell, B Salzer, J Sanchez, A Wang, D Jungreis, I Tomkins-Tinch, C Kislyuk, A Lin, MF Chapman, S MacInnis, B Matthews, A Bochicchio, J Hensley, LE Kuhn, JH Nusbaum, C Schieffelin, JS Birren, BW Forget, M Nichol, ST Palacios, GF Ndiaye, D Happi, C Gevao, SM Vandi, MA Kargbo, B Holmes, EC Bedford, T Gnirke, A Stroher, U Rambaut, A Garry, RF Sabeti, PC AF Park, Daniel J. Dudas, Gytis Wohl, Shirlee Goba, Augustine Whitmer, Shannon L. M. Andersen, Kristian G. Sealfon, Rachel S. Ladner, Jason T. Kugelman, Jeffrey R. Matranga, Christian B. Winnicki, Sarah M. Qu, James Gire, Stephen K. Gladden-Young, Adrianne Jalloh, Simbirie Nosamiefan, Dolo Yozwiak, Nathan L. Moses, Lina M. Jiang, Pan-Pan Lin, Aaron E. Schaffner, Stephen F. Bird, Brian Towner, Jonathan Mamoh, Mambu Gbakie, Michael Kanneh, Lansana Kargbo, David Massally, James L. B. Kamara, Fatima K. Konuwa, Edwin Sellu, Josephine Jalloh, Abdul A. Mustapha, Ibrahim Foday, Momoh Yillah, Mohamed Erickson, Bobbie R. Sealy, Tara Blau, Dianna Paddock, Christopher Brault, Aaron Amman, Brian Basile, Jane Bearden, Scott Belser, Jessica Bergeron, Eric Campbell, Shelley Chakrabarti, Ayan Dodd, Kimberly Flint, Mike Gibbons, Aridth Goodman, Christin Klena, John McMullan, Laura Morgan, Laura Russell, Brandy Salzer, Johanna Sanchez, Angela Wang, David Jungreis, Irwin Tomkins-Tinch, Christopher Kislyuk, Andrey Lin, Michael F. Chapman, Sinead MacInnis, Bronwyn Matthews, Ashley Bochicchio, James Hensley, Lisa E. Kuhn, Jens H. Nusbaum, Chad Schieffelin, John S. Birren, Bruce W. Forget, Marc Nichol, Stuart T. Palacios, Gustavo F. Ndiaye, Daouda Happi, Christian Gevao, Sahr M. Vandi, Mohamed A. Kargbo, Brima Holmes, Edward C. Bedford, Trevor Gnirke, Andreas Stroeher, Ute Rambaut, Andrew Garry, Robert F. Sabeti, Pardis C. TI Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone SO CELL LA English DT Article ID RNA VIRUSES; SELECTION; OUTBREAK; DATABASE AB The 2013-2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission. C1 [Park, Daniel J.; Wohl, Shirlee; Sealfon, Rachel S.; Matranga, Christian B.; Winnicki, Sarah M.; Qu, James; Gire, Stephen K.; Gladden-Young, Adrianne; Nosamiefan, Dolo; Yozwiak, Nathan L.; Jiang, Pan-Pan; Lin, Aaron E.; Schaffner, Stephen F.; Tomkins-Tinch, Christopher; Chapman, Sinead; MacInnis, Bronwyn; Matthews, Ashley; Bochicchio, James; Nusbaum, Chad; Birren, Bruce W.; Gnirke, Andreas; Sabeti, Pardis C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Dudas, Gytis; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh EH9 3FL, Midlothian, Scotland. [Wohl, Shirlee; Winnicki, Sarah M.; Gire, Stephen K.; Yozwiak, Nathan L.; Jiang, Pan-Pan; Lin, Aaron E.; Schaffner, Stephen F.; Matthews, Ashley] Harvard Univ, Cambridge, MA 02138 USA. [Goba, Augustine; Jalloh, Simbirie; Mamoh, Mambu; Gbakie, Michael; Kanneh, Lansana; Kargbo, David; Massally, James L. B.; Kamara, Fatima K.; Konuwa, Edwin; Sellu, Josephine; Jalloh, Abdul A.; Mustapha, Ibrahim; Foday, Momoh; Yillah, Mohamed] Kenema Govt Hosp, Kenema, Sierra Leone. [Whitmer, Shannon L. M.; Bird, Brian; Towner, Jonathan; Erickson, Bobbie R.; Sealy, Tara; Blau, Dianna; Paddock, Christopher; Brault, Aaron; Amman, Brian; Basile, Jane; Bearden, Scott; Belser, Jessica; Bergeron, Eric; Campbell, Shelley; Chakrabarti, Ayan; Dodd, Kimberly; Flint, Mike; Gibbons, Aridth; Goodman, Christin; Klena, John; McMullan, Laura; Morgan, Laura; Russell, Brandy; Salzer, Johanna; Sanchez, Angela; Wang, David; Nichol, Stuart T.; Stroeher, Ute] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Whitmer, Shannon L. M.; Bird, Brian; Towner, Jonathan; Erickson, Bobbie R.; Sealy, Tara; Blau, Dianna; Paddock, Christopher; Brault, Aaron; Amman, Brian; Basile, Jane; Bearden, Scott; Belser, Jessica; Bergeron, Eric; Campbell, Shelley; Chakrabarti, Ayan; Dodd, Kimberly; Flint, Mike; Gibbons, Aridth; Goodman, Christin; Klena, John; McMullan, Laura; Morgan, Laura; Russell, Brandy; Salzer, Johanna; Sanchez, Angela; Wang, David; Nichol, Stuart T.; Stroeher, Ute] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Andersen, Kristian G.] Scripps Res Inst, Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Sealfon, Rachel S.; Jungreis, Irwin] MIT, Cambridge, MA 02139 USA. [Ladner, Jason T.; Kugelman, Jeffrey R.; Palacios, Gustavo F.] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Moses, Lina M.; Schieffelin, John S.; Garry, Robert F.] Tulane Univ, New Orleans, LA 70112 USA. [Kislyuk, Andrey; Lin, Michael F.] DNAnexus, Mountain View, CA 94040 USA. [Hensley, Lisa E.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD 21702 USA. [Forget, Marc] Med Sans Frontieres, B-1050 Brussels, Belgium. [Ndiaye, Daouda] Univ Cheikh Anta Diop, Dakar, Senegal. [Happi, Christian] Redeemers Univ Nigeria, Redemption City, Ogun State, Nigeria. [Gevao, Sahr M.] Univ Sierra Leone, Freetown, Sierra Leone. [Vandi, Mohamed A.; Kargbo, Brima] Sierra Leone Minist Hlth & Sanitat, Freetown, Sierra Leone. [Holmes, Edward C.] Univ Sydney, Johns Hopkins Dr, Camperdown, NSW 2050, Australia. [Bedford, Trevor] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Ashworth Labs, Edinburgh EH9 3FL, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Park, DJ (reprint author), Broad Inst Harvard & MIT, 75 Ames St, Cambridge, MA 02142 USA. EM dpark@broadinstitute.org; a.rambaut@ed.ac.uk; pardis@broadinstitute.org RI Palacios, Gustavo/I-7773-2015; Schaffner, Stephen/D-1189-2011; OI Palacios, Gustavo/0000-0001-5062-1938; Flint, Michael/0000-0002-5373-787X; Dudas, Gytis/0000-0002-0227-4158; Tomkins-Tinch, Christopher/0000-0002-9114-6421; Holmes, Edward/0000-0001-9596-3552 FU European Union grant FP7 [278433-PREDEMICS]; European Research Council [260864]; Natural Environment Research Council [D76739X]; NIH [U54 GM111274, GM080177, 1U01HG007480-01]; National Science Foundation Graduate Research Fellowship [DGE 1144152]; National Health and Medical Research Council, Australia; Defense Threat Reduction Agency (USAMRIID); NIH/NIAID (Broad Institute) [U19AI110818]; Bill and Melinda Gates Foundation (Broad Institute) [OPP1123407]; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201400028C]; NIAID (Harvard/Tulane) [HHSN272200900049C]; Zalgen Labs FX This work was supported by European Union grant FP7/2007-2013 278433-PREDEMICS and European Research Council grant 260864 (A.R.); Natural Environment Research Council grant D76739X (G.D.); NIH U54 GM111274 (T.B.); NIH grant GM080177 (S.W.); NIH grant 1U01HG007480-01 (C.H.); National Science Foundation Graduate Research Fellowship Grant No. DGE 1144152 (A.E.L.); the National Health and Medical Research Council, Australia (E.C.H.); the Defense Threat Reduction Agency (USAMRIID); NIH/NIAID U19AI110818 (Broad Institute); the Bill and Melinda Gates Foundation OPP1123407 (Broad Institute); and NIAID HHSN272200900049C (Harvard/Tulane). This work was funded, in part, through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under contract number HHSN272200700016I. Subcontractors to Battelle Memorial Institute who performed this work are: J.H.K., an employee of Tunnell Government Services, Inc. R.F.G. is co-founder of Zalgen Labs.; The Virus Pathogen Database and Analysis Resource (ViPR) has been wholly 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 number HHSN272201400028C. NR 30 TC 65 Z9 67 U1 6 U2 76 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 18 PY 2015 VL 161 IS 7 BP 1516 EP 1526 DI 10.1016/j.cell.2015.06.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL0GG UT WOS:000356618200010 PM 26091036 ER PT J AU Akbani, R Akdemir, KC Aksoy, BA Albert, M Ally, A Amin, SB Arachchi, H Arora, A Auman, JT Ayala, B Baboud, J Balasundaram, M Balu, S Barnabas, N Bartlett, J Bartlett, P Bastian, BC Baylin, SB Behera, M Belyaev, D Benz, C Bernard, B Beroukhim, R Bir, N Black, AD Bodenheimer, T Boice, L Boland, GM Bono, R Bootwalla, MS Bosenberg, M Bowen, J Bowlby, R Bristow, CA Brockway-Lunardi, L Brooks, D Brzezinski, J Bshara, W Buda, E Burns, WR Butterfield, YSN Button, M Calderone, T Cappellini, GA Carter, C Carter, SL Cherney, L Cherniack, AD Chevalier, A Chin, L Cho, J Cho, RJ Choi, YL Chu, A Chudamani, S Cibulskis, K Ciriello, G Clarke, A Coons, S Cope, L Crain, D Curley, E Danilova, L D'Atri, S Davidsen, T Davies, MA Delman, KA Demchok, JA Deng, QA Deribe, YL Dhalla, N Dhir, R DiCara, D Dinikin, M Dubina, M Ebrom, JS Egea, S Eley, G Engel, J Eschbacher, JM Fedosenko, KV Felau, I Fennell, T Ferguson, ML Fisher, S Flaherty, KT Frazer, S Frick, J Fulidou, V Gabriel, SB Gao, J Gardner, J Garraway, LA Gastier-Foster, JM Gaudioso, C Gehlenborg, N Genovese, G Gerken, M Gershenwald, JE Getz, G Gomez-Fernandez, C Gribbin, T Grimsby, J Gross, B Guin, R Gutschner, T Hadjipanayis, A Halaban, R Hanf, B Haussler, D Haydu, LE Hayes, DN Hayward, NK Heiman, DI Herbert, L Herman, JG Hersey, P Hoadley, KA Hodis, E Holt, RA Hoon, DSB Hoppough, S Hoyle, AP Huang, FW Huang, M Huang, S Hutter, CM Ibbs, M Iype, L Jacobsen, A Jakrot, V Janning, A Jeck, WR Jefferys, SR Jensen, MA Jones, CD Jones, SJM Ju, Z Kakavand, H Kang, H Kefford, RF Khuri, FR Kim, J Kirkwood, JM Klode, J Korkut, A Korski, K Krauthammer, M Kucherlapati, R Kwong, LN Kycler, W Ladanyi, M Lai, PH Laird, PW Lander, E Lawrence, MS Lazar, AJ Qazniak, R Lee, D Lee, JE Lee, J Lee, K Lee, S Lee, W Leporowska, E Leraas, KM Li, HI Lichtenberg, TM Lichtenstein, L Lin, P Ling, SY Liu, J Liu, O Liu, W Long, GV Lu, Y Ma, S Ma, Y Mackiewicz, A Mahadeshwar, HS Malke, J Mallery, D Manikhas, GM Mann, GJ Marra, MA Matejka, B Mayo, M Mehrabi, S Meng, S Meyerson, M Mieczkowski, PA Miller, JP Miller, ML Mills, GB Moiseenko, F Moore, RA Morris, S Morrison, C Morton, DL Moschos, S Mose, LE Muller, FL Mungall, AJ Murawa, D Murawa, P Murray, BA Nezi, L Ng, S Nicholson, D Noble, MS Osunkoya, A Owonikoko, TK Ozenberger, BA Pagani, E Paklina, OV Pantazi, A Parfenov, M Parfitt, J Park, PJ Park, WY Parker, JS Passarelli, F Penny, R Perou, CM Pihl, TD Potapova, O Prieto, VG Protopopov, A Quinn, MJ Radenbaugh, A Rai, K Ramalingam, SS Raman, AT Ramirez, NC Ramirez, R Rao, U Rathmell, WK Ren, XJ Reynolds, SM Roach, J Robertson, AG Ross, MI Roszik, J Russo, G Saksena, G Saller, C Samuels, Y Sander, C Sander, C Sandusky, G Santoso, N Saul, M Saw, RPM Schadendorf, D Schein, JE Schultz, N Schumacher, SE Schwallier, C Scolyer, RA Seidman, J Sekhar, PC Sekhon, HS Senbabaoglu, Y Seth, S Shannon, KF Sharpe, S Sharpless, NE Shaw, KRM Shelton, C Shelton, T Shen, R Sheth, M Shi, Y Shiau, CJ Shmulevich, I Sica, GL Simons, JV Sinha, R Sipahimalani, P Sofia, HJ Soloway, MG Song, XZ Sougnez, C Spillane, AJ Spychaa, A Stretch, JR Stuart, J Suchorska, WM Sucker, A Sumer, SO Sun, YC Synott, M Tabak, B Tabler, TR Tam, A Tan, DH Tang, JB Tarnuzzer, R Tarvin, K Tatka, H Taylor, BS Teresiak, M Thiessen, N Thompson, JF Thorne, L Thorsson, V Trent, JM Triche, TJ Tsai, KY Tsou, P Van den Berg, DJ Van Allen, EM Veluvolu, U Verhaak, RG Voet, D Voronina, O Walter, V Walton, JS Wan, YH Wang, YL Wang, ZN Waring, S Watson, IR Weinhold, N Weinstein, JN Weisenberger, DJ White, P Wilkerson, MD Wilmott, JS Wise, L Wiznerowicz, M Woodman, SE Wu, CJ Wu, CC Wu, JY Wu, Y Xi, RB Xu, AW Yang, D Yang, LM Yang, LX Zack, TI Zen-Klusen, JC Zhang, HL Zhang, JH Zhang, W Zhao, XB Zhu, JC Zhu, K Zimmer, L Zmuda, E Zou, LH AF Akbani, Rehan Akdemir, Kadir C. Aksoy, B. Arman Albert, Monique Ally, Adrian Amin, Samirkumar B. Arachchi, Harindra Arora, Arshi Auman, J. Todd Ayala, Brenda Baboud, Julien Balasundaram, Miruna Balu, Saianand Barnabas, Nandita Bartlett, John Bartlett, Pam Bastian, Boris C. Baylin, Stephen B. Behera, Madhusmita Belyaev, Dmitry Benz, Christopher Bernard, Brady Beroukhim, Rameen Bir, Natalie Black, Aaron D. Bodenheimer, Tom Boice, Lori Boland, Genevieve M. Bono, Riccardo Bootwalla, Moiz S. Bosenberg, Marcus Bowen, Jay Bowlby, Reanne Bristow, Christopher A. Brockway-Lunardi, Laura Brooks, Denise Brzezinski, Jakub Bshara, Wiam Buda, Elizabeth Burns, William R. Butterfield, Yaron S. N. Button, Michael Calderone, Tiffany Cappellini, Giancarlo Antonini Carter, Candace Carter, Scott L. Cherney, Lynn Cherniack, Andrew D. Chevalier, Aaron Chin, Lynda Cho, Juok Cho, Raymond J. Choi, Yoon-La Chu, Andy Chudamani, Sudha Cibulskis, Kristian Ciriello, Giovanni Clarke, Amanda Coons, Stephen Cope, Leslie Crain, Daniel Curley, Erin Danilova, Ludmila D'Atri, Stefania Davidsen, Tanja Davies, Michael A. Delman, Keith A. Demchok, John A. Deng, Qixia A. Deribe, Yonathan Lissanu Dhalla, Noreen Dhir, Rajiv DiCara, Daniel Dinikin, Michael Dubina, Michael Ebrom, J. Stephen Egea, Sophie Eley, Greg Engel, Jay Eschbacher, Jennifer M. Fedosenko, Konstantin V. Felau, Ina Fennell, Timothy Ferguson, Martin L. Fisher, Sheila Flaherty, Keith T. Frazer, Scott Frick, Jessica Fulidou, Victoria Gabriel, Stacey B. Gao, Jianjiong Gardner, Johanna Garraway, Levi A. Gastier-Foster, Julie M. Gaudioso, Carmelo Gehlenborg, Nils Genovese, Giannicola Gerken, Mark Gershenwald, Jeffrey E. Getz, Gad Gomez-Fernandez, Carmen Gribbin, Thomas Grimsby, Jonna Gross, Benjamin Guin, Ranabir Gutschner, Tony Hadjipanayis, Angela Halaban, Ruth Hanf, Benjamin Haussler, David Haydu, Lauren E. Hayes, D. Neil Hayward, Nicholas K. Heiman, David I. Herbert, Lynn Herman, James G. Hersey, Peter Hoadley, Katherine A. Hodis, Eran Holt, Robert A. Hoon, Dave S. B. Hoppough, Susan Hoyle, Alan P. Huang, Franklin W. Huang, Mei Huang, Sharon Hutter, Carolyn M. Ibbs, Matthew Iype, Lisa Jacobsen, Anders Jakrot, Valerie Janning, Alyssa Jeck, William R. Jefferys, Stuart R. Jensen, Mark A. Jones, Corbin D. Jones, Steven J. M. Ju, Zhenlin Kakavand, Hojabr Kang, Hyojin Kefford, Richard F. Khuri, Fadlo R. Kim, Jaegil Kirkwood, John M. Klode, Joachim Korkut, Anil Korski, Konstanty Krauthammer, Michael Kucherlapati, Raju Kwong, Lawrence N. Kycler, Witold Ladanyi, Marc Lai, Phillip H. Laird, Peter W. Lander, Eric Lawrence, Michael S. Lazar, Alexander J. Qazniak, Radoslaw Lee, Darlene Lee, Jeffrey E. Lee, Junehawk Lee, Kenneth Lee, Semin Lee, William Leporowska, Ewa Leraas, Kristen M. Li, Haiyan I. Lichtenberg, Tara M. Lichtenstein, Lee Lin, Pei Ling, Shiyun Liu, Jia Liu, Ouida Liu, Wenbin Long, Georgina V. Lu, Yiling Ma, Singer Ma, Yussanne Mackiewicz, Andrzej Mahadeshwar, Harshad S. Malke, Jared Mallery, David Manikhas, Georgy M. Mann, Graham J. Marra, Marco A. Matejka, Brenna Mayo, Michael Mehrabi, Sousan Meng, Shaowu Meyerson, Matthew Mieczkowski, Piotr A. Miller, John P. Miller, Martin L. Mills, Gordon B. Moiseenko, Fedor Moore, Richard A. Morris, Scott Morrison, Carl Morton, Donald L. Moschos, Stergios Mose, Lisle E. Muller, Florian L. Mungall, Andrew J. Murawa, Dawid Murawa, Pawel Murray, Bradley A. Nezi, Luigi Ng, Sam Nicholson, Dana Noble, Michael S. Osunkoya, Adeboye Owonikoko, Taofeek K. Ozenberger, Bradley A. Pagani, Elena Paklina, Oxana V. Pantazi, Angeliki Parfenov, Michael Parfitt, Jeremy Park, Peter J. Park, Woong-Yang Parker, Joel S. Passarelli, Francesca Penny, Robert Perou, Charles M. Pihl, Todd D. Potapova, Olga Prieto, Victor G. Protopopov, Alexei Quinn, Michael J. Radenbaugh, Amie Rai, Kunal Ramalingam, Suresh S. Raman, Ayush T. Ramirez, Nilsa C. Ramirez, Ricardo Rao, Uma Rathmell, W. Kimryn Ren, Xiaojia Reynolds, Sheila M. Roach, Jeffrey Robertson, A. Gordon Ross, Merrick I. Roszik, Jason Russo, Giandomenico Saksena, Gordon Saller, Charles Samuels, Yardena Sander, Chris Sander, Cindy Sandusky, George Santoso, Netty Saul, Melissa Saw, Robyn P. M. Schadendorf, Dirk Schein, Jacqueline E. Schultz, Nikolaus Schumacher, Steven E. Schwallier, Charles Scolyer, Richard A. Seidman, Jonathan Sekhar, Pedamallu Chandra Sekhon, Harmanjatinder S. Senbabaoglu, Yasin Seth, Sahil Shannon, Kerwin F. Sharpe, Samantha Sharpless, Norman E. Shaw, Kenna R. Mills Shelton, Candace Shelton, Troy Shen, Ronglai Sheth, Margi Shi, Yan Shiau, Carolyn J. Shmulevich, Ilya Sica, Gabriel L. Simons, Janae V. Sinha, Rileen Sipahimalani, Payal Sofia, Heidi J. Soloway, Matthew G. Song, Xingzhi Sougnez, Carrie Spillane, Andrew J. Spychaa, Arkadiusz Stretch, Jonathan R. Stuart, Joshua Suchorska, Wiktoria M. Sucker, Antje Sumer, S. Onur Sun, Yichao Synott, Maria Tabak, Barbara Tabler, Teresa R. Tam, Angela Tan, Donghui Tang, Jiabin Tarnuzzer, Roy Tarvin, Katherine Tatka, Honorata Taylor, Barry S. Teresiak, Marek Thiessen, Nina Thompson, John F. Thorne, Leigh Thorsson, Vesteinn Trent, Jeffrey M. Triche, Timothy J., Jr. Tsai, Kenneth Y. Tsou, Peiling Van den Berg, David J. Van Allen, Eliezer M. Veluvolu, Umadevi Verhaak, Roeland G. Voet, Douglas Voronina, Olga Walter, Vonn Walton, Jessica S. Wan, Yunhu Wang, Yuling Wang, Zhining Waring, Scot Watson, Ian R. Weinhold, Nils Weinstein, John N. Weisenberger, Daniel J. White, Peter Wilkerson, Matthew D. Wilmott, James S. Wise, Lisa Wiznerowicz, Maciej Woodman, Scott E. Wu, Chang-Jiun Wu, Chia-Chin Wu, Junyuan Wu, Ye Xi, Ruibin Xu, Andrew Wei Yang, Da Yang, Liming Yang, Lixing Zack, Travis I. Zen-Klusen, Jean C. Zhang, Hailei Zhang, Jianhua Zhang, Wei Zhao, Xiaobei Zhu, Jingchun Zhu, Kelsey Zimmer, Lisa Zmuda, Erik Zou, Lihua CA Canc Genome Atlas Network TI Genomic Classification of Cutaneous Melanoma SO CELL LA English DT Article ID TERT PROMOTER MUTATIONS; STAGE-III MELANOMA; METASTATIC MELANOMA; ADJUVANT THERAPY; RAF INHIBITION; NODE BIOPSY; CANCER; RESISTANCE; LANDSCAPE; SAFETY AB We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four sub-types based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making. C1 NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. [Akbani, Rehan; Akdemir, Kadir C.; Aksoy, B. Arman; Albert, Monique; Ally, Adrian; Amin, Samirkumar B.; Arachchi, Harindra; Arora, Arshi; Auman, J. Todd; Ayala, Brenda; Baboud, Julien; Balasundaram, Miruna; Balu, Saianand; Barnabas, Nandita; Bartlett, John; Bartlett, Pam; Bastian, Boris C.; Baylin, Stephen B.; Behera, Madhusmita; Belyaev, Dmitry; Benz, Christopher; Bernard, Brady; Beroukhim, Rameen; Bir, Natalie; Black, Aaron D.; Bodenheimer, Tom; Boice, Lori; Boland, Genevieve M.; Bono, Riccardo; Bootwalla, Moiz S.; Bosenberg, Marcus; Bowen, Jay; Bowlby, Reanne; Bristow, Christopher A.; Brockway-Lunardi, Laura; Brooks, Denise; Brzezinski, Jakub; Bshara, Wiam; Buda, Elizabeth; Burns, William R.; Butterfield, Yaron S. N.; Button, Michael; Calderone, Tiffany; Cappellini, Giancarlo Antonini; Carter, Candace; Carter, Scott L.; Cherney, Lynn; Cherniack, Andrew D.; Chevalier, Aaron; Chin, Lynda; Cho, Juok; Cho, Raymond J.; Choi, Yoon-La; Chu, Andy; Chudamani, Sudha; Cibulskis, Kristian; Ciriello, Giovanni; Clarke, Amanda; Coons, Stephen; Cope, Leslie; Crain, Daniel; Curley, Erin; Danilova, Ludmila; D'Atri, Stefania; Davidsen, Tanja; Davies, Michael A.; Delman, Keith A.; Demchok, John A.; Deng, Qixia A.; Deribe, Yonathan Lissanu; Dhalla, Noreen; Dhir, Rajiv; DiCara, Daniel; Dinikin, Michael; Dubina, Michael; Ebrom, J. Stephen; Egea, Sophie; Eley, Greg; Engel, Jay; Eschbacher, Jennifer M.; Fedosenko, Konstantin V.; Felau, Ina; Fennell, Timothy; Ferguson, Martin L.; Fisher, Sheila; Flaherty, Keith T.; Frazer, Scott; Frick, Jessica; Fulidou, Victoria; Gabriel, Stacey B.; Gao, Jianjiong; Gardner, Johanna; Garraway, Levi A.; Gastier-Foster, Julie M.; Gaudioso, Carmelo; Gehlenborg, Nils; Genovese, Giannicola; Gerken, Mark; Gershenwald, Jeffrey E.; Getz, Gad; Gomez-Fernandez, Carmen; Gribbin, Thomas; Grimsby, Jonna; Gross, Benjamin; Guin, Ranabir; Gutschner, Tony; Hadjipanayis, Angela; Halaban, Ruth; Hanf, Benjamin; Haussler, David; Haydu, Lauren E.; Hayes, D. Neil; Hayward, Nicholas K.; Heiman, David I.; Herbert, Lynn; Herman, James G.; Hersey, Peter; Hoadley, Katherine A.; Hodis, Eran; Holt, Robert A.; Hoon, Dave S. B.; Hoppough, Susan; Hoyle, Alan P.; Huang, Franklin W.; Huang, Mei; Huang, Sharon; Hutter, Carolyn M.; Ibbs, Matthew; Iype, Lisa; Jacobsen, Anders; Jakrot, Valerie; Janning, Alyssa; Jeck, William R.; Jefferys, Stuart R.; Jensen, Mark A.; Jones, Corbin D.; Jones, Steven J. M.; Ju, Zhenlin; Kakavand, Hojabr; Kang, Hyojin; Kefford, Richard F.; Khuri, Fadlo R.; Kim, Jaegil; Kirkwood, John M.; Klode, Joachim; Korkut, Anil; Korski, Konstanty; Krauthammer, Michael; Kucherlapati, Raju; Kwong, Lawrence N.; Kycler, Witold; Ladanyi, Marc; Lai, Phillip H.; Laird, Peter W.; Lander, Eric; Lawrence, Michael S.; Lazar, Alexander J.; Qazniak, Radoslaw; Lee, Darlene; Lee, Jeffrey E.; Lee, Junehawk; Lee, Kenneth; Lee, Semin; Lee, William; Leporowska, Ewa; Leraas, Kristen M.; Li, Haiyan I.; Lichtenberg, Tara M.; Lichtenstein, Lee; Lin, Pei; Ling, Shiyun; Liu, Jia; Liu, Ouida; Liu, Wenbin; Long, Georgina V.; Lu, Yiling; Ma, Singer; Ma, Yussanne; Mackiewicz, Andrzej; Mahadeshwar, Harshad S.; Malke, Jared; Mallery, David; Manikhas, Georgy M.; Mann, Graham J.; Marra, Marco A.; Matejka, Brenna; Mayo, Michael; Mehrabi, Sousan; Meng, Shaowu; Meyerson, Matthew; Mieczkowski, Piotr A.; Miller, John P.; Miller, Martin L.; Mills, Gordon B.; Moiseenko, Fedor; Moore, Richard A.; Morris, Scott; Morrison, Carl; Morton, Donald L.; Moschos, Stergios; Mose, Lisle E.; Muller, Florian L.; Mungall, Andrew J.; Murawa, Dawid; Murawa, Pawel; Murray, Bradley A.; Nezi, Luigi; Ng, Sam; Nicholson, Dana; Noble, Michael S.; Osunkoya, Adeboye; Owonikoko, Taofeek K.; Ozenberger, Bradley A.; Pagani, Elena; Paklina, Oxana V.; Pantazi, Angeliki; Parfenov, Michael; Parfitt, Jeremy; Park, Peter J.; Park, Woong-Yang; Parker, Joel S.; Passarelli, Francesca; Penny, Robert; Perou, Charles M.; Pihl, Todd D.; Potapova, Olga; Prieto, Victor G.; Protopopov, Alexei; Quinn, Michael J.; Radenbaugh, Amie; Rai, Kunal; Ramalingam, Suresh S.; Raman, Ayush T.; Ramirez, Nilsa C.; Ramirez, Ricardo; Rao, Uma; Rathmell, W. Kimryn; Ren, Xiaojia; Reynolds, Sheila M.; Roach, Jeffrey; Robertson, A. Gordon; Ross, Merrick I.; Roszik, Jason; Russo, Giandomenico; Saksena, Gordon; Saller, Charles; Samuels, Yardena; Sander, Chris; Sander, Cindy; Sandusky, George; Santoso, Netty; Saul, Melissa; Saw, Robyn P. M.; Schadendorf, Dirk; Schein, Jacqueline E.; Schultz, Nikolaus; Schumacher, Steven E.; Schwallier, Charles; Scolyer, Richard A.; Seidman, Jonathan; Sekhar, Pedamallu Chandra; Sekhon, Harmanjatinder S.; Senbabaoglu, Yasin; Seth, Sahil; Shannon, Kerwin F.; Sharpe, Samantha; Sharpless, Norman E.; Shaw, Kenna R. Mills; Shelton, Candace; Shelton, Troy; Shen, Ronglai; Sheth, Margi; Shi, Yan; Shiau, Carolyn J.; Shmulevich, Ilya; Sica, Gabriel L.; Simons, Janae V.; Sinha, Rileen; Sipahimalani, Payal; Sofia, Heidi J.; Soloway, Matthew G.; Song, Xingzhi; Sougnez, Carrie; Spillane, Andrew J.; Spychaa, Arkadiusz; Stretch, Jonathan R.; Stuart, Joshua; Suchorska, Wiktoria M.; Sucker, Antje; Sumer, S. Onur; Sun, Yichao; Synott, Maria; Tabak, Barbara; Tabler, Teresa R.; Tam, Angela; Tan, Donghui; Tang, Jiabin; Tarnuzzer, Roy; Tarvin, Katherine; Tatka, Honorata; Taylor, Barry S.; Teresiak, Marek; Thiessen, Nina; Thompson, John F.; Thorne, Leigh; Thorsson, Vesteinn; Trent, Jeffrey M.; Triche, Timothy J., Jr.; Tsai, Kenneth Y.; Tsou, Peiling; Van den Berg, David J.; Van Allen, Eliezer M.; Veluvolu, Umadevi; Verhaak, Roeland G.; Voet, Douglas; Voronina, Olga; Walter, Vonn; Walton, Jessica S.; Wan, Yunhu; Wang, Yuling; Wang, Zhining; Waring, Scot; Watson, Ian R.; Weinhold, Nils; Weinstein, John N.; Weisenberger, Daniel J.; White, Peter; Wilkerson, Matthew D.; Wilmott, James S.; Wise, Lisa; Wiznerowicz, Maciej; Woodman, Scott E.; Wu, Chang-Jiun; Wu, Chia-Chin; Wu, Junyuan; Wu, Ye; Xi, Ruibin; Xu, Andrew Wei; Yang, Da; Yang, Liming; Yang, Lixing; Zack, Travis I.; Zen-Klusen, Jean C.; Zhang, Hailei; Zhang, Jianhua; Zhang, Wei; Zhao, Xiaobei; Zhu, Jingchun; Zhu, Kelsey; Zimmer, Lisa; Zmuda, Erik; Zou, Lihua; Canc Genome Atlas Network] NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. RP Watson, IR (reprint author), NCI, Canc Genome Atlas Program Off, NIH, 31 Ctr Dr,Bldg 31,Suite 3A20, Bethesda, MD 20892 USA. EM lchin@mdanderson.org; jgershen@mdanderson.org; irwatson@mdanderson.org RI Lazar, Alexander/A-3416-2008; Holt, Robert/C-3303-2009; hayward, nicholas/C-1367-2015; Jacobsen, Anders/K-1081-2013; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; OI Sinha, Rileen/0000-0001-5497-5055; Scolyer, Richard/0000-0002-8991-0013; Yang, Da/0000-0002-8336-9457; Perou, Charles/0000-0001-9827-2247; Amin, Samir/0000-0002-3207-9505; Gehlenborg, Nils/0000-0003-0327-8297; Lazar, Alexander/0000-0002-6395-4499; hayward, nicholas/0000-0003-4760-1033; Jacobsen, Anders/0000-0001-6847-4980; Lee, Semin/0000-0002-9015-6046; Hoon, Dave/0000-0003-1915-3683; Miller, Martin L/0000-0003-3161-8690; D'Atri, Stefania/0000-0001-9852-7377; Moiseenko, Fedor/0000-0003-2544-9042; Seth, Sahil/0000-0003-4579-3959 FU NIH [U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672]; Bayer AG; Novartis; Zymo Research FX We thank all patients and families who contributed to this study. We are grateful to Chris Gunter for manuscript editing and Ina Felau and Margi Sheth for project management. This article is dedicated to the memory of Donald L. Morton, M.D., a pioneer in melanoma oncology, who passed away on January 10, 2014. This study was supported by NIH grants: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, and P30 CA016672.; A.D.C. and M.M. receive research funding from Bayer AG. M.M. is a founder of, equity holder in, and consultant for Foundation Medicine, a next-generation sequencing-based cancer diagnostics company. L.A.G. received a commercial research grant from Novartis and is a consultant/advisory board member for Novartis, Foundation Medicine, and Boehringer Ingelheim. L.A.G. also has equity interest in Foundation Medicine. D.J.W. is a consultant for Zymo Research Corporation, which distributes commercially available products for DNA methylation-based experiments. Zymo Research neither supported this work nor has an interest in the outcome of this research. O.P and O.V. are co-founders and shareholders of Cureline, Inc., which received a contract payment from the NIH for this work. J.E.G. is an advisory board member for Merck. NR 68 TC 135 Z9 136 U1 12 U2 52 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 18 PY 2015 VL 161 IS 7 BP 1681 EP 1696 DI 10.1016/j.cell.2015.05.044 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL0GG UT WOS:000356618200023 ER PT J AU Liu, Y Holmstrom, E Zhang, JW Yu, P Wang, JB Dyba, MA Chen, D Ying, JF Lockett, S Nesbitt, DJ Ferre-D'Amare, AR Sousa, R Stagno, JR Wang, YX AF Liu, Yu Holmstrom, Erik Zhang, Jinwei Yu, Ping Wang, Jinbu Dyba, Marzena A. Chen, De Ying, Jinfa Lockett, Stephen Nesbitt, David J. Ferre-D'Amare, Adrian R. Sousa, Rui Stagno, Jason R. Wang, Yun-Xing TI Synthesis and applications of RNAs with position-selective labelling and mosaic composition SO NATURE LA English DT Article ID SINGLE-MOLECULE; TRANSCRIPTION INITIATION; MESSENGER-RNAS; DNA TEMPLATES; POLYMERASE; RIBOSWITCH; STABILITY; LIGAND; DISSOCIATION; SPECIFICITY AB Knowledge of the structure and dynamics of RNA molecules is critical to understanding their many biological functions. Furthermore, synthetic RNAs have applications as therapeutics and molecular sensors. Both research and technological applications of RNA would be dramatically enhanced by methods that enable incorporation of modified or labelled nucleotides into specifically designated positions or regions of RNA. However, the synthesis of tens of milligrams of such RNAs using existing methods has been impossible. Here we develop a hybrid solid-liquid phase transcription method and automated robotic platform for the synthesis of RNAs with position-selective labelling. We demonstrate its use by successfully preparing various isotope- or fluorescently labelled versions of the 71-nucleotide aptamer domain of an adenine riboswitch(1) for nuclear magnetic resonance spectroscopy or single-molecule Forster resonance energy transfer, respectively. Those RNAs includemolecules that were selectively isotope-labelled in specific loops, linkers, a helix, several discrete positions, or a single internal position, as well as RNA molecules that were fluorescently labelled in and near kissing loops. These selectively labelled RNAs have the same fold as those transcribed using conventional methods, but they greatly simplify the interpretation of NMR spectra. The single-position isotope-and fluorescently labelled RNA samples reveal multiple conformational states of the adenine riboswitch. Lastly, we describe a robotic platform- and the operation that automates this technology. Our selective labelling method may be useful for studying RNA structure and dynamics and for making RNA sensors for a variety of applications including cell-biological studies, substance detection(2), and disease diagnostics(3,4). C1 [Liu, Yu; Wang, Jinbu; Stagno, Jason R.; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Holmstrom, Erik; Nesbitt, David J.] Univ Colorado, NIST, Joint Inst Lab Astrophys, Boulder, CO 80309 USA. [Holmstrom, Erik; Nesbitt, David J.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Zhang, Jinwei; Ferre-D'Amare, Adrian R.] NHLBI, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. [Yu, Ping; Dyba, Marzena A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Struct Biophys Lab, Frederick, MD 21702 USA. [Chen, De; Lockett, Stephen] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. [Ying, Jinfa] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. [Sousa, Rui] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Wang, YX (reprint author), NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM wangyunx@mail.nih.gov FU National Cancer Institute, the National Institute of Diabetes, Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute; Intramural Antiviral Target Program (IATAP) of the Office of the Director, National Institutes of Health; National Institutes of Health; National Cancer Institute [HHSN261200800001E]; National Science Foundation [CHE1266416, PHYS1125844]; National Institutes of Health Molecular Biophysics Training Program [T32 GM-065103]; W. M. Keck Foundation; National Institute of Standards and Technology FX We thank D. E. Draper, A. Bax, A. Byrd, M. Summers, A. Rein, and J. Strathern for discussions. This work was supported in part by the Intramural Research Programs of the National Cancer Institute, the National Institute of Diabetes, Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute; by the Intramural Antiviral Target Program (IATAP) of the Office of the Director, National Institutes of Health; by the 2013 Director's Challenge Innovation Award of the National Institutes of Health; by the fund from the National Cancer Institute under contract number HHSN261200800001E; by the National Science Foundation (CHE1266416, PHYS1125844); by the National Institutes of Health Molecular Biophysics Training Program (T32 GM-065103); and by the W. M. Keck Foundation, and the National Institute of Standards and Technology. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 45 TC 10 Z9 10 U1 14 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 18 PY 2015 VL 522 IS 7556 BP 368 EP + DI 10.1038/nature14352 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK7PU UT WOS:000356425400059 PM 25938715 ER PT J AU Wang, LM Zhang, LN Li, S Zheng, YY Yan, XX Chen, M Wang, HY Putney, JW Luo, DL AF Wang, Limin Zhang, Lane Li, Shu Zheng, Yuanyuan Yan, Xinxin Chen, Min Wang, Haoyang Putney, James W. Luo, Dali TI Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin SO SCIENTIFIC REPORTS LA English DT Article ID MUSCLE SARCOPLASMIC-RETICULUM; SKELETAL-MUSCLE; PLASMA-MEMBRANE; CRAC CHANNEL; RYANODINE RECEPTOR; CALCIUM-CHANNEL; ACTIVATION; TRIADIN; BINDING; ORAI1 AB Interaction between the endoplasmic reticulum (ER)-located stromal interaction molecue1 (STIM1) and the plasma membrane-located Ca2+ channel subunit, Orai1, underlies store-operated Ca2+ entry (SOCE). Calsequestrin1 (CSQ1), a sarcoplasmic reticulum Ca2+ buffering protein, inhibits SOCE, but the mechanism of action is unknown. We identified an interaction between CSQ1 and STIM1 in HEK293 cells. An increase in monomeric CSQ1 induced by depleted Ca2+ stores, or trifluoperazine (TFP), a blocker of CSQ folding and aggregation, enhanced the CSQ1-STIM1 interaction. In cells with Ca2+ stores depleted, TFP further increased CSQ1 monomerization and CSQ1-STIM1 interaction, but reduced the association of STIM1 with Orai1 and SOCE. Over-expression of CSQ1 or a C-terminal (amino acid 388-396) deletion mutant significantly promoted the association of CSQ1 with STIM1, but suppressed both STIM1-Orai1 interaction and SOCE, while over-expression of the C-terminal (amino acid 362-396) deletion mutant had no effect. The physical interaction between low polymeric forms of CSQ1 and STIM1 likely acts by interfering with STIM1 oligimerization and inhibits STIM1-Orai1 interaction, providing a brake to SOCE under physiological conditions. This novel regulatory mechanism for SOCE may also contribute to the pathological Ca2+ overload in calsequestrin deficient diseases, such as malignant hyperthermia and ventricular tachycardia. C1 [Wang, Limin; Zhang, Lane; Li, Shu; Zheng, Yuanyuan; Yan, Xinxin; Chen, Min; Wang, Haoyang; Luo, Dali] Capital Med Univ, Dept Pharmacol, Beijing 100069, Peoples R China. [Putney, James W.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov; luodl@ccmu.edu.cn FU National Natural Science Foundation [81370339, 30973537]; Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance [Z13111000280000]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This work was supported by grants from National Natural Science Foundation (81370339, 30973537) and Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance (Z13111000280000), and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank Dr. Junqi He from Department of Biochemistry, Capital Medical University, China and Dr. Gary Bird from Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, U.S. for their helpful discussion and suggestions. NR 40 TC 3 Z9 4 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 18 PY 2015 VL 5 AR 11349 DI 10.1038/srep11349 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK8ZV UT WOS:000356529900001 PM 26087026 ER PT J AU Reznick, JS Koyle, KM AF Reznick, Jeffrey S. Koyle, Kenneth M. TI Combat and the Medical Mindset - The Enduring Effect of Civil War Medical Innovation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Reznick, Jeffrey S.; Koyle, Kenneth M.] US Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 20894 USA. RP Reznick, JS (reprint author), US Natl Lib Med, Hist Med Div, NIH, Bethesda, MD 20894 USA. NR 5 TC 0 Z9 0 U1 0 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 18 PY 2015 VL 372 IS 25 BP 2377 EP 2380 DI 10.1056/NEJMp1502748 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CK6RF UT WOS:000356354600002 PM 26083204 ER PT J AU Akerlund, E Prescott, J Tampellini, L AF Akerlund, Emma Prescott, Joseph Tampellini, Livia TI Shedding of Ebola Virus in an Asymptomatic Pregnant Woman SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID HEMORRHAGIC-FEVER C1 [Akerlund, Emma; Tampellini, Livia] Med Sans Frontieres, Brussels, Belgium. [Prescott, Joseph] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Akerlund, E (reprint author), Med Sans Frontieres, Brussels, Belgium. EM livi.tamp@gmail.com NR 5 TC 16 Z9 16 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 18 PY 2015 VL 372 IS 25 BP 2467 EP 2469 DI 10.1056/NEJMc1503275 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CK6RF UT WOS:000356354600028 PM 26083224 ER PT J AU Gonzalez-Castillo, J Bandettini, PA AF Gonzalez-Castillo, Javier Bandettini, Peter A. TI What Cascade Spreading Models Can Teach Us about the Brain SO NEURON LA English DT Editorial Material ID FUNCTIONAL CONNECTIVITY; STRUCTURAL CONNECTIVITY; WHOLE-BRAIN; NETWORKS AB The precise relationship between functional and structural connectivity in the brain is not well understood. Research in this area has, so far, mostly remained descriptive. In this issue of Neuron, Misic et al. (2015) forge a promising new direction by modeling the propagation of information as it relates to spatially constrained network properties. From these preliminary results a glimmer of hope in uncovering deep principles of brain organization begins to emerge. C1 [Gonzalez-Castillo, Javier; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIH, Funct MRI Core, Bethesda, MD 20892 USA. RP Bandettini, PA (reprint author), NIMH, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. EM bandettp@mail.nih.gov OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 NR 15 TC 2 Z9 2 U1 3 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 17 PY 2015 VL 86 IS 6 BP 1327 EP 1329 DI 10.1016/j.neuron.2015.06.006 PG 3 WC Neurosciences SC Neurosciences & Neurology GA CQ9ZJ UT WOS:000360976300004 PM 26087160 ER PT J AU Cao, VY Ye, YZ Mastwal, S Ren, M Coon, M Liu, Q Costa, RM Wang, KH AF Cao, Vania Yu Ye, Yizhou Mastwal, Surjeet Ren, Ming Coon, Matthew Liu, Qing Costa, Rui M. Wang, Kuan Hong TI Motor Learning Consolidates Arc-Expressing Neuronal Ensembles in Secondary Motor Cortex SO NEURON LA English DT Article ID PREFRONTAL CORTEX; PROTEIN-SYNTHESIS; SKILL; RATS; ORGANIZATION; PLASTICITY; EXPERIENCE; CIRCUITS; FORELIMB AB Motor behaviors recruit task-specific neuronal ensembles in motor cortices, which are consolidated over subsequent learning. However, little is known about the molecules that can identify the participating neurons and predict the outcomes of the consolidation process. Using a mouse rotarod-learning task, we showed that lesion or inactivation of the secondary motor (M2) cortex disrupts learning of skilled movements. We tracked the endogenous promoter activity of the neuronal activity-regulated gene Arc in individual M2 neurons during rotarod learning by in vivo two-photon imaging of a knockin reporter. We found that task training initially recruits Arc-promoter-activated neurons and then consolidates them into a specific ensemble exhibiting persistent reactivation of Arc-promoter. The intensity of a neuron's initial Arc-promoter activation predicts its reactivation probability and neurons with weak initial Arc-promoter activation are dismissed from the ensemble during subsequent training. Our findings demonstrate a task-specific Arc-dependent cellular consolidation process in M2 cortex during motor learning. C1 [Cao, Vania Yu; Ye, Yizhou; Mastwal, Surjeet; Ren, Ming; Coon, Matthew; Liu, Qing; Wang, Kuan Hong] NIMH, Unit Neural Circuits & Adapt Behav, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Cao, Vania Yu] Brown Univ, NIH, Dept Neurosci, Hlth Grad Partnerships Program, Providence, RI 02912 USA. [Costa, Rui M.] Champalimaud Ctr Unknown, Champalimaud Neurosci Programme, P-1400038 Lisbon, Portugal. [Costa, Rui M.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Costa, RM (reprint author), Champalimaud Ctr Unknown, Champalimaud Neurosci Programme, P-1400038 Lisbon, Portugal. EM rui.costa@neuro.fchampalimaud.org; wkuan@mail.nih.gov RI Wang, Kuan Hong/J-1150-2016 OI Wang, Kuan Hong/0000-0002-2249-5417 FU Brown-NIH GPP Program; National Institute of Mental Health (NIMH) Intramural Research Program; National Institute on Alcohol Abuse and Alcoholism (NIAAA) FX The authors thank B. Connors, L. Belluscio, C. McBain, Y. Zuo, C. Gremel, W. Chen, and D. Kwon for scientific discussion and technical advice. This work was supported by the Brown-NIH GPP Program (V.C.), the National Institute of Mental Health (NIMH) Intramural Research Program (V.C., Y.Y., M.R., S.M., M.C, Q.L, K.W.), and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (R.C.). NR 32 TC 19 Z9 19 U1 3 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 17 PY 2015 VL 86 IS 6 BP 1385 EP 1392 DI 10.1016/j.neuron.2015.05.022 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CQ9ZJ UT WOS:000360976300009 PM 26051420 ER PT J AU Zhai, JB Zhang, L Mojsilovic-Petrovic, J Jian, XY Thomas, J Homma, K Schmitz, A Famulok, M Ichijo, H Argon, Y Randazzo, PA Kalb, RG AF Zhai, Jinbin Zhang, Lei Mojsilovic-Petrovic, Jelena Jian, Xiaoying Thomas, Jeffrey Homma, Kengo Schmitz, Anton Famulok, Michael Ichijo, Hidenori Argon, Yair Randazzo, Paul A. Kalb, Robert G. TI Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ALS; autophagy; ER stress; proteotoxicity; unfolded protein response ID AMYOTROPHIC-LATERAL-SCLEROSIS; SYNUCLEINOPATHY IN-VIVO; SUPEROXIDE-DISMUTASE; MUTANT SOD1; MOUSE MODEL; ER STRESS; H+-ATPASE; V-ATPASE; AUTOPHAGY; ARF AB Mutant genes that underlie Mendelian forms of amyotrophic lateral sclerosis (ALS) and biochemical investigations of genetic disease models point to potential driver pathophysiological events involving endoplasmic reticulum (ER) stress and autophagy. Several steps in these cell biological processes are known to be controlled physiologically by small ADP-ribosylation factor (ARF) signaling. Here, we investigated the role of ARF guanine nucleotide exchange factors (GEFs), cytohesins, in models of ALS. Genetic or pharmacological inhibition of cytohesins protects motor neurons in vitro from proteotoxic insults and rescues locomotor defects in a Caenorhabditis elegans model of disease. Cytohesins form a complex with mutant superoxide dismutase 1 (SOD1), a known cause of familial ALS, but this is not associated with a change in GEF activity or ARF activation. ER stress evoked by mutant SOD1 expression is alleviated by antagonism of cytohesin activity. In the setting of mutant SOD1 toxicity, inhibition of cytohesin activity enhances autophagic flux and reduces the burden of misfolded SOD1. These observations suggest that targeting cytohesins may have potential benefits for the treatment of ALS. C1 [Zhai, Jinbin; Zhang, Lei; Mojsilovic-Petrovic, Jelena; Kalb, Robert G.] Childrens Hosp Philadelphia, Div Pediat Neurol, Res Inst, Philadelphia, PA 19104 USA. [Thomas, Jeffrey; Argon, Yair] Childrens Hosp Philadelphia, Div Cell Pathol, Res Inst, Philadelphia, PA 19104 USA. [Kalb, Robert G.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kalb, Robert G.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Jian, Xiaoying; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Schmitz, Anton; Famulok, Michael] Univ Bonn, Life & Med Sci Inst, D-53121 Bonn, Germany. [Homma, Kengo; Ichijo, Hidenori] Univ Tokyo, Lab Cell Signaling, Tokyo 1130033, Japan. RP Kalb, RG (reprint author), Childrens Hosp Philadelphia, 3615 Civ Ctr Blvd,CHOP ARC 814, Philadelphia, PA 19104 USA. EM kalb@email.chop.edu FU National Institutes of Health (NIH) [AG042179, NS077909, NS052325, AG-18001, CA-009140]; Muscular Dystrophy Association [MDA4264]; intramural program of the NIH [BC007365]; Deutsche Forschungsgemeinschaft [SFB704]; KAKENHI; Japan Society for the Promotion of Science; Strategic Research Program for Brain Sciences; Ministry of Education, Culture, Sports, Science and Technology, Japan; NIH Office of Research Infrastructure Programs [P40 OD010440] FX This work was supported by the National Institutes of Health (NIH Grants AG042179, NS077909, and NS052325 to R.G.K.; Grant AG-18001 to Y.A., and Grant CA-009140 to J.T.) and the Muscular Dystrophy Association (Development Grant MDA4264 to J.Z.). X.J. and P.A.R. are supported by the intramural program of the NIH (Project BC007365). M.F. and A.S. are supported by the Deutsche Forschungsgemeinschaft (Grant SFB704). H.I. is supported by KAKENHI from the Japan Society for the Promotion of Science and the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology, Japan. Stable cell lines were generous gift from Nava Zisapels (NSC-34 cells inducibly expressingWTor mutant SOD). We thank Angela Jablonski, John Flibotte, Vladimir Marshansky, Marco Boccitto, and Ria Lim for thoughtful discussions of this work; Daniel Klionsky, Beth Levine, and David Rubinzstein for measurements and interpretations of autophagic flux experiments; Samuel Todd Lamitina for help in imaging reporter worms in Figure 3; Meera Sundurum for help interpreting the genotyping data for the Arf-1.1 deletion allele (RB1535); Brigid Jensen and Judith Grinspan for the oligodendrite cultures that were used in Figure 4C; and Robert Baloh and Jacqueline O'Rourke for consultation on assays for monitoring misfolded proteins. Some C. elegans strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (Grant P40 OD010440). The tm1447 and tm1877 strains were generously provided by the Shohei Mitani Laboratory (Tokyo Women's Medical University School of Medicine, Japan). NR 77 TC 2 Z9 2 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 17 PY 2015 VL 35 IS 24 BP 9088 EP 9105 DI 10.1523/JNEUROSCI.5032-13.2015 PG 18 WC Neurosciences SC Neurosciences & Neurology GA CN2KU UT WOS:000358250700013 PM 26085633 ER PT J AU Giese, AK Mascher, H Grittner, U Eichler, S Kramp, G Lukas, J Vruchte, DT Al Eisa, N Cortina-Borja, M Porter, FD Platt, FM Rolfs, A AF Giese, Anne-Katrin Mascher, Hermann Grittner, Ulrike Eichler, Sabrina Kramp, Guido Lukas, Jan Vruchte, Danielle Te Al Eisa, Nada Cortina-Borja, Mario Porter, Forbes D. Platt, Frances M. Rolfs, Arndt TI A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Niemann-Pick type C1 disease; NPC1; Biomarker; HPLC-MS/MS ID DRIED BLOOD SPOTS; KRABBE DISEASE; PLASMA AB Background: Lysosomal storage disorders (LSDs), are a heterogeneous group of rare disorders caused by defects in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur at a frequency of about 1 in 5,000 live births, though recent neonatal screening suggests a higher incidence. New treatment options for LSDs demand a rapid, early diagnosis of LSDs if maximal clinical benefit is to be achieved. Methods: Here, we describe a novel, highly specific and sensitive biomarker for Niemann-Pick Type C disease type 1 (NPC1), lyso-sphingomyelin-509. We cross-validate this biomarker with cholestane-3 beta,5 alpha,6 beta-triol and relative lysosomal volume. The primary cohort for establishment of the biomarker contained 135 NPC1 patients, 66 NPC1 carriers, 241 patients with other LSDs and 46 healthy controls. Results: With a sensitivity of 100.0% and specificity of 91.0% a cut-off of 1.4 ng/ml was established. Comparison with cholestane-3 beta,5 alpha,6 beta-triol and relative acidic compartment volume measurements were carried out with a subset of 125 subjects. Both cholestane-3 beta,5 alpha,6 beta-triol and lyso-Sphingomyelin-509 were sufficient in establishing the diagnosis of NPC1 and correlated with disease severity. Conclusion: In summary, we have established a new biomarker for the diagnosis of NPC1, and further studies will be conducted to assess correlation to disease progress and monitoring treatment. C1 [Giese, Anne-Katrin; Lukas, Jan; Rolfs, Arndt] Med Univ Rostock, Albrecht Kossel Inst Neuroregenerat, D-18147 Rostock, Germany. [Mascher, Hermann] PharmAnalyt Labor GmbH, A-2500 Baden, Austria. [Grittner, Ulrike] Charite Univ Med Ctr, Dept Biostat & Clin Epidemiol, Berlin, Germany. [Eichler, Sabrina; Kramp, Guido; Rolfs, Arndt] Centogene AG, D-18055 Rostock, Germany. [Vruchte, Danielle Te; Al Eisa, Nada; Platt, Frances M.] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. [Cortina-Borja, Mario] UCL, Inst Child Hlth, Populat Policy & Practice Programme, London WC1N 1EH, England. [Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, NIH, Bethesda, MD 20892 USA. RP Rolfs, A (reprint author), Med Univ Rostock, Albrecht Kossel Inst Neuroregenerat, Gehlsheimer Str 20, D-18147 Rostock, Germany. EM arndt.rolfs@med.uni-rostock.de RI Cortina Borja, Mario/A-3847-2009; OI Grittner, Ulrike/0000-0003-2595-0224 FU UK Department of Health's NIH Research Biomedical Research Funding Centres funding scheme; Action Medical Research; Actelion; intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX The authors would like to thank all patients and clinical partners who have contributed to the recruitment of the patients. Special thanks are extended to Susanne Zielke, Sabine Rosner, Frances Konig, Vivian Kersten and Lea Maciolek for important support in the organization of the clinical study. F.M.P. is a Royal Society Wolfson Research Merit Award holder. The University College London Institute of Child Health receives a portion of its funding from the UK Department of Health's NIH Research Biomedical Research Funding Centres funding scheme. DtV is supported by Action Medical Research and an unrestricted grant from Actelion. FDP is supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 20 TC 18 Z9 18 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD JUN 17 PY 2015 VL 10 AR 78 DI 10.1186/s13023-015-0274-1 PG 8 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA CL0RV UT WOS:000356651700001 PM 26082315 ER PT J AU Kaushik, G Spenlehauer, A Sessions, AO Trujillo, AS Fuhrmann, A Fu, ZM Venkatraman, V Pohl, D Tuler, J Wang, MY Lakatta, EG Ocorr, K Bodmer, R Bernstein, SI Van Eyk, JE Cammarato, A Engler, AJ AF Kaushik, Gaurav Spenlehauer, Alice Sessions, Ayla O. Trujillo, Adriana S. Fuhrmann, Alexander Fu, Zongming Venkatraman, Vidya Pohl, Danielle Tuler, Jeremy Wang, Mingyi Lakatta, Edward G. Ocorr, Karen Bodmer, Rolf Bernstein, Sanford I. Van Eyk, Jennifer E. Cammarato, Anthony Engler, Adam J. TI Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ADULT-RAT CARDIOMYOCYTES; ASSIST DEVICE SUPPORT; DROSOPHILA-MELANOGASTER; DILATED CARDIOMYOPATHY; DIASTOLIC DYSFUNCTION; CELL-CELL; MECHANOTRANSDUCTION; FAILURE; FORCE; MYOCARDIUM AB The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. A broad array of potential therapeutic targets and regulators of age-associated modifications, specifically for vinculin, are presented. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts. C1 [Kaushik, Gaurav; Spenlehauer, Alice; Fuhrmann, Alexander; Pohl, Danielle; Tuler, Jeremy; Engler, Adam J.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Sessions, Ayla O.; Engler, Adam J.] Univ Calif San Diego, Program Biomed Sci, La Jolla, CA 92093 USA. [Trujillo, Adriana S.; Bernstein, Sanford I.] San Diego State Univ, Heart Inst & Mol Biol, Dept Biol, San Diego, CA 92182 USA. [Fu, Zongming; Van Eyk, Jennifer E.; Cammarato, Anthony] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Venkatraman, Vidya; Van Eyk, Jennifer E.; Cammarato, Anthony] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, Adv Clin Biosyst Res Inst, Los Angeles, CA 90048 USA. [Wang, Mingyi; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Ocorr, Karen; Bodmer, Rolf] Sanford Burnham Med Res Inst, Dev & Aging Program, La Jolla, CA 92037 USA. [Engler, Adam J.] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA. RP Cammarato, A (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. EM acammar3@jhmi.edu; aengler@ucsd.edu OI Engler, Adam/0000-0003-1642-5380 FU NIH [HHSN268201000032C, P01HL077180, T32HL105373, R01AG045428, DP02OD006460, R01GM32443, R56HL124091, R21HL106529]; American Heart Association [10SDG4180089, 13PRE14410037]; American Federation for Aging Research FX This work was supported by grants from the NIH (HHSN268201000032C, P01HL077180, T32HL105373, R01AG045428, DP02OD006460, R01GM32443, R56HL124091, and R21HL106529), the American Heart Association (10SDG4180089 and 13PRE14410037), the American Federation for Aging Research, and intramural support from the NIA. A.S.T. is a fellow of the Rees-Stealy Research Foundation and the San Diego State University Heart Institute. NR 47 TC 0 Z9 0 U1 4 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUN 17 PY 2015 VL 7 IS 292 AR 292ra99 DI 10.1126/scitranslmed.aaa5843 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CK7DG UT WOS:000356390500004 PM 26084806 ER PT J AU Brigman, JL Daut, RA Saksida, L Bussey, TJ Nakazawa, K Holmes, A AF Brigman, Jonathan L. Daut, Rachel A. Saksida, Lisa Bussey, Timothy J. Nakazawa, Kazu Holmes, Andrew TI Impaired discrimination learning in interneuronal NMDAR-GluN2B mutant mice SO NEUROREPORT LA English DT Article DE addiction; instrumental; N-methyl-D-aspartate; prefrontal cortex; reward; schizophrenia; striatum; touchscreen ID NMDA RECEPTOR SUBUNITS; ORBITOFRONTAL CORTEX; SYNAPTIC PLASTICITY; GLUN2B; BEHAVIOR; SCHIZOPHRENIA; ANTAGONISM; STRESS; CHOICE; RISKY AB Previous studies have established a role for N-methyl-D-aspartate receptor (NMDAR) containing the GluN2B subunit in efficient learning behavior on a variety of tasks. Recent findings have suggested that NMDAR on GABAergic interneurons may underlie the modulation of striatal function necessary to balance efficient action with cortical excitatory input. Here we investigated how loss of GluN2B-containing NMDAR on GABAergic interneurons altered corticostriatal-mediated associative learning. Mutant mice (floxed-GluN2B x Ppp1r2-Cre) were generated to produce loss of GluN2B on forebrain interneurons and phenotyped on a touchscreen-based pairwise visual learning paradigm. We found that the mutants showed normal performance during Pavlovian and instrumental pretraining, but were significantly impaired on a discrimination learning task. Detailed analysis of the microstructure of discrimination performance revealed reduced win. stay behavior in the mutants. These results further support the role of NMDAR, and GluN2B in particular, on modulation of striatal function necessary for efficient choice behavior and suggest that NMDAR on interneurons may play a critical role in associative learning. NeuroReport 26:489-494 Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Brigman, Jonathan L.] Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. [Daut, Rachel A.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Rockville, MD 20852 USA. [Nakazawa, Kazu] Univ Alabama Birmingham, Sch Med, Dept Psychiat, Birmingham, AL USA. [Saksida, Lisa; Bussey, Timothy J.] Univ Cambridge, MRC, Dept Expt Psychol, Cambridge, England. [Saksida, Lisa; Bussey, Timothy J.] Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England. RP Brigman, JL (reprint author), Univ New Mexico, Sch Med, Dept Neurosci, MSC08 4740,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM jbrigman@salud.unm.edu RI Bussey, Timothy/M-2758-2016; Saksida, Lisa/M-2753-2016; Brigman, Jonathan/O-4978-2016 OI Bussey, Timothy/0000-0001-7518-4041; Nakazawa, Kazutoshi/0000-0001-5699-9093; Saksida, Lisa/0000-0002-8416-8171; FU National Institutes of Health [1K22AA020303-01]; National Institute on Alcohol Abuse and Alcoholism Intramural Research Program FX Research supported by National Institutes of Health grant 1K22AA020303-01 and the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 28 TC 0 Z9 0 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-4965 EI 1473-558X J9 NEUROREPORT JI Neuroreport PD JUN 17 PY 2015 VL 26 IS 9 BP 489 EP 494 DI 10.1097/WNR.0000000000000373 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CJ2OG UT WOS:000355323700001 PM 25968910 ER PT J AU Shah, S Luby, M Poole, K Morella, T Keller, E Benson, RT Lynch, JK Nadareishvili, Z Hsia, AW AF Shah, Shreyansh Luby, Marie Poole, Karen Morella, Teresa Keller, Elizabeth Benson, Richard T. Lynch, John K. Nadareishvili, Zurab Hsia, Amie W. TI Screening with MRI for Accurate and Rapid Stroke Treatment SMART SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; TO-NEEDLE TIMES; PLASMINOGEN-ACTIVATOR; HOSPITAL PRENOTIFICATION; COMPUTED-TOMOGRAPHY; THROMBOLYSIS; TISSUE; FEASIBILITY; PROTOCOL; MINUTES AB Objective: The objective of this study was to demonstrate the feasibility of timely multimodal MRI screening before thrombolysis in acute stroke patients. Methods: Quality improvement processes were initiated in 2013 to reduce door-to-needle (DTN) time at the 2 hospitals where the NIH stroke team provides clinical care. Acute ischemic stroke (AIS) patients who received IV tissue plasminogen activator (tPA) <= 4.5 hours from last known normal were identified. Demographic and clinical characteristics and timing metrics were analyzed comparing the time periods before, during, and after the quality improvement processes. Results: There were 157 patients treated with IV tPA for AIS during 2012-2013, of whom 135 (86%) were screened with MRI. DTN time was significantly reduced by 40% during this period from a median of 93 minutes in the first half of 2012 to 55 minutes in the last half of 2013 (p < 0.0001) with a significant 4-fold increase in the proportion of treated patients with DTN time <= 60 minutes from 13.0% to 61.5%, respectively (p < 0.00001). Improvement in DTN time was associated with reduced door-to-MRI time, and there were no differences in demographic or clinical characteristics (p = 0.21-0.76). Conclusions: It is feasible and practical to consistently and rapidly deliver IV tPA to AIS patients within national benchmark times using MRI as the routine screening modality. The processes used in the SMART (Screening with MRI for Accurate and Rapid Stroke Treatment) Study to reduce DTN time have the potential to be widely applicable to other hospitals. C1 [Shah, Shreyansh; Luby, Marie; Poole, Karen; Morella, Teresa; Benson, Richard T.; Lynch, John K.; Nadareishvili, Zurab; Hsia, Amie W.] NINDS, Sect Stroke Diagnost & Therapeut, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Poole, Karen; Keller, Elizabeth; Benson, Richard T.; Hsia, Amie W.] MedStar Washington Hosp Ctr, Stroke Ctr, Washington, DC USA. [Morella, Teresa; Nadareishvili, Zurab] Suburban Hosp Stroke Program, Bethesda, MD USA. RP Hsia, AW (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM amie.hsia@medstar.net FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH FX This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH. NR 22 TC 13 Z9 15 U1 3 U2 4 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 JUN 16 PY 2015 VL 84 IS 24 BP 2438 EP 2444 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DC2VX UT WOS:000369077700013 PM 25972494 ER PT J AU Suchankova, P Yan, J Schwandt, ML Stangl, BL Caparelli, EC Momenan, R Jerlhag, E Engel, JA Hodgkinson, CA Egli, M Lopez, MF Becker, HC Goldman, D Heilig, M Ramchandani, VA Leggio, L AF Suchankova, P. Yan, J. Schwandt, M. L. Stangl, B. L. Caparelli, E. C. Momenan, R. Jerlhag, E. Engel, J. A. Hodgkinson, C. A. Egli, M. Lopez, M. F. Becker, H. C. Goldman, D. Heilig, M. Ramchandani, V. A. Leggio, L. TI The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID POPULATION-BASED SAMPLE; VENTRAL TEGMENTAL AREA; FOOD-INTAKE; REWARD ANTICIPATION; GLP-1; POLYMORPHISM; EXENDIN-4; CORRELATE; SMOKING; ANALOG AB The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD. C1 [Suchankova, P.; Leggio, L.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Suchankova, P.; Jerlhag, E.; Engel, J. A.] Univ Gothenburg, Sahlgrenska Acad, Dept Pharmacol, Gothenburg, Sweden. [Yan, J.; Stangl, B. L.; Ramchandani, V. A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Yan, J.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Schwandt, M. L.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Caparelli, E. C.; Leggio, L.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Momenan, R.] NIAAA, Sect Brain Electrophysiol & Imaging, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Hodgkinson, C. A.; Goldman, D.] NIAAA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Egli, M.] NIAAA, Div Neurosci & Behav, Bethesda, MD 20892 USA. [Lopez, M. F.; Becker, H. C.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston Alcohol Res Ctr, Charleston, SC 29425 USA. [Becker, H. C.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Becker, H. C.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Leggio, L.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, 10 Ctr Dr 10CRC 15330 MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016; Leggio, Lorenzo/M-2972-2016 OI Goldman, David/0000-0002-1724-5405; FU Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIAAA Extramural Division of Neuroscience and Behavior via the NIH/NIAAA contract 'Preclinical Medications Screening in Alcohol Dependence and Anxiety Models' [HHSN267200700038C]; Swedish Brain Foundation; LUA/ALF grant from the Sahlgrenska University Hospital [148251]; Indiana Alcohol Research Center [NIH P60 AA007611]; NIH Genes, Environment and Health Initiative (GEI) [U01HG004422]; Gene Environment Association Studies under GEI; NIH GEI [U01HG004438]; NIAAA; NIDA; NIH [HHSN268200782096C] FX This work was supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA; PS, JY, MLS, BLS, RM, CAH, DG, MH, VAR, LL), the Intramural Research Program of the National Institute on Drug Abuse (NIDA; PS, ECC, LL). This work was also supported by the NIAAA Extramural Division of Neuroscience and Behavior via the NIH/NIAAA contract 'Preclinical Medications Screening in Alcohol Dependence and Anxiety Models' (HHSN267200700038C; ME, MFL, HCB), under which the compound AC3174 was provided to NIAAA for testing by Medical University of South Carolina (MUSC). AC3174 was manufactured by Amylin Pharmaceuticals and is now owned by MedImmune, LLC (a wholly owned subsidiary of AstraZeneca), whose staff reviewed and authorized the use of the data described in the 'Study 5'. In addition, this work was supported by the Swedish Brain Foundation (PS), and a LUA/ALF grant (no. 148251) from the Sahlgrenska University Hospital (PS, EJ, JAE). Development of the Computerized Alcohol Infusion System (CAIS) software used in the IV-ASA study was supported by the Indiana Alcohol Research Center (NIH P60 AA007611). Finally, funding support for the Study of Addiction: Genetics and Environment (SAGE; Study 2) was provided through the NIH Genes, Environment and Health Initiative (GEI; U01HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), NIAAA, NIDA and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. NR 50 TC 10 Z9 10 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUN 16 PY 2015 VL 5 AR e583 DI 10.1038/tp.2015.68 PG 11 WC Psychiatry SC Psychiatry GA DA2WW UT WOS:000367658900004 PM 26080318 ER PT J AU Beg, I Minton, AP Hassan, MI Islam, A Ahmad, F AF Beg, Ilyas Minton, Allen P. Hassan, Md. Imtaiyaz Islam, Asimul Ahmad, Faizan TI Thermal Stabilization of Proteins by Mono- and Oligosaccharides: Measurement and Analysis in the Context of an Excluded Volume Model SO BIOCHEMISTRY LA English DT Article ID NATURALLY-OCCURRING OSMOLYTES; PREFERENTIAL INTERACTIONS; GUANIDINE-HYDROCHLORIDE; CONCENTRATED-SOLUTIONS; STABILITY PARAMETERS; UNFOLDED PROTEINS; RIBONUCLEASE-A; DENATURATION; EQUILIBRIA; HYDRATION AB The reversible thermal denaturation of apo a-lactalbumin and lysozyme was monitored via measurement of changes in absorbance and ellipticity in the presence of varying concentrations of seven mono- and oligosaccharides: glucose, galactose, fructose, sucrose, trehalose, raffinose, and stachyose. The temperature dependence of the unfolding curves was quantitatively accounted for by a two-state model, according to which the free energy of unfolding is increased by an amount that is independent of temperature and depends linearly upon the concentration of added saccharide. The increment of added unfolding free energy per mole of added saccharide was found to depend approximately linearly upon the extent of oligomerization of the saccharide. The relative strength of stabilization of different saccharide oligomers could be accounted for by a simplified statistical-thermodynamic model attributing the stabilization effect to volume exclusion deriving from steric repulsion between protein and saccharide molecules. C1 [Beg, Ilyas; Hassan, Md. Imtaiyaz; Islam, Asimul; Ahmad, Faizan] Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India. [Minton, Allen P.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP Ahmad, F (reprint author), Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi 110025, India. EM minton@helix.nih.gov; fahmad@jmi.ac.in OI Minton, Allen/0000-0001-8459-1247 FU Council of Scientific and Industrial Research, India [37(1603)/13/EMRII, 37(1604)/13/EMRII]; National Institute of Diabetes and Digestive and Kidney Diseases FX The research of F.A. and A.I. was supported by the Council of Scientific and Industrial Research, India [Grants 37(1603)/13/EMRII and 37(1604)/13/EMRII]. The research of A.P.M. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 53 TC 5 Z9 5 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 16 PY 2015 VL 54 IS 23 BP 3594 EP 3603 DI 10.1021/acs.biochem.5b00415 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CL2DQ UT WOS:000356754200005 PM 26000826 ER PT J AU Green, CR Cowan, P Elk, R O'Neil, KM Rasmussen, AL AF Green, Carmen R. Cowan, Penney Elk, Ronit O'Neil, Kathleen M. Rasmussen, Angela L. TI National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome SO ANNALS OF INTERNAL MEDICINE LA English DT Article AB The National Institutes of Health (NIH) Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome was cosponsored by the NIH Office of Disease Prevention and the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Working Group. A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion. During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the NIH Office of Disease Prevention Web site for 4 weeks for public comment. C1 [Green, Carmen R.] Univ Michigan Hlth Syst, Off Hlth Equ & Inclus, Ann Arbor, MI 48109 USA. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA 95677 USA. [Elk, Ronit] Univ S Carolina, Coll Nursing, Columbia, SC 29208 USA. [O'Neil, Kathleen M.] Indiana Univ Hlth, Riley Hosp Children, Indianapolis, IN 46202 USA. [Rasmussen, Angela L.] Univ Washington, Katze Lab, Seattle, WA 98109 USA. RP Green, CR (reprint author), NIH, Off Dis Prevent, 6100 Execut Blvd,Room 2B03,MSC 7523, Rockville, MD 20852 USA. OI Rasmussen, Angela/0000-0001-9462-3169 NR 0 TC 12 Z9 12 U1 0 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 16 PY 2015 VL 162 IS 12 BP 860 EP + DI 10.7326/M15-0338 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK8VC UT WOS:000356516300021 PM 26075757 ER PT J AU Marinelli, F Faraldo-Gomez, JD AF Marinelli, Fabrizio Faraldo-Gomez, Jose D. TI Ensemble-Biased Metadynamics: A Molecular Simulation Method to Sample Experimental Distributions SO BIOPHYSICAL JOURNAL LA English DT Article ID LYSOZYME AB We introduce an enhanced-sampling method for molecular dynamics (MD) simulations referred to as ensemble-biased metadynamics (EBMetaD). The method biases a conventional MD simulation to sample a molecular ensemble that is consistent with one or more probability distributions known a priori, e.g., experimental intramolecular distance distributions obtained by double electron-electron resonance or other spectroscopic techniques. To this end, EBMetaD adds an adaptive biasing potential throughout the simulation that discourages sampling of configurations inconsistent with the target probability distributions. The bias introduced is the minimum necessary to fulfill the target distributions, i.e., EBMetaD satisfies the maximum-entropy principle. Unlike other methods, EBMetaD does not require multiple simulation replicas or the introduction of Lagrange multipliers, and is therefore computationally efficient and straightforward in practice. We demonstrate the performance and accuracy of the method for a model system as well as for spin-labeled T4 lysozyme in explicit water, and show how EBMetaD reproduces three double electron-electron resonance distance distributions concurrently within a few tens of nanoseconds of simulation time. EBMetaD is integrated in the open-source PLUMED plug-in (www.plumed-code.org), and can be therefore readily used with multiple MD engines. C1 [Marinelli, Fabrizio; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Marinelli, F (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM fabrizio.marinelli@nih.gov; jose.faraldo@nih.gov RI Faraldo-Gomez, Jose/H-7127-2016 FU Division of Intramural Research of the National, Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD FX This work was funded by the Division of Intramural Research of the National, Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. NR 14 TC 6 Z9 6 U1 1 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUN 16 PY 2015 VL 108 IS 12 BP 2779 EP 2782 DI 10.1016/j.bpj.2015.05.024 PG 4 WC Biophysics SC Biophysics GA CK6UO UT WOS:000356364000009 PM 26083917 ER PT J AU Solon-Biet, SM Mitchell, SJ Coogan, SCP Cogger, VC Gokarn, R McMahon, AC Raubenheimer, D de Cabo, R Simpson, SJ Le Couteur, DG AF Solon-Biet, Samantha M. Mitchell, Sarah J. Coogan, Sean C. P. Cogger, Victoria C. Gokarn, Rahul McMahon, Aisling C. Raubenheimer, David de Cabo, Rafael Simpson, Stephen J. Le Couteur, David G. TI Dietary Protein to Carbohydrate Ratio and Caloric Restriction: Comparing Metabolic Outcomes in Mice SO CELL REPORTS LA English DT Article ID FATTY LIVER-DISEASE; LIFE-SPAN; ENERGY-INTAKE; INSULIN ACTION; OBESITY; LEVERAGE; BALANCE; HUMANS; THERMOGENESIS; LONGEVITY AB Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake. C1 [Solon-Biet, Samantha M.; Coogan, Sean C. P.; Cogger, Victoria C.; McMahon, Aisling C.; Raubenheimer, David; Simpson, Stephen J.; Le Couteur, David G.] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Solon-Biet, Samantha M.; Cogger, Victoria C.; Gokarn, Rahul; McMahon, Aisling C.; Le Couteur, David G.] Univ Sydney, Concord Hosp, Ageing & Alzheimers Inst, Sydney, NSW 2139, Australia. [Solon-Biet, Samantha M.; Cogger, Victoria C.; Gokarn, Rahul; McMahon, Aisling C.; Le Couteur, David G.] Univ Sydney, Concord Hosp, ANZAC Res Inst, Sydney, NSW 2139, Australia. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Solon-Biet, Samantha M.; Coogan, Sean C. P.; Raubenheimer, David; Simpson, Stephen J.] Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. [Raubenheimer, David] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. RP Solon-Biet, SM (reprint author), Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. EM samantha.solon-biet@sydney.edu.au; stephen.simpson@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Simpson, Stephen J./0000-0003-0256-7687; , rafael/0000-0003-2830-5693 FU National Health and Medical Research Council (NHMRC) of Australia [571328, 571408]; Ageing and Alzheimers Institute (AAAI) of Concord Hospital; National Institute on Aging Intramural Research Program of the National Institutes of Health; National Medical Health and Research Council of Australia CJ Martin Early Career Fellowship (RGMS) [2010-01671]; Intramural Research Program of the National Institute on Aging FX This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (Project grant 571328, Program grant 571408), and the Ageing and Alzheimers Institute (AAAI) of Concord Hospital. This study was funded in part by the National Institute on Aging Intramural Research Program of the National Institutes of Health. S.J.M. was supported by a National Medical Health and Research Council of Australia CJ Martin Early Career Fellowship (RGMS ID 2010-01671). R.d.C is supported by the Intramural Research Program of the National Institute on Aging. D.R. is an Adjunct Professor in the New Zealand Institute for Advanced Study, Massey University, Auckland. We are grateful to Dawn Nines, Justine Lucas, and Dawn Phillips-Boyer for their animal care and assistance. We also thank Dr. Alistair Senior for his helpful comments and advice. NR 36 TC 20 Z9 20 U1 7 U2 94 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 16 PY 2015 VL 11 IS 10 BP 1529 EP 1534 DI 10.1016/j.celrep.2015.05.007 PG 6 WC Cell Biology SC Cell Biology GA CK6XM UT WOS:000356372100005 PM 26027933 ER PT J AU Liu, N Hadj-Bouziane, F Jones, KB Turchi, JN Averbeck, BB Ungerleider, LG AF Liu, Ning Hadj-Bouziane, Fadila Jones, Katherine B. Turchi, Janita N. Averbeck, Bruno B. Ungerleider, Leslie G. TI Oxytocin modulates fMRI responses to facial expression in macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oxytocin; neuroimaging; nonhuman primate; social stimuli ID INFERIOR TEMPORAL CORTEX; FRONTAL EYE FIELD; INTRANASAL OXYTOCIN; RHESUS MACAQUES; CORTICAL CONNECTIONS; PREFRONTAL CORTEX; NEURAL CIRCUITRY; RECEPTOR-BINDING; CONTRAST AGENT; MACACA-MULATTA AB Increasing evidence has shown that oxytocin (OT), a mammalian hormone, modifies the way social stimuli are perceived and the way they affect behavior. Thus, OT may serve as a treatment for psychiatric disorders, many of which are characterized by dysfunctional social behavior. To explore the neural mechanisms mediating the effects of OT in macaque monkeys, we investigated whether OT would modulate functional magnetic resonance imaging (fMRI) responses in face-responsive regions (faces vs. blank screen) evoked by the perception of various facial expressions (neutral, fearful, aggressive, and appeasing). In the placebo condition, we found significantly increased activation for emotional (mainly fearful and appeasing) faces compared with neutral faces across the face-responsive regions. OT selectively, and differentially, altered fMRI responses to emotional expressions, significantly reducing responses to both fearful and aggressive faces in face-responsive regions while leaving responses to appeasing as well as neutral faces unchanged. We also found that OT administration selectively reduced functional coupling between the amygdala and areas in the occipital and inferior temporal cortex during the viewing of fearful and aggressive faces, but not during the viewing of neutral or appeasing faces. Taken together, our results indicate homologies between monkeys and humans in the neural circuits mediating the effects of OT. Thus, the monkey may be an ideal animal model to explore the development of OT-based pharmacological strategies for treating patients with dysfunctional social behavior. C1 [Liu, Ning; Hadj-Bouziane, Fadila; Jones, Katherine B.; Ungerleider, Leslie G.] NIMH, Sect Neurocircuitry, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Turchi, Janita N.] NIMH, Sect Cognit Neurosci, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Averbeck, Bruno B.] NIMH, Unit Learning & Decis Making, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Liu, N (reprint author), NIMH, Sect Neurocircuitry, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM lning@mail.nih.gov; ungerlel@mail.nih.gov FU National Institute of Mental Health Intramural Research Program FX This work was supported by the National Institute of Mental Health Intramural Research Program (N.L., F.H-B., K.B.J., J.N.T., B.B.A., and L.G.U.). We thank Frank Q. Ye, Charles C. Zhu, and David C. Ide for technical assistance; Katalin M. Gothard for providing the original monkey facial expression stimuli; and Biying Xu for providing the exogenous contrast agent. NR 59 TC 13 Z9 13 U1 3 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 16 PY 2015 VL 112 IS 24 BP E3123 EP E3130 DI 10.1073/pnas.1508097112 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK5GS UT WOS:000356251800008 PM 26015576 ER PT J AU Kolev, M Dimeloe, S Le Friec, G Navarini, A Arbore, G Povoleri, GA Fischer, M Belle, R Loeliger, J Develioglu, L Bantug, GR Watson, J Couzi, L Afzali, B Lavender, P Hess, C Kemper, C AF Kolev, Martin Dimeloe, Sarah Le Friec, Gaelle Navarini, Alexander Arbore, Giuseppina Povoleri, Giovanni A. Fischer, Marco Belle, Reka Loeliger, Jordan Develioglu, Leyla Bantug, Glenn R. Watson, Julie Couzi, Lionel Afzali, Behdad Lavender, Paul Hess, Christoph Kemper, Claudia TI Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses SO IMMUNITY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; COFACTOR PROTEIN CD46; T-CELLS; EFFECTOR FUNCTION; MAMMALIAN TARGET; GLUCOSE-UPTAKE; GLYCOLYTIC SWITCH; AMINO-ACIDS; ACTIVATION; EXPRESSION AB Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-gamma production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4(+) T cell effector function. C1 [Kolev, Martin; Le Friec, Gaelle; Arbore, Giuseppina; Povoleri, Giovanni A.; Afzali, Behdad; Kemper, Claudia] Guys Hosp, Kings Coll London, MRC Ctr Transplantat, Div Transplant Immunol & Mucosal Biol, London SE1 9RT, England. [Dimeloe, Sarah; Fischer, Marco; Belle, Reka; Loeliger, Jordan; Develioglu, Leyla; Bantug, Glenn R.; Hess, Christoph] Univ Basel, Dept Biomed Immunobiol, CH-4031 Basel, Switzerland. [Navarini, Alexander] Univ Zurich Hosp, Dept Dermatol, Zurich, Switzerland. [Povoleri, Giovanni A.; Afzali, Behdad] Guys Hosp, Biomed Res Ctr, Kings Hlth Partners, London SE1 9RT, England. [Watson, Julie; Lavender, Paul] Guys Hosp, Kings Coll London, MRC & Asthma UK Ctr Allerg Mech Asthma, London SE1 9RT, England. [Couzi, Lionel] Hosp Pellegrin, CNRS, CHU Bordeaux, Nephrol Transplantat,UMR 1564, F-33076 Bordeaux, France. [Afzali, Behdad] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Hess, C (reprint author), Univ Basel, Dept Biomed Immunobiol, 20 Hebelstr, CH-4031 Basel, Switzerland. EM chess@uhbs.ch; claudia.kemper@kcl.ac.uk RI kolev, mihail/D-1476-2015; Afzali, Behdad/H-8565-2013 OI kolev, mihail/0000-0002-5226-4759; Dimeloe, Sarah/0000-0002-4598-6518; Afzali, Behdad/0000-0003-2968-1156 FU MRC [G1002165, MR/J006742/1]; EU; Wellcome Trust; National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust, and King's College London; Roche; Gebert Ruf Foundation [GRS-058/14]; Swiss National Science Foundation [310030-153059, 323530-139181] FX We thank the donors and the patients for their support, Margaret So (University of Arizona) for the anti-CD46 CYT-1 and CYT-2 antibodies and Erez Dror (University of Basel) for help with nutrient uptake studies. This work was supported by the MRC grants G1002165 (C.K.) and MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (C.K.), a Wellcome Trust Investigator Award (C.K), a Wellcome Trust Intermediate Research Fellowship (B.A.), the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust, and King's College London. S.D. was supported by the Roche Postdoctoral Fellowship Program, C.H. by the Gebert Ruf Foundation (GRS-058/14), and both C.H. and M.F. by the Swiss National Science Foundation (310030-153059 and 323530-139181, respectively). NR 56 TC 21 Z9 23 U1 4 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 16 PY 2015 VL 42 IS 6 BP 1033 EP 1047 DI 10.1016/j.immuni.2015.05.024 PG 15 WC Immunology SC Immunology GA CK6UC UT WOS:000356362800010 PM 26084023 ER PT J AU Askenase, MH Han, SJ Byrd, AL da Fonseca, DM Bouladoux, N Wilhelm, C Konkel, JE Hand, TW Lacerda-Queiroz, N Su, XZ Trinchieri, G Grainger, JR Belkaid, Y AF Askenase, Michael H. Han, Seong-Ji Byrd, Allyson L. da Fonseca, Denise Morais Bouladoux, Nicolas Wilhelm, Christoph Konkel, Joanne E. Hand, Timothy W. Lacerda-Queiroz, Norinne Su, Xin-zhuan Trinchieri, Giorgio Grainger, John R. Belkaid, Yasmine TI Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function during Infection SO IMMUNITY LA English DT Article ID CD8-ALPHA(+) DENDRITIC CELLS; TOXOPLASMA-GONDII; INFLAMMATORY MONOCYTES; T-CELLS; MACROPHAGES; DIFFERENTIATION; HOMEOSTASIS; GAMMA; PROGENITOR; RESISTANCE AB Tissue-infiltrating Ly6C(hi) monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-gamma promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DCs) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals after tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function. C1 [Askenase, Michael H.; Han, Seong-Ji; Byrd, Allyson L.; da Fonseca, Denise Morais; Bouladoux, Nicolas; Wilhelm, Christoph; Hand, Timothy W.; Grainger, John R.; Belkaid, Yasmine] NIAID, Program Barrier Immun & Repair, Mucosal Immunol Sect, Parasit Dis Lab,NIH, Bethesda, MD 20892 USA. [Askenase, Michael H.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Byrd, Allyson L.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Konkel, Joanne E.; Grainger, John R.] Univ Manchester, MCCIR, Manchester M13 9NT, Lancs, England. [Konkel, Joanne E.; Grainger, John R.] Univ Manchester, Fac Life Sci, Manchester M13 9NT, Lancs, England. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Trinchieri, Giorgio] NCI, Expt Immunol Lab, Head Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Grainger, JR (reprint author), NIAID, Program Barrier Immun & Repair, Mucosal Immunol Sect, Parasit Dis Lab,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.grainger-2@manchester.ac.uk; ybelkaid@niaid.nih.gov OI Grainger, John/0000-0002-4052-5923; Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research of NIAID; Wellcome Trust; Royal Society [104195/Z/14/Z] FX This work was supported by the Division of Intramural Research of NIAID. J.R.G. is a Sir Henry Dale fellow, jointly funded by The Wellcome Trust and The Royal Society (grant number 104195/Z/14/Z). We thank the NIAID animal facility staff, Dr. K. Holmes, Dr. E. Stregevsky, N. Bubunenko, M. Solano-Dias, J. LeGrand, and K. Beacht, for technical assistance. We also thank Dr. A. J. Radtke, Dr. M. Guilliams, Dr. J. Hettinger, and Dr. M. Feuerer for technical advice and discussion. Dr. G. Hart and Dr. E.O. Long graciously provided the protocol for NK depletion as well as purified antibody to perform this study. Dr. I. E. Brodsky generously provided Y. pseudotuberculosis. Additionally, we thank Dr. S. Henri and Dr. S. Tamoutounour for thoughtful discussions and critical reading of the manuscript. NR 40 TC 19 Z9 19 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 16 PY 2015 VL 42 IS 6 BP 1130 EP 1142 DI 10.1016/j.immuni.2015.05.011 PG 13 WC Immunology SC Immunology GA CK6UC UT WOS:000356362800017 PM 26070484 ER PT J AU Fennessey, CM Reid, C Lipkey, L Newman, L Oswald, K Piatak, M Roser, JD Chertova, E Smedley, J Alvord, WG Del Prete, GQ Estes, JD Lifson, JD Keele, BF AF Fennessey, Christine M. Reid, Carolyn Lipkey, Leslie Newman, Laura Oswald, Kelli Piatak, Michael, Jr. Roser, James D. Chertova, Elena Smedley, Jeremy Alvord, W. Gregory Del Prete, Gregory Q. Estes, Jacob D. Lifson, Jeffrey D. Keele, Brandon F. TI Generation and characterization of a SIVmac239 clone corrected at four suboptimal nucleotides SO RETROVIROLOGY LA English DT Article DE SIV; Evolution; Models of AIDS ID SIMIAN IMMUNODEFICIENCY VIRUS; REVERSE-TRANSCRIPTASE; RHESUS MACAQUES; HIV-1 INFECTION; TRANSFER-RNAS; REPLICATION; TYPE-1; IDENTIFICATION; VARIANTS; SEQUENCE AB Background: SIVmac239 is a commonly used virus in non-human primate models of HIV transmission and pathogenesis. Previous studies identified four suboptimal nucleotides in the SIVmac239 genome, which putatively inhibit its replicative capacity. Since all four suboptimal changes revert to the optimal nucleotide consensus sequence during viral replication in vitro and in vivo, we sought to eliminate the variability of generating these mutations de novo and increase the overall consistency of viral replication by introducing the optimal nucleotides directly to the infectious molecular clone. Results: Using site directed mutagenesis of the full-length/nef-open SIVmac239 clone, we reverted all four nucleotides to the consensus/optimal base to generate SIVmac239Opt and subsequently tested its infectivity and replicative capacity in vitro and in vivo. In primary and cell line cultures, we observed that the optimized virus displayed consistent modest but not statistically significant increases in replicative kinetics compared to wild type. In vivo, SIVmac239Opt replicated to high peak titers with an average of 1.2 x 10(8) viral RNA copies/ml at day 12 following intrarectal challenge, reaching set-point viremia of 1.2 x 10(6) viral RNA copies/ml by day 28. Although the peak and set point viremia means were not statistically different from the original "wild type" SIVmac239, viral load variation at set point was greater for SIVmac239WT compared to SIVmac239Opt (p = 0.0015) demonstrating a greater consistency of the optimized virus. Synonymous mutations were added to the integrase gene of SIVmac239Opt to generate a molecular tag consisting of ten genetically distinguishable viral variants referred to as SIVmac239OptX (Del Prete et al., J Virol. doi:10.1128/JVI.01026-14, 2014). Replication dynamics in vitro of these optimized clones were not statistically different from the parental clones. Interestingly, the consistently observed rapid reversion of the primer binding site suboptimal nucleotide is not due to viral RT error but is changed post-integration of a mismatched base via host proofreading mechanisms. Conclusions: Overall, our results demonstrate that SIVmac239Opt is a functional alternative to parental SIVmac239 with marginally faster replication dynamics and with increased replication uniformity providing a more consistent and reproducible infection model in nonhuman primates. C1 [Fennessey, Christine M.; Reid, Carolyn; Lipkey, Leslie; Newman, Laura; Oswald, Kelli; Piatak, Michael, Jr.; Roser, James D.; Chertova, Elena; Del Prete, Gregory Q.; Estes, Jacob D.; Lifson, Jeffrey D.; Keele, Brandon F.] Leidos Biomed Res Inc, Retroviral Evolut Sect, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Smedley, Jeremy] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Smedley, Jeremy] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Alvord, W. Gregory] Leidos Biomed Res Inc, Stat Consulting, Data Management Serv, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Keele, BF (reprint author), Leidos Biomed Res Inc, Retroviral Evolut Sect, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Bldg 535,Rm 408, Frederick, MD 21702 USA. EM keelebf@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We acknowledge Drs. Rob Gorelick and David Ott from the AIDS and Cancer Virus Program for helpful discussions. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 28 TC 3 Z9 3 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUN 16 PY 2015 VL 12 AR 49 DI 10.1186/s12977-015-0175-3 PG 14 WC Virology SC Virology GA CK7LF UT WOS:000356413200001 PM 26076651 ER PT J AU Amyot, F Kenney, K Chernomordik, V Turtzo, LC Harburg, L Moore, C Spessert, E Silverman, E Diaz-Arrastia, R AF Amyot, Franck Kenney, Kimbra Chernomordik, Victor Turtzo, L. Christine Harburg, Leah Moore, Carol Spessert, Emily Silverman, Erika Diaz-Arrastia, Ramon TI FUNCTIONAL NEAR INFRARED SPECTROSCOPY (FNIRS)-2 NON-INVASIVE METHODS TO ASSESS TRAUMATIC VASCULAR INJURY AFTER TBI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Near InfraRed Spectroscopy; cerebrovascular reactivity; hypercapnia challenge; functional NIRS testing C1 [Amyot, Franck; Kenney, Kimbra; Harburg, Leah; Moore, Carol; Spessert, Emily; Silverman, Erika; Diaz-Arrastia, Ramon] USUHS, Neurol, Bethesda, MD USA. [Chernomordik, Victor] NICHD, NIH, Bethesda, MD USA. [Turtzo, L. Christine] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA D9-08 BP A125 EP A126 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000341 ER PT J AU Bogoslovsky, T Wilson, D Chen, Y Hanlon, D Gill, J Jeromin, A Song, LA Gong, YH Kenney, K Moore, C Diaz-Arrastia, R AF Bogoslovsky, Tanya Wilson, David Chen, Yao Hanlon, David Gill, Jessica Jeromin, Andreas Song, Linan Gong, Yunhua Kenney, Kimbra Moore, Carol Diaz-Arrastia, Ramon TI SINGLE MOLECULAR ARRAY GLIAL FIBRILLARY ACID PROTEIN AND TOTAL TAU ARE INCREASED UP TO 90 DAYS AFTER TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE highly sensitive immunoassays; glial fibrillary acid protein; total tau; diagnostic and prognostic biomarkers C1 [Bogoslovsky, Tanya; Gill, Jessica; Gong, Yunhua; Kenney, Kimbra; Moore, Carol; Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Rockville, MD USA. [Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. [Wilson, David; Chen, Yao; Hanlon, David; Jeromin, Andreas; Song, Linan] Quanterix, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA A5-01 BP A29 EP A29 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000075 ER PT J AU Butman, J van der Merwe, A Shenouda, C Leighton, C Lawrence, L AF Butman, John van der Merwe, Andre Shenouda, Christian Leighton, Chan Lawrence, Latour TI MICROHEMORRHAGE IS NOT FOREVER: CROSS-SECTIONAL ANALYSIS INDICATES RESOLUTION OVER EXTENDED FOLLOW UP INTERVALS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE susceptibility weighted imaging; microhemorrhage; severe C1 [Butman, John; Leighton, Chan] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Butman, John; van der Merwe, Andre; Shenouda, Christian; Leighton, Chan; Lawrence, Latour] CNRM, Bethesda, MD USA. [Lawrence, Latour] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-11 BP A62 EP A62 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000165 ER PT J AU Castro, M Pham, D Butman, J AF Castro, Marcelo Pham, Dzung Butman, John TI IMPROVED VISUALIZATION OF SUPERFICIAL HEMORRHAGE IN SUSCEPTIBILITY WEIGHTED IMAGES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE susceptibility weighted imaging; microhemorrhage; contusion C1 [Butman, John] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Castro, Marcelo; Pham, Dzung; Butman, John] CNRM, Image Proc Core, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-12 BP A62 EP A62 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000166 ER PT J AU Devi, T Shenouda, C Yousefi, M Han, DF Dsurney, J Chan, L AF Devi, Tanvi Shenouda, Christian Yousefi, Mitra Han, Dingfen Dsurney, John Chan, Leighton TI THE EFFECT OF SINGLE VS. MULTIPLE HEAD INJURIES ON BEHAVIORAL AND COGNITIVE OUTCOMES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Behavioral Outcomes; Multiple Head Injuries; TBI; Subconcussive blows C1 [Devi, Tanvi; Han, Dingfen; Chan, Leighton] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Devi, Tanvi; Shenouda, Christian; Yousefi, Mitra; Dsurney, John; Chan, Leighton] Ctr Neurosci & Regenerat Med, NA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA C1-06 BP A73 EP A73 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000196 ER PT J AU Dsurney, J McNally, S van der Merwe, A Chan, L AF Dsurney, John McNally, Shannon van der Merwe, Andre Chan, Leighton TI AN INITIAL EVALUATION OF THE NINDS PHENOTYPING COMMON DATA ELEMENTS FOR TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Common Data Elements; Neuropsychological; Outcomes; Phenotyping C1 [McNally, Shannon; Chan, Leighton] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Dsurney, John; van der Merwe, Andre; Chan, Leighton] Ctr Neurosci & Regenerat Med, Phenotyping Core, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA S12-02 BP A14 EP A14 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000033 ER PT J AU Gill, J Livingston, W Lawrence, L AF Gill, Jessica Livingston, Whitney Lawrence, Lawrence TI MENINGEAL INJURY DETECTED BY CONTRAST ENHANCED FLUID-ATTENUATED INVERSION RECOVERY IMAGES AND DIFFERENTIAL GENE EXPRESSION SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE imaging; meningeal; biomarkers; gene-expression C1 [Gill, Jessica; Livingston, Whitney] NINR, Tissue Injury Branch, Bethesda, MD 20892 USA. [Lawrence, Lawrence] NINDS, Stroke Diagnost & Therapeut Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA C2-01 BP A76 EP A77 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000205 ER PT J AU Gill, J Olivera, A Lejbman, N Jeromin, A French, L Diaz-Arrastia, R AF Gill, Jessica Olivera, Anlys Lejbman, Natasha Jeromin, Andreas French, Louis Diaz-Arrastia, Ramon TI PERIPHERAL CONCENTRATIONS OF TOTAL TAU ARE INCREASED IN MILITARY PERSONNEL WHO SUSTAIN TRAUMATIC BRAIN INJURIES DURING DEPLOYMENT SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE highly sensitive immunoassays; total tau; prognostic biomarkers; chronic symptoms C1 [Gill, Jessica; Olivera, Anlys; Lejbman, Natasha] NIH, Tissue Injury Branch, Bethesda, MD 20892 USA. [French, Louis; Diaz-Arrastia, Ramon] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [French, Louis] Natl Intrepid Ctr Excellence, Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. Madigan Army Med Ctr, Tacoma, WA 98431 USA. [Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. [Jeromin, Andreas] Quanterix Corp, Lexington, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA A5-08 BP A32 EP A32 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000082 ER PT J AU Griffin, A Parikh, G Ostuni, J Moses, A Edwards, N Nair, G Ray-Chaudhury, A Latour, L AF Griffin, Allison Parikh, Gunjan Ostuni, John Moses, Anita Edwards, Nancy Nair, Govind Ray-Chaudhury, Abhik Latour, Lawrence TI INJECTABLE FIDUCIAL MARKER IN MRI GUIDED PATHOLOGY OF BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE MRI Guided Pathology; TBI; Fiducial C1 [Griffin, Allison; Moses, Anita] NINDS, SB, CNRM HJF, NIH, Bethesda, MD 20892 USA. [Parikh, Gunjan; Ostuni, John; Edwards, Nancy; Nair, Govind; Ray-Chaudhury, Abhik; Latour, Lawrence] NINDS, NIH, Bethesda, MD 20892 USA. [Parikh, Gunjan] Univ Maryland, Shock Trauma, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B7-03 BP A68 EP A69 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000183 ER PT J AU Hoffer, B Hoffer, A Baratz, R Pick, C Greig, N AF Hoffer, Barry Hoffer, Alan Baratz, Renana Pick, Chaim Greig, Nigel TI LOWERING TUMOR NECROSIS FACTOR-alpha SYNTHESIS AMELIORATES NEURONAL AND COGNITIVE LOSS AFTER MILD TRAUMATIC BRAIN INJURY IN MICE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Neuroprotection; Inflammation; Neurodegeneration; Cognition C1 [Hoffer, Barry; Hoffer, Alan] Case Western Reserve Univ, Neurosurg, Cleveland, OH 44106 USA. [Baratz, Renana; Pick, Chaim] Tel Aviv Univ, Sackler Sch Med, Anat, IL-69978 Tel Aviv, Israel. [Greig, Nigel] NIA, NIH, Drug Design & Dev Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA D8-05 BP A115 EP A115 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000312 ER PT J AU Joshi, S Afzal, MM Latour, LL Roberts, K Roy, MJ Taylor, PL Diaz-Arrastia, RR AF Joshi, S. Afzal, M. M. Latour, L. L. Roberts, K. Roy, M. J. Taylor, P. L. Diaz-Arrastia, R. R. TI STREAMLINING PARTICIPANT RECRUITMENT FOR TBI AND PTSD RESEARCH STUDIES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Recruitment; TBI; PTSD; Screening; Mult-disciplinary; Referral C1 [Joshi, S.; Afzal, M. M.; Roberts, K.; Taylor, P. L.] CNRM, Bethesda, MD USA. [Roy, M. J.] USUHS, Med, Bethesda, MD USA. [Latour, L. L.] NINDS, Stroke Branch, Bethesda, MD 20892 USA. [Diaz-Arrastia, R. R.] USUHS, Neurol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-02 BP A59 EP A59 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000156 ER PT J AU Lopez, K Dsurney, J Leary, J Pham, D Chou, YY vander Merwe, A Chan, L AF Lopez, Katherine Dsurney, John Leary, Jacob Pham, Dzung Chou, Yi-Yu vander Merwe, Andre Chan, Leighton TI NEUROANATOMICAL AND COGNITIVE DIFFERENCES IN MILD TRAUMATIC BRAIN INJURY PATIENTS WITH AND WITHOUT POST-TRAUMATIC STRESS DISORDER SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Post Traumatic Stress Disorder; Neuropsychological; Brain Volume; Comorbid disorders C1 [Leary, Jacob; Chan, Leighton] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lopez, Katherine; Dsurney, John; Pham, Dzung; vander Merwe, Andre; Chan, Leighton] Ctr Neurosci & Regenerat Med, Phenotyping Core, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA C1-05 BP A73 EP A73 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000195 ER PT J AU McNally, S Lopez, K Pham, D Chou, YY Dsurney, J Chan, L AF McNally, Shannon Lopez, Katherine Dzung Pham Chou, Yi-Yu Dsurney, John Chan, Leighton TI DTI CORRELATES OF ATTENTION AND PROCESSING SPEED IN SUB-ACUTE AND CHRONICTRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Diffusion Tensor Imaging; Neuropsychology; Attention; Traumatic Brain Injury C1 [McNally, Shannon; Chan, Leighton] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lopez, Katherine; Dzung Pham; Chou, Yi-Yu; Dsurney, John; Chan, Leighton] Ctr Neurosci & Regenerat Med, Phenotyping Core, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B3-04 BP A51 EP A51 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000136 ER PT J AU Meier, T Bergamino, M Bellgowan, P Ling, J Mayer, A AF Meier, Timothy Bergamino, Maurizio Bellgowan, Patrick Ling, Josef Mayer, Andrew TI CROSS-SECTIONAL DIFFERENCES IN FRACTIONAL ANISOTROPY WITHOUT LONGITUDINAL EVIDENCE OF RECOVERY BY ONE MONTH POST-CONCUSSION SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE concussion; diffusion; athletes C1 [Meier, Timothy; Ling, Josef; Mayer, Andrew] LBERI, Mind Res Network, Albuquerque, NM USA. [Meier, Timothy; Bergamino, Maurizio] LIBR, Tulsa, OK USA. [Bellgowan, Patrick] NINDS, NIH, North Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B3-06 BP A52 EP A52 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000138 ER PT J AU Merchant-Borna, K Bazarian, J Lee, H Gill, J AF Merchant-Borna, Kian Bazarian, Jeffrey Lee, Hyunhwa Gill, Jessica TI GENOME-WIDE CHANGES IN GENE EXPRESSION FOLLOWING SPORTS-RELATED CONCUSSION SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE gene expression; concussion; sports; clinical research C1 [Merchant-Borna, Kian; Bazarian, Jeffrey] Univ Rochester, Med Ctr, Emergency Med, Rochester, NY 14627 USA. [Lee, Hyunhwa] Univ Nevada, Sch Nursing, Las Vegas, NV 89154 USA. [Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA C2-08 BP A79 EP A79 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000212 ER PT J AU Michel, ME AF Michel, Mary Ellen TI CAREER DEVELOPMENT IN NEUROTRAUMA RESEARCH SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE NIH; career development C1 [Michel, Mary Ellen] NICHD, NIH, NCMRR, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA WNR1 BP A152 EP A152 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000431 ER PT J AU Smith, DH Hicks, RR Johnson, VE Cummings, DM Bergstrom, DA Noble, LJ Hovda, D Whalen, M Ahlers, ST LaPlaca, M Tortella, FC Duhaime, AC Dixon, CE AF Smith, Douglas H. Hicks, Ramona R. Johnson, Victoria E. Cummings, Diana M. Bergstrom, Debra A. Noble, Linda J. Hovda, David Whalen, Michael Ahlers, Stephen T. LaPlaca, Michelle Tortella, Frank C. Duhaime, Ann-Christine Dixon, C. Edward TI PRECLINICAL TRAUMATIC BRAIN INJURY COMMON DATA ELEMENTS: TOWARDS A COMMON LANGUAGE ACROSS LABORATORIES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE Modeling C1 [Smith, Douglas H.; Johnson, Victoria E.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Hicks, Ramona R.; Cummings, Diana M.; Bergstrom, Debra A.] NINDS, NIH, Bethesda, MD 20892 USA. [Hicks, Ramona R.] One Mind, Leadership Team, Seattle, WA USA. [Noble, Linda J.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Hovda, David] Univ Calif Los Angeles, Neurosurg, Los Angeles, CA USA. [Whalen, Michael] Massachusetts Gen Hosp, Neurosci Ctr, Charlestown, MA USA. [Ahlers, Stephen T.] Naval Med Res Ctr, Operat & Undersea Med, Silver Spring, MD USA. [LaPlaca, Michelle] Georgia Tech, Atlanta, GA USA. [LaPlaca, Michelle] Emory Univ, Biomed Engn, Atlanta, GA 30322 USA. [Tortella, Frank C.] Walter Reed Army Inst Res, Brain Trauma Neuroprotect & Neurorestorat, Silver Spring, MD USA. [Duhaime, Ann-Christine] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Dixon, C. Edward] Univ Pittsburgh, Dept Neurol Surg, Pittsburg, KS USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA PL07-03 BP A135 EP A135 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000375 ER PT J AU Tu, TW Williams, R Jikaria, N Turtzo, LC Frank, JA AF Tu, Tsang-Wei Williams, Rashida Jikaria, Neekita Turtzo, L. Christine Frank, Joseph A. TI IN VIVO GLUCO-CEST MRI DETECTS METABOLIC CRISIS IN MILD TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE glucose metabolic disorders; in vivo; glucoCEST C1 [Tu, Tsang-Wei; Williams, Rashida; Jikaria, Neekita; Turtzo, L. Christine; Frank, Joseph A.] NIH, Radiol & Imaging Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-10 BP A61 EP A62 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000164 ER PT J AU Williford, J MacLaren, J Cota, M Castro, M Dardzinski, B Pham, D Latour, L AF Williford, Josh MacLaren, Judy Cota, Martin Castro, Marcelo Dardzinski, Bernard Pham, Dzung Latour, Lawrence TI KINETICS OF TRAUMATIC MENINGEAL INJURY USING DYNAMIC CONTRAST ENHANCED FLUID ATTENUATED INVERSION RECOVERY IMAGING SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 33rd Annual National Neurotrauma Symposium CY JUN 28-JUL 01, 2015 CL Santa Fe, NM DE TBI; DCE FLAIR MRI; Meninges; Traumatic Meningeal Injury; Kinetics; Blood Brain Barrier C1 [Williford, Josh; Cota, Martin; Castro, Marcelo; Dardzinski, Bernard; Pham, Dzung; Latour, Lawrence] Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [MacLaren, Judy] Johns Hopkins Suburban Hosp, Bethesda, MD USA. [Dardzinski, Bernard] Uniformed Serv Univ Hlth Sci, Radiol & Radiol Sci, Bethesda, MD 20814 USA. [Latour, Lawrence] NINDS, Stroke Diagnost & Therapeut Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2015 VL 32 IS 12 MA B6-04 BP A59 EP A60 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0OB UT WOS:000363949000158 ER PT J AU Mandal, S Mandal, A Park, MH AF Mandal, Swati Mandal, Ajeet Park, Myung Hee TI Depletion of the polyamines spermidine and spermine by overexpression of spermidine/spermine N-1-acetyltransferase 1 (SAT1) leads to mitochondria-mediated apoptosis in mammalian cells SO BIOCHEMICAL JOURNAL LA English DT Article DE acetyltransferase; electron microscopy (EM); mitochondrial apoptosis; polyamine; spermidine; spermine ID INITIATION-FACTOR 5A; SACCHAROMYCES-CEREVISIAE; ELECTRON-MICROSCOPY; SPE2-DELTA MUTANT; EPITHELIAL-CELLS; INHIBITION; CANCER; ALPHA; GROWTH; DIFLUOROMETHYLORNITHINE AB The polyamines putrescine, spermidine and spermine are intimately involved in the regulation of cellular growth and viability. Transduction of human embryonic kidney (HEK) 293T cells with an adenovirus encoding a key polyamine catabolic enzyme, spermidine N-1-acetyltransferase 1 (SSAT1)/SAT1 (AdSAT1), leads to a rapid depletion of spermidine and spermine, arrest in cell growth and a decline in cell viability. Annexin V/propidium iodide FACS analyses, terminal uridine nucleotide end-labelling (TUNEL) and caspase 3 assays showed a clear indication of apoptosis in AdSAT1-transduced cells (at 24-72 h), but not in cells transduced with GFP-encoding adenovirus (AdGFP). Apoptosis in the polyamine-depleted cells occurs by the mitochondrial intrinsic pathway, as evidenced by loss of mitochondrial membrane potential, increase in pro-apoptotic Bax, decrease in anti-apoptotic Bcl-xl, Bcl2 and Mcl-1 and release of cytochrome c from mitochondria, upon transduction with AdSAT1. Moreover, TEM images of AdSAT1-transduced cells revealed morphological changes commonly associated with apoptosis, including cell shrinkage, nuclear fragmentation, mitochondrial alteration, vacuolization and membrane blebbing. The apoptosis appears to result largely from depletion of the polyamines spermidine and spermine, as the polyamine analogues alpha-methylspermidine (alpha-MeSpd) and N-1, N-12-dimethylspermine (Me2Spm) that are not substrates for SAT1 could partially restore growth and prevent apoptosis of AdSAT1-transduced cells. Inhibition of polyamine oxidases did not restore the growth of AdSAT1-transduced cells or block apoptosis, suggesting that the growth arrest and apoptosis were not induced by oxidative stress resulting from accelerated polyamine catabolism. Taken together, these data provide strong evidence that the depletion of the polyamines spermidine and spermine leads to mitochondria-mediated apoptosis. C1 [Mandal, Swati; Mandal, Ajeet; Park, Myung Hee] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Park, MH (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM mhpark@nih.gov FU NIDCR, NIH FX The research was supported by intramural research programme of NIDCR, NIH. NR 46 TC 4 Z9 5 U1 2 U2 6 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUN 15 PY 2015 VL 468 BP 435 EP 447 DI 10.1042/BJ20150168 PN 3 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CQ9WS UT WOS:000360966500008 PM 25849284 ER PT J AU Chahal, H Heckbert, SR Barr, RG Bluemke, DA Jain, A Habibi, M Alonso, A Kronmal, R Jacobs, DR Lima, JAC Watson, KE Liu, K Smith, LJ Greenland, P AF Chahal, Harjit Heckbert, Susan R. Barr, R. Graham Bluemke, David A. Jain, Aditya Habibi, Mohammadali Alonso, Alvaro Kronmal, Richard Jacobs, David R., Jr. Lima, Joao A. C. Watson, Karol E. Liu, Kiang Smith, Lewis J. Greenland, Philip TI Ability of Reduced Lung Function to Predict Development of Atrial Fibrillation in Persons Aged 45 to 84 Years (from the Multi-Ethnic Study of Atherosclerosis-Lung Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID AIR-FLOW OBSTRUCTION; LEFT-VENTRICULAR MASS; RISK-FACTORS; COPD; PREVALENCE; MECHANISMS; INFLAMMATION; COMMUNITIES; DISEASE AB Atrial fibrillation (AF) occurs frequently in patients with chronic obstructive pulmonary disease. Epidemiologic studies have found inconsistent associations between lung function and AF, and none have studied pulmonary emphysema, which overlaps only partially with chronic obstructive pulmonary disease in the general population. The aim of this study was to assess the relation among lung function measured by spirometry, the percentage of emphysema-like lung on computed tomography, and incident AF. The Multi-Ethnic Study of Atherosclerosis (MESA) is a multicenter cohort study following 6,814 subjects free of clinical cardiovascular disease, including AF, at baseline. Spirometry was performed in a subset of 3,965 participants. Percentage emphysema was defined on baseline computed tomographic scans as lung regions <950 Hounsfield units. Incident AF was identified from hospital discharge diagnosis and Medicare claims data. Cox proportional hazards models were used to assess independent associations of lung volumes and percentage emphysema with AF. A total of 3,811 participants with valid spirometric results were included in this study. The mean age was 64.5 +/- 9.8 years, and 49.4% were men. AF developed in 149 subjects (3.8%) over a mean follow-up period of 4.1 years after spirometry. Lower levels of forced expiratory volume at 1 second and forced vital capacity were associated with a higher risk for AF (hazard ratios 1.21 and 1.19 per 500 ml, respectively, p <0.001) after adjustment for demographic and cardiovascular risk factors. Percentage emphysema was not significantly related to AF. In conclusion, in a multiethnic community-based sample of subjects free of cardiovascular disease at baseline, functional airflow limitation was related to a higher risk for AF. (C) 2015 Elsevier Inc. All rights reserved. C1 [Chahal, Harjit] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Cardiol, Bronx, NY 10467 USA. [Heckbert, Susan R.] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Barr, R. Graham; Kronmal, Richard] Columbia Univ, Dept Epidemiol, New York, NY USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Jain, Aditya; Habibi, Mohammadali; Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Alonso, Alvaro; Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Watson, Karol E.] Univ Calif Los Angeles, Sch Med, Div Cardiol, Los Angeles, CA 90024 USA. [Liu, Kiang] Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Smith, Lewis J.] Northwestern Univ, Sch Med, Dept Pulm Med, Chicago, IL USA. RP Greenland, P (reprint author), Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. EM p-greenland@northwestern.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Smith, Lewis J/0000-0002-4728-1562; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95166, N01-HC95169] FX The Multi-Ethnic Study of Atherosclerosis is sponsored by contracts from the National Heart, Lung, and Blood Institute (N01-HC-95159 through N01-HC-95166 and N01-HC95169). NR 28 TC 3 Z9 3 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2015 VL 115 IS 12 BP 1700 EP 1704 DI 10.1016/j.amjcard.2015.03.018 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM5BR UT WOS:000357702300013 PM 25900353 ER PT J AU Martucci, VL Emaminia, A del Rivero, J Lechan, RM Magoon, BT Galia, A Fojo, T Leung, S Lorusso, R Jimenez, C Shulkin, BL Audibert, JL Adams, KT Rosing, DR Vaidya, A Dluhy, RG Horvath, KA Pacak, K AF Martucci, Victoria L. Emaminia, Abbas del Rivero, Jaydira Lechan, Ronald M. Magoon, Bindiya T. Galia, Analyza Fojo, Tito Leung, Steve Lorusso, Roberto Jimenez, Camilo Shulkin, Barry L. Audibert, Jennifer L. Adams, Karen T. Rosing, Douglas R. Vaidya, Anand Dluhy, Robert G. Horvath, Keith A. Pacak, Karel TI Succinate Dehydrogenase Gene Mutations in Cardiac Paragangliomas SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MALIGNANT PHEOCHROMOCYTOMA; TOMOGRAPHY; CARCINOMA; THERAPY; TUMORS AB Pheochromocytomas and paragangliomas are chromaffin cell tumors arising from neuroendocrine cells. At least 1/3 of paragangliomas are related to germline mutations in 1 of 17 genes. Although these tumors can occur throughout the body, cardiac paragangliomas are very rare, accounting for <0.3% of mediastinal tumors. The purpose of this study was to determine the clinical characteristics of patients with cardiac paragangliomas, particularly focusing on their genetic backgrounds. A retrospective chart analysis of 15 patients with cardiac paragangliomas was performed to determine clinical presentation, genetic background, diagnostic workup, and outcomes. The average age at diagnosis was 41.9 years. Typical symptoms of paraganglioma (e.g., hypertension, sweating, palpitations, headache) were reported at initial presentation in 13 patients (86.7%); the remaining 2, as well as 4 symptomatic patients, initially presented with cardiac-specific symptoms (e.g., chest pain, dyspnea). Genetic testing was done in 13 patients (86.7%); 10 (76.9%) were positive for mutations in succinate dehydrogenase (SDHx) subunits B, C, or D. Thirteen patients (86.7%) underwent surgery to remove the paraganglioma with no intraoperative morbidity or mortality; 1 additional patient underwent surgical resection but experienced intraoperative complications after removal of the tumor due to co-morbidities and did not survive. SDHx mutations are known to be associated with mediastinal locations and malignant behavior of paragangliomas. In this report, the investigators extend the locations of predominantly SDHx-related paragangliomas to cardiac tumors. In conclusion, cardiac paragangliomas are frequently associated with underlying SDHx gerinline mutations, suggesting a need for genetic testing of all patients with this rare tumor. Published by Elsevier Inc. C1 [Martucci, Victoria L.; del Rivero, Jaydira; Galia, Analyza; Adams, Karen T.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Emaminia, Abbas; Horvath, Keith A.] NHLBI, Cardiothorac Surg Res Program, Bethesda, MD 20892 USA. [Leung, Steve; Audibert, Jennifer L.; Rosing, Douglas R.] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lechan, Ronald M.; Magoon, Bindiya T.] Tufts Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA. [Galia, Analyza] Univ Santo Tomas Hosp, Sect Endocrinol & Metab, Manila, Philippines. [Leung, Steve] Univ Kentucky, Dept Med, Div Cardiovasc Med, Lexington, KY 40506 USA. [Lorusso, Roberto] Spedali Civili Hosp, Cardiac Surg Unit, Brescia, Italy. [Jimenez, Camilo] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. [Shulkin, Barry L.] St Jude Childrens Res Hosp, Div Nucl Med, Memphis, TN 38105 USA. [Vaidya, Anand; Dluhy, Robert G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Leung, Steve/E-5624-2011 OI Leung, Steve/0000-0003-2832-2258 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 30 TC 1 Z9 1 U1 1 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2015 VL 115 IS 12 BP 1753 EP 1759 DI 10.1016/j.amjcard.2015.03.020 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM5BR UT WOS:000357702300021 PM 25896150 ER PT J AU Sidharthan, S Kohli, A Sims, Z Nelson, A Osinusi, A Masur, H Kottilil, S AF Sidharthan, Sreetha Kohli, Anita Sims, Zayani Nelson, Amy Osinusi, Anu Masur, Henry Kottilil, Shyam TI Utility of Hepatitis C Viral Load Monitoring on Direct-Acting Antiviral Therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE viral load; direct-acting antiviral; HCV RNA; hepatitis C ID GENOTYPE 1 INFECTION; TREATMENT-NAIVE PATIENTS; VIROLOGICAL RESPONSE; HCV; VIRUS; RIBAVIRIN; SOFOSBUVIR; ABT-450/R-OMBITASVIR; DACLATASVIR; LEDIPASVIR AB Background. Hepatitis C virus (HCV) RNA loads serve as predictors of treatment response during interferon-based therapy. We evaluated the predictive ability of HCV RNA levels at end of treatment (EOT) for sustained virologic response (SVR12) during interferon-sparing direct-acting antiviral therapies. Methods. HCV genotype 1-infected, treatment-naive patients were treated with sofosbuvir and ribavirin for 24 weeks (n = 55), sofosbuvir and ledipasvir for 12 weeks (n = 20), sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (n = 20), or sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (n = 19). Measurements of HCV RNA were performed using the Roche COBAS TaqMan HCV test and the Abbott RealTime HCV assay. Positive predictive value (PPV) and negative predictive value (NPV) of HCV RNA less than the lower limit of quantification (= LLOQ at EOT (range, 14-64 IU/mL) achieved SVR12 (NPV, 0%). Quantifiable HCV RNA (range, 15-57 IU/mL) was measured 2 weeks posttreatment in 4 individuals, and 4 weeks posttreatment in 1 patient (14 IU/mL). Conclusions. Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at EOT do not preclude treatment success. C1 [Sidharthan, Sreetha; Kohli, Anita; Sims, Zayani; Masur, Henry] NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. [Nelson, Amy; Kottilil, Shyam] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Nelson, Amy; Osinusi, Anu; Kottilil, Shyam] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu] Gilead Sci Inc, Foster City, CA 94404 USA. RP Kottilil, S (reprint author), Inst Human Virol, Room S222,725 W Lombard St, Baltimore, MD 21201 USA. EM skottilil@ihv.umaryland.edu FU National Cancer Institute at the National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This work was supported in whole or in part with federal funds from the National Cancer Institute at the National Institutes of Health (contract number HHSN261200800001E). This research was supported in part by the National Institute of Allergy and Infectious Diseases. NR 23 TC 21 Z9 21 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2015 VL 60 IS 12 BP 1743 EP 1751 DI 10.1093/cid/civ170 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CN0BC UT WOS:000358075800004 PM 25733369 ER PT J AU Ofotokun, I Na, LH Landovitz, RJ Ribaudo, HJ McComsey, GA Godfrey, C Aweeka, F Cohn, SE Sagar, M Kuritzkes, DR Brown, TT Patterson, KB Para, MF Leavitt, RY Villasis-Keever, A Baugh, BP Lennox, JL Currier, JS AF Ofotokun, Ighovwerha Na, Lumine H. Landovitz, Raphael J. Ribaudo, Heather J. McComsey, Grace A. Godfrey, Catherine Aweeka, Francesca Cohn, Susan E. Sagar, Manish Kuritzkes, Daniel R. Brown, Todd T. Patterson, Kristine B. Para, Michael F. Leavitt, Randi Y. Villasis-Keever, Angelina Baugh, Bryan P. Lennox, Jeffrey L. Currier, Judith S. CA AIDS Clinical Trials Grp ACTG A525 TI Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257 SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV/AIDS; cART; lipids; metabolic syndrome ID HIV-INFECTED PATIENTS; TREATMENT-NAIVE; PROTEASE INHIBITORS; ANTIRETROVIRAL THERAPY; DEFINITIONS; INDIVIDUALS; NELFINAVIR; MANAGEMENT; REGIMENS; EFFICACY AB Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C-24). Methods. Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C-24 and lipid changes at week 48 were evaluated via linear regression. Results. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P <= .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C-24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). Conclusions. Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C-24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. C1 [Ofotokun, Ighovwerha; Lennox, Jeffrey L.] Grady Mem Hosp, Atlanta, GA USA. [Ofotokun, Ighovwerha; Lennox, Jeffrey L.] Emory Univ, Sch Med, Atlanta, GA 30303 USA. [Na, Lumine H.; Ribaudo, Heather J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Landovitz, Raphael J.; Currier, Judith S.] Univ Calif Los Angeles, Ctr Clin AIDS Res & Educ, Div Infect Dis, Los Angeles, CA USA. [McComsey, Grace A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Godfrey, Catherine] NIAID, NIH, Bethesda, MD 20892 USA. [Aweeka, Francesca] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. [Cohn, Susan E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Sagar, Manish] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kuritzkes, Daniel R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Boston, MA USA. [Brown, Todd T.] Johns Hopkins Univ, Baltimore, MD USA. [Patterson, Kristine B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Para, Michael F.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Leavitt, Randi Y.] Merck & Co Inc, Whitehouse Stn, NJ USA. [Villasis-Keever, Angelina] Bristol Myers Squibb Co, New York, NY 10154 USA. [Baugh, Bryan P.] Janssen Sci Affairs LLC, Titusville, NJ USA. RP Ofotokun, I (reprint author), Emory Univ, Sch Med, Dept Med, Div Infect Dis, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303 USA. EM iofotok@emory.edu RI Ofotokun, Ighovwerha/L-6545-2015 OI Ofotokun, Ighovwerha/0000-0003-2735-1903 FU NIAID [UM1AI068636]; National Institute of Mental Health; National Institute of Dental and Craniofacial Research; AIDS Clinical Trial Group (ACTG); Site Data Management Center [UM1AI68634] FX The project described was supported by the NIAID (award number UM1AI068636); the National Institute of Mental Health; and the National Institute of Dental and Craniofacial Research. The protocol received support from the AIDS Clinical Trial Group (ACTG); the Site Data Management Center (grant number UM1AI68634); the ACTG specialty laboratories listed in the manuscript; and the 37 clinical research sites. NR 31 TC 13 Z9 13 U1 1 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2015 VL 60 IS 12 BP 1842 EP 1851 DI 10.1093/cid/civ193 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CN0BC UT WOS:000358075800020 PM 25767256 ER PT J AU Chaturvedi, AK Graubard, BI Broutian, T Pickard, RKL Tong, ZY Xiao, WH Kahle, L Gillison, ML AF Chaturvedi, Anil K. Graubard, Barry I. Broutian, Tatevik Pickard, Robert K. L. Tong, Zhen-yue Xiao, Weihong Kahle, Lisa Gillison, Maura L. TI NHANES 2009-2012 Findings: Association of Sexual Behaviors with Higher Prevalence of Oral Oncogenic Human Papillomavirus Infections in US Men SO CANCER RESEARCH LA English DT Article ID NUTRITION EXAMINATION SURVEY; UNITED-STATES; OROPHARYNGEAL CANCER; NATIONAL-HEALTH; HPV INFECTION; SERUM ANTIBODY; RISK; SEROPREVALENCE; TRANSMISSION; POPULATION AB The incidence of human papillomavirus (HPV)-positive oropharyngeal cancers is higher and increasing more rapidly among men than women in the United States for unknown reasons. We compared the epidemiology of oral oncogenic HPV infection between men and women ages 14 to 69 years (N = 9,480) within the U.S. National Health and Nutritional Examination Surveys (NHANES) 2009-2012. HPV presence was detected in oral DNA by PCR. Analyses were stratified by gender and used NHANES sample weights. Oral oncogenic HPV prevalence was higher among men than women (6.6% vs. 1.5%, P < 0.001), corresponding to 7.07 million men versus 1.54 million women with prevalent infection at any point in time during 2009-2012. Prevalence increased significantly with age, current smoking, and lifetime number of sexual partners for both genders (adjusted P-trend < 0.02). However, men had more partners than women (mean = 18 vs. 7, P < 0.001). Although oncogenic HPV prevalence was similar for men and women with 0 to 1 lifetime partners, the male-female difference in prevalence significantly increased with number of lifetime partners (adjusted prevalence differences for none, 1, 2-5, 6-10, 11-20, and 20+ partners = 1.0%, 0.5%, 3.0%, 5.7%, 4.6%, and 9.3%, respectively). Importantly, the per-sexual partner increase in prevalence was significantly stronger among men than among women (adjusted synergy index = 3.3; 95% confidence interval, 1.1-9.7), and this increase plateaued at 25 lifetime partners among men versus10 partners among women. Our data suggest that the higher burden of oral oncogenic HPV infections and HPV-positive oropharyngeal cancers among men than women arises in part from higher number of lifetime sexual partners and stronger associations with sexual behaviors among men. (C) 2015 AACR. C1 [Chaturvedi, Anil K.; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Broutian, Tatevik; Pickard, Robert K. L.; Tong, Zhen-yue; Xiao, Weihong; Gillison, Maura L.] Ohio State Univ, Columbus, OH 43210 USA. [Kahle, Lisa] Informat Management Serv Inc, Calverton, MD USA. RP Gillison, ML (reprint author), Ohio State Univ, 420 West 12th Ave,Room 620, Columbus, OH 43210 USA. EM Maura.gillison@osumc.edu RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Merck Inc.; National Institute of Dental and Craniofacial Research; Intramural Program of the National Cancer Institute; Ohio State University Comprehensive Cancer Center; Oral Cancer Foundation FX The study was funded in part by Merck Inc., the National Institute of Dental and Craniofacial Research, the Intramural Program of the National Cancer Institute, the Ohio State University Comprehensive Cancer Center, and the Oral Cancer Foundation. NR 39 TC 14 Z9 14 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2015 VL 75 IS 12 BP 2468 EP 2477 DI 10.1158/0008-5472.CAN-14-2843 PG 10 WC Oncology SC Oncology GA CL9YG UT WOS:000357334400008 PM 25873485 ER PT J AU Chowdhury, SA Gertz, EM Wangsa, D Heselmeyer-Haddad, K Ried, T Schaffer, AA Schwartz, R AF Chowdhury, Salim Akhter Gertz, E. Michael Wangsa, Darawalee Heselmeyer-Haddad, Kerstin Ried, Thomas Schaeffer, Alejandro A. Schwartz, Russell TI Inferring models of multiscale copy number evolution for single-tumor phylogenetics SO BIOINFORMATICS LA English DT Article ID CANCER PROGRESSION; HYBRIDIZATION DATA; CLONAL EVOLUTION; CELL POPULATIONS; TREE MODELS; IN-SITU; HETEROGENEITY; ONCOGENESIS; RECONSTRUCTION; AMPLIFICATION AB Motivation: Phylogenetic algorithms have begun to see widespread use in cancer research to reconstruct processes of evolution in tumor progression. Developing reliable phylogenies for tumor data requires quantitative models of cancer evolution that include the unusual genetic mechanisms by which tumors evolve, such as chromosome abnormalities, and allow for heterogeneity between tumor types and individual patients. Previous work on inferring phylogenies of single tumors by copy number evolution assumed models of uniform rates of genomic gain and loss across different genomic sites and scales, a substantial oversimplification necessitated by a lack of algorithms and quantitative parameters for fitting to more realistic tumor evolution models. Results: We propose a framework for inferring models of tumor progression from single-cell gene copy number data, including variable rates for different gain and loss events. We propose a new algorithm for identification of most parsimonious combinations of single gene and single chromosome events. We extend it via dynamic programming to include genome duplications. We implement an expectation maximization (EM)-like method to estimate mutation-specific and tumor-specific event rates concurrently with tree reconstruction. Application of our algorithms to real cervical cancer data identifies key genomic events in disease progression consistent with prior literature. Classification experiments on cervical and tongue cancer datasets lead to improved prediction accuracy for the metastasis of primary cervical cancers and for tongue cancer survival. C1 [Chowdhury, Salim Akhter] Joint Carnegie Mellon Univ Pittsburgh, PhD Program Computat Biol, Pittsburgh, PA USA. [Chowdhury, Salim Akhter; Schwartz, Russell] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15213 USA. [Gertz, E. Michael; Schaeffer, Alejandro A.] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, US Natl Inst Hlth, Bethesda, MD 20894 USA. [Wangsa, Darawalee; Heselmeyer-Haddad, Kerstin; Ried, Thomas] NCI, Sect Canc Gen, Genet Branch, Ctr Canc Res,US NIH, Bethesda, MD 20892 USA. [Schwartz, Russell] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Schwartz, R (reprint author), Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15213 USA. RI Schwartz, Russell/A-1998-2016 OI Schwartz, Russell/0000-0002-4970-2252 FU U.S. National Institutes of Health, National Cancer Institute; National Library of Medicine; U.S. National Institutes of Health [1R01CA140214, 1R01AI076318] FX This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, and National Library of Medicine, and by U.S. National Institutes of Health grants 1R01CA140214 (R.S. and S.A.C.) and 1R01AI076318 (R.S.). NR 38 TC 3 Z9 3 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2015 VL 31 IS 12 BP 258 EP 267 DI 10.1093/bioinformatics/btv233 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CL0IO UT WOS:000356625700030 ER PT J AU Kim, YA Cho, DY Dao, P Przytycka, TM AF Kim, Yoo-Ah Cho, Dong-Yeon Dao, Phuong Przytycka, Teresa M. TI MEMCover: integrated analysis of mutual exclusivity and functional network reveals dysregulated pathways across multiple cancer types SO BIOINFORMATICS LA English DT Article ID COMPREHENSIVE GENOMIC CHARACTERIZATION; GENES; DISCOVERY; MUTATIONS; COHESIN; SF3B1 AB Motivation: The data gathered by the Pan-Cancer initiative has created an unprecedented opportunity for illuminating common features across different cancer types. However, separating tissue-specific features from across cancer signatures has proven to be challenging. One of the often-observed properties of the mutational landscape of cancer is the mutual exclusivity of cancer driving mutations. Even though studies based on individual cancer types suggested that mutually exclusive pairs often share the same functional pathway, the relationship between across cancer mutual exclusivity and functional connectivity has not been previously investigated. Results: We introduce a classification of mutual exclusivity into three basic classes: within tissue type exclusivity, across tissue type exclusivity and between tissue type exclusivity. We then combined across-cancer mutual exclusivity with interactions data to uncover pan-cancer dysregulated pathways. Our new method, Mutual Exclusivity Module Cover (MEMCover) not only identified previously known Pan-Cancer dysregulated subnetworks but also novel subnetworks whose across cancer role has not been appreciated well before. In addition, we demonstrate the existence of mutual exclusivity hubs, putatively corresponding to cancer drivers with strong growth advantages. Finally, we show that while mutually exclusive pairs within or across cancer types are predominantly functionally interacting, the pairs in between cancer mutual exclusivity class are more often disconnected in functional networks. C1 [Kim, Yoo-Ah; Cho, Dong-Yeon; Dao, Phuong; Przytycka, Teresa M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Przytycka, TM (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 28 TC 10 Z9 10 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2015 VL 31 IS 12 BP 284 EP 292 DI 10.1093/bioinformatics/btv247 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CL0IO UT WOS:000356625700033 ER PT J AU Zhao, Z Basilio, J Hanson, S Little, RR Sumner, AE Sacks, DB AF Zhao, Zhen Basilio, Jeffrey Hanson, Steven Little, Randie R. Sumner, Anne E. Sacks, David B. TI Evaluation of hemoglobin A(1c) measurement by Capillarys 2 electrophoresis for detection of abnormal glucose tolerance in African immigrants to the United States SO CLINICA CHIMICA ACTA LA English DT Article DE Hemoglobin A1c; Capillarys 2; Diabetes; Abnormal glucose tolerance; Sickle cell; Africans ID INSULIN-RESISTANCE ATHEROSCLEROSIS; S-TRAITS; DIABETES-MELLITUS; HBA(1C); PERFORMANCE; SEBIA; RISK; A1C; GLYCOHEMOGLOBIN; CRITERIA AB Background: Hemoglobin A(1c) (HbA(1c)) is used to monitor long-term glycemic control in individuals with diabetes, guide therapy, predict the risk of microvascular complications, and more recently to diagnose diabetes. An automated liquid-flow capillary electrophoresis method was recently developed to measure HbA(1c) using the Capillarys 2 Flex Piercing instrument. Methods: Analytical evaluation was performed at 2 clinical centers. A clinical analysis was conducted in 109 African-born individuals, 24% of whom have variant hemoglobin (HbAS or HbAC). Abnormal glucose tolerance (which includes both diabetes and prediabetes) was defined as 2 h glucose of >= 140 mg/dl (7.8 mmol/l) during an oral glucose tolerance test. Results: Interlaboratoty CVs were <= 2.1%. The method showed satisfactory correlation with 2 other analyzers that measure HbA(1c) by high-performance liquid chromatography. Neither labile HbA(1c) carbamylated hemoglobin, uremia, bilirubin nor common hemoglobin variants (HbC/HbS/HbE) interfered. Forty-five individuals (41%) had abnormal glucose tolerance. The sensitivity of HbA(1c) for diagnosing abnormal glucose tolerance was 38%, 36% and 42% for total, normal and variant hemoglobin groups, respectively. Conclusions: The analytical performance of HbA(1c) on the Capillarys 2 is suitable for clinical application. Variant hemoglobin in Africans did not interfere with the detection of abnormal glucose tolerance by HbA(1c) measured on the Capillarys 2. Published by Elsevier B.V. C1 [Zhao, Zhen; Basilio, Jeffrey; Sacks, David B.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Hanson, Steven; Little, Randie R.] Univ Missouri, Dept Pathol & Anat Sci, Columbia, MO USA. [Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDK, Bldg 10-CRC,Room 6-5940,MSC 1612, Bethesda, MD 20892 USA. EM annes@intra.niddk.nih.gov; david.sacks2@nih.gov OI Sacks, David/0000-0003-3100-0735 FU Intramural Research Programs of the Clinical Center; National Institute of Diabetes and Digestive and Kidney Diseases (AES) of the National Institutes of Health FX This research was supported by the Intramural Research Programs of the Clinical Center (ZZ, JB and DBS) and the National Institute of Diabetes and Digestive and Kidney Diseases (AES) of the National Institutes of Health. The authors are grateful to Sebia for providing the equipment, reagents and technical support. We also thank Ms. Khanh Nghiem for analyzing the samples on the Bio-Rad D10 analyzer. NR 40 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 EI 1873-3492 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUN 15 PY 2015 VL 446 BP 54 EP 60 DI 10.1016/j.cca.2015.03.025 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CL2AI UT WOS:000356745600009 PM 25861848 ER PT J AU Li, Y Abu-Asab, M Su, JW Qiu, P Feng, J Ohanjanian, L Kumar, HS Fitz, Y Eichacker, PQ Cui, XZ AF Li, Yan Abu-Asab, Mones Su, Junwu Qiu, Ping Feng, Jing Ohanjanian, Lernik Kumar, Hanish Sampath Fitz, Yvonne Eichacker, Peter Q. Cui, Xizhong TI Bacillus anthracis edema but not lethal toxin challenge in rats is associated with depressed myocardial function in hearts isolated and tested in a Langendorff system SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE anthrax; edema toxin; lethal toxin; heart function ID ESCHERICHIA-COLI; PROTECTIVE ANTIGEN; NITRIC-OXIDE; DYSFUNCTION; SHOCK; MODEL; SURVIVAL; PHOSPHORYLATION; PURIFICATION; CONTRACTION AB Although direct myocardial depression has been implicated in the lethal effects of Bacillus anthracis lethal toxin (LT), in hearts isolated from healthy rats and perfused under constant pressure, neither LT or edema toxin (ET) in typically lethal concentrations depressed myocardial function. In the present study, we challenged rats with LT and ET and performed in vivo and ex vivo heart measures. Sprague-Dawley rats infused over 24 h with LT (n = 94), ET (n = 99), or diluent (controls; n = 50) were studied at 8, 24, or 48 h. Compared with control rats (all survived), survival rates with LT (56.1%) and ET (37.3%) were reduced (P < 0.0001) similarly (P = 0.66 for LT vs. ET). LT decreased mean arterial blood pressure from 12 to 20 h (P < 0.05), whereas ET decreased it progressively throughout (P < 0.05). On echocardiography, LT decreased left ventricular (LV) ejection fraction at 8 and 48 h but increased it at 24 h and decreased cardiac output (P <= 0.05 for the time interaction or averaged over time). ET decreased systolic and diastolic volumes and increased LV ejection fraction at 24 h (P <= 0.05). In isolated hearts perfused for 120 min under constant pressure, LT did not significantly alter LV systolic or developed pressures at any time point, whereas ET decreased both of these at 24 h (P < 0.0001 initially). ET but not LT progressively increased plasma creatine phosphokinase and cardiac troponin levels (P < 0.05). In conclusion, despite echocardiographic changes, in vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts. While lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia. C1 [Li, Yan; Feng, Jing; Ohanjanian, Lernik; Kumar, Hanish Sampath; Fitz, Yvonne; Eichacker, Peter Q.; Cui, Xizhong] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, NIH, Bethesda, MD 20892 USA. [Su, Junwu] Capital Med Univ, Anzhen Hosp, Beijing, Peoples R China. [Qiu, Ping] OncoImmune Inc, Rockville, MD USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 2C145,9000 Rockville Pike, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU National Institutes of Health Intramural Program FX This work was supported by the National Institutes of Health Intramural Program. NR 30 TC 2 Z9 2 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN 15 PY 2015 VL 308 IS 12 BP H1592 EP H1602 DI 10.1152/ajpheart.00851.2014 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA CK5NZ UT WOS:000356273200016 PM 25862834 ER PT J AU Kiley, J Mockrin, S Lauer, M Mensah, G Hoots, WK Patel, Y Cook, N Patterson, A Gibbons, G AF Kiley, James Mockrin, Stephen Lauer, Michael Mensah, George Hoots, W. Keith Patel, Yasin Cook, Nakela Patterson, Amy Gibbons, Gary TI Smoking Control Is a Priority to Promote Heart, Lung, Blood, and Sleep Health Reply SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter C1 [Kiley, James; Mockrin, Stephen; Lauer, Michael; Mensah, George; Hoots, W. Keith; Patel, Yasin; Cook, Nakela; Patterson, Amy; Gibbons, Gary] NIH, Bethesda, MD 20892 USA. RP Kiley, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2015 VL 191 IS 12 BP 1473 EP 1473 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CK8DZ UT WOS:000356470000028 PM 26075432 ER PT J AU Liu, K Lin, Q Wei, YX He, RB Shao, XM Ding, ZH Zhang, JC Zhu, MY Weinstein, LS Hong, Y Li, HC Li, HS AF Liu, Ke Lin, Quan Wei, Yanxia He, Renbing Shao, Ximing Ding, Zhihao Zhang, Jianchao Zhu, Minyan Weinstein, Lee S. Hong, Yang Li, Hongchang Li, Huashun TI G alpha s regulates asymmetric cell division of cortical progenitors by controlling Numb mediated Notch signaling suppression SO NEUROSCIENCE LETTERS LA English DT Article DE G alpha subunit; Neurogenesis; Asymmetric cell division ID GNAS GENE-PRODUCTS; NERVOUS-SYSTEM; FATE SPECIFICATION; NEUROGENESIS; POLARITY; NEURONS; LOCALIZATION; CDC42; APKC; PAR6 AB Asymmetric cell division, which plays fundamental roles in generating cell diversity during development, requires elaborate interactions between extrinsic cues and intrinsic cues. However, the precise nature of this type of interaction and its involving signaling mechanisms are poorly understood. Here, we demonstrate that Gas is present in the proliferative region of ventricular zone in mouse developing neocortex and co-localizes with intrinsic cell fate determinant protein Numb in dividing apical progenitors. Targeted ablation of Gas subunit in the cortical progenitor causes an alteration from asymmetric to symmetric cell division, consequently leading to increased progenitor proliferation. Mechanistically, we show that Gas deletion significantly reduces Numb expression and activates notch signaling. Therefore, these results reveal a novel role of Gas in control of neural progenitor asymmetric cell division via suppressing Numb mediated Notch signaling inhibition. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Liu, Ke; Lin, Quan; Wei, Yanxia; He, Renbing; Li, Huashun] Sichuan Univ, West China Hosp 2, West China Dev & Stem Cell Inst, Chengdu 610064, Peoples R China. [Liu, Ke; Lin, Quan; Wei, Yanxia; He, Renbing; Li, Huashun] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610064, Peoples R China. [Liu, Ke; Shao, Ximing; Ding, Zhihao; Zhang, Jianchao; Li, Hongchang; Li, Huashun] Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen Key Lab Mol Biol Neural Dev, Lab Dev & Regenerat Biol,Inst Biomed & Biotechnol, Shenzhen 518055, Guangdong, Peoples R China. [Zhu, Minyan; Li, Huashun] Tongji Univ, Sch Med, Shanghai East Hosp, SARITEX Ctr Stem Cell Engn Translat Med, Shanghai 200123, Peoples R China. [Li, Huashun] Nerdbio Inc, SIP Biobay, Nanjing 215213, Jiangsu, Peoples R China. [Weinstein, Lee S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Hong, Yang] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. RP Li, HC (reprint author), Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen Key Lab Mol Biol Neural Dev, Lab Dev & Regenerat Biol,Inst Biomed & Biotechnol, Shenzhen 518055, Guangdong, Peoples R China. EM hc.li@siat.ac.cn; huashunli@tongji.edu.cn FU Ministry of Science & Technology - China [2014CB964600, 2012CB966800]; National Science Foundation of China [31301125, 31071283]; Shenzhen Peacock Plan [KQCX20130628112914292]; Shenzhen Key Laboratory for Molecular Biology of Neural Development [ZDSY20120617112838879] FX This work was partially supported by grants from the Ministry of Science & Technology - China (2014CB964600, 2012CB966800), the National Science Foundation of China (31301125, 31071283), Shenzhen Peacock Plan (No. KQCX20130628112914292), Shenzhen Key Laboratory for Molecular Biology of Neural Development (ZDSY20120617112838879), and faculty development support (West China Women's & Children Hospital & Shenzhen Institutes of Advanced Technology-CAS & Tongji University Shanghai East Hospital). NR 26 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 15 PY 2015 VL 597 BP 97 EP 103 DI 10.1016/j.neulet.2015.04.034 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CK4HY UT WOS:000356186100018 PM 25916881 ER PT J AU Espinosa-Carrasco, G Villard, M Le Saout, C Louis-Plence, P Vicente, R Hernandez, J AF Espinosa-Carrasco, Gabriel Villard, Marine Le Saout, Cecile Louis-Plence, Pascale Vicente, Rita Hernandez, Javier TI Systemic LPS Translocation Activates Cross-Presenting Dendritic Cells but Is Dispensable for the Breakdown of CD8(+) T Cell Peripheral Tolerance in Irradiated Mice SO PLOS ONE LA English DT Article ID VERSUS-HOST-DISEASE; TOTAL-BODY IRRADIATION; MEMORY-LIKE CD8(+); HOMEOSTATIC PROLIFERATION; CUTTING EDGE; MICROBIAL TRANSLOCATION; IMMUNE-SYSTEM; IN-VIVO; SELF-ANTIGENS; HELPER-CELLS AB Lymphodepletion is currently used to enhance the efficacy of cytotoxic T lymphocyte adoptive transfer immunotherapy against cancer. This beneficial effect of conditioning regimens is due, at least in part, to promoting the breakdown of peripheral CD8(+) T cell tolerance. Lymphodepletion by total body irradiation induces systemic translocation of commensal bacteria LPS from the gastrointestinal tract. Since LPS is a potent activator of the innate immune system, including antigen presenting dendritic cells, we hypothesized that LPS translocation could be required for the breakdown of peripheral tolerance observed in irradiated mice. To address this issue, we have treated irradiated mice with antibiotics in order to prevent LPS translocation and utilized them in T cell adoptive transfer experiments. Surprisingly, we found that despite of completely blocking LPS translocation into the bloodstream, antibiotic treatment did not prevent the breakdown of peripheral tolerance. Although irradiation induced the activation of cross-presenting CD8(+) dendritic cells in the lymphoid tissue, LPS could not solely account for this effect. Activation of dendritic cells by mechanisms other than LPS translocation is sufficient to promote the differentiation of potentially autoreactive CD8(+) T cells into effectors in irradiated mice. Our data indicate that LPS translocation is dispensable for the breakdown of CD8(+) T cell tolerance in irradiated mice. C1 [Espinosa-Carrasco, Gabriel; Villard, Marine; Louis-Plence, Pascale; Vicente, Rita; Hernandez, Javier] INSERM, Inst Regenerat Med & Biotherapy, U1183, F-34295 Montpellier, France. [Espinosa-Carrasco, Gabriel; Villard, Marine; Louis-Plence, Pascale; Vicente, Rita; Hernandez, Javier] Univ Montpellier, UFR Med, F-34000 Montpellier, France. [Le Saout, Cecile] NIAID, CMRS, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Hernandez, J (reprint author), INSERM, Inst Regenerat Med & Biotherapy, U1183, F-34295 Montpellier, France. EM francisco-javier.hernandez@inserm.fr FU European Community SUDOE-FEDER [IMMUNONET SOE1/P1/E014]; La Ligue Contre le Cancer Herault FX This work was supported by grants from the European Community SUDOE-FEDER (Contract # IMMUNONET SOE1/P1/E014) and La Ligue Contre le Cancer Herault to JH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 15 PY 2015 VL 10 IS 6 AR e0130041 DI 10.1371/journal.pone.0130041 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK6HU UT WOS:000356329900127 PM 26075613 ER PT J AU Magpantay, FMG Rohani, P AF Magpantay, F. M. G. Rohani, P. TI Dynamics of Pertussis Transmission in the United States SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE early vaccine era; interepidemic periods; pertussis; susceptible recruitment; vaccines; whooping cough ID BORDETELLA-PERTUSSIS; WHOOPING-COUGH; TIME-SERIES; VACCINE; RESURGENCE; EPIDEMICS; IMMUNITY; DISEASES; MEASLES; LEGACY AB Past patterns of infectious disease transmission set the stage on which modern epidemiologic dynamics are played out. Here, we present a comprehensive account of pertussis (whooping cough) transmission in the United States during the early vaccine era. We analyzed recently digitized weekly incidence records from Morbidity and Mortality Weekly Reports from 1938 to 1955, when the whole-cell pertussis vaccine was rolled out, and related them to contemporary patterns of transmission and resurgence documented in monthly incidence data from the National Notifiable Diseases Surveillance System. We found that, during the early vaccine era, pertussis epidemics in US states could be categorized as 1) annual, 2) initially annual and later multiennial, or 3) multiennial. States with predominantly annual cycles tended to have higher per capita birth rates, more household crowding, more children per family, and lower rates of school attendance than the states with multiennial cycles. Additionally, states that exhibited annual epidemics during 1938-1955 have had the highest recent (2001-2010) incidence, while those states that transitioned from annual cycles to multiennial cycles have had relatively low recent incidence. Our study provides an extensive picture of pertussis epidemiology in the United States dating back to the onset of vaccination, a back-story that could aid epidemiologists in understanding contemporary transmission patterns. C1 [Magpantay, F. M. G.; Rohani, P.] Univ Michigan, Dept Ecol & Evolutionary Biol, Coll Literature Sci & Arts, Ann Arbor, MI 48109 USA. [Rohani, P.] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, P.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Magpantay, FMG (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Coll Literature Sci & Arts, 830 N Univ Ave, Ann Arbor, MI 48109 USA. EM felicigm@umich.edu FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institutes of Health [1R01AI101155]; National Institute of General Medical Sciences [U54-GM111274] FX This work was supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; by the Fogarty International Center, National Institutes of Health; and by research grants from the National Institutes of Health (grant 1R01AI101155) and the National Institute of General Medical Sciences (grant U54-GM111274). NR 58 TC 4 Z9 4 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2015 VL 181 IS 12 BP 921 EP 931 DI 10.1093/aje/kwv024 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK4GE UT WOS:000356180600001 PM 26022662 ER PT J AU Thompson, FE Dixit-Joshi, S Potischman, N Dodd, KW Kirkpatrick, SI Kushi, LH Alexander, GL Coleman, LA Zimmerman, TP Sundaram, ME Clancy, HA Groesbeck, M Douglass, D George, SM Schap, TE Subar, AF AF Thompson, Frances E. Dixit-Joshi, Sujata Potischman, Nancy Dodd, Kevin W. Kirkpatrick, Sharon I. Kushi, Lawrence H. Alexander, Gwen L. Coleman, Laura A. Zimmerman, Thea P. Sundaram, Maria E. Clancy, Heather A. Groesbeck, Michelle Douglass, Deirdre George, Stephanie M. Schap, TusaRebecca E. Subar, Amy F. TI Comparison of Interviewer-Administered and Automated Self-Administered 24-Hour Dietary Recalls in 3 Diverse Integrated Health Systems SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE comparative study; diet survey; experimental design; nutritional assessment; population ID MULTIPLE-PASS METHOD; RECOVERY BIOMARKERS; ENERGY; PROTEIN; INSTRUMENTS; NUTRITION; DESIGN; COHORT AB Twenty-four-hour dietary recalls provide high-quality intake data but have been prohibitively expensive for large epidemiologic studies. This study's goal was to assess whether the web-based Automated Self-Administered 24-Hour Recall (ASA24) performs similarly enough to the standard interviewer-administered, Automated Multiple-Pass Method (AMPM) 24-hour dietary recall to be considered a viable alternative. In 2010-2011, 1,081 adults from 3 integrated health systems in Detroit, Michigan; Marshfield, Wisconsin; and Kaiser-Permanente Northern California participated in a field trial. A quota design ensured a diverse sample by sex, age, and race/ethnicity. Each participant was asked to complete 2 recalls and was randomly assigned to 1 of 4 protocols differing by type of recall and administration order. For energy, the mean intakes were 2,425 versus 2,374 kcal for men and 1,876 versus 1,906 kcal for women by AMPM and ASA24, respectively. Of 20 nutrients/food groups analyzed and controlling for false discovery rate, 87% were judged equivalent at the 20% bound. ASA24 was preferred over AMPM by 70% of the respondents. Attrition was lower in the ASA24/AMPM study group than in the AMPM/ASA24 group, and it was lower in the ASA24/ASA24 group than in the AMPM/AMPM group. ASA24 offers the potential to collect high-quality dietary intake information at low cost with less attrition. C1 [Thompson, Frances E.; Potischman, Nancy; Kirkpatrick, Sharon I.; George, Stephanie M.; Schap, TusaRebecca E.; Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dixit-Joshi, Sujata; Zimmerman, Thea P.; Douglass, Deirdre] Westat Corp, Dept Hlth Studies, Rockville, MD USA. [Dodd, Kevin W.; Schap, TusaRebecca E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Kushi, Lawrence H.; Clancy, Heather A.] Kaiser Permanente, Div Res, Oakland, CA USA. [Alexander, Gwen L.; Groesbeck, Michelle] Henry Ford Hlth Syst, Biostat & Res Epidemiol, Detroit, MI USA. [Coleman, Laura A.; Sundaram, Maria E.] Marshfield Clin Res Fdn, Epidemiol Res Ctr, Marshfield, WI USA. RP Thompson, FE (reprint author), NCI, Div Canc Control & Populat Sci, Room 4E120,9609 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM thompsof@mail.nih.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU National Cancer Institute FX This work was supported by the National Cancer Institute. NR 17 TC 14 Z9 14 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2015 VL 181 IS 12 BP 970 EP 978 DI 10.1093/aje/kwu467 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK4GE UT WOS:000356180600006 PM 25964261 ER PT J AU Moore, LV Dodd, KW Thompson, FE Grimm, KA Kim, SA Scanlon, KS AF Moore, Latetia V. Dodd, Kevin W. Thompson, Frances E. Grimm, Kirsten A. Kim, Sonia A. Scanlon, Kelley S. TI Using Behavioral Risk Factor Surveillance System Data to Estimate the Percentage of the Population Meeting US Department of Agriculture Food Patterns Fruit and Vegetable Intake Recommendations SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE fruits; recommended intake; states; vegetables ID TELL US; CONSUMPTION; METAANALYSIS; FREQUENCY; WEIGHT; ISSUES; COHORT AB Most Americans do not eat enough fruits and vegetables with significant variation by state. State-level self-reported frequency of fruit and vegetable consumption is available from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System (BRFSS). However, BRFSS cannot be used to directly compare states' progress toward national goals because of incongruence in units used to measure intake and because distributions from frequency data are not reflective of usual intake. To help states track progress, we developed scoring algorithms from external data and applied them to BRFSS 2011 data to estimate the percentage of each state's adult population meeting US Department of Agriculture Food Patterns fruit and vegetable intake recommendations. We used 24-hour dietary recall data from the National Health and Nutrition Examination Survey, 2007-2010, to fit sex-and age-specific models that estimate probabilities of meeting recommendations as functions of reported consumption frequency, race/ethnicity, and poverty-income ratio adjusting for intraindividual variation. Regression parameters derived from these models were applied to BRFSS to estimate the percentage meeting recommendations. We estimate that 7%-18% of state populations met fruit recommendations and 5%-12% met vegetable recommendations. Our method provides a new tool for states to track progress toward meeting dietary recommendations. C1 [Moore, Latetia V.; Grimm, Kirsten A.; Kim, Sonia A.; Scanlon, Kelley S.] Ctr Dis Control & Prevent, Nutr Branch, Div Nutr Phys Act & Obes, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Dodd, Kevin W.] NCI, Biometry Res Grp, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Thompson, Frances E.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Moore, LV (reprint author), Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway NE,Mailstop F77, Atlanta, GA 30341 USA. EM lvmoore@cdc.gov FU Intramural CDC HHS [CC999999] NR 35 TC 8 Z9 8 U1 2 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2015 VL 181 IS 12 BP 979 EP 988 DI 10.1093/aje/kwu461 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK4GE UT WOS:000356180600007 PM 25935424 ER PT J AU Shui, IM Mondul, AM Lindstrom, S Tsilidis, KK Travis, RC Gerke, T Albanes, D Mucci, LA Giovannucci, E Kraft, P AF Shui, Irene M. Mondul, Alison M. Lindstroem, Sara Tsilidis, Konstantinos K. Travis, Ruth C. Gerke, Travis Albanes, Demetrius Mucci, Lorelei A. Giovannucci, Edward Kraft, Peter CA Breast Prostate Canc Cohort TI Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium SO CANCER LA English DT Article DE circulating 25-hydroxyvitamin D; fatal prostate cancer; gene-environment interaction; single-nucleotide polymorphisms; vitamin D genes ID GENOME-WIDE ASSOCIATION; D-RECEPTOR GENE; 25-HYDROXYVITAMIN D; D PATHWAY; UNITED-STATES; POLYMORPHISMS; PROGRESSION; PROGNOSIS; VARIANTS; TRIAL AB BACKGROUNDEvidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25-hydroxyvitamin D (25(OH)D) and common variations in key vitamin D-related genes with fatal PCa. METHODSIn a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single-nucleotide polymorphisms (SNPs) in 7 vitamin D-related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor ) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls. RESULTSNo statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend=.22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002. CONCLUSIONSStatistically significant associations were not observed for either 25(OH)D or vitamin D-related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration. Cancer 2015;121:1949-1956. (c) 2015 American Cancer Society. Because of the high prevalence of prostate cancer (PCa) and the wide international variation in vitamin D status, identifying causal links between the two could have a large public health impact. Few studies have addressed the risk of fatal PCa. In this study, a convincing association is not observed between circulating 25-hydroxyvitamin D (25(OH)D) or single-nucleotide polymorphisms (SNPs) in key vitamin D-related genes and fatal PCa. However, interactions between biologically relevant SNPs and circulating 25(OH)D with respect to fatal PCa may deserve further investigation. C1 [Shui, Irene M.; Lindstroem, Sara; Gerke, Travis; Mucci, Lorelei A.; Giovannucci, Edward; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Shui, Irene M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Mondul, Alison M.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Tsilidis, Konstantinos K.; Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Tsilidis, Konstantinos K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Gerke, Travis] Univ Florida, Dept Epidemiol, Gainesville, FL USA. [Mucci, Lorelei A.; Giovannucci, Edward] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Shui, IM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North, Seattle, WA 98109 USA. EM ishui@fhcrc.org OI Johansson, Mattias/0000-0002-3116-5081; Mondul, Alison/0000-0002-8843-1416 FU National Institutes of Health/National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758, R01 CA63464, P01 CA33619, R37 CA54281, UM1 CA164973]; Intramural Research Program of the National Institutes of Health/National Cancer Institute; Danish Cancer Society for Diet, Cancer, and Health (Danish study); Cancer Research UK (United Kingdom); Medical Research Council (United Kingdom); Hellenic Health Foundation for EPIC-Greece; Regional Government of Andalusia; Regional Government of Asturias; Regional Government of Basque Country; Regional Government of Murcia; Regional Government of Navarra; Carlos III Institute of Health Networks for Cooperative Research in Health [RD06/0020]; Sicilian government; Aire-Onlus Ragusa for EPIC-Italy; European Commission (Health and Consumer Protection Directorate General); International Agency for Research on Cancer; Dutch Ministry of Public Health, Welfare, and Sports; Statistics Netherlands for Monitoring project on frisk factors for chronic disease (MORGEN)-EPIC; National Cancer Institute National Research Service Award [T32 CA09001]; US Army Department of Defense Prostate Cancer Postdoctoral Fellowship; Prostate Cancer Foundation FX The Breast and Prostate Cancer Cohort Consortium was supported by the National Institutes of Health/National Cancer Institute under cooperative agreements (U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758, R01 CA63464, P01 CA33619, R37 CA54281, and UM1 CA164973) and by the Intramural Research Program of the National Institutes of Health/National Cancer Institute. Additional funding was supplied by the following: Danish Cancer Society for Diet, Cancer, and Health (Danish study); Cancer Research UK and Medical Research Council (United Kingdom) for the European Prospective Investigation Into Cancer and Nutrition (EPIC) study of vitamin D and prostate cancer and the EPIC-UK cohorts; Hellenic Health Foundation for EPIC-Greece; Health Research Fund (Fund for Health of Spain), Regional Governments of Andalusia, Asturias, Basque Country, Murcia, and Navarra, and Carlos III Institute of Health Networks for Cooperative Research in Health (RD06/0020) for EPIC-Spain; Sicilian government and Aire-Onlus Ragusa for EPIC-Italy; and European Commission (Health and Consumer Protection Directorate General), International Agency for Research on Cancer, Dutch Ministry of Public Health, Welfare, and Sports, and Statistics Netherlands for Monitoring project on frisk factors for chronic disease (MORGEN)-EPIC. Irene M. Shui and Travis Gerke were supported by the National Cancer Institute National Research Service Award (T32 CA09001), Irene M. Shui was supported by the US Army Department of Defense Prostate Cancer Postdoctoral Fellowship, and Lorelei A. Mucci was supported by the Prostate Cancer Foundation. NR 39 TC 16 Z9 16 U1 4 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2015 VL 121 IS 12 BP 1949 EP 1956 DI 10.1002/cncr.29320 PG 8 WC Oncology SC Oncology GA CJ8QJ UT WOS:000355768300009 PM 25731953 ER PT J AU Lewis, DR Chen, HS Midthune, DN Cronin, KA Krapcho, MF Feuer, EJ AF Lewis, Denise Riedel Chen, Huann-Sheng Midthune, Douglas N. Cronin, Kathleen A. Krapcho, Martin F. Feuer, Eric J. TI Early estimates of SEER cancer incidence for 2012: Approaches, opportunities, and cautions for obtaining preliminary estimates of cancer incidence SO CANCER LA English DT Article DE annual percent change; average annual percent change; cancer incidence trends; delay adjustment; population-based registry data ID REGRESSION; IMPACT; RATES AB BACKGROUNDThe National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program collects and publishes population-based cancer incidence data from registries covering approximately 28% () of the US population. SEER incidence rates are released annually in April from data submitted the prior November. The time needed to identify, consolidate, clean, and submit data requires the latest diagnosis year included to be 3 years before release. Approaches, opportunities, and cautions for an earlier release of data based on a February submission are described. METHODSFirst, cases submitted in February for the latest diagnosis year represented 92% to 98% of those in the following November submission. A reporting delay model was used to statistically adjust counts in recent diagnosis years for cases projected in the future. February submissions required larger adjustment factors than November submissions. Second, trends were checked to assess the validity. RESULTSMost cancer sites had similar annual percent change (APC) trends for February and November 2013. Male colon and rectum cancer and female lung and bronchus cancer showed an acceleration in declining APC trends only in February. Average annual percent change (AAPC) trends for the 2 submissions were similar for all sites. CONCLUSIONSFor the first time, preliminary 2012 incidence rates, based on February submissions, are provided. An accelerated decline starting in 2008 for male colon and rectum cancer rates and male lung cancer rates did not persist when 2012 data were added. An earlier release of SEER data is possible. Caution must be exercised when one is interpreting changing trends. Use of the more conservative AAPC is advised. Cancer 2015;121:2053-2062. (c) 2015 American Cancer Society. Surveillance, Epidemiology, and End Results (SEER) data submissions from November and February are evaluated to make decisions about the possibility of earlier data release. Although earlier release of SEER data is possible, considerations and cautions are presented for interpreting rates and trends from earlier data. C1 [Lewis, Denise Riedel; Chen, Huann-Sheng; Cronin, Kathleen A.; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Midthune, Douglas N.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Krapcho, Martin F.] Informat Management Syst Inc, Silver Spring, MD USA. RP Lewis, DR (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr Room 4E538 MSC 9765, Bethesda, MD 20892 USA. EM lewisde@mail.nih.gov FU National Cancer Institute FX No extramural funding was provided for this project. This work was conducted as part of the authors' official duties to the National Cancer Institute with assistance from an Information Management Systems contract with the National Cancer Institute. NR 10 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2015 VL 121 IS 12 BP 2053 EP 2062 DI 10.1002/cncr.29304 PG 10 WC Oncology SC Oncology GA CJ8QJ UT WOS:000355768300021 PM 25739953 ER PT J AU Shiels, MS Copeland, G Goodman, MT Harrell, J Lynch, CF Pawlish, K Pfeiffer, RM Engels, EA AF Shiels, Meredith S. Copeland, Glenn Goodman, Marc T. Harrell, Janna Lynch, Charles F. Pawlish, Karen Pfeiffer, Ruth M. Engels, Eric A. TI Cancer stage at diagnosis in patients infected with the human immunodeficiency virus and transplant recipients SO CANCER LA English DT Article DE cancer; stage; transplant; human immunodeficiency virus (HIV) ID UNITED-STATES; LUNG-CANCER; HIV; GUIDELINES; RISK; CARE; IMMUNOTHERAPY; DISPARITIES; POPULATION; MORTALITY AB BACKGROUNDIt is unknown whether immunosuppression results in more aggressive, advanced stage cancers. Because cancer stage is influenced both by tumor biology and medical surveillance, the authors assessed cancer stage in individuals infected with the human immunodeficiency virus (HIV) and solid organ transplant recipients, 2 immunosuppressed groups with differences in their health care use. METHODSThe authors used data on all cases of 15 cancer types diagnosed during 1996 through 2010 in 2 studies that linked US cancer registries with HIV and transplant registries. Odds ratios (ORs) for advanced (vs local) disease were estimated comparing HIV and transplant populations with immunocompetent individuals in polytomous logistic regression models adjusted for age, sex, race, registry, and year. RESULTSA total of 8411 of 4.5 million cancer cases occurred in HIV-infected individuals and 7322 of 6.4 million cancer cases occurred in transplant recipients. Compared with immunocompetent patients with cancer, those infected with HIV were more likely to be diagnosed with distant stage lung (OR, 1.13), female breast (OR, 1.99), and prostate (OR, 1.57) cancers, whereas transplant recipients had fewer distant stage lung (OR, 0.54), female breast (OR, 0.75), and prostate (OR, 0.72) cancers. Both immunosuppressed populations had a shift toward advanced stage melanoma (ORs of 1.97 for HIV-infected individuals and 1.82 for transplant recipients) and bladder cancer (ORs of 1.42 for HIV-infected individuals and 1.54 for transplant recipients). CONCLUSIONSBladder cancer and melanoma were more likely to be diagnosed at a nonlocal stage in both HIV-infected individuals and transplant recipients, suggesting a role for immunosuppression in their progression. In addition, we observed a shift for some common cancers toward later stages in HIV-infected individuals and toward earlier stages in transplant recipients, which is consistent with differential access to medical care or surveillance. Cancer 2015;121:2063-2071. (c) 2015 American Cancer Society. Bladder cancer and melanoma are more likely to be diagnosed at an advanced stage in both individuals infected with the human immunodeficiency virus and transplant recipients, thereby suggesting a role for immunosuppression in their progression. Some common cancers are shifted toward later stages in human immunodeficiency virus-infected individuals and earlier stages in transplant recipients, which is consistent with differences in medical surveillance noted in these populations. C1 [Shiels, Meredith S.; Pfeiffer, Ruth M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Copeland, Glenn] Michigan Dept Community Hlth, Michigan Canc Surveillance Program, Lansing, MI USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Harrell, Janna] Utah Canc Registry, Salt Lake City, UT USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Pawlish, Karen] New Jersey Dept Hlth, New Jersey State Canc Registry, Trenton, NJ USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU Intramural Research Program of the National Cancer Institute; National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; National Cancer Institute: Connecticut [HHSN2612 01000024C]; National Cancer Institute: Hawaii [HHSN261201000037C, N01-PC-35137, N01-PC-35139]; National Cancer Institute: Iowa [HSN2612010000 32C, N01-PC-35143]; National Cancer Institute: New Jersey [HHSN26120 1300021I, N01-PC-2013-00021]; National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; National Cancer Institute: Utah [HHSN2612010000 26C]; Centers for Disease Control and Prevention: California [1U58 DP000807-01]; Centers for Disease Control and Prevention: Colorado [U58DP000848-04]; Centers for Disease Control and Prevention: Georgia [5U58DP0038 75-01]; Centers for Disease Control and Prevention: Illinois [5U58DP003883-03]; Centers for Disease Control and Prevention: Maryland [U58DP12-1205 3919-03]; Centers for Disease Control and Prevention: Michigan [5U58DP00 3921-03]; Centers for Disease Control and Prevention: New Jersey [5U58/DP003931-02]; Centers for Disease Control and Prevention: New York [U58DP003879]; Centers for Disease Control and Prevention: North Carolina [U58DP00 0832]; Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement) [5458DP003920]; state of New Jersey; state of New York (including the Cancer Surveillance Improvement Initiative); state of Texas; state of Washington; Fred Hutchinson Cancer Research Center in Seattle, Washington; HIV Incidence and Case Surveillance Branch of the Centers for Disease Control and Prevention, National HIV Surveillance Systems: Colorado; HIV Incidence and Case Surveillance Branch of the Centers for Disease Control and Prevention, National HIV Surveillance Systems: Connecticut [5U62PS001005-05]; HIV Incidence and Case Surveillance Branch of the Centers for Disease Control and Prevention, National HIV Surveillance Systems: Washington, DC [5U62PS004015]; HIV Incidence and Case Surveillance Branch of the Centers for Disease Control and Prevention, National HIV Surveillance Systems: Michigan [5U62PS004011-02]; HIV Incidence and Case Surveillance Branch of the Centers for Disease Control and Prevention, National HIV Surveillance Systems: New Jersey [U62PS004001-2]; Arbor Research Collaborative for Health in Ann Arbor, Michigan [HHSH234200537009C]; Minneapolis Medical Research Foundation in Minneapolis, Minnesota [HHSH250201000018C] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute. The following cancer registries were supported by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (contract HHSN2612 01000024C), Hawaii (contracts HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (contracts HSN2612010000 32C and N01-PC-35143), New Jersey (contracts HHSN26120 1300021I and N01-PC-2013-00021), Seattle-Puget Sound (contract N01-PC-35142), and Utah (contract HHSN2612010000 26C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (agreement U58DP000848-04), Georgia (agreement 5U58DP0038 75-01), Illinois (agreement 5U58DP003883-03), Maryland (agreement U58DP12-1205 3919-03), Michigan (agreement 5U58DP00 3921-03), New Jersey (agreement 5U58/DP003931-02), New York (agreement U58DP003879), North Carolina (agreement U58DP00 0832), and Texas (agreement 5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey, New York (including the Cancer Surveillance Improvement Initiative), Texas, and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, Washington. The following human immunodeficiency virus (HIV) registries were supported by the HIV Incidence and Case Surveillance Branch of the Centers for Disease Control and Prevention, National HIV Surveillance Systems: Colorado; Connecticut (5U62PS001005-05); Washington, DC (5U62PS004015); Michigan (5U62PS004011-02); and New Jersey (U62PS004001-2). The views expressed in this article are those of the authors and should not be interpreted to reflect the views or policies of the Health Resources and Services Administration or the US Scientific Registry of Transplant Recipients (SRTR). During the initial period when registry linkages were performed, the SRTR was managed by the Arbor Research Collaborative for Health in Ann Arbor, Michigan (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by the Minneapolis Medical Research Foundation in Minneapolis, Minnesota (contract HHSH250201000018C). NR 24 TC 6 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2015 VL 121 IS 12 BP 2063 EP 2071 DI 10.1002/cncr.29324 PG 9 WC Oncology SC Oncology GA CJ8QJ UT WOS:000355768300022 PM 25739496 ER PT J AU Joe, MK Nakaya, N Abu-Asab, M Tomarev, SI AF Joe, Myung Kuk Nakaya, Naoki Abu-Asab, Mones Tomarev, Stanislav I. TI Mutated myocilin and heterozygous Sod2 deficiency act synergistically in a mouse model of open-angle glaucoma SO HUMAN MOLECULAR GENETICS LA English DT Article ID HUMAN TRABECULAR MESHWORK; MANGANESE SUPEROXIDE-DISMUTASE; ENDOPLASMIC-RETICULUM STRESS; AQUEOUS OUTFLOW PATHWAY; GENE-EXPRESSION PROFILE; SEQUENCE TAG ANALYSIS; OXIDATIVE STRESS; MUTANT MYOCILIN; INTRAOCULAR-PRESSURE; RISK-FACTORS AB Glaucoma is a multifactorial optic neuropathy characterized by retinal ganglion cell (RGC) death and axonal degeneration leading to irreversible blindness. Mutations in the MYOCILIN (MYOC) gene are the most common genetic factors of primary open-angle glaucoma. To develop a genetic mouse model induced by the synergistic interaction of mutated myocilin and another significant risk factor, oxidative stress, we produced double-mutant mice (Tg-MYOCY437H/+/Sod2(+/-)) bearing human MYOC with a Y437H point mutation and a heterozygous deletion of the gene for the primary antioxidant enzyme, superoxide dismutase 2 (SOD2). Sod2 is broadly expressed in most tissues including the trabecular meshwork (TM) and heterozygous Sod2 knockout mice exhibit the reduced SOD2 activity and oxidative stress in all studied tissues. Accumulation of Y437H myocilin in the TM induced endoplasmic reticulum stress and led to a 45% loss of smooth muscle alpha-actin positive cells in the eye drainage structure of 10- to 12-month-old Tg-MYOCY437H/+/Sod2(+/-) mice as compared with wild-type littermates. Tg-MYOCY437H/+/Sod2(+/-) mice had higher intraocular pressure, lost about 37% of RGCs in the peripheral retina, and exhibited axonal degeneration in the retina and optic nerve as compared with their wild-type littermates. Single-mutant littermates containing MYOCY437H/+ or Sod2(+/-) exhibited no significant pathological changes until 12 months of age. Additionally, we observed elevated expression of endothelial leukocyte adhesion molecule-1, a human glaucoma marker, in the TM of Tg-MYOCY437H/+/Sod2(+/-) mice. This is the first reported animal glaucoma model that combines expression of a glaucoma-causing mutant gene and an additional mutation mimicking a deleterious environment factor that acts synergistically. C1 [Joe, Myung Kuk; Nakaya, Naoki; Tomarev, Stanislav I.] NEI, Sect Retinal Gangl Cell Biol, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20895 USA. [Abu-Asab, Mones] NEI, Histol Core, NIH, Bethesda, MD 20895 USA. RP Tomarev, SI (reprint author), NEI, SRGCB, LRCMB, NIH, Bldg 6,Room 212,6 Ctr Dr, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Eye Institute, National Institutes of Health. NR 74 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2015 VL 24 IS 12 BP 3322 EP 3334 DI 10.1093/hmg/ddv082 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CJ7KR UT WOS:000355674400003 PM 25740847 ER PT J AU Phad, GE Bernat, NV Feng, Y Ingale, J Murillo, PAM O'Dell, S Li, YX Mascola, JR Sundling, C Wyatt, RT Hedestam, GBK AF Phad, Ganesh E. Bernat, Nestor Vazquez Feng, Yu Ingale, Jidnyasa Murillo, Paola Andrea Martinez O'Dell, Sijy Li, Yuxing Mascola, John R. Sundling, Christopher Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI Diverse Antibody Genetic and Recognition Properties Revealed following HIV-1 Envelope Glycoprotein Immunization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; VACCINE EFFICACY TRIAL; B-CELL RESPONSES; NEUTRALIZING ANTIBODIES; CD4 BINDING; IMMUNOGEN DESIGN; SINGLE-CELL; BROAD NEUTRALIZATION; NONHUMAN-PRIMATES; SEQUENCE-ANALYSIS AB Isolation of mAbs elicited by vaccination provides opportunities to define the development of effective immunity. Ab responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens display narrow neutralizing activity with limited capacity to block infection by tier 2 viruses. Intense work in the field suggests that improved Env immunogens are forthcoming, and it is therefore important to concurrently develop approaches to investigate the quality of vaccine-elicited responses at a higher level of resolution. In this study, we cloned a representative set of mAbs elicited by a model Env immunogen in rhesus macaques and comprehensively characterized their genetic and functional properties. The mAbs were genetically diverse, even within groups of Abs targeting the same subregion of Env, consistent with a highly polyclonal response. mAbs directed against two subdeterminants of Env, the CD4 binding site and V region 3, could in part account for the neutralizing activity observed in the plasma of the animal from which they were cloned, demonstrating the power of mAb isolation for a detailed understanding of the elicited response. Finally, through comparative analyses of mAb binding and neutralizing capacity of HIV-1 using matched Envs, we demonstrate complex relationships between epitope recognition and accessibility, highlighting the protective quaternary packing of the HIV-1 spike relative to vaccine-induced mAbs. C1 [Phad, Ganesh E.; Bernat, Nestor Vazquez; Murillo, Paola Andrea Martinez; Sundling, Christopher; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. [Feng, Yu; Ingale, Jidnyasa; Li, Yuxing; Wyatt, Richard T.] Scripps Res Inst, Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat, La Jolla, CA 92037 USA. [O'Dell, Sijy; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Li, Yuxing] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Sundling, Christopher] Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Box 280, S-17177 Stockholm, Sweden. EM Gunilla.Karlsson.Hedestam@ki.se OI Sundling, Christopher/0000-0002-6138-690X FU Swedish Research Council; Karolinska Institutet; National Institutes of Health [1P01AI104722-01A1]; National Institutes of Health Intramural Research Program; International AIDS Vaccine Initiative FX This work was supported by the Swedish Research Council, Karolinska Institutet, National Institutes of Health Grant 1P01AI104722-01A1, the National Institutes of Health Intramural Research Program, and the International AIDS Vaccine Initiative. Funding of the International AIDS Vaccine Initiative is made possible by support from many donors, the full list of which is available at http://www.iavi.org. NR 65 TC 11 Z9 11 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2015 VL 194 IS 12 BP 5903 EP 5914 DI 10.4049/jimmunol.1500122 PG 12 WC Immunology SC Immunology GA CJ8MY UT WOS:000355757800036 PM 25964491 ER PT J AU Byrareddy, SN Sidell, N Arthos, J Cicala, C Zhao, CX Little, DM Dunbar, P Yang, GX Pierzchalski, K Kane, MA Mayne, AE Song, B Soares, MA Villinger, F Fauci, AS Ansari, AA AF Byrareddy, Siddappa N. Sidell, Neil Arthos, James Cicala, Claudia Zhao, Chunxia Little, Dawn M. Dunbar, Paul Yang, Gui X. Pierzchalski, Keely Kane, Maureen A. Mayne, Ann E. Song, Byeongwoon Soares, Marcelo A. Villinger, Francois Fauci, Anthony S. Ansari, Aftab A. TI Species-Specific Differences in the Expression and Regulation of alpha 4 beta 7 Integrin in Various Nonhuman Primates SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL DEPLETION; VERSUS-HOST-DISEASE; RETINOIC ACID; SIV INFECTION; GASTROINTESTINAL-TRACT; IMMUNE ACTIVATION; HIV-1 ENVELOPE; MUCOSAL TRANSMISSION; MAXIMUM-LIKELIHOOD AB Among nonhuman primates, SIV-infected Asian pigtailed macaques (PM) are relatively more susceptible to infection and disease progression than SIV-infected rhesus macaques (RM). In addition, SIV-infected African natural hosts such as the sooty mangabeys (SM) are resistant to disease. The mechanisms associated with such species-related variable clinical outcomes remain ill-defined but hold the potential to provide insights into the underlying mechanisms surrounding HIV pathogenesis. Recent findings indicate that the expression of the heterodimeric gut homing integrin alpha 4 beta 7 can influence both susceptibility and disease progression in RM. It was reasoned that differences in the frequencies/surface densities of alpha 4 beta 7-expressing lymphocytes might contribute to the differences in the clinical outcome of SIV infection among NHPs. In this article, we report that CD4(+) T cells from PM constitutively express significantly higher levels of alpha 4 beta 7 than RM or SM. Retinoic acid, a key regulator of alpha 4 beta 7 expression, was paradoxically found at higher levels in the plasma of SM versus RM or PM. We also observed pairing of beta 7 with alpha E (alpha E beta 7) on CD4(+) T cells in the peripheral blood of SM, but not PM or RM. Finally, the differential mean density of expression of alpha 4 beta 7 in RM versus SM versus PM was predominantly dictated by species-specific sequence differences at the level of the beta 7 promoters, as determined by in vitro reporter/promoter construct transfection studies. We propose that differences in the regulation and expression of alpha 4 beta 7 may explain, in part, the differences in susceptibility and SIV disease progression in these NHP models. C1 [Byrareddy, Siddappa N.; Little, Dawn M.; Dunbar, Paul; Mayne, Ann E.; Villinger, Francois; Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Sidell, Neil; Yang, Gui X.] Emory Univ, Dept Gynecol & Obstet, Sch Med, Atlanta, GA 30322 USA. [Arthos, James; Cicala, Claudia; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Chunxia; Villinger, Francois] Yerkes Natl Primate Ctr, Div Microbiol & Immunol, Atlanta, GA 30329 USA. [Pierzchalski, Keely; Kane, Maureen A.] Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. [Song, Byeongwoon] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Soares, Marcelo A.] Univ Fed Rio de Janeiro, Lab Human Virol, BR-20231050 Rio De Janeiro, Brazil. RP Ansari, AA (reprint author), Emory Univ, Sch Med, Dept Pathol & Lab Med, 101Woodruff Circle,Room 2309 WMB, Atlanta, GA 30322 USA. EM pathaaa@emory.edu FU National Institutes of Health [AI078773, AI98628]; Yerkes National Primate Research Center of Emory University [NIH-OD 51POD1113]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the National Institutes of Health (Grants AI078773 and AI98628 to A.A.A.), the Yerkes National Primate Research Center of Emory University (Base Grant NIH-OD 51POD1113), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 56 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2015 VL 194 IS 12 BP 5968 EP 5979 DI 10.4049/jimmunol.1402866 PG 12 WC Immunology SC Immunology GA CJ8MY UT WOS:000355757800043 PM 25948815 ER PT J AU Eastman, AJ He, XM Qiu, YF Davis, MJ Vedula, P Lyons, DM Park, YD Hardison, SE Malachowski, AN Osterholzer, JJ Wormley, FL Williamson, PR Olszewski, MA AF Eastman, Alison J. He, Xiumiao Qiu, Yafeng Davis, Michael J. Vedula, Priya Lyons, Daniel M. Park, Yoon-Dong Hardison, Sarah E. Malachowski, Antoni N. Osterholzer, John J. Wormley, Floyd L., Jr. Williamson, Peter R. Olszewski, Michal A. TI Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ALLERGIC BRONCHOPULMONARY-MYCOSIS; ALTERNATIVELY ACTIVATED MACROPHAGES; VIRULENCE FACTOR; DENDRITIC CELLS; ALVEOLAR MACROPHAGES; TOXOPLASMA-GONDII; HOST-DEFENSE; T2 IMMUNITY; INFECTION; EXPRESSION AB Numerous virulence factors expressed by Cryptococcus neoformans modulate host defenses by promoting nonprotective Th2-biased adaptive immune responses. Prior studies demonstrate that the heat shock protein 70 homolog, Ssa1, significantly contributes to serotype D C. neoformans virulence through the induction of laccase, a Th2-skewing and CNS tropic factor. In the present study, we sought to determine whether Ssa1 modulates host defenses in mice infected with a highly virulent serotype A strain of C. neoformans (H99). To investigate this, we assessed pulmonary fungal growth, CNS dissemination, and survival in mice infected with either H99, an SSA1-deleted H99 strain (Delta ssa1), and a complement strain with restored SSA1 expression (Delta ssa1:: SSA1). Mice infected with the Delta ssa1 strain displayed substantial reductions in lung fungal burden during the innate phase (days 3 and 7) of the host response, whereas less pronounced reductions were observed during the adaptive phase (day 14) and mouse survival increased only by 5 d. Surprisingly, laccase activity assays revealed that Delta ssa1 was not laccase deficient, demonstrating that H99 does not require Ssa1 for laccase expression, which explains the CNS tropism we still observed in the Ssa1-deficient strain. Lastly, our immuno-phenotyping studies showed that Ssa1 directly promotes early M2 skewing of lung mononuclear phagocytes during the innate phase, but not the adaptive phase, of the immune response. We conclude that Ssa1's virulence mechanism in H99 is distinct and laccase-independent. Ssa1 directly interferes with early macrophage polarization, limiting innate control of C. neoformans, but ultimately has no effect on cryptococcal control by adaptive immunity. C1 [Eastman, Alison J.; Osterholzer, John J.; Olszewski, Michal A.] Univ Michigan, Grad Program Immunol, Ann Arbor, MI 48109 USA. [Eastman, Alison J.; He, Xiumiao; Qiu, Yafeng; Davis, Michael J.; Vedula, Priya; Lyons, Daniel M.; Malachowski, Antoni N.; Osterholzer, John J.; Olszewski, Michal A.] Vet Affairs Hosp, Ann Arbor, MI 48105 USA. [He, Xiumiao; Qiu, Yafeng; Davis, Michael J.; Malachowski, Antoni N.; Osterholzer, John J.; Olszewski, Michal A.] Univ Michigan, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Park, Yoon-Dong; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hardison, Sarah E.; Wormley, Floyd L., Jr.] Univ Texas San Antonio, Dept Biol, San Antonio, TX 78458 USA. [Hardison, Sarah E.; Wormley, Floyd L., Jr.] Univ Texas San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX 78249 USA. [Williamson, Peter R.] Univ Illinois, Coll Med, Infect Dis Sect, Dept Med, Chicago, IL 60612 USA. RP Olszewski, MA (reprint author), Univ Michigan, Vet Affairs Ann Arbor Hlth Syst, 2215 Fuller Rd, Ann Arbor, MI 48105 USA. EM olszewsm@umich.edu FU Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases; National Institutes of Health T32 Immunology Training Grant [T32AI007413]; University of Michigan Rackham Fellowship; Merit Review Awards from Biomedical Laboratory Research and Development Service, Department of Veterans Affairs Grants [1I01BX000656, BX002120-01]; National Institutes of Health/Heart, Lung and Blood Institute Training Program in Pulmonary Diseases Grant [T32-HL07749-19]; National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant [2RO1 AI071752]; Army Research Office of the Department of Defense Grant [W911NF-11-1-0136]; University of Michigan Undergraduate Research Opportunity Program FX This work was supported in part by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases (to P.R.W.). A.J.E. was supported by National Institutes of Health T32 Immunology Training Grant T32AI007413 and a University of Michigan Rackham Fellowship. The laboratories of M.A.O. and J.J.O. were supported by Merit Review Awards from Biomedical Laboratory Research and Development Service, Department of Veterans Affairs Grants 1I01BX000656 (to M.A.O.) and BX002120-01 (to J.J.O.), as well as by National Institutes of Health/Heart, Lung and Blood Institute Training Program in Pulmonary Diseases Grant T32-HL07749-19 (to M.J.D.). F.L.W. and S.E.H. were supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant 2RO1 AI071752 and by Army Research Office of the Department of Defense Grant W911NF-11-1-0136. Work of undergraduate students was supported by University of Michigan Undergraduate Research Opportunity Program. NR 61 TC 6 Z9 7 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2015 VL 194 IS 12 BP 5999 EP 6010 DI 10.4049/jimmunol.1402719 PG 12 WC Immunology SC Immunology GA CJ8MY UT WOS:000355757800046 PM 25972480 ER PT J AU Petersen, J van Bergen, J Loh, KL Kooy-Winkelaar, Y Beringer, DX Thompson, A Bakker, SF Mulder, CJJ Ladell, K McLaren, JE Price, DA Rossjohn, J Reid, HH Koning, F AF Petersen, Jan van Bergen, Jeroen Loh, Khai Lee Kooy-Winkelaar, Yvonne Beringer, Dennis X. Thompson, Allan Bakker, Sjoerd F. Mulder, Chris J. J. Ladell, Kristin McLaren, James E. Price, David A. Rossjohn, Jamie Reid, Hugh H. Koning, Frits TI Determinants of Gliadin-Specific T Cell Selection in Celiac Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR RECOGNITION; MOLECULES; PEPTIDES; USAGE; CRYSTALLIZATION; DIVERSITY; RESPONSES; HLA-DQ8; SYSTEM AB In HLA-DQ8-associated celiac disease (CD), the pathogenic T cell response is directed toward an immunodominant alpha-gliadin-derived peptide (DQ8-glia-alpha 1). However, our knowledge of TCR gene usage within the primary intestinal tissue of HLA-DQ8(+) CD patients is limited. We identified two populations of HLA-DQ8-glia-alpha 1 tetramer(+) CD4(+) T cells that were essentially undetectable in biopsy samples from patients on a gluten-free diet but expanded rapidly and specifically after antigenic stimulation. Distinguished by expression of TRBV9, both T cell populations displayed biased clonotypic repertoires and reacted similarly against HLA-DQ8-glia-alpha 1. In particular, TRBV9 paired most often with TRAV26-2, whereas the majority of TRBV9(-) TCRs used TRBV6-1 with no clear TRAV gene preference. Strikingly, both tetramer (+)/TRBV9(+) and tetramer (+)/TRBV9(-) T cells possessed a non-germline-encoded arginine residue in their CDR3 alpha and CDR3 beta loops, respectively. Comparison of the crystal structures of three TRBV9(+) TCRs and a TRBV9(-) TCR revealed that, as a result of distinct TCR docking modes, the HLA-DQ8-glia-a1 contacts mediated by the CDR3-encoded arginine were almost identical between TRBV9(+) and TRBV9(-) TCRs. In all cases, this interaction centered on two hydrogen bonds with a specific serine residue in the bound peptide. Replacement of serine with alanine at this position abrogated TRBV9(+) and TRBV9(-) clonal T cell proliferation in response to HLA-DQ8-glia-alpha 1. Gluten-specific memory CD4(+) T cells with structurally and functionally conserved TCRs therefore predominate in the disease-affected tissue of patients with HLA-DQ8-mediated CD. C1 [Petersen, Jan; Loh, Khai Lee; Beringer, Dennis X.; Rossjohn, Jamie; Reid, Hugh H.] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Petersen, Jan; Rossjohn, Jamie] Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic 3800, Australia. [van Bergen, Jeroen; Kooy-Winkelaar, Yvonne; Thompson, Allan; Koning, Frits] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 ZA Leiden, Netherlands. [Bakker, Sjoerd F.; Mulder, Chris J. J.] Free Univ Med Ctr, Dept Gastroenterol, NL-1081 HZ Amsterdam, Netherlands. [Ladell, Kristin; McLaren, James E.; Price, David A.; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Rossjohn, J (reprint author), Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. EM jamie.rossjohn@monash.edu; hugh.reid@monash.edu; F.Koning@lumc.nl RI Price, David/C-7876-2013; Ladell, Kristin/C-8301-2013; OI Price, David/0000-0001-9416-2737; Ladell, Kristin/0000-0002-9856-2938; Rossjohn, Jamie/0000-0002-2020-7522 FU Australian Research Council; National Health and Medical Research Council of Australia [1085875]; Celiac Disease Consortium; Dutch government [BSIK03009]; Wellcome Trust; National Health and Medical Research Council; Wellcome Trust Senior Investigator Award FX This work was supported by the Australian Research Council, the National Health and Medical Research Council of Australia (No. 1085875), the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and supported by the Dutch government (No. BSIK03009), and the Wellcome Trust. J.R. is supported by an Australia Fellowship from the National Health and Medical Research Council. D.A.P. is supported by a Wellcome Trust Senior Investigator Award. NR 30 TC 8 Z9 8 U1 0 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2015 VL 194 IS 12 BP 6112 EP 6122 DI 10.4049/jimmunol.1500161 PG 11 WC Immunology SC Immunology GA CJ8MY UT WOS:000355757800056 PM 25948817 ER PT J AU Deng, Q Waxse, B Riquelme, D Zhang, JB Aguilera, G AF Deng, Qiong Waxse, Bennett Riquelme, Denise Zhang, Jiabao Aguilera, Greti TI Helix 8 of the ligand binding domain of the glucocorticoid receptor (GR) is essential for ligand binding SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 16th Biennial Conference on the Adrenal Cortex (Adrenal) CY JUN 17-20, 2014 CL Chicago, IL SP Eunice Kennedy Shriver Natl Inst Child Hlth & Hum Dev, Natl Inst Hlth, Off Rare Dis, Univ Michigan Millie Schembechler Adrenal Canc Program, GWT TUD, Univ Buffalo, Dept Biochem DE Glucocorticoid receptor; Palmitoylation; Ligand binding domain; Helix 8; Dexamethasone binding; HSP90 ID STEROID-HORMONE ACTION; PLASMA-MEMBRANE; LOCALIZATION; ACTIVATION; ALPHA; ASSOCIATION; MECHANISMS; CORTISOL; NEURONS; HSP90 AB Membrane association of estrogen receptors (ER) depends on cysteine palmitoylation and two leucines in the ligand binding domain (LBD), conserved in most steroid receptors. The role of this region, corresponding to helix 8 of the glucocorticoid receptor (GR) LBD, on membrane association of GR was studied in 4B cells, expressing endogenous GR, and Cos-7 cells transfected EGFP-GR constructs. 4B cells preloaded with radiolabeled palmitic acid showed no radioactivity incorporation into immunoprecipitated GR. Moreover, mutation C683A (corresponding to ER palmitoylation site) did not affect corticosterone-induced membrane association of GR. Mutations L687-690A, L682A, E680G and K685G prevented membrane and also nuclear localization through reduced ligand binding. L687-690A mutation decreased association of GR with heat shock protein 90 and transcriptional activity, without overt effects on receptor protein stability. The data demonstrate that palmitoylation does not mediate membrane association of GR, but that the region 680-690 (helix 8) is critical for ligand binding and receptor function. Published by Elsevier Ireland Ltd. C1 [Deng, Qiong; Riquelme, Denise; Aguilera, Greti] NICHD, Sect Endocrine Physiol, PDEGEN, NIH, Bethesda, MD USA. [Deng, Qiong; Zhang, Jiabao] Jilin Univ, Coll Anim Sci, Changchun, Peoples R China. [Waxse, Bennett] NICHD, Sect Organelle Biol, CBMP, NIH, Bethesda, MD USA. RP Aguilera, G (reprint author), Eunice Kennedy Shriver Inst Child Hlth & Human De, Sect Endocrine Physiol, NIH, Bldg 10 CRC,Rm 1E-3330, Bethesda, MD 20892 USA. EM Greti_Aguilera@nih.gov FU Intramural NIH HHS [Z01 HD000631-19] NR 37 TC 3 Z9 3 U1 2 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUN 15 PY 2015 VL 408 IS C SI SI BP 23 EP 32 DI 10.1016/j.mce.2015.01.044 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CI8UT UT WOS:000355047900005 PM 25676569 ER PT J AU Drelon, C Berthon, A Mathieu, M Martinez, A Val, P AF Drelon, Coralie Berthon, Annabel Mathieu, Mickael Martinez, Antoine Val, Pierre TI Adrenal cortex tissue homeostasis and zonation: A WNT perspective SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 16th Biennial Conference on the Adrenal Cortex (Adrenal) CY JUN 17-20, 2014 CL Chicago, IL SP Eunice Kennedy Shriver Natl Inst Child Hlth & Hum Dev, Natl Inst Hlth, Off Rare Dis, Univ Michigan Millie Schembechler Adrenal Canc Program, GWT TUD, Univ Buffalo, Dept Biochem DE Adrenal cortex; Zonation; Differentiation; Hedgehog; WNT/beta-catenin; ACTH/PKA ID FAMILIAL GLUCOCORTICOID DEFICIENCY; DEPENDENT PROTEIN-KINASE; BETA-CATENIN ACTIVATION; ALDOSTERONE PRODUCTION; WNT/BETA-CATENIN; SONIC HEDGEHOG; ADRENOCORTICAL DEVELOPMENT; TARGETED DISRUPTION; FUNCTIONAL ZONATION; SIGNALING PATHWAYS AB The adrenal cortex plays essential roles in the control of sodium and water homeostasis, stress response, inflammation and metabolism, through secretion of glucocorticoids and mineralocorticoids. Coordinated production of these hormones relies on functional zonation of the cortex, characterised by expression of Cyp11b2 under the control of angiotensin II and plasma potassium level in zona glomerulosa (ZG) and Cyp11b1 under the control of ACTH in zona fasciculata (ZF). The mechanisms involved in the establishment of functional zonation and its maintenance during centripetal cortex cell renewal are still poorly understood. Here, we hypothesise that the hormonal and signalling pathways that control adrenal cortex function are also involved in cortical zonation. In particular, we summarise evidence on the role of WNT/beta-catenin signalling in ZG differentiation and how tight control of its activity is required to shape the adult cortex. In this context, we discuss the potential role of known WNT regulators and the possibility of a reciprocal cross-talk between PICA and WNT signalling. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Drelon, Coralie; Berthon, Annabel; Mathieu, Mickael; Martinez, Antoine; Val, Pierre] Clermont Univ, CNRS, INSERM, Lab Genet Reprod & Dev GReD,U1103,UMR 6293, F-63171 Aubiere, France. [Berthon, Annabel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Val, P (reprint author), Clermont Univ, CNRS, INSERM, GReD,U1103,UMR6293, BP80026,24 Ave Landais, F-63171 Aubiere, France. EM pierre.val@univ-bpclermont.fr NR 79 TC 8 Z9 8 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUN 15 PY 2015 VL 408 IS C SI SI BP 156 EP 164 DI 10.1016/j.mce.2014.12.014 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CI8UT UT WOS:000355047900021 PM 25542843 ER PT J AU Lee, JH Kim, TH Kim, HS Kim, AR Kim, DK Nam, ST Kim, HW Park, YH Her, E Park, YM Kim, HS Kim, YM Choi, WS AF Lee, Jun Ho Kim, Tae Hyung Kim, Hyuk Soon Kim, A-Ram Kim, Do-Kyun Nam, Seung Taek Kim, Hyun Woo Park, Young Hwan Her, Erk Park, Yeong Min Kim, Hyung Sik Kim, Young Mi Choi, Wahn Soo TI An indoxyl compound 5-bromo-4-chloro-3-indoly 1,3-diacetate, CAC-0982, suppresses activation of Fyn kinase in mast cells and IgE-mediated allergic responses in mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE 5-Bromo-4-chloro-3-indolyl; 1,3-diacetate CAC-0982; Mast cells; Allergy; Fyn kinase; Syk kinase ID FC-EPSILON-RI; PASSIVE CUTANEOUS ANAPHYLAXIS; NECROSIS-FACTOR-ALPHA; TYROSINE KINASE; GENE-EXPRESSION; SYK; ASTHMA; DISEASE; PROTEIN; INFLAMMATION AB Mast cells, constituents of virtually all organs and tissues, are critical cells in IgE-mediated allergic responses. The aim of this study was to investigate the effect and mechanism of an indoxyl chromogenic compound, 5-bromo-4chloro-3-indolyl 1,3-diacetate, CAC-0982, on IgE-mediated mast cell activation and allergic responses in mice. CAC-0982 reversibly suppressed antigen-stimulated degranulation in murine mast cells (IC50, similar to 3.8 mu M) and human mast cells (IC50, similar to 3.0 mu M). CAC-0982 also inhibited the expression and secretion of IL-4 and TNF-alpha in mast cells. Furthermore, CAC-0982 suppressed the mast cell-mediated allergic responses in mice in a dose-dependent manner (ED50 27.9 mg/kg). As for the mechanism, CAC-0982 largely suppressed the phosphorylation of Syk and its downstream signaling molecules, including LAT, Akt, Erk1/2, p38, and JNK. Notably, the tyrosine kinase assay of antigen-stimulated mast cells showed that CAC-0982 inhibited Fyn kinase, one of the upstream tyrosine kinases for Syk activation in mast cells. Taken together, these results suggest that CAC-0982 may be used as a new treatment for regulating IgE-mediated allergic diseases through the inhibition of the Fyn/Syk pathway in mast cells. (C) 2015 Elsevier Inc. All rights reserved. C1 [Lee, Jun Ho; Kim, Hyuk Soon; Kim, A-Ram; Kim, Do-Kyun; Nam, Seung Taek; Kim, Hyun Woo; Park, Young Hwan; Her, Erk; Park, Yeong Min; Choi, Wahn Soo] Konkuk Univ, Sch Med, Dept Immunol, Chungju 380701, South Korea. [Lee, Jun Ho] Korea Univ, Coll Med, Seoul 136701, South Korea. [Kim, Tae Hyung; Kim, Hyung Sik] Sungkyunkwan Univ, Coll Pharm, Suwon 440746, South Korea. [Kim, Do-Kyun] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul 132714, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Sch Med, Dept Immunol, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU Basic Research Laboratory Program through the National Research Foundation of Korea (NRF) [2013R1A4A1069575]; NRF - Ministry of Science, ICT Future Planning, the Korea government [2012R1A2A1A03670516] FX This work was supported by Basic Research Laboratory Program through the National Research Foundation of Korea (NRF) (No.2013R1A4A1069575) and in part by the NRF grant (No. 2012R1A2A1A03670516) funded by the Ministry of Science, ICT Future Planning, the Korea government. The chemical library used in this study was kindly provided by Korea Chemical Bank of Korea Research Institute of Chemical Technology. NR 48 TC 4 Z9 4 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2015 VL 285 IS 3 BP 179 EP 186 DI 10.1016/j.taap.2015.04.009 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CJ1KH UT WOS:000355242000004 PM 25902337 ER PT J AU Uygur, B Abramo, K Leikina, E Vary, C Liaw, L Wu, WS AF Uygur, Berna Abramo, Katrina Leikina, Evgenia Vary, Calvin Liaw, Lucy Wu, Wen-Shu TI SLUG is a Direct Transcriptional Repressor of PTEN Tumor Suppressor SO PROSTATE LA English DT Article DE slug; prostate cancer; cell growth; PTEN; tumor suppressor ID PROSTATE-CANCER CELLS; RADIATION-INDUCED APOPTOSIS; P53-MEDIATED APOPTOSIS; PROGENITOR CELLS; DRUG-RESISTANCE; STEM-CELLS; GENE; EXPRESSION; DELETION; SNAIL AB BACKGROUNDPTEN/AKT signaling plays a key role in prostate cancer development and maintenance of prostate cancer stem cells. How other oncogenes or tumor suppressors interact with this pathway remain to be elucidated. SLUG is an zinc finger transcription factor of the Snail superfamily, and it promotes cancer metastasis and determines the mammary stem cell state. METHODSSLUG was overexpressed in cells by retroviral vector and knockdown of SLUG and PTEN was mediated by shRNAs-expressing lentiviruses. Expression level of SLUG and PTEN was examined by Western blot, RT-PCR, and qPCR analyses. PTEN promoter activity was measured by luciferase reporter assay. ChIP assay was used to measure the binding between SLUG and the PTEN promoter in vivo. RESULTWe showed that overexpression of SLUG decreased expression of PTEN tumor repressor in prostate cancer cell lines 22RV1 and DU145; conversely, knockdown of SLUG expression elevated PTEN expresson at both protein and RNA level in these cells. We demonstrated that SLUG overexpression inhibits PTEN promoter activity through the proximal promoter region in prostate cancer cells. By ChIP assay, we confirmed that SLUG directly binds to the PTEN promoter region covering the E-box sites. We also showed that Slug deficiency leads to an increased expression of PTEN in mouse embryo fibroblasts and prostate tissues. Importantly, we found that overexpression of SLUG increases drug resistance of DU145 prostate cancer cell line and knockdown of SLUG by shRNA sensitizes DU145 cell line to chemotherapeutic drugs. We further demonstrated that PTEN knockdown converts drug sensitivity of DU145 cells expressing SLUG shRNA to anticancer drugs. CONCLUSIONWe provide compelling evidence showing that PTEN is a direct functional target of SLUG. Our findings offer new insight in the regulation of the PTEN/AKT pathway and provide a molecular basis for potential targeted therapies of prostate cancer Prostate 75:907-916, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Uygur, Berna; Abramo, Katrina; Vary, Calvin; Liaw, Lucy; Wu, Wen-Shu] Maine Med Ctr, Res Inst, Ctr Mol Med, Scarborough, ME USA. [Uygur, Berna] Univ Maine, Program Biochem & Mol Biol, Orono, ME USA. [Uygur, Berna; Leikina, Evgenia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Program Phys Biol, NIH, Bethesda, MD USA. [Wu, Wen-Shu] Univ Illinois, Coll Med, Dept Med, Chicago, IL 60612 USA. RP Wu, WS (reprint author), Univ Illinois, Coll Med, Dept Med, M-C 787,840 S Wood St, Chicago, IL 60612 USA. EM wuwenshu@uic.edu FU NIH/NIA [R01AG040182]; NIDDK [R01DK090478, 2008610038]; MMCRI PhD Student Fund FX Grant sponsor: NIH/NIA; Grant number: R01AG040182; Grant sponsor: NIDDK; Grant numbers: R01DK090478; 2008610038; Grant sponsor: MMCRI PhD Student Fund. NR 34 TC 3 Z9 3 U1 4 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD JUN 15 PY 2015 VL 75 IS 9 BP 907 EP 916 DI 10.1002/pros.22974 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CH7GD UT WOS:000354203000002 PM 25728608 ER PT J AU Bergeron, C Ronco, G Reuschenbach, M Wentzensen, N Arbyn, M Stoler, M Doeberitz, MV AF Bergeron, Christine Ronco, Guglielmo Reuschenbach, Miriam Wentzensen, Nicolas Arbyn, Marc Stoler, Mark Doeberitz, Magnus von Knebel TI The clinical impact of using p16(INK4a) immunochemistry in cervical histopathology and cytology: An update of recent developments SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE p16(INK4a); cervical cancer; early detection; HPV; cervical pathology ID RANDOMIZED CONTROLLED-TRIAL; DUAL-STAINED CYTOLOGY; LIQUID-BASED CYTOLOGY; TERMINOLOGY STANDARDIZATION PROJECT; HUMAN-PAPILLOMAVIRUS INFECTION; OF-AMERICAN-PATHOLOGISTS; IN-SITU HYBRIDIZATION; HPV-POSITIVE WOMEN; INTRAEPITHELIAL NEOPLASIA; PAP CYTOLOGY AB Cervical cancer screening test performance has been hampered by either lack of sensitivity of Pap cytology or lack of specificity of Human Papillomavirus (HPV) testing. This uncertainty can lead to unnecessary referral and treatment, which is disturbing for patients and increases costs for health care providers. The identification of p16(INK4a) as a marker for neoplastic transformation of cervical squamous epithelial cells by HPVs allows the identification of HPV-transformed cells in histopathology or cytopathology specimens. Diagnostic studies have demonstrated that the use of p16(INK4a) immunohistochemistry substantially improves the reproducibility and diagnostic accuracy of histopathologic diagnoses. p16(INK4a) cytology has substantially higher sensitivity for detection of cervical precancer in comparison to conventional Pap tests. Compared to HPV DNA tests, immunochemical detection of p16(INK4a)-stained cells demonstrates a significantly improved specificity with remarkably good sensitivity. About 15 years after the initial observation that p16(INK4a) is overexpressed in HPV-transformed cells we review the accumulated clinical evidence suggesting that p16(INK4a) can serve as a useful biomarker in the routine diagnostic work up of patients with HPV infections and associated lesions of the female anogenital tract. C1 [Bergeron, Christine] Lab Cerba, F-95066 Cergy Pontoise 9, France. [Ronco, Guglielmo] Ctr Canc Epidemiol & Prevent CPO, Citta Salute & Sci, I-10123 Turin, Italy. [Reuschenbach, Miriam; Doeberitz, Magnus von Knebel] Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, D-69120 Heidelberg, Germany. [Reuschenbach, Miriam; Doeberitz, Magnus von Knebel] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Stoler, Mark] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. RP Doeberitz, MV (reprint author), Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany. EM knebel@med.uni-heidelberg.de RI von Knebel Doeberitz, Magnus/D-2372-2016 OI von Knebel Doeberitz, Magnus/0000-0002-0498-6781 FU 7th Framework Program of DG Research of the European Commission [603019]; Belgian Foundation against Cancer (Brussels, Belgium); FNRS (Fonds national de la Recherche scientifique), through TELEVIE, Brussels, Belgium [7.4.628.07.F] FX Marc Arbyn received support from the 7th Framework Program of DG Research of the European Commission (CoheaHr Project [603019], coordinated by the VU University Medical Center of Amsterdam, the Netherlands); the Belgian Foundation against Cancer (Brussels, Belgium); and FNRS (Fonds national de la Recherche scientifique), through TELEVIE, Brussels, Belgium (ref 7.4.628.07.F). NR 74 TC 19 Z9 20 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 15 PY 2015 VL 136 IS 12 BP 2741 EP 2751 DI 10.1002/ijc.28900 PG 11 WC Oncology SC Oncology GA CF8FA UT WOS:000352790300001 PM 24740700 ER PT J AU Giuliano, AR Nyitray, AG Kreimer, AR Campbell, CMP Goodman, MT Sudenga, SL Monsonego, J Franceschi, S AF Giuliano, Anna R. Nyitray, Alan G. Kreimer, Aimee R. Campbell, Christine M. Pierce Goodman, Marc T. Sudenga, Staci L. Monsonego, Joseph Franceschi, Silvia TI EUROGIN 2014 roadmap: Differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE human papillomavirus; epidemiology; gender differences; natural history; cancer ID ANAL HUMAN-PAPILLOMAVIRUS; ORAL HUMAN-PAPILLOMAVIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; HAWAII HPV COHORT; NUTRITION EXAMINATION SURVEY; AGE-SPECIFIC PREVALENCE; HIV-POSITIVE MEN; UNITED-STATES; RISK-FACTORS; INTRAEPITHELIAL NEOPLASIA AB Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and <50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often, mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet, HPV-related cancer incidence at this site is several-fold higher than at either the anal canal or the penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age-specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts. C1 [Giuliano, Anna R.; Campbell, Christine M. Pierce; Sudenga, Staci L.] Univ S Florida, H Lee Moffitt Canc Ctr, Ctr Infect Res Canc, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Nyitray, Alan G.] Univ Texas Sch Publ Hlth Houston, Ctr Infect Dis, Houston, TX USA. [Kreimer, Aimee R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Biomed Sci Canc Prevent & Control, Los Angeles, CA 90048 USA. [Monsonego, Joseph] Inst Cervix, Paris, France. [Franceschi, Silvia] Int Agcy Res Canc, F-69372 Lyon, France. RP Giuliano, AR (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, CIRC,MRC CANCONT, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Anna.Giuliano@moffitt.org RI Kreimer, Aimee/H-1687-2015; Sudenga, Staci/A-7726-2015; OI Pierce Campbell, Christine/0000-0002-0233-4894 FU National Cancer Institute at the National Institutes of Health [R25T CA147832]; American Cancer Society [PF-13-222-01] FX Grant sponsor: The National Cancer Institute at the National Institutes of Health; Grant number: Cancer Prevention Fellowship R25T CA147832; Grant sponsor: The American Cancer Society; Grant number: Postdoctoral Fellowship PF-13-222-01 NR 104 TC 27 Z9 29 U1 1 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 15 PY 2015 VL 136 IS 12 BP 2752 EP 2760 DI 10.1002/ijc.29082 PG 9 WC Oncology SC Oncology GA CF8FA UT WOS:000352790300002 PM 25043222 ER PT J AU Wakeham, K Johnston, WT Nalwoga, A Webb, EL Mayanja, BN Miley, W Elliott, AM Whitby, D Newton, R AF Wakeham, Katie Johnston, W. Thomas Nalwoga, Angela Webb, Emily L. Mayanja, Billy N. Miley, Wendell Elliott, Alison M. Whitby, Denise Newton, Robert TI Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: A nested case-control study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HIV-associated Kaposi's sarcoma; sub-Saharan Africa; Kaposi's sarcoma associated-herpesvirus; HIV; AIDS ID EPSTEIN-BARR-VIRUS; RISK-FACTORS; HUMAN-HERPESVIRUS-8 INFECTION; ANTIRETROVIRAL THERAPY; UGANDA; POPULATION; COHORT; TRANSMISSION; CHILDREN; DISEASE AB HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p<0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting. What's New? Infection with Kaposi sarcoma associated-herpesvirus (KSHV) and HIV, the major risk factor for Kaposi sarcoma, is common in sub-Saharan Africa. However, little is known about the evolution of KSHV antibody responses in HIV-infected individuals prior to the clinical onset of KS. This study shows that antibody titres against KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) increase significantly in the six years leading up to HIV-associated KS. Titres of K8.1, a lytic antigen, rose more than LANA titres, indicating that the activation of genes in the lytic cycle of viral replication is important in KS development. C1 [Wakeham, Katie; Nalwoga, Angela; Mayanja, Billy N.; Elliott, Alison M.; Newton, Robert] MRC, Uganda Virus Res Inst, Uganda Res Unit AIDS, Entebbe, Uganda. [Wakeham, Katie; Johnston, W. Thomas; Newton, Robert] Univ York, Epidemiol & Canc Stat Grp, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Wakeham, Katie] Univ Glasgow, Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. [Webb, Emily L.; Elliott, Alison M.] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol ELW, London WC1, England. [Webb, Emily L.; Elliott, Alison M.] London Sch Hyg & Trop Med, Dept Clin Res AME, London WC1, England. [Miley, Wendell; Whitby, Denise] Frederick Natl Lab Canc Res, Viral Oncol Sect, AIDS & Canc Virus Program, Leidos Biomed, Frederick, MD USA. [Newton, Robert] Int Agcy Res Canc, F-69372 Lyon, France. RP Wakeham, K (reprint author), Univ Glasgow, Inst Canc Sci, Garscube Estate, Glasgow G61 1BD, Lanark, Scotland. EM Katie.Wakeham@glasgow.ac.uk OI Webb, Emily/0000-0002-4019-7456; Elliott, Alison/0000-0003-2818-9549 FU Wellcome Trust [090132]; Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services [HSN261200800001E] FX Grant sponsor: Wellcome Trust; Grant number: 090132, Grant sponsors: Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (contract HSN261200800001E) NR 36 TC 2 Z9 2 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 15 PY 2015 VL 136 IS 12 BP 2822 EP 2830 DI 10.1002/ijc.29329 PG 9 WC Oncology SC Oncology GA CF8FA UT WOS:000352790300008 PM 25395177 ER PT J AU Rasooly, R Balsam, J Hernlem, BJ Rasooly, A AF Rasooly, Reuven Balsam, Josh Hernlem, Bradley J. Rasooly, Avraham TI Sensitive detection of active Shiga toxin using low cost CCD based optical detector SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Food; Shiga toxin; CCD camera; Adenovirus ID LINKED-IMMUNOSORBENT-ASSAY; ESCHERICHIA-COLI O157-H7; STAPHYLOCOCCAL-ENTEROTOXIN; UNITED-STATES; FOOD; PCR AB To reduce the sources and incidence of food-borne illness there is a need to develop affordable, sensitive devices for detection of active toxins, such as Shiga toxin type 2 (Stx2). Currently the widely used methods for measuring Shiga toxin are immunoassay that cannot distinguish between the active form of the toxin, which poses a threat to life, to the inactive form which can bind to antibodies but show no toxicity. In this work, we determine toxin activity based on Shiga toxin inhibition of green fluorescent protein (GFP) combined with low cost charge-coupled device (CCD) fluorescence detection, which is more clinically relevant than immunoassay. For assay detection, a simple low cost fluorescence detection system was constructed using a CCD camera and light emitting diode (LED) excitation source, to measure GFP expression. The system was evaluated and compared to a commercial fluorometer using photo-multiplier detection for detecting active Stx2 in the range 100 ng/mL-0.01 pg/mL. The result shows that there is a negative linear relationship between Stx2 concentrations and luminous intensity of GFP, imaged by the CCD camera (R-2=0.85) or fluorometer (R-2=0.86). The low cost (similar to$300) CCD camera is capable of detecting Shiga toxin activity at comparable levels as a more expensive (similar to$30,000) fluorometer. These results demonstrate the utility and the potential of low cost detectors for toxin activity; this approach may increase the availability of foodborne bacterial toxin diagnostics in regions where there are limited resources and could be readily adapted to the detection of other food-borne toxins. Published by Elsevier B.V. C1 [Rasooly, Reuven; Hernlem, Bradley J.] ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. [Balsam, Josh; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Balsam, Josh] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Off Canc Complementary & Alternat Med, Rockville, MD 20850 USA. RP Rasooly, R (reprint author), ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. EM reuven.rasooly@ars.usda.gov NR 20 TC 3 Z9 3 U1 5 U2 47 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD JUN 15 PY 2015 VL 68 BP 705 EP 711 DI 10.1016/j.bios.2015.01.065 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA CD7CL UT WOS:000351248300100 PM 25677808 ER PT J AU Campa, D Barrdahl, M Gaudet, MM Black, A Chanock, SJ Diver, WR Gapstur, SM Haiman, C Hankinson, S Hazra, A Henderson, B Hoover, RN Hunter, DJ Joshi, AD Kraft, P Le Marchand, L Lindstrom, S Willett, W Travis, RC Amiano, P Siddiq, A Trichopoulos, D Sund, M Tjonneland, A Weiderpass, E Peeters, PH Panico, S Dossus, L Ziegler, RG Canzian, F Kaaks, R AF Campa, Daniele Barrdahl, Myrto Gaudet, Mia M. Black, Amanda Chanock, Stephen J. Diver, W. Ryan Gapstur, Susan M. Haiman, Christopher Hankinson, Susan Hazra, Aditi Henderson, Brian Hoover, Robert N. Hunter, David J. Joshi, Amit D. Kraft, Peter Le Marchand, Loic Lindstrom, Sara Willett, Walter Travis, Ruth C. Amiano, Pilar Siddiq, Afshan Trichopoulos, Dimitrios Sund, Malin Tjonneland, Anne Weiderpass, Elisabete Peeters, Petra H. Panico, Salvatore Dossus, Laure Ziegler, Regina G. Canzian, Federico Kaaks, Rudolf TI Genetic risk variants associated with in situ breast cancer SO BREAST CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; COMMON VARIANTS; CONFER SUSCEPTIBILITY; CLINICAL-SIGNIFICANCE; COHORT CONSORTIUM; IDENTIFIES 2; CARCINOMA; WOMEN AB Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS. Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile. Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies. Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus. C1 [Campa, Daniele; Barrdahl, Myrto; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Gaudet, Mia M.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Black, Amanda; Chanock, Stephen J.; Hoover, Robert N.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chanock, Stephen J.] Frederick Natl Lab Canc Res, Core Genotyping Facil, Gaithersburg, MD 20877 USA. [Haiman, Christopher; Henderson, Brian] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hankinson, Susan] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Epidemiol, Amherst, MA 01003 USA. [Hankinson, Susan] Brigham & Womens Hosp, Canc Res Ctr, Boston, MA 02115 USA. [Hankinson, Susan; Hazra, Aditi; Hunter, David J.; Joshi, Amit D.; Kraft, Peter; Lindstrom, Sara; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hazra, Aditi] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Hazra, Aditi] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Amiano, Pilar] BIODonostia Res Inst, Basque Hlth Dept, Publ Hlth Div Gipuzkoa, San Sebastian 20013, Spain. [Amiano, Pilar] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid 28029, Spain. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens 11527, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens 11527, Greece. [Sund, Malin] Umea Univ, Dept Surg & Perioperat Sci, S-90187 Umea, Sweden. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark. [Weiderpass, Elisabete] Univ Tromso, Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, N-0304 Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Dept Genet Epidemiol, Helsinki 00014, Finland. [Peeters, Petra H.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3584 CG Utrecht, Netherlands. [Panico, Salvatore] Univ Naples Federico II, Dipartimento Med Clin & Chirurg, I-80131 Naples, Italy. [Dossus, Laure] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, U1018, Nutr Hormones & Womens Hlth Team, F-94805 Villejuif, France. [Dossus, Laure] Univ Paris 11, UMRS 1018, F-94805 Villejuif, France. [Dossus, Laure] IGR, F-94805 Villejuif, France. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany. RP Kaaks, R (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM r.kaaks@dkfz.de RI Campa, Daniele/K-1617-2016; Panico, Salvatore/K-6506-2016; Weiderpass, Elisabete/M-4029-2016 OI Campa, Daniele/0000-0003-3220-9944; Panico, Salvatore/0000-0002-5498-8312; Weiderpass, Elisabete/0000-0003-2237-0128 FU Hellenic Health Foundation FX The Greece EPIC center has been supported by the Hellenic Health Foundation. The BPC3 project was approved by the ethics committee of the International Agency for Research on Cancer (IARC) for the EPIC cohort, by the Emory University Institutional Review Board for the CPS-II cohort, by the Institutional Review Board of the University of Hawaii and University of Southern California for the MEC cohort, by the ethics committee of the Brigham and Women's Hospital for the NHS cohort and the NCI Institutional Review Board for the PLCO cohort. The authors would like to pay tribute to our deceased colleague Dimitrios Trichopoulos, who will be missed. NR 52 TC 6 Z9 6 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JUN 13 PY 2015 VL 17 AR 82 DI 10.1186/s13058-015-0596-x PG 10 WC Oncology SC Oncology GA CL6KY UT WOS:000357077200001 PM 26070784 ER PT J AU Richiardi, J Altmann, A Milazzo, AC Chang, C Chakravarty, MM Banaschewski, T Barker, GJ Bokde, ALW Bromberg, U Buchel, C Conrod, P Fauth-Buhler, M Flor, H Frouin, V Gallinat, J Garavan, H Gowland, P Heinz, A Lemaitre, H Mann, KF Martinot, JL Nees, F Paus, T Pausova, Z Rietschel, M Robbins, TW Smolka, MN Spanagel, R Strohle, A Schumann, G Hawrylycz, M Poline, JB Greicius, MD AF Richiardi, Jonas Altmann, Andre Milazzo, Anna-Clare Chang, Catie Chakravarty, M. Mallar Banaschewski, Tobias Barker, Gareth J. Bokde, Arun L. W. Bromberg, Uli Buechel, Christian Conrod, Patricia Fauth-Buehler, Mira Flor, Herta Frouin, Vincent Gallinat, Juergen Garavan, Hugh Gowland, Penny Heinz, Andreas Lemaitre, Herve Mann, Karl F. Martinot, Jean-Luc Nees, Frauke Paus, Tomas Pausova, Zdenka Rietschel, Marcella Robbins, Trevor W. Smolka, Michael N. Spanagel, Rainer Stroehle, Andreas Schumann, Gunter Hawrylycz, Mike Poline, Jean-Baptiste Greicius, Michael D. CA IMAGEN Consortium TI Correlated gene expression supports synchronous activity in brain networks SO SCIENCE LA English DT Article ID RESTING STATE NETWORKS; MOUSE-BRAIN; TRANSCRIPTOME; CONNECTIVITY; ATLAS AB During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set. The set of 136 genes we identify is significantly enriched for ion channels. Polymorphisms in this set of genes significantly affect resting-state functional connectivity in a large sample of healthy adolescents. Expression levels of these genes are also significantly associated with axonal connectivity in the mouse. The results provide convergent, multimodal evidence that resting-state functional networks correlate with the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function. C1 [Richiardi, Jonas; Altmann, Andre; Milazzo, Anna-Clare; Greicius, Michael D.] Stanford Univ, Dept Neurol & Neurol Sci, Funct Imaging Neuropsychiat Disorders Lab, Stanford, CA 94305 USA. [Richiardi, Jonas] Univ Geneva, Dept Neurosci, Lab Neurol & Imaging Cognit, Geneva, Switzerland. [Milazzo, Anna-Clare] VA Palo Alto Hlth Care Syst, War Related Illness & Injury Study Ctr, Palo Alto, CA USA. [Chang, Catie] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Chakravarty, M. Mallar] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada. [Chakravarty, M. Mallar] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Chakravarty, M. Mallar] McGill Univ, Dept Biomed Engn, Montreal, PQ, Canada. [Banaschewski, Tobias] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat, Mannheim, Germany. [Barker, Gareth J.; Conrod, Patricia; Schumann, Gunter] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Bokde, Arun L. W.; Garavan, Hugh] Trinity Coll Dublin, Inst Neurosci, Dublin, Ireland. [Bromberg, Uli; Buechel, Christian] Univ Klinikum Hamburg Eppendorf, Hamburg, Germany. [Conrod, Patricia] Univ Montreal, Dept Psychiat, Ctr Hosp Univ CHU, Ste Justine Hosp, Montreal, PQ H3C 3J7, Canada. [Fauth-Buehler, Mira; Mann, Karl F.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, Mannheim, Germany. [Flor, Herta; Nees, Frauke] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, Mannheim, Germany. [Frouin, Vincent] Commissariat Energie Atom & Energies Alternat, Neurospin, Paris, France. [Gallinat, Juergen; Heinz, Andreas; Stroehle, Andreas] Charite, Campus Charite Mitte, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Garavan, Hugh] Univ Vermont, Dept Psychiat, Burlington, VT USA. [Garavan, Hugh] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Gowland, Penny] Univ Nottingham, Sch Phys & Astron, Nottingham NG7 2RD, England. [Lemaitre, Herve; Martinot, Jean-Luc] Univ Paris 11, INSERM, U1000, Neuroimaging & Psychiat, F-91405 Orsay, France. [Lemaitre, Herve; Martinot, Jean-Luc] Univ Paris 05, Cochin Hosp, APHP, INSERM,U1000,Maison Solenn,Sorbonne Paris Cite, Paris, France. [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Paus, Tomas] Univ Nottingham, Sch Psychol, Nottingham NG7 2RD, England. [Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Rietschel, Marcella] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Robbins, Trevor W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. [Robbins, Trevor W.] Univ Cambridge, Dept Psychol, Cambridge, England. [Smolka, Michael N.] Tech Univ Dresden, Dept Psychiat & Psychotherapy, D-01062 Dresden, Germany. [Smolka, Michael N.] Tech Univ Dresden, Neuroimaging Ctr, D-01062 Dresden, Germany. [Spanagel, Rainer] Fac Clin Med Mannheim, Cent Inst Mental Hlth, Dept Psychopharmacol, Mannheim, Germany. [Schumann, Gunter] MRC, Social Genet & Dev Psychiat SGDP Ctr, London, England. [Hawrylycz, Mike] Allen Inst Brain Sci, Seattle, WA USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. RP Richiardi, J (reprint author), Stanford Univ, Dept Neurol & Neurol Sci, Funct Imaging Neuropsychiat Disorders Lab, Stanford, CA 94305 USA. EM jonas.richiardi@unige.ch; greicius@stanford.edu RI Williams, Steve/D-6979-2011; Barker, Gareth/C-9616-2009; Gowland, Penny/I-9016-2012; Lubbe, Steven/L-8261-2013; Poustka, Luise/D-9299-2017 OI Williams, Steve/0000-0003-4299-1941; Barker, Gareth/0000-0002-5214-7421; Gowland, Penny/0000-0002-4900-4817; FU European Union [299500, LSHM-CT-2007-037286, 602450, 603016]; Feldman Family Foundation; National Institutes of Health [RO1NS073498]; Innovative Medicine Initiative Project EU-AIMS [115300-2]; Medical Research Council [93558]; Swedish funding agency FORMAS; Medical Research Council; Wellcome Trust (Behavioral and Clinical Neuroscience Institute, University of Cambridge); National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; Bundesministerium fur Bildung und Forschung (BMBF) [01GS08152, 01EV0711, eMED SysAlc01ZX1311A]; Bundesministerium fur Bildung und Forschung (BMBF Forschungsnetz AERIAL); Deutsche Forschungsgemeinschaft (DFG) [FOR 1617, EXC 257, SM 80/7-1, SM 80/7-2, SFB 940/1]; U.S. National Institutes of Health [RO1 MH085772-01A1]; Eranet-Neuron grant [AF12-NEUR0008-01 - WM2NA]; MILDECA; Fondation pour la Recherche Medicale; NIH [U54 EB020403]; Allen Institute for Brain Science FX We thank C.-K. Lee for help with AIBS data normalization and C. Quairiaux for help with mouse brain anatomy. Functional networks imaging data are at http://findlab.stanford.edu/functional_ROIs.html. Human microarray data are at http://human.brain-map.org. IMAGEN data are available by application to consortium coordinator G. Schumann (http://imagen-europe.com) after evaluation according to an established procedure. Mouse gene expression data are at http://mouse.brain-map.org. Connectivity model data are from (23). J.R. is supported by a Marie Curie Fellowship from the European Union (299500). M.D.G. is supported by grants from the Feldman Family Foundation and the National Institutes of Health (RO1NS073498). This work received additional support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the FP7 projects IMAGEMEND (602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300-2), a Medical Research Council Programme Grant "Developmental pathways into adolescent substance abuse" (93558), the Swedish funding agency FORMAS, the Medical Research Council and the Wellcome Trust (Behavioral and Clinical Neuroscience Institute, University of Cambridge), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministerium fur Bildung und Forschung (BMBF; grants 01GS08152, 01EV0711, eMED SysAlc01ZX1311A, and Forschungsnetz AERIAL), the Deutsche Forschungsgemeinschaft (DFG; grants FOR 1617, EXC 257, SM 80/7-1, SM 80/7-2, and SFB 940/1), the U.S. National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), Eranet-Neuron grant (project AF12-NEUR0008-01 - WM2NA), MILDECA, Fondation pour la Recherche Medicale, NIH Consortium grant U54 EB020403, which is supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence, and the Allen Institute for Brain Science. NR 27 TC 44 Z9 44 U1 6 U2 42 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 12 PY 2015 VL 348 IS 6240 BP 1241 EP 1244 DI 10.1126/science.1255905 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK2AK UT WOS:000356011500051 PM 26068849 ER PT J AU Oronsky, B Oronsky, AL Lybeck, M Oronsky, NC Scicinski, JJ Carter, C Day, RM Orengo, JFR Rodriguez-Torres, M Fanger, GF Reid, TR AF Oronsky, BryanT. Oronsky, Arnold L. Lybeck, Michelle Oronsky, Neil C. Scicinski, Jan J. Carter, Corey Day, Regina M. Orengo, Jose F. Rodriguez Rodriguez-Torres, Maribel Fanger, Gary F. Reid, Tony R. TI Episensitization: defying time's arrow SO FRONTIERS IN ONCOLOGY LA English DT Review DE episensitization; epigenetics; epigenomic; resensitization; RRx-001; oncology ID ADVANCED COLORECTAL-CANCER; MRC COIN TRIAL; DRUG-RESISTANCE; OVARIAN-CANCER; COMBINATION CHEMOTHERAPY; OXALIPLATIN; EPIGENETICS; RETREATMENT; PLASTICITY; IRINOTECAN AB The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of "episensitization," or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses, and RRx-001. C1 [Oronsky, BryanT.; Lybeck, Michelle; Scicinski, Jan J.; Fanger, Gary F.] EpicentRx Inc, Mountain View, CA 94040 USA. [Oronsky, Arnold L.] InterWest Partners, Menlo Pk, CA USA. [Oronsky, Neil C.] CFLS LLC, San Jose, CA USA. [Carter, Corey] NCI, Walter Reed Natl Mil Med Ctr, Bethesda, MD 20892 USA. [Day, Regina M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Orengo, Jose F. Rodriguez; Rodriguez-Torres, Maribel] Fdn Invest, Rio Piedras, PR USA. [Reid, Tony R.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Oronsky, B (reprint author), EpicentRx Inc, 800W El Camino Real,Suite 180, Mountain View, CA 94040 USA. EM boronsky@epicentrx.com NR 74 TC 9 Z9 9 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD JUN 11 PY 2015 VL 5 AR 134 DI 10.3389/fonc.2015.00134 PG 10 WC Oncology SC Oncology GA CO4QG UT WOS:000359145100001 PM 26125013 ER PT J AU Wang, L Li, FH Sheng, JT Wong, STC AF Wang, Lin Li, Fuhai Sheng, Jianting Wong, Stephen T. C. TI A computational method for clinically relevant cancer stratification and driver mutation module discovery using personal genomics profiles SO BMC GENOMICS LA English DT Article ID EVEROLIMUS SENSITIVITY; DRUG-SENSITIVITY; CARCINOMA AB Background: Personalized genomics instability, e.g., somatic mutations, is believed to contribute to the heterogeneous drug responses in patient cohorts. However, it is difficult to discover personalized driver mutations that are predictive of drug sensitivity owing to diverse and complex mutations of individual patients. To circumvent this problem, a novel computational method is presented to discover potential drug sensitivity relevant cancer subtypes and identify driver mutation modules of individual subtypes by coupling differentially expressed genes (DEGs) based subtyping analysis with the driver mutation network analysis. Results: The proposed method was applied to breast cancer and lung cancer samples available from The Cancer Genome Atlas (TCGA). Cancer subtypes were uncovered with significantly different survival rates, and more interestingly, distinct driver mutation modules were also discovered among different subtypes, indicating the potential mechanism of heterogeneous drug sensitivity. Conclusions: The research findings can be used to help guide the repurposing of known drugs and their combinations in order to target these dysfunctional modules and their downstream signaling effectively for achieving personalized or precision medicine treatment. C1 [Wang, Lin; Li, Fuhai; Sheng, Jianting; Wong, Stephen T. C.] Weill Cornell Med Coll, NCI Ctr Modeling Canc Dev, Dept Syst Med & Bioengn, Houston Methodist Res Inst, Houston, TX 77030 USA. RP Wong, STC (reprint author), Weill Cornell Med Coll, NCI Ctr Modeling Canc Dev, Dept Syst Med & Bioengn, Houston Methodist Res Inst, Houston, TX 77030 USA. EM stwong@houstonmethodist.org FU CPRIT [RP110532]; NIH [U54 CA149196]; TT & WF Chao Center for BRAIN; John S Dunn Research Foundation FX This work is supported by CPRIT RP110532, NIH U54 CA149196, TT & WF Chao Center for BRAIN, and John S Dunn Research Foundation. NR 22 TC 3 Z9 3 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 11 PY 2015 VL 16 SU 7 AR S6 DI 10.1186/1471-2164-16-S7-S6 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CN1FX UT WOS:000358164700006 PM 26099165 ER PT J AU Pescatori, L Metifiot, M Chung, SM Masoaka, T Crucitti, GC Messore, A Pupo, G Madia, VN Saccoliti, F Scipione, L Tortorella, S Di Leva, FS Cosconati, S Marinelli, L Novellino, E Le Grice, SFJ Pommier, Y Marchand, C Costi, R Di Santo, R AF Pescatori, Luca Metifiot, Mathieu Chung, Suhman Masoaka, Takashi Crucitti, Giuliana Cuzzucoli Messore, Antonella Pupo, Giovanni Madia, Valentina Noemi Saccoliti, Francesco Scipione, Luigi Tortorella, Silvano Di Leva, Francesco Saverio Cosconati, Sandro Marinelli, Luciana Novellino, Ettore Le Grice, Stuart F. J. Pommier, Yves Marchand, Christophe Costi, Roberta Di Santo, Roberto TI N-Substituted Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and Their Activity against RNase H Function of Reverse Transcriptase SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RIBONUCLEASE-H; DUAL INHIBITORS; BIOLOGICAL EVALUATION; IN-VITRO; DNA; DESIGN; SITE; HYDROXYTROPOLONES; RALTEGRAVIR AB Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 mu M. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity. C1 [Pescatori, Luca; Metifiot, Mathieu; Crucitti, Giuliana Cuzzucoli; Messore, Antonella; Pupo, Giovanni; Madia, Valentina Noemi; Saccoliti, Francesco; Scipione, Luigi; Tortorella, Silvano; Costi, Roberta; Di Santo, Roberto] Univ Roma La Sapienza, Ist Pasteur, Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy. [Pommier, Yves; Marchand, Christophe] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Pommier, Yves; Marchand, Christophe] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chung, Suhman; Masoaka, Takashi; Le Grice, Stuart F. J.] NCI, Resistance Mech Lab, HIV Drug Resistance Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Di Leva, Francesco Saverio; Marinelli, Luciana; Novellino, Ettore] Univ Naples Federico II, Dipartimento Farm, I-80131 Naples, Italy. [Cosconati, Sandro] Univ Naples 2, DiSTABiF, I-81100 Caserta, Italy. RP Costi, R (reprint author), Univ Roma La Sapienza, Ist Pasteur, Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farmaco, P Le Aldo Moro 5, I-00185 Rome, Italy. EM roberta.costi@uniroma1.it; roberto.disanto@uniroma1.it RI Marchand, Christophe/D-8559-2016; Pescatori, Luca/H-5917-2016; OI Pescatori, Luca/0000-0003-4734-7856; COSTI, Roberta/0000-0002-1314-9029; TORTORELLA, Silvano/0000-0002-3279-9182; Di Santo, Roberto/0000-0002-4279-7666; scipione, luigi/0000-0002-2006-7005; Cosconati, Sandro/0000-0002-8900-0968; Madia, Valentina Noemi/0000-0002-5724-612X FU Italian MIUR [2010W2KM5L_002]; "Sapienza" Ateneo [C26A133H7B]; FP7 CHAARM project; NIH, Center for Cancer Research, National Cancer Institute [Z01 BC 007333] FX The authors thank the Italian MIUR for financial support, PRIN 2010-2011 (2010W2KM5L_002) and "Sapienza" Ateneo C26A133H7B. R. Di Santo and R. Costi thank the FP7 CHAARM project for support. This work was also supported by the NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute (Z01 BC 007333). NR 49 TC 3 Z9 3 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 11 PY 2015 VL 58 IS 11 BP 4610 EP 4623 DI 10.1021/acs.jmedchem.5b00159 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CK6CR UT WOS:000356316600015 PM 25961960 ER PT J AU Najm, FJ Madhavan, M Zaremba, A Shick, E Karl, RT Factor, DC Miller, TE Nevin, ZS Kantor, C Sargent, A Quick, KL Schlatzer, DM Tang, H Papoian, R Brimacombe, KR Shen, M Boxer, MB Jadhav, A Robinson, AP Podojil, JR Miller, SD Miller, RH Tesar, PJ AF Najm, Fadi J. Madhavan, Mayur Zaremba, Anita Shick, Elizabeth Karl, Robert T. Factor, Daniel C. Miller, Tyler E. Nevin, Zachary S. Kantor, Christopher Sargent, Alex Quick, Kevin L. Schlatzer, Daniela M. Tang, Hong Papoian, Ruben Brimacombe, Kyle R. Shen, Min Boxer, Matthew B. Jadhav, Ajit Robinson, Andrew P. Podojil, Joseph R. Miller, Stephen D. Miller, Robert H. Tesar, Paul J. TI Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo SO NATURE LA English DT Article ID OLIGODENDROCYTE PROGENITOR CELLS; CENTRAL-NERVOUS-SYSTEM; MYELIN BASIC-PROTEIN; MULTIPLE-SCLEROSIS; SPINAL-CORD; RNA-SEQ; DIFFERENTIATION; GLUCOCORTICOIDS; LYSOLECITHIN; TRANSCRIPTS AB Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes(1). These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention(2). To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells(3-5). Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. C1 [Najm, Fadi J.; Madhavan, Mayur; Shick, Elizabeth; Karl, Robert T.; Factor, Daniel C.; Miller, Tyler E.; Nevin, Zachary S.; Tesar, Paul J.] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. [Zaremba, Anita; Kantor, Christopher; Sargent, Alex; Miller, Robert H.; Tesar, Paul J.] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. [Miller, Tyler E.] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. [Miller, Tyler E.] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USA. [Quick, Kevin L.] PerkinElmer, Waltham, MA 02451 USA. [Schlatzer, Daniela M.] Case Western Reserve Univ, Sch Med, Ctr Prote & Bioinformat, Cleveland, OH 44106 USA. [Tang, Hong; Papoian, Ruben] Univ Cincinnati, Coll Med, Ctr Drug Discovery, Cincinnati, OH 45237 USA. [Brimacombe, Kyle R.; Shen, Min; Boxer, Matthew B.; Jadhav, Ajit] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20852 USA. [Robinson, Andrew P.; Podojil, Joseph R.; Miller, Stephen D.] Northwestern Univ, Feinberg Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. [Robinson, Andrew P.; Podojil, Joseph R.; Miller, Stephen D.] Northwestern Univ, Feinberg Sch Med, Interdept Immunobiol Ctr, Chicago, IL 60611 USA. RP Tesar, PJ (reprint author), Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. EM rhm3@gwu.edu; paul.tesar@case.edu OI Robinson, Andrew/0000-0002-1867-5634; Miller, Tyler E/0000-0002-1269-1895 FU US NIH [NS085246, NS030800, NS026543]; NewYork Stem Cell Foundation; Myelin Repair Foundation; Mt. Sinai Health Care Foundation; NIH [T32GM008056, F30CA183510]; Cytometry & Imaging Microscopy, Proteomics, and Genomics core facilities of the Case Comprehensive Cancer Center [P30CA043703]; CWRU Council FX This research was supported by grants from the US NIH NS085246 (P.J.T. and R.H.M.), NS030800 (R.H.M.), and NS026543 (S.D.M.); NewYork Stem Cell Foundation (P.J.T.); Myelin Repair Foundation (P.J.T., R.H.M., and S.D.M.); Mt. Sinai Health Care Foundation (P.J.T.); and NIH predoctoral training grants T32GM008056 (R.T.K.) and F30CA183510 (T.E.M). Additional support was provided by the Cytometry & Imaging Microscopy, Proteomics, and Genomics core facilities of the Case Comprehensive Cancer Center (P30CA043703), the CWRU Council to Advance Human Health, and philanthropic support from the Goodman, Long, and Geller families. P.J.T. is a New York Stem Cell Foundation-Robertson Investigator. We are grateful to M. Hitomi, W. Harte, D. Adams, W. Seibel, M. Haag, P. Scacheri, J. Wanta, C. Fang, H. Olsen, T. LaFramboise, J. Song, F. Van den Akker, and M. Shoham for technical assistance and discussion, A. Lager and M. Elitt for comments on the manuscript, B. Trapp for the PLP1 antibody, and B. Barres and B. Zuchero for RNA from in vivo isolated OPCs. NR 30 TC 48 Z9 49 U1 17 U2 75 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 11 PY 2015 VL 522 IS 7555 BP 216 EP + DI 10.1038/nature14335 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK2CI UT WOS:000356016700039 PM 25896324 ER PT J AU Zarin, DA Tse, T Ross, JS AF Zarin, Deborah A. Tse, Tony Ross, Joseph S. TI Trial-Results Reporting and Academic Medical Centers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Zarin, Deborah A.; Tse, Tony] Natl Lib Med, Bethesda, MD 20894 USA. [Ross, Joseph S.] Yale Univ, Sch Med, New Haven, CT USA. RP Zarin, DA (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov OI Tse, Tony/0000-0002-9906-6864 FU Intramural NIH HHS NR 4 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 11 PY 2015 VL 372 IS 24 BP 2371 EP 2372 DI 10.1056/NEJMc1505965 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CK2DB UT WOS:000356019200030 PM 25992618 ER PT J AU Pacheco-Colon, I Washington, SD Sprouse, C Helman, G Gropman, AL VanMeter, JW AF Pacheco-Colon, Ileana Washington, Stuart D. Sprouse, Courtney Helman, Guy Gropman, Andrea L. VanMeter, John W. TI Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency SO PLOS ONE LA English DT Article ID ACETYLGLUTAMATE SYNTHASE GENE; UREA-CYCLE ENZYMOPATHIES; SUPERIOR FRONTAL GYRUS; WORKING-MEMORY; BRAIN CONNECTIVITY; CINGULATE CORTEX; INBORN-ERRORS; DISEASE; MRI; ACTIVATION AB Background and Purpose Ornithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks-default mode and set-maintenance-between OTCD patients and healthy controls. Methods Sixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity. Results Group comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG. Conclusion Internodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain. C1 [Pacheco-Colon, Ileana; Washington, Stuart D.; Gropman, Andrea L.; VanMeter, John W.] Georgetown Univ, Ctr Funct & Mol Imaging, Washington, DC 20057 USA. [Pacheco-Colon, Ileana; Washington, Stuart D.; VanMeter, John W.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC USA. [Sprouse, Courtney; Helman, Guy; Gropman, Andrea L.] Childrens Natl Hlth Syst, Dept Neurogenet, Washington, DC USA. [Sprouse, Courtney; Gropman, Andrea L.] George Washington Univ Hlth Sci, Washington, DC USA. [Gropman, Andrea L.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Pacheco-Colon, I (reprint author), Georgetown Univ, Ctr Funct & Mol Imaging, Washington, DC 20057 USA. EM pachecoileana@gmail.com RI Helman, Guy/C-7935-2017 OI Helman, Guy/0000-0002-4784-7423 FU NIH-National Institute of Child Health and Human Development [5U54HD061221, 1KL2RR031974-01, 2P30HD040677-11] FX This study was completed as part of NIH-funded grants National Institute of Child Health and Human Development 5U54HD061221, 1KL2RR031974-01, and 2P30HD040677-11. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 1 Z9 1 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2015 VL 10 IS 6 AR e0129595 DI 10.1371/journal.pone.0129595 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK3FB UT WOS:000356100900061 PM 26067829 ER PT J AU Wandu, WS Tan, CY Ogbeifun, O Vistica, BP Shi, GP Hinshaw, SJH Xie, C Chen, X Klinman, DM Cai, HB Gery, I AF Wandu, Wambui S. Tan, Cuiyan Ogbeifun, Osato Vistica, Barbara P. Shi, Guangpu Hinshaw, Samuel J. H. Xie, Chengsong Chen, Xi Klinman, Dennis M. Cai, Huaibin Gery, Igal TI Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response SO PLOS ONE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; SUSCEPTIBILITY LOCI; CROHNS-DISEASE; T-CELLS; TH17; INNATE AB Background Mutations in LRRK2 are related to certain forms of Parkinson's disease and, possibly, to the pathogenesis of Crohn's disease. In both these diseases inflammatory processes participate in the pathogenic process. LRRK2 is expressed in lymphoid cells and, interestingly, Lrrk2 (-/-) mice were reported to develop more severe experimental colitis than their wild type (WT) controls. Here, we examined the possible involvement of LRRK2 in the pathogenesis of experimental autoimmune uveitis (EAU), an animal model for human uveitis, by testing Lrrk2 (-/-) mice for their capacity to develop this experimental eye disease and related immune responses. Methods Lrrk2 (-/-) mice and their WT controls (C57Bl/6) were immunized with interphotoreceptor retinoid-binding protein (IRBP) and compared for their development of EAU, delayed type hypersensitivity (DTH) by skin tests, production of cytokines in culture, and expression of interferon (IFN)-gamma, interleukin (IL)-17 and FoxP3 by spleen cells, using flow cytometry. Peritoneal macrophages were examined for their production of cytokines/chemokines in culture following stimulation with LPS or the oligodeoxynucleotide CpG. The Lrrk2 (-/-) and WT mice were also compared for their response to bovine serum albumin (BSA). Results The Lrrk2 (-/-) mice developed lower levels of EAU, DTH responses and cytokine production by lymphocytes than did their WT controls. Intracellular expression of IFN-gamma and IL-17, by spleen cells, and secretion of cytokines/chemokines by activated peritoneal macrophages of Lrrk2 (-/-) mice trended toward diminished levels, although variabilities were noted. The expression levels of FoxP3 by Lrrk2 (-/-) spleen cells, however, were similar to those seen in WT controls. Consistent with their low response to IRBP, Lrrk2 (-/-) mice responded to BSA less vigorously than their WT controls. Conclusions Lrrk2 deficiency in mice diminished the development of EAU and the related adaptive immune responses to IRBP as compared to the WT controls. C1 [Wandu, Wambui S.; Tan, Cuiyan; Ogbeifun, Osato; Vistica, Barbara P.; Shi, Guangpu; Hinshaw, Samuel J. H.; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Xie, Chengsong; Chen, Xi; Cai, Huaibin] NIA, Neurogenet Lab, NIH, Transgen Sect, Bethesda, MD 20892 USA. [Klinman, Dennis M.] NCI, NIH, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov FU National Eye Institute; National Institute on Aging, National Institutes of Health FX This work was supported by intramural funding by National Eye Institute (IG) and National Institute on Aging (HC), National Institutes of Health. The National Eye Institute and National Institute on Aging had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 5 Z9 5 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2015 VL 10 IS 6 AR e0128906 DI 10.1371/journal.pone.0128906 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK3FB UT WOS:000356100900033 PM 26067490 ER PT J AU Beers, J Linask, KL Chen, JA Siniscalchi, LI Lin, YS Zheng, W Rao, M Chen, GK AF Beers, Jeanette Linask, Kaari L. Chen, Jane A. Siniscalchi, Lauren I. Lin, Yongshun Zheng, Wei Rao, Mahendra Chen, Guokai TI A cost-effective and efficient reprogramming platform for large-scale production of integration-free human induced pluripotent stem cells in chemically defined culture SO SCIENTIFIC REPORTS LA English DT Article ID BIOLOGY; GENERATION; INDUCTION; VECTOR; RNA AB Factors limiting the adoption of iPSC technology include the cost of developing lines and the time period that it takes to characterize and bank them, particularly when integration free, feeder free, and Xeno-free components are used. In this manuscript we describe our optimization procedure that enables a single technician to make 20-40 lines at a time in a 24-96 well format in a reliable and reproducible fashion. Improvements spanned the entire workflow and included using RNA virus, reducing cytotoxicity of reagents, developing improved transfection and freezing efficiencies, modifying the manual colony picking steps, enhancing passaging efficiency and developing early criteria of success. These modifications allowed us to make more than two hundred well-characterized lines per year. C1 [Beers, Jeanette; Linask, Kaari L.; Chen, Jane A.; Siniscalchi, Lauren I.; Lin, Yongshun; Chen, Guokai] NHLBI, Ctr Mol Med, Bethesda, MD 20892 USA. [Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Chen, Guokai] Univ Macau, Fac Hlth Sci, Macau, Peoples R China. RP Chen, GK (reprint author), NHLBI, Ctr Mol Med, Bldg 10, Bethesda, MD 20892 USA. EM GuokaiChen@umac.edu RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Program of the National Heart, Lung and Blood Institute; Common Fund at the National Institutes of Health; NHLBI Intramural Research Program; University of Macau [MYRG2015-00228-FHS] FX This project is supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, and the Common Fund at the National Institutes of Health. G.C. is supported by the NHLBI Intramural Research Program and MYRG2015-00228-FHS from the University of Macau. We thank Drs. Toren Finkel, Manfred Boehm, Gary Gibbon and late Dr. Kuan-Teh Jeang for their advices. We thank Dr. Gustavo Mostoslavsky for the STEMCCA lentivirus. We thank the technical support from the NHLBI Sequencing Core Facility. We thank WiCell Institute for the Karyotyping Services. NR 12 TC 7 Z9 7 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 11 PY 2015 VL 5 AR 11319 DI 10.1038/srep11319 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK3ES UT WOS:000356100000001 PM 26066579 ER PT J AU Kapulu, MC Da, DF Miura, K Li, Y Blagborough, AM Churcher, TS Nikolaeva, D Williams, AR Goodman, AL Sangare, I Turner, AV Cottingham, MG Nicosia, A Straschil, U Tsuboi, T Gilbert, SC Long, CA Sinden, RE Draper, SJ Hill, AVS Cohuet, A Biswas, S AF Kapulu, M. C. Da, D. F. Miura, K. Li, Y. Blagborough, A. M. Churcher, T. S. Nikolaeva, D. Williams, A. R. Goodman, A. L. Sangare, I. Turner, A. V. Cottingham, M. G. Nicosia, A. Straschil, U. Tsuboi, T. Gilbert, S. C. Long, Carole A. Sinden, R. E. Draper, S. J. Hill, A. V. S. Cohuet, A. Biswas, S. TI Comparative Assessment of Transmission-Blocking Vaccine Candidates against Plasmodium falciparum SO SCIENTIFIC REPORTS LA English DT Article ID SURFACE-ANTIGEN PFS230; MEMBRANE-FEEDING ASSAY; CELL-FREE SYSTEM; MALARIA TRANSMISSION; SEXUAL-STAGE; ADJUVANT VACCINES; VIVAX MALARIA; ANTIBODIES; PROTEIN; RESPONSES AB Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasites within the mosquito, with the aim of preventing malaria transmission from one infected individual to another. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leading candidate antigens, have been developed independently and have reported varied transmission-blocking activities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modified vaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated. Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/c mice were boosted by the administration of MVA expressing the same antigen. These antibodies exhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum in Anopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with anti-Pfs230-C and anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibition was replicated against P. falciparum African field isolates in A. gambiae in direct membrane feeding assays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first head-to-head comparative analysis of leading antigens using two different parasite sources in two different vector species, and can be used to guide selection of TBVs for future clinical development using the viral-vectored delivery platform. C1 [Kapulu, M. C.; Li, Y.; Nikolaeva, D.; Williams, A. R.; Goodman, A. L.; Turner, A. V.; Cottingham, M. G.; Gilbert, S. C.; Sinden, R. E.; Draper, S. J.; Hill, A. V. S.; Biswas, S.] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Da, D. F.; Sangare, I.; Cohuet, A.] UMR MIVEGEC, IRSS, Bobo Dioulasso, Burkina Faso. [Da, D. F.; Sangare, I.; Cohuet, A.] UMR MIVEGEC, IRD, Bobo Dioulasso, Burkina Faso. [Miura, K.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Blagborough, A. M.; Straschil, U.; Sinden, R. E.] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, London, England. [Churcher, T. S.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London, England. [Nicosia, A.] ReiThera Srl, Rome, Italy. [Nicosia, A.] CEINGE, Naples, Italy. [Nicosia, A.] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Tsuboi, T.] Ehime Univ, Cell Free Sci & Technol Res Ctr, Matsuyama, Ehime 790, Japan. RP Biswas, S (reprint author), Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. EM sumi.biswas@ndm.ox.ac.uk RI Morlais, Isabelle/F-5078-2014; Cohuet, Anna/B-2745-2017; OI Morlais, Isabelle/0000-0002-2962-7670; Cohuet, Anna/0000-0002-1876-5656; Li, Yuanyuan/0000-0002-9143-8029; Williams, Andrew/0000-0002-8231-282X; Churcher, Thomas/0000-0002-8442-0525; Draper, Simon/0000-0002-9415-1357 FU Commonwealth Scholarship; Wellcome Trust [WT100157MA]; MRC Career Development Fellowship [G1000527]; European Community's Seventh Framework Program (FP7) [242095, 223736]; IRD fellowship; Fraunhofer Institute; Medicines for Malaria Venture; intramural program of the NIAID; NIH; PATH Malaria Vaccine Initiative; MEXT/JSPS KAKENHI [23117008, 23406007]; MRC clinical training fellowship [G0600424] FX We thank J. Furze and the Jenner Institute Vector Core Facility for generating the recombinant viral vectors. We would also like to thank S. Moretz, A. Diouf, G. Tullo, and B. Deng for performing the SMFA; Dr Y. Wu for providing the recombinant Pfs25 protein and reference serum used in ELISAs; and Dr G. Christophides for providing the mosquitoes for midgut ELISA. As. MCK was a recipient of a Commonwealth Scholarship. SB is a NDM Leadership Fellow and a Junior Research Fellow of St. Catherine's College at the University of Oxford. This work was funded by a Wellcome Trust grant (WT100157MA) to AVSH. SJD holds a MRC Career Development Fellowship (grant number G1000527) and is a Lister Institute Research Prize Fellow. S.C.G., S.J.D. and A.V.S.H. are Jenner Investigators. AC received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreements numbers 242095 and 223736 and DFD received an IRD fellowship. AMB is funded by Fraunhofer Institute and Medicines for Malaria Venture. SMFA work at NIH MFA Evaluation Centre was supported in part by the intramural program of the NIAID, NIH and in part by the PATH Malaria Vaccine Initiative. TT was supported in part by MEXT/JSPS KAKENHI grant numbers 23117008 and 23406007. ALG was funded by a MRC clinical training fellowship grant number G0600424. NR 62 TC 10 Z9 11 U1 6 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 11 PY 2015 VL 5 AR 11193 DI 10.1038/srep11193 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK3DY UT WOS:000356098000001 PM 26063320 ER PT J AU Harami, GM Nagy, NT Martina, M Neuman, KC Kovacs, M AF Harami, Gabor M. Nagy, Nikolett T. Martina, Mate Neuman, Keir C. Kovacs, Mihaly TI The HRDC domain of E-coli RecQ helicase controls single-stranded DNA translocation and double-stranded DNA unwinding rates without affecting mechanoenzymatic coupling SO SCIENTIFIC REPORTS LA English DT Article AB DNA-restructuring activities of RecQ-family helicases play key roles in genome maintenance. These activities, driven by two tandem RecA-like core domains, are thought to be controlled by accessory DNA-binding elements including the helicase-and-RnaseD-C-terminal (HRDC) domain. The HRDC domain of human Bloom's syndrome (BLM) helicase was shown to interact with the RecA core, raising the possibility that it may affect the coupling between ATP hydrolysis, translocation along single-stranded (ss) DNA and/or unwinding of double-stranded (ds) DNA. Here, we determined how these activities are affected by the abolition of the ssDNA interaction of the HRDC domain or the deletion of the entire domain in E. coli RecQ helicase. Our data show that the HRDC domain suppresses the rate of DNA-activated ATPase activity in parallel with those of ssDNA translocation and dsDNA unwinding, regardless of the ssDNA binding capability of this domain. The HRDC domain does not affect either the processivity of ssDNA translocation or the tight coupling between the ATPase, translocation, and unwinding activities. Thus, the mechanochemical coupling of E. coli RecQ appears to be independent of HRDC-ssDNA and HRDC-RecA core interactions, which may play roles in more specialized functions of the enzyme. C1 [Harami, Gabor M.; Nagy, Nikolett T.; Martina, Mate; Kovacs, Mihaly] Eotvos Lorand Univ, ELTE MTA Momentum Motor Enzymol Res Grp, Dept Biochem, Pazmany PS 1-C, H-1117 Budapest, Hungary. [Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Kovacs, M (reprint author), Eotvos Lorand Univ, ELTE MTA Momentum Motor Enzymol Res Grp, Dept Biochem, Pazmany PS 1-C, H-1117 Budapest, Hungary. EM mihaly.kovacs@ttk.elte.hu RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Human Frontier Science Program [RGY0072/2010]; "Momentum" Program of the Hungarian Academy of Sciences [LP2011-006/2011]; Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health [HL001056-07]; [ELTE KMOP-4.2.1/B-10-2011-0002] FX This work was supported by the Human Frontier Science Program (RGY0072/2010 to M.K. and K.C.N.), the "Momentum" Program of the Hungarian Academy of Sciences (LP2011-006/2011 to M.K.) and ELTE KMOP-4.2.1/B-10-2011-0002 Grant to M.K. This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (HL001056-07 to K.C.N.). We are grateful to Dr. Tunde Juhasz for assistance with CD measurements and to Dr. Yeonee Seol for discussions. NR 47 TC 2 Z9 2 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 11 PY 2015 VL 5 AR 11091 DI 10.1038/srep11091 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V46IP UT WOS:000209878200001 PM 26067769 ER PT J AU Grover, S Balogun, OD Yamoah, K Groen, R Shah, M Rodin, D Martei, Y Olson, AC Slone, JS Shulman, LN Coleman, CN Hahn, SM AF Grover, Surbhi Balogun, Onyinye D. Yamoah, Kosj Groen, Reinou Shah, Mira Rodin, Danielle Martei, Yehoda Olson, Adam C. Slone, Jeremy S. Shulman, Lawrence N. Coleman, C. Norman Hahn, Stephen M. TI Training global oncologists: addressing the global cancer control problem (vol 5, pg 80, 2015) SO FRONTIERS IN ONCOLOGY LA English DT Correction DE global health; oncology training; radiation oncology; surgical oncology; medical oncology; corrigendum C1 [Grover, Surbhi; Hahn, Stephen M.] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Balogun, Onyinye D.] NYU, Perlmutter Canc Ctr, Dept Radiat Oncol, New York, NY USA. [Yamoah, Kosj] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Groen, Reinou] Johns Hopkins Univ Hosp, Dept Gynecol & Obstet, Baltimore, MD 21287 USA. [Shah, Mira] Henry Ford Hlth Syst, Dept Radiat Oncol, Detroit, MI USA. [Rodin, Danielle] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Martei, Yehoda] Hosp Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Olson, Adam C.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27708 USA. [Slone, Jeremy S.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Shulman, Lawrence N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Coleman, C. Norman] NCI, Radiat Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Coleman, C. Norman] Int Canc Expert Corps, Chevy Chase, MD USA. RP Olson, AC (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27708 USA. EM adam.olson@duke.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD JUN 10 PY 2015 VL 5 AR 133 DI 10.3389/fonc.2015.00133 PG 1 WC Oncology SC Oncology GA CO4QD UT WOS:000359144700002 PM 26114095 ER PT J AU McKinnon, T Venier, R Dickson, BC Kabaroff, L Alkema, M Chen, L Shern, JF Yohe, ME Khan, J Gladdy, RA AF McKinnon, Timothy Venier, Rosemarie Dickson, Brendan C. Kabaroff, Leah Alkema, Manon Chen, Li Shern, Jack F. Yohe, Marielle E. Khan, Javed Gladdy, Rebecca A. TI Kras activation in p53-deficient myoblasts results in high-grade sarcoma formation with impaired myogenic differentiation SO ONCOTARGET LA English DT Article DE sarcoma; rhabdomyosarcoma; mouse models of cancer; Kras; myogenic differentiation ID CHILDRENS ONCOLOGY GROUP; EMBRYONAL RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; LIVER-CANCER; MUSCLE-CELLS; MOUSE MODEL; GENE; RAS; EXPRESSION; P53 AB While genomic studies have improved our ability to classify sarcomas, the molecular mechanisms involved in the formation and progression of many sarcoma subtypes are unknown. To better understand developmental origins and genetic drivers involved in rhabdomyosarcomagenesis, we describe a novel sarcoma model system employing primary murine p53-deficient myoblasts that were isolated and lentivirally transduced with Kras(G12D). Myoblast cell lines were characterized and subjected to proliferation, anchorage-independent growth and differentiation assays to assess the effects of transgenic Kras(G12D) expression. Kras(G12D) overexpression transformed p53(-/-) myoblasts as demonstrated by an increased anchorage-independent growth. Induction of differentiation in parental myoblasts resulted in activation of key myogenic regulators. In contrast, Kras-transduced myoblasts had impaired terminal differentiation. p53(-/-) myoblasts transformed by Kras(G12D) overexpression resulted in rapid, reproducible tumor formation following orthotopic injection into syngeneic host hindlimbs. Pathological analysis revealed high-grade sarcomas with myogenic differentiation based on the expression of muscle-specific markers, such as Myod1 and Myog. Gene expression patterns of murine sarcomas shared biological pathways with RMS gene sets as determined by gene set enrichment analysis (GSEA) and were 61% similar to human RMS as determined by metagene analysis. Thus, our novel model system is an effective means to model high-grade sarcomas along the RMS spectrum. C1 [McKinnon, Timothy; Venier, Rosemarie; Kabaroff, Leah; Alkema, Manon; Gladdy, Rebecca A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Gladdy, Rebecca A.] Ontario Inst Canc Res, Canc Stem Cell Program, Toronto, ON, Canada. [Gladdy, Rebecca A.] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Dickson, Brendan C.] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada. [Chen, Li; Shern, Jack F.; Yohe, Marielle E.; Khan, Javed] NIH, Genet Branch, Oncogen Sect, Ctr Canc Res, Gaithersburg, MD USA. RP Gladdy, RA (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. EM gladdy@lunenfeld.ca RI Gladdy, Rebecca/A-2516-2013; Khan, Javed/P-9157-2014; Dickson, Brendan/J-2347-2016 OI Gladdy, Rebecca/0000-0003-4143-6620; Khan, Javed/0000-0002-5858-0488; Dickson, Brendan/0000-0003-2269-6216 FU Kristen Ann Carr Foundation; Ontario Institute for Cancer Research Clinician-Scientist Award FX Work was supported with funding from the Kristen Ann Carr Foundation (R.G.) and Ontario Institute for Cancer Research Clinician-Scientist Award (R.G.) NR 33 TC 2 Z9 2 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 10 PY 2015 VL 6 IS 16 BP 14220 EP 14232 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2TR UT WOS:000359010000032 PM 25992772 ER PT J AU Cohen, O Ma, Y Drake, JJ Glocer, A Garraffo, C Bell, JM Gombosi, TI AF Cohen, O. Ma, Y. Drake, J. J. Glocer, A. Garraffo, C. Bell, J. M. Gombosi, T. I. TI THE INTERACTION OF VENUS-LIKE, M-DWARF PLANETS WITH THE STELLAR WIND OF THEIR HOST STAR SO ASTROPHYSICAL JOURNAL LA English DT Article DE magnetohydrodynamics (MHD); planets and satellites: atmospheres; planets and satellites: magnetic fields; planets and satellites: terrestrial planets ID RESISTIVE MHD SIMULATIONS; EARTH-LIKE EXOPLANETS; EJECTION CME ACTIVITY; CLOSE-IN EXOPLANETS; MASS M-STARS; HABITABLE ZONES; HOT JUPITERS; GANYMEDES MAGNETOSPHERE; TERRESTRIAL EXOPLANETS; ATMOSPHERIC ESCAPE AB We study the interaction between the atmospheres of Venus-like, non-magnetized exoplanets orbiting an M-dwarf star, and the stellar wind using a multi-species MHD model. We focus our investigation on the effect of enhanced stellar wind and enhanced EUV flux as the planetary distance from the star decreases. Our simulations reveal different topologies of the planetary space environment for sub- and super-Alfvenic stellar wind conditions, which could lead to dynamic energy deposition into the atmosphere during the transition along the planetary orbit. We find that the stellar wind penetration for non-magnetized planets is very deep, up to a few hundreds of kilometers. We estimate a lower limit for the atmospheric mass-loss rate and find that it is insignificant over the lifetime of the planet. However, we predict that when accounting for atmospheric ion acceleration, a significant amount of the planetary atmosphere could be eroded over the course of a billion years. C1 [Cohen, O.; Drake, J. J.; Garraffo, C.] Harvard Smithsonian Ctr Astrophys, Cambridge, MA 02138 USA. [Ma, Y.] Univ Calif Los Angeles, Inst Geophys & Planetary Phys, Los Angeles, CA 90024 USA. [Glocer, A.] NASA, GSFC, Greenbelt, MD 20771 USA. [Bell, J. M.] NIA, Ctr Planetary Atmospheres & Flight Sci, Hampton, VA 23666 USA. [Gombosi, T. I.] Univ Michigan, Ctr Space Environm Modeling, Ann Arbor, MI 48109 USA. RP Cohen, O (reprint author), Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA. RI Gombosi, Tamas/G-4238-2011; OI Gombosi, Tamas/0000-0001-9360-4951; Cohen, Ofer/0000-0003-3721-0215 FU Smithsonian Institution Consortium; Smithsonian Institute Competitive Grants Program for Science (CGPS) grant "Can Exoplanets Around Red Dwarfs Maintain Habitable Atmospheres?"; NASA Astrobiology Institute grant [NNX15AE05G]; NASA ESS; NASA ESTO-CT; NSF KDI; DoD MURI; NASA [NAS8-03060] FX We thank an anonymous referee for his/her useful comments. The work presented here was funded by the Smithsonian Institution Consortium for Unlocking the Mysteries of the Universe grant "Lessons from Mars: Are Habitable Atmospheres on Planets around M Dwarfs Viable?", by the Smithsonian Institute Competitive Grants Program for Science (CGPS) grant "Can Exoplanets Around Red Dwarfs Maintain Habitable Atmospheres?", and by NASA Astrobiology Institute grant NNX15AE05G. Simulation results were obtained using the Space Weather Modeling Framework, developed by the Center for Space Environment Modeling, at the University of Michigan with funding support from NASA ESS, NASA ESTO-CT, NSF KDI, and DoD MURI. The simulations were performed on the Smithsonian Institute HYDRA cluster. J.J.D. was supported by NASA contract NAS8-03060 to the Chandra X-ray Center during the course of this research and thanks the Director, B. Wilkes, for continuing support and encouragement. NR 69 TC 7 Z9 7 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0004-637X EI 1538-4357 J9 ASTROPHYS J JI Astrophys. J. PD JUN 10 PY 2015 VL 806 IS 1 AR 41 DI 10.1088/0004-637X/806/1/41 PG 10 WC Astronomy & Astrophysics SC Astronomy & Astrophysics GA CL2XF UT WOS:000356810300041 ER PT J AU Gianella, S Smith, DM Daar, ES Dube, MP Lisco, A Vanpouille, C Margolis, L Haubrich, RH Morris, SR AF Gianella, Sara Smith, Davey M. Daar, Eric S. Dube, Michael P. Lisco, Andrea Vanpouille, Christophe Margolis, Leonid Haubrich, Richard H. Morris, Sheldon R. TI Genital Cytomegalovirus Replication Predicts Syphilis Acquisition among HIV-1 Infected Men Who Have Sex with Men SO PLOS ONE LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; HIV-INFECTION; TRANSMISSION; HERPESVIRUSES; ASSOCIATION; ACTIVATION; NETWORK; VIRUSES; TRACT; BLOOD AB Objective Sexually transmitted infections (STI) are common among HIV-infected men who have sex with men (MSM). While behavioral factors are important in STI acquisition, other biological factors such as immune modulation due to chronic viral infection may further predispose to STI acquisition. Design Post Hoc analysis including data collected over 12 months of follow-up from 131 HIV-infected MSM receiving antiretroviral therapy and screened for incident bacterial STI every 3 months. Methods Genital secretions collected at baseline were used to measure herpesvirus replication and inflammatory cytokines. Baseline predictors of STI were determined using survival analysis of time to incident STI. Results All participants were seropositive for cytomegalovirus (CMV), and 52% had detectable genital CMV at baseline. Thirty-five individuals acquired STI during follow-up, sometimes with multiple pathogen (17 syphilis, 21 gonorrhea, 14 chlamydia). Syphilis acquisition was associated with genital CMV replication at baseline (19.1% CMV-shedders versus 4.8% nonshedders, p=0.03) and younger age (p=0.02). Lower seminal MCP-1 was associated with higher seminal CMV levels and with syphilis acquisition (p<0.01). For syphilis acquisition, in multivariable Cox-Proportional Hazard model adjusted hazard rates were 3.56 (95% CI: 1.00-12.73) for baseline CMV replication and 2.50 (0.92-6.77) for younger age. Conclusions This post hoc analysis suggest that CMV-associated decrease in seminal MCP-1 levels might predispose HIV-infected MSM to syphilis acquisition, but not other STI. Future studies should determine underlying mechanisms and if a causal association exists. C1 [Gianella, Sara; Smith, Davey M.; Haubrich, Richard H.; Morris, Sheldon R.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Smith, Davey M.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Daar, Eric S.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Dube, Michael P.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Lisco, Andrea] NIAID, NIH, Bethesda, MD 20892 USA. [Vanpouille, Christophe; Margolis, Leonid] NICHHD, NIH, Bethesda, MD 20892 USA. RP Gianella, S (reprint author), Univ Calif San Diego, La Jolla, CA 92093 USA. EM gianella@ucsd.edu FU Department of Veterans Affairs; James Pendleton Charitable Trust; amfAR grant [108537]; FAIR; U.S. National Institutes of Health (NIH) [P30-AI027763, R24AI106039, AI69432, AI043638, MH62512, MH083552, MH101012, AI100665, AI077304, AI36214, AI047745, AI74621, GM093939, AI080353, AI306214, AI27670, AI064086, AI43638, 7-UM1 AI068636-07]; CTRI grant [UL1TR000100]; California HIV/AIDS Research Program [RN07-SD-702, MC08-SD-700, EI-11-SD-005]; National Center for Advancing Translational Sciences through UCLA CTSI Grant [UL1TR000124]; National Institute of General Medical Sciences grant [GM093939] FX This work was supported by the Department of Veterans Affairs; by the James Pendleton Charitable Trust; by amfAR grant 108537 with support from FAIR; by U.S. National Institutes of Health (NIH) awards P30-AI027763 (CNIHR), R24AI106039, AI69432, AI043638, MH62512, MH083552, MH101012, AI100665, AI077304, AI36214, AI047745, AI74621, GM093939, AI080353, AI306214 (CFAR), AI27670 (ACTU), AI064086 (K24 to RHH), AI43638, and 7-UM1 AI068636-07; by CTRI grant: UL1TR000100; by California HIV/AIDS Research Program RN07-SD-702, MC08-SD-700 and EI-11-SD-005; by the National Center for Advancing Translational Sciences through UCLA CTSI Grant UL1TR000124; and by National Institute of General Medical Sciences grant GM093939. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 10 PY 2015 VL 10 IS 6 AR e0130410 DI 10.1371/journal.pone.0130410 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1PO UT WOS:000355979500172 PM 26061824 ER PT J AU Kiris, E Nuss, JE Stanford, SM Wanner, LM Cazares, L Maestre, MF Du, HT Gomba, GY Burnett, JC Gussio, R Bottini, N Panchal, RG Kane, CD Tessarollo, L Bavari, S AF Kiris, Erkan Nuss, Jonathan E. Stanford, Stephanie M. Wanner, Laura M. Cazares, Lisa Maestre, Michael F. Du, Hao T. Gomba, Glenn Y. Burnett, James C. Gussio, Rick Bottini, Nunzio Panchal, Rekha G. Kane, Christopher D. Tessarollo, Lino Bavari, Sina TI Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays SO PLOS ONE LA English DT Article ID PROTEIN-KINASE-C; SYNAPTOSOME-ASSOCIATED PROTEIN; TYROSINE PHOSPHORYLATION; NEUROTRANSMITTER RELEASE; DIFFERENTIAL PHOSPHORYLATION; DEPENDENT PHOSPHORYLATION; DIRECTED DIFFERENTIATION; POSSIBLE INVOLVEMENT; PRL PHOSPHATASES; CATALYTIC DOMAIN AB There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway( s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonismin the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists. C1 [Kiris, Erkan] Geneva Fdn, Tacoma, WA 98402 USA. [Kiris, Erkan; Nuss, Jonathan E.; Wanner, Laura M.; Cazares, Lisa; Du, Hao T.; Gomba, Glenn Y.; Panchal, Rekha G.; Kane, Christopher D.; Bavari, Sina] US Army, Med Res Inst Infect Dis, Dept Mol & Translat Sci, Frederick, MD USA. [Kiris, Erkan; Tessarollo, Lino] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21701 USA. [Stanford, Stephanie M.; Maestre, Michael F.; Bottini, Nunzio] La Jolla Inst Allergy & Immunol, Div Cellular Biol, La Jolla, CA USA. [Burnett, James C.] NCI, Leidos Biomed Res Inc, CDDG, Frederick, MD 21701 USA. [Burnett, James C.; Gussio, Rick] NCI, CDDG, Dev Therapeut Program, Frederick, MD 21701 USA. [Tessarollo, Lino] Henry M Jackson Fdn, Bethesda, MD USA. [Kane, Christopher D.] US Army, Med Res & Mat Command, TATRC, DoD Biotechnol High Performance Comp Software App, Frederick, MD USA. RP Kiris, E (reprint author), Geneva Fdn, Tacoma, WA 98402 USA. EM erkan.kiris@nih.gov; sina.bavari.civ@mail.mil FU Defense Threat Reduction Agency; National Institutes of Health [4R33AI101387-03]; National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NCI, Center for Cancer Research, NIH; Leidos Biomedical Research, Inc. FX This research was supported by grants from the Defense Threat Reduction Agency and National Institutes of Health (4R33AI101387-03). For JCB this project has been funded in whole or in part with federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under contract no. HHSN261200800001E. LT has been supported by the Intramural Research Program of the NCI, Center for Cancer Research, NIH. Leidos Biomedical Research, Inc. provided support in the form of salary for author JCB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section. NR 87 TC 2 Z9 2 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 10 PY 2015 VL 10 IS 6 AR e0129264 DI 10.1371/journal.pone.0129264 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1PO UT WOS:000355979500135 PM 26061731 ER PT J AU Palanee-Phillips, T Schwartz, K Brown, ER Govender, V Mgodi, N Kiweewa, FM Nair, G Mhlanga, F Siva, S Bekker, LG Jeenarain, N Gaffoor, Z Martinson, F Makanani, B Naidoo, S Pather, A Phillip, J Husnik, MJ van der Straten, A Soto-Torres, L Baeten, J AF Palanee-Phillips, Thesla Schwartz, Katie Brown, Elizabeth R. Govender, Vaneshree Mgodi, Nyaradzo Kiweewa, Flavia Matovu Nair, Gonasagrie Mhlanga, Felix Siva, Samantha Bekker, Linda-Gail Jeenarain, Nitesha Gaffoor, Zakir Martinson, Francis Makanani, Bonus Naidoo, Sarita Pather, Arendevi Phillip, Jessica Husnik, Marla J. van der Straten, Ariane Soto-Torres, Lydia Baeten, Jared TI Characteristics of Women Enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention SO PLOS ONE LA English DT Article ID PREEXPOSURE PROPHYLAXIS; ANTIRETROVIRAL CHEMOPROPHYLAXIS; MICROBICIDE GEL; NEGATIVE WOMEN; AFRICAN WOMEN; INFECTION; SAFETY; TRANSMISSION; HEALTHY; TMC120 AB Introduction Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre-exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges. Methods ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial. Results Between August 2012 and June 2014, 5516 women were screened and 2629 HIV-1 seronegative women between 18-45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22-31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis. Conclusions African HIV-1 seronegative women at risk of HIV-1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention. C1 [Palanee-Phillips, Thesla] Univ Witwatersrand, Sch Clin Med, Wits Reprod Hlth & HIV Res Inst, Johannesburg, South Africa. [Schwartz, Katie] FHI 360, Durham, NC USA. [Brown, Elizabeth R.; Husnik, Marla J.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Govender, Vaneshree; Siva, Samantha; Jeenarain, Nitesha; Gaffoor, Zakir; Naidoo, Sarita; Pather, Arendevi; Phillip, Jessica] South African Med Res Council, HIV Prevent Res Unit, Durban, South Africa. [Mgodi, Nyaradzo; Mhlanga, Felix] Univ Calif San Francisco, Univ Zimbabwe, Collaborat Res Program UZ UCSF, Harare, Zimbabwe. [Kiweewa, Flavia Matovu] Johns Hopkins Univ, Makerere Univ, Res Collaborat, Kampala, Uganda. [Nair, Gonasagrie] Ctr AIDS Programme Res SA CAPRISA, Durban, South Africa. [Bekker, Linda-Gail] Desmond Tutu HIV Fdn Clin Res Site, Cape Town, South Africa. [Martinson, Francis] UNC Lilongwe Clin Res Site, Lilongwe, Malawi. [Makanani, Bonus] Johns Hopkins Univ, Coll Med, Res Project Queen Elizabeth Cent Hosp, Blantyre, Malawi. [van der Straten, Ariane] RTI Int, San Francisco, CA USA. [Soto-Torres, Lydia] NIAID, Div Aids, Natl Inst Mental Hlth, Bethesda, MD 20892 USA. [Soto-Torres, Lydia] NICHHD, NIH, Bethesda, MD 20892 USA. [Baeten, Jared] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Baeten, Jared] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Baeten, Jared] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Baeten, J (reprint author), Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. EM jbaeten@uw.edu FU National Institute of Allergy and Infectious Diseases [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health, all components of the U.S. National Institutes of Health FX The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors designed and executed the study, had full access to the raw data, performed all analyses, wrote the manuscript, and had final responsibility for the decision to submit for publication. NR 29 TC 6 Z9 6 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 10 PY 2015 VL 10 IS 6 AR e0128857 DI 10.1371/journal.pone.0128857 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1PO UT WOS:000355979500103 PM 26061040 ER PT J AU Hershman, DL Unger, JM Crew, KD Awad, D Dakhil, SR Gralow, J Greenlee, H Lew, DL Minasian, LM Till, C Wade, JL Meyskens, FL Moinpour, CM AF Hershman, Dawn L. Unger, Joseph M. Crew, Katherine D. Awad, Danielle Dakhil, Shaker R. Gralow, Julie Greenlee, Heather Lew, Danika L. Minasian, Lori M. Till, Cathee Wade, James L., III Meyskens, Frank L. Moinpour, Carol M. TI Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor-Induced Musculoskeletal Pain: SWOG S0927 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STAGE BREAST-CANCER; DIETARY FISH OIL; N-3 FATTY-ACIDS; RHEUMATOID-ARTHRITIS; POSTMENOPAUSAL WOMEN; DOUBLE-BLIND; ADJUVANT TREATMENT; ENDOCRINE THERAPY; CLINICAL-TRIALS; JOINT SYMPTOMS AB Purpose Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides. Patients and Methods Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score >= 5 of 10 using the Brief Pain Inventory-Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as >= 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis. Results Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein. Conclusion We found a substantial (> 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups. (C) 2015 by American Society of Clinical Oncology C1 [Hershman, Dawn L.; Crew, Katherine D.; Awad, Danielle; Greenlee, Heather] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Unger, Joseph M.; Lew, Danika L.; Till, Cathee] South West Oncol Grp Stat Ctr, Seattle, WA USA. [Unger, Joseph M.; Gralow, Julie; Lew, Danika L.; Till, Cathee; Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Dakhil, Shaker R.] Canc Ctr Kansas, Wichita, KS USA. [Minasian, Lori M.] NCI, Bethesda, MD 20892 USA. [Wade, James L., III] Canc Care Specialists Cent Illinois, Cent Illinois Community Clin Oncol Program, Decatur, IL USA. [Meyskens, Frank L.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. RP Hershman, DL (reprint author), Columbia Univ, 161 Ft Washington Ave, New York, NY 10032 USA. EM dlh23@columbia.edu FU Breast Cancer Research Foundation; National Cancer Institute (NCI) Division of Cancer Prevention; NCI Community Oncology Research Program Research Base Grant [1UG1CA189974-01] FX Supported by the Breast Cancer Research Foundation, by the National Cancer Institute (NCI) Division of Cancer Prevention, and by NCI Community Oncology Research Program Research Base Grant No. 1UG1CA189974-01. NR 44 TC 8 Z9 8 U1 0 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1910 EP U78 DI 10.1200/JCO.2014.59.5595 PG 11 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800011 PM 25940724 ER PT J AU Wei, WQ Chen, ZF He, YT Feng, H Hou, J Lin, DM Li, XQ Guo, CL Li, SS Wang, GQ Dong, ZW Abnet, CC Qiao, YL AF Wei, Wen-Qiang Chen, Zhi-Feng He, Yu-Tong Feng, Hao Hou, Jun Lin, Dong-Mei Li, Xin-Qing Guo, Cui-Lan Li, Shao-Sen Wang, Guo-Qing Dong, Zhi-Wei Abnet, Christian C. Qiao, You-Lin TI Long-Term Follow-Up of a Community Assignment, One-Time Endoscopic Screening Study of Esophageal Cancer in China SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; BLOOD BEAD DETECTOR; ASYMPTOMATIC ADULTS; CYTOLOGIC DETECTION; UNITED-STATES; LINXIAN; POPULATION; BALLOON; LESIONS; DYSPLASIA AB Purpose There are no global screening recommendations for esophageal squamous cell carcinoma (ESCC). Endoscopic screening has been investigated in areas of high incidence in China since the 1970s. This study aimed to evaluate whether an endoscopic screening and intervention program could reduce mortality caused by ESCC. Methods Residents age 40 to 69 years were recruited from communities with high rates of ESCC. Fourteen villages were selected as the intervention communities. Ten villages not geographically adjacent to intervention villages were selected for comparison. Participants in the intervention group were screened once by endoscopy with Lugol's iodine staining, and those with dysplasia or occult cancer were treated. All intervention participants and a sample consisting of one tenth of the control group completed questionnaires. We compared cumulative ESCC incidence and mortality between the two groups. Results Three thousand three hundred nineteen volunteers (48.62%) from an eligible population of 6,827 were screened in the intervention group. Seven hundred ninety-seven volunteers from an eligible population of 6,200 in the control group were interviewed. Six hundred fifty-two incident and 542 fatal ESCCs were identified during the 10-year follow-up. A reduction in cumulative mortality in the intervention group versus the control group was apparent (3.35% v 5.05%, respectively; P < .001). Furthermore, the intervention group had a significantly lower cumulative incidence of ESCC versus the control group (4.17% v 5.92%, respectively; P < .001). Conclusion We showed that endoscopic screening and intervention significantly reduced mortality caused by esophageal cancer. Detection and treatment of preneoplastic lesions also led to a reduction in the incidence of this highly fatal cancer. (C) 2015 by American Society of Clinical Oncology C1 [Wei, Wen-Qiang; Feng, Hao; Lin, Dong-Mei; Li, Xin-Qing; Wang, Guo-Qing; Dong, Zhi-Wei; Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100021, Peoples R China. [Wei, Wen-Qiang; Feng, Hao; Lin, Dong-Mei; Li, Xin-Qing; Wang, Guo-Qing; Dong, Zhi-Wei; Qiao, You-Lin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Chen, Zhi-Feng; He, Yu-Tong; Hou, Jun] Canc Inst Hebei Prov, Shijiazhuang, Hebei, Peoples R China. [Guo, Cui-Lan; Li, Shao-Sen] Hosp Ci Cty, Canc Inst Hosp, Handan, Peoples R China. [Abnet, Christian C.] NCI, Bethesda, MD 20892 USA. RP Qiao, YL (reprint author), Chinese Acad Med Sci, Inst Canc, 17 South Panjiayuan Lane, Beijing 100021, Peoples R China. EM qiaoy@cicams.ac.cn RI Abnet, Christian/C-4111-2015; Qiao, You-Lin/B-4139-2012 OI Abnet, Christian/0000-0002-3008-7843; Qiao, You-Lin/0000-0001-6380-0871 FU Ministry of Science and Technology of the People's Republic of China [2001BA703B10] FX Supported by Grant No. 2001BA703B10 from the Ministry of Science and Technology of the People's Republic of China. NR 25 TC 17 Z9 22 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 10 PY 2015 VL 33 IS 17 BP 1951 EP U131 DI 10.1200/JCO.2014.58.0423 PG 9 WC Oncology SC Oncology GA CK1WQ UT WOS:000355999800016 PM 25940715 ER PT J AU Desikan, RS Schork, AJ Wang, Y Thompson, WK Dehghan, A Ridker, PM Chasman, DI McEvoy, LK Holland, D Chen, CH Karow, DS Brewer, JB Hess, CP Williams, J Sims, R O'Donovan, MC Choi, SH Bis, JC Ikram, MA Gudnason, V DeStefano, AL van der Lee, SJ Psaty, BM van Duijn, CM Launer, L Seshadri, S Pericak-Vance, MA Mayeux, R Haines, JL Farrer, LA Hardy, J Ulstein, ID Aarsland, D Fladby, T White, LR Sando, SB Rongve, A Witoelar, A Djurovic, S Hyman, BT Snaedal, J Steinberg, S Stefansson, H Stefansson, K Schellenberg, GD Andreassen, OA Dale, AM AF Desikan, Rahul S. Schork, Andrew J. Wang, Yunpeng Thompson, Wesley K. Dehghan, Abbas Ridker, Paul M. Chasman, Daniel I. McEvoy, Linda K. Holland, Dominic Chen, Chi-Hua Karow, David S. Brewer, James B. Hess, Christopher P. Williams, Julie Sims, Rebecca O'Donovan, Michael C. Choi, Seung Hoan Bis, Joshua C. Ikram, M. Arfan Gudnason, Vilmundur DeStefano, Anita L. van der Lee, Sven J. Psaty, Bruce M. van Duijn, Cornelia M. Launer, Lenore Seshadri, Sudha Pericak-Vance, Margaret A. Mayeux, Richard Haines, Jonathan L. Farrer, Lindsay A. Hardy, John Ulstein, Ingun Dina Aarsland, Dag Fladby, Tormod White, Linda R. Sando, Sigrid B. Rongve, Arvid Witoelar, Aree Djurovic, Srdjan Hyman, Bradley T. Snaedal, Jon Steinberg, Stacy Stefansson, Hreinn Stefansson, Kari Schellenberg, Gerard D. Andreassen, Ole A. Dale, Anders M. CA Inflammation Working Grp Int Genomics Alzheimer's Dis Proje DemGene Investigators TI Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease SO CIRCULATION LA English DT Article DE Alzheimer Disease; Genome-Wide Association Study; inflammation; lipids ID COMMON VARIANTS; BLOOD-LIPIDS; RISK; ASSOCIATION; ONSET; LOCI; METAANALYSIS; CHOLESTEROL; PLEIOTROPY; DIAGNOSIS AB Background-Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results-Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high-and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86x10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38x10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions-We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD. C1 [Desikan, Rahul S.; McEvoy, Linda K.; Chen, Chi-Hua; Karow, David S.; Brewer, James B.; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, 8950 Villa Jolla Dr,Ste C10, La Jolla, CA 92037 USA. [Schork, Andrew J.; Dale, Anders M.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Wang, Yunpeng; Holland, Dominic; Brewer, James B.; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Thompson, Wesley K.; Andreassen, Ole A.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Wang, Yunpeng; Chen, Chi-Hua; Fladby, Tormod; Witoelar, Aree; Andreassen, Ole A.; Dale, Anders M.] Univ Oslo, Inst Clin Med, NORMENT, N-0316 Oslo, Norway. [Wang, Yunpeng; Chen, Chi-Hua; Witoelar, Aree; Andreassen, Ole A.; Dale, Anders M.] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0450 Oslo, Norway. [Ulstein, Ingun Dina] Oslo Univ Hosp, Norwegian Ctr Dementia Res, Dept Old Age Psychiat, N-0450 Oslo, Norway. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, N-0450 Oslo, Norway. [Dehghan, Abbas; Ikram, M. Arfan; van der Lee, Sven J.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Cardiovasc Dis Prevent,Div Preventat Med, Boston, MA 02115 USA. [Hess, Christopher P.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Williams, Julie; Sims, Rebecca; O'Donovan, Michael C.] Cardiff Univ, Sch Med, Med Res Council Ctr Neuropsychiatr Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Choi, Seung Hoan; DeStefano, Anita L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bis, Joshua C.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Bis, Joshua C.] Univ Washington, Seattle, WA 98195 USA. [Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [DeStefano, Anita L.; Seshadri, Sudha] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Washington, DC USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol Ophthalmol, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat & Epidemiol, Boston, MA 02215 USA. [Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Coral Gables, FL 33124 USA. [Mayeux, Richard] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Mayeux, Richard] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Inst Computat Biol, Cleveland, OH 44106 USA. [Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Aarsland, Dag] Karolinska Inst, Alzheimers Dis Res Ctr, Dept Neurobiol, Care Sci & Soc, Stockholm, Sweden. [Aarsland, Dag] Stavanger Univ Hosp, Ctr Age Related Med, Stavanger, Norway. [Aarsland, Dag] Akershus Univ Hosp, Dept Geriatr Psychiat, Oslo, Norway. [Fladby, Tormod] Akershus Univ Hosp, Dept Neurol, Akershus, Norway. [White, Linda R.; Sando, Sigrid B.] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [White, Linda R.; Sando, Sigrid B.] Univ Trondheim Hosp, St Olavs Hosp, Dept Neurol, Trondheim, Norway. [Rongve, Arvid] Haugesund Hosp, Dept Psychiat, Haugesund, Norway. [Djurovic, Srdjan] Univ Bergen, NORMENT, KG Jebsen Ctr Psychosis Res, Dept Clin Sci, N-5020 Bergen, Norway. [Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Snaedal, Jon] Univ Hosp Reykjavik, Dept Geriatr Med, Reykjavik, Iceland. [Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. RP Desikan, RS (reprint author), Univ Calif San Diego, Dept Radiol, 8950 Villa Jolla Dr,Ste C10, La Jolla, CA 92037 USA. EM rdesikan@ucsd.edu; o.a.andreassen@medisin.uio.no RI Hardy, John/C-2451-2009; Gudnason, Vilmundur/K-6885-2015; OI Farrer, Lindsay/0000-0001-5533-4225; Seshadri, Sudha/0000-0001-6135-2622; Dehghan, Abbas/0000-0001-6403-016X; Aarsland, Dag/0000-0001-6314-216X; Gudnason, Vilmundur/0000-0001-5696-0084; Stefansson, Hreinn/0000-0002-9331-6666 FU National Institutes of Health [K02 NS067427, T32 EB005970, R01GM104400-01A, R01MH100351, AG033193, U0149505, RC2DA029475, R01HD061414]; Research Council of Norway [213837, 225989, 223273, 237250/EU JPND]; South East Norway Health Authority [2013-123]; Norwegian Health Association; KG Jebsen Foundation; Robert J. Glushko and Pamela Samuelson Graduate Fellowship; NWO [916.12.154]; Erasmus University Rotterdam Fellowship FX This research was supported by grants from the National Institutes of Health (K02 NS067427, T32 EB005970, R01GM104400-01A, R01MH100351, AG033193, and U0149505), the Research Council of Norway (grants 213837, 225989, 223273, 237250/EU JPND), the South East Norway Health Authority (2013-123), the Norwegian Health Association, and the KG Jebsen Foundation. A.J. Schork was supported by National Institutes of Health grants RC2DA029475 and R01HD061414 and the Robert J. Glushko and Pamela Samuelson Graduate Fellowship. Dr Dehghan was supported by an NWO grant (veni, 916.12.154) and the Erasmus University Rotterdam Fellowship. Please see the Acknowledgments in the online-only Data Supplement for IGAP funding sources. NR 32 TC 15 Z9 16 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUN 9 PY 2015 VL 131 IS 23 BP 2061 EP 2069 DI 10.1161/CIRCULATIONAHA.115.015489 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IJ UT WOS:000369254400010 PM 25862742 ER PT J AU Papadopoulou, A Siamatras, T Delgado-Morales, R Amin, ND Shukla, V Zheng, YL Pant, HC Almeida, OFX Kino, T AF Papadopoulou, A. Siamatras, T. Delgado-Morales, R. Amin, N. D. Shukla, V. Zheng, Y-L Pant, H. C. Almeida, O. F. X. Kino, T. TI Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID CDK5 INHIBITORY PEPTIDE; TRANSCRIPTIONAL ACTIVITY; HIPPOCAMPAL NEUROGENESIS; PREFRONTAL CORTEX; GENE-EXPRESSION; BIOCHEMICAL MANIFESTATIONS; CLINICAL-IMPLICATIONS; NEUROTROPHIC FACTOR; SEX-DIFFERENCES; MOOD DISORDERS AB Stress activates the hypothalamic-pituitary-adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR. C1 [Papadopoulou, A.; Siamatras, T.; Kino, T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Delgado-Morales, R.; Almeida, O. F. X.] Max Planck Inst Psychiat, NeuroAdaptat Grp, D-80804 Munich, Germany. [Amin, N. D.; Shukla, V.; Zheng, Y-L; Pant, H. C.] NINDS, Neuronal Cytoskeletal Prot Regulat Sect, Bethesda, MD 20892 USA. [Kino, T.] Sidra Med & Res Ctr, Dept Expt Therapeut, Div Expt Biol, Doha 26999, Qatar. RP Kino, T (reprint author), Sidra Med & Res Ctr, Dept Expt Therapeut, Div Expt Biol, 9th Floor,Burj Tower,POB 26999, Doha 26999, Qatar. EM tkino@sidra.org RI Delgado-Morales, Raul/F-8839-2013; OI Delgado-Morales, Raul/0000-0002-8538-4087; Siamatras, Thomas/0000-0001-7717-1869 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Integrated Project (Switchbox) [259772]; Fulbright Grant; Greek Ministry of Defense; EU [273720] FX This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA and the Integrated Project (Switchbox, Contract No. 259772) to OFXA. TK is at the Sidra Medical and Reserarch Center. AP, TS and RD-M were supported by a Fulbright Grant, an Educational Grant from the Greek Ministry of Defense and EU FP7 Marie Curie IEF Fellowship (No. 273720), respectively. We thank Dr N. Sousa (University of Minho, Guimaraes, Portugal) for neuroanatomical advice and the Netherlands Brain Bank and the Human Brain and Spinal Fluid Resource Center of the West L.A. Healthcare Center for providing valuable postmortem human brain tissues. NR 70 TC 10 Z9 10 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUN 9 PY 2015 VL 5 AR e578 DI 10.1038/tp.2015.72 PG 10 WC Psychiatry SC Psychiatry GA DA2WT UT WOS:000367658600002 PM 26057048 ER PT J AU Santella, A Catena, R Kovacevic, I Shah, P Yu, ZD Marquina-Solis, J Kumar, A Wu, YC Schaff, J Colon-Ramos, D Shroff, H Mohler, WA Bao, ZR AF Santella, Anthony Catena, Raul Kovacevic, Ismar Shah, Pavak Yu, Zidong Marquina-Solis, Javier Kumar, Abhishek Wu, Yicong Schaff, James Colon-Ramos, Daniel Shroff, Hari Mohler, William A. Bao, Zhirong TI WormGUIDES: an interactive single cell developmental atlas and tool for collaborative multidimensional data exploration SO BMC BIOINFORMATICS LA English DT Article DE Visualization; C. elegans; Morphogenesis; Neurons; Single-cell analysis ID PLANE ILLUMINATION MICROSCOPY; CAENORHABDITIS-ELEGANS; C. ELEGANS; GENE-EXPRESSION; IMAGE DATA; RECONSTRUCTION; EMBRYOGENESIS; RESOLUTION; EMBRYO; SYSTEM AB Background: Imaging and image analysis advances are yielding increasingly complete and complicated records of cellular events in tissues and whole embryos. The ability to follow hundreds to thousands of cells at the individual level demands a spatio-temporal data infrastructure: tools to assemble and collate knowledge about development spatially in a manner analogous to geographic information systems (GIS). Just as GIS indexes items or events based on their spatio-temporal or 4D location on the Earth these tools would organize knowledge based on location within the tissues or embryos. Developmental processes are highly context-specific, but the complexity of the 4D environment in which they unfold is a barrier to assembling an understanding of any particular process from diverse sources of information. In the same way that GIS aids the understanding and use of geo-located large data sets, software can, with a proper frame of reference, allow large biological data sets to be understood spatially. Intuitive tools are needed to navigate the spatial structure of complex tissue, collate large data sets and existing knowledge with this spatial structure and help users derive hypotheses about developmental mechanisms. Results: Toward this goal we have developed WormGUIDES, a mobile application that presents a 4D developmental atlas for Caenorhabditis elegans. The WormGUIDES mobile app enables users to navigate a 3D model depicting the nuclear positions of all cells in the developing embryo. The identity of each cell can be queried with a tap, and community databases searched for available information about that cell. Information about ancestry, fate and gene expression can be used to label cells and craft customized visualizations that highlight cells as potential players in an event of interest. Scenes are easily saved, shared and published to other WormGUIDES users. The mobile app is available for Android and iOS platforms. Conclusion: WormGUIDES provides an important tool for examining developmental processes and developing mechanistic hypotheses about their control. Critically, it provides the typical end user with an intuitive interface for developing and sharing custom visualizations of developmental processes. Equally important, because users can select cells based on their position and search for information about them, the app also serves as a spatially organized index into the large body of knowledge available to the C. elegans community online. Moreover, the app can be used to create and publish the result of exploration: interactive content that brings other researchers and students directly to the spatio-temporal point of insight. Ultimately the app will incorporate a detailed time lapse record of cell shape, beginning with neurons. This will add the key ability to navigate and understand the developmental events that result in the coordinated and precise emergence of anatomy, particularly the wiring of the nervous system. C1 [Santella, Anthony; Catena, Raul; Kovacevic, Ismar; Shah, Pavak; Yu, Zidong; Bao, Zhirong] Sloan Kettering Inst, Dev Biol Program, New York, NY USA. [Yu, Zidong] Jiangsu Univ Sci & Technol, Sch Energy & Power Engn, Zhenjiang 212003, Jiangsu, Peoples R China. [Marquina-Solis, Javier; Kumar, Abhishek; Colon-Ramos, Daniel] Yale Univ, Sch Med, Dept Cell Biol, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06510 USA. [Kumar, Abhishek; Wu, Yicong; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD USA. [Mohler, William A.] Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Schaff, James; Mohler, William A.] Univ Connecticut, Ctr Hlth, Ctr Cell Anal & Modeling, Farmington, CT USA. RP Mohler, WA (reprint author), Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. EM mohler.william@gmail.com; baoz@mskcc.org RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Bao, Zhirong/0000-0002-2201-2745 FU Marine Biological Laboratories at Woods Hole; Intramural Research Programs of the NIH National Institute of Biomedical Imaging and Bioengineering; NIH [U01 HD075602, R24OD016474] FX Thanks to Amelia White, Zhuo Du, Thomas Flott, Teagan Marshall, Nhan Nguyen and Ryan Christensen for advice, imaging, segmentation and lineage editing assistance. Thanks to Oliver Hobert's lab for providing worms with the lim-4:GFP transgene. We also thank the Research Center for Minority Institutions program and the Institute of Neurobiology at the University of Puerto Rico for providing a meeting and brainstorming platform. This work was partially conducted at the Marine Biological Laboratories at Woods Hole, under a Whitman research award (to D.A.C.-R., Z.B., W.A.M. and H.S.). This work was supported by the Intramural Research Programs of the NIH National Institute of Biomedical Imaging and Bioengineering and by NIH grants U01 HD075602 and R24OD016474. NR 31 TC 5 Z9 5 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 9 PY 2015 VL 16 AR 189 DI 10.1186/s12859-015-0627-8 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CK3RD UT WOS:000356132300001 PM 26051157 ER PT J AU Smircich, P Eastman, G Bispo, S Duhagon, MA Guerra-Slompo, EP Garat, B Goldenberg, S Munroe, DJ Dallagiovanna, B Holetz, F Sotelo-Silveira, JR AF Smircich, Pablo Eastman, Guillermo Bispo, Saloe Ana Duhagon, Maria Guerra-Slompo, Eloise P. Garat, Beatriz Goldenberg, Samuel Munroe, David J. Dallagiovanna, Bruno Holetz, Fabiola Sotelo-Silveira, Jose R. TI Ribosome profiling reveals translation control as a key mechanism generating differential gene expression in Trypanosoma cruzi SO BMC GENOMICS LA English DT Article DE Trypanosoma cruzi; Neglected disease; Transcriptome; Ribosome profiling; Translatome; Translation regulation; Ribosomal proteins; Trans-sialidases ID LIFE-CYCLE STAGES; STAGE-SPECIFIC EXPRESSION; GENOME-WIDE ANALYSIS; PROTEOMIC ANALYSIS; MESSENGER-RNA; METACYCLIC TRYPOMASTIGOTES; TRANSCRIPTIONAL CONTROL; IN-VIVO; METACYCLOGENESIS; PROTEINS AB Background: Due to the absence of transcription initiation regulation of protein coding genes transcribed by RNA polymerase II, posttranscriptional regulation is responsible for the majority of gene expression changes in trypanosomatids. Therefore, cataloging the abundance of mRNAs (transcriptome) and the level of their translation (translatome) is a key step to understand control of gene expression in these organisms. Results: Here we assess the extent of regulation of the transcriptome and the translatome in the Chagas disease causing agent, Trypanosoma cruzi, in both the non-infective (epimastigote) and infective (metacyclic trypomastigote) insect's life stages using RNA-seq and ribosome profiling. The observed steady state transcript levels support constitutive transcription and maturation implying the existence of distinctive posttranscriptional regulatory mechanisms controlling gene expression levels at those parasite stages. Meanwhile, the downregulation of a large proportion of the translatome indicates a key role of translation control in differentiation into the infective form. The previously described proteomic data correlate better with the translatomes than with the transcriptomes and translational efficiency analysis shows a wide dynamic range, reinforcing the importance of translatability as a regulatory step. Translation efficiencies for protein families like ribosomal components are diminished while translation of the transialidase virulence factors is upregulated in the quiescent infective metacyclic trypomastigote stage. Conclusions: A large subset of genes is modulated at the translation level in two different stages of Trypanosoma cruzi life cycle. Translation upregulation of virulence factors and downregulation of ribosomal proteins indicates different degrees of control operating to prepare the parasite for an infective life form. Taking together our results show that translational regulation, in addition to regulation of steady state level of mRNA, is a major factor playing a role during the parasite differentiation. C1 [Eastman, Guillermo; Sotelo-Silveira, Jose R.] Inst Invest Biol Clemente Estable, Dept Genom, Montevideo 11600, Uruguay. [Smircich, Pablo; Ana Duhagon, Maria; Garat, Beatriz] Univ Republica, Sch Sci, Lab Mol Interact, Montevideo, Uruguay. [Smircich, Pablo; Ana Duhagon, Maria] Univ Republica, Sch Sci, Dept Genet, Montevideo, Uruguay. [Bispo, Saloe; Guerra-Slompo, Eloise P.; Goldenberg, Samuel; Dallagiovanna, Bruno; Holetz, Fabiola] Fiocruz MS, Carlos Chagas Inst, Lab Gene Express Regulat Studies, BR-81350010 Curitiba, Parana, Brazil. [Munroe, David J.] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Sotelo-Silveira, Jose R.] Univ Republica, Sch Sci, Dept Cell & Mol Biol, Montevideo, Uruguay. RP Holetz, F (reprint author), Fiocruz MS, Carlos Chagas Inst, Lab Gene Express Regulat Studies, BR-81350010 Curitiba, Parana, Brazil. EM holetz@fiocruz.br; jsotelosilveira@iibce.edu.uy FU CNPq; Fiocruz-PAPES; Fundacao Araucaria; Programa de Desarrollo de las Ciencias Basicas; Agencia Nacional de Investigacion e Innovacion; Comision Sectorial de Investigacion Cientifica FX We acknowledge Dr. Najib El-Sayed for his useful comments. This work received financial support from: CNPq. Fiocruz-PAPES. Fundacao Araucaria. Programa de Desarrollo de las Ciencias Basicas. Agencia Nacional de Investigacion e Innovacion. Comision Sectorial de Investigacion Cientifica. Program for Technological Development in Tools for Health-PDTIS-FIOCRUZ for use of its facilities. NR 57 TC 11 Z9 11 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 9 PY 2015 VL 16 AR 443 DI 10.1186/s12864-015-1563-8 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CK4AE UT WOS:000356158300001 PM 26054634 ER PT J AU Korn, EL Freidlin, B AF Korn, E. L. Freidlin, B. TI Response to Comment on: 'Evaluation of chemoresponse assays as predictive biomarkers' SO BRITISH JOURNAL OF CANCER LA English DT Editorial Material ID RECURRENT OVARIAN-CANCER C1 [Korn, E. L.; Freidlin, B.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, MSC 9735, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 5 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 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 9 PY 2015 VL 112 IS 12 BP 1978 EP 1978 DI 10.1038/bjc.2015.157 PG 1 WC Oncology SC Oncology GA CK2FA UT WOS:000356024800019 PM 25965166 ER PT J AU Kim, H Frederick, DT Levesque, MP Cooper, ZA Feng, YM Krepler, C Brill, L Samuels, Y Hayward, NK Perlina, A Piris, A Zhang, TW Halaban, R Herlyn, MM Brown, KM Wargo, JA Dummer, R Flaherty, KT Ronai, ZA AF Kim, Hyungsoo Frederick, Dennie T. Levesque, Mitchell P. Cooper, Zachary A. Feng, Yongmei Krepler, Clemens Brill, Laurence Samuels, Yardena Hayward, Nicholas K. Perlina, Ally Piris, Adriano Zhang, Tongwu Halaban, Ruth Herlyn, Meenhard M. Brown, Kevin M. Wargo, Jennifer A. Dummer, Reinhard Flaherty, Keith T. Ronai, Ze'ev A. TI Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation SO CELL REPORTS LA English DT Article ID BRAF(V600E) INHIBITION; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; DRIVEN RESISTANCE; UP-REGULATION; EGF RECEPTOR; CANCER; VEMURAFENIB; ACTIVATION; MUTATIONS AB Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression. C1 [Kim, Hyungsoo; Feng, Yongmei; Brill, Laurence; Perlina, Ally; Ronai, Ze'ev A.] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. [Frederick, Dennie T.; Piris, Adriano; Flaherty, Keith T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02114 USA. [Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich, CH-8091 Zurich, Switzerland. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Krepler, Clemens] Wistar Inst Anat & Biol, Melanoma Res Ctr, Philadelphia, PA 19104 USA. [Samuels, Yardena] Weizmann Inst Sci, IL-76100 Rehovot, Israel. [Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Zhang, Tongwu; Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Halaban, Ruth] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. RP Kim, H (reprint author), Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. EM hkim@sbmri.org; ronai@sbmri.org RI Zhang, Tongwu/M-4975-2015; hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; RONAI, ZEEV/0000-0002-3859-0400; Cooper, Zachary/0000-0003-1059-0940 FU NCI [CA128814]; Melanoma Research Foundation; Hervey Family Non-endowment Fund at The San Diego Foundation FX We thank Holly Yin for providing the UACC cell lines used in this study. We also thank members of Z.A.R.'s laboratory for extensive discussions. This work was supported by grants from the NCI (CA128814), the Melanoma Research Foundation, and the Hervey Family Non-endowment Fund at The San Diego Foundation (to Z.A.R.). NR 44 TC 6 Z9 6 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 9 PY 2015 VL 11 IS 9 BP 1458 EP 1473 DI 10.1016/j.celrep.2015.04.049 PG 16 WC Cell Biology SC Cell Biology GA CK2UR UT WOS:000356069500013 PM 26027934 ER PT J AU Xiao, Y Thoresen, DT Williams, JS Wang, CC Perna, J Petrova, R Brownell, I AF Xiao, Ying Thoresen, Daniel T. Williams, Jonathan S. Wang, Chaochen Perna, James Petrova, Ralitsa Brownell, Isaac TI Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stem cell; perineural niche; touch dome; Merkel cell; Hedgehog ID MERKEL CELLS; HAIR FOLLICLE; PROGENITOR CELLS; NICHE; SKIN; INNERVATION; DENERVATION; CARCINOMA; REGENERATION; LINEAGE AB The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis. C1 [Xiao, Ying; Thoresen, Daniel T.; Williams, Jonathan S.; Brownell, Isaac] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Chaochen] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Perna, James] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Petrova, Ralitsa] Sloan Kettering Inst, Dev Biol Program, New York, NY 10065 USA. [Petrova, Ralitsa] Weill Cornell Med Sch, Biochem & Struct Biol Cell & Dev Biol & Mol Biol, New York, NY 10065 USA. RP Brownell, I (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM isaac.brownell@nih.gov FU NIH Intramural Research Program, CCR, NCI FX We thank Dr. Alexandra Joyner (Memorial Sloan Kettering Cancer Center) for supplying mice and for extensive scientific discussions, Dr. Sunny Wong (University of Michigan) and Dr. Mark Udey (NCI) for scientific discussions and critical reading of the manuscript, Dr. Amy Coxon and Mr. Eric Wang for technical assistance, and the Center of Cancer Research (CCR) ConfocalMicroscopy Core Facility for assistance in confocal imaging. This work was supported by the NIH Intramural Research Program, CCR, NCI. NR 46 TC 10 Z9 10 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 2015 VL 112 IS 23 BP 7195 EP 7200 DI 10.1073/pnas.1504177112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ9LG UT WOS:000355823200040 PM 26015562 ER PT J AU Mo, AXY Pesce, J Hall, BF AF Mo, Annie X. Y. Pesce, John Hall, B. Fenton TI Exploring immunological mechanisms of the whole sporozoite vaccination against P. falciparum malaria SO VACCINE LA English DT Article DE Malaria; Plasmodium falciparum; Sporozoite; Vaccine Immunology ID PLASMODIUM-BERGHEI; MAMMALIAN HOST; PROTECTION; IMMUNIZATION; CELL; IMMUNITY; INFECTION; PARASITE; SKIN; IDENTIFICATION AB Great progress has been made in the development of whole sporozoite vaccines including the manufacturing of cryopreserved Plasmodium falciparum sporozoites (PfSPZ) suitable for clinical application. Such whole sporozoites are being used for clinical studies of controlled human malaria infection (CHMI) as well as for evaluation of candidate vaccine approaches (both attenuated sporozoites and infectious sporozoites administered with chemoprophylaxis) and as reagents for immunology and cell biology assays. CHMI studies with whole sporozoites provide a great opportunity to better understand the intrinsic mechanisms of resistance to P. falciparum (e.g. due to sickle cell trait and other hemoglobinopathies) as well as host responses to an initial P. falciparum infection. High-level protective efficacy has been demonstrated in a small number of volunteers after intravenous (IV) inoculation of radiation-attenuated PfSPZ or in those who were exposed to live PfSPZ while on malaria chemoprophylaxis. These advances and data warrant further investigations of the immunological mechanism(s) whereby whole sporozoite inoculation elicits protective immunity in order to facilitate whole sporozoite vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on Sept. 2-3, 2014 involving participation of international experts in the field of malaria vaccine development, and in basic and clinical immunology research. The workshop discussed the current understanding of host immune responses to whole malaria sporozoite inoculation, identified gaps in knowledge, resources to facilitate progress, and applicable new technologies and approaches to accelerate immunologic and vaccinologic studies and biomarker identification. This report summarizes the discussions and major conclusions from the workshop participants. C1 [Mo, Annie X. Y.; Pesce, John; Hall, B. Fenton] NIAID, NIH, US Dept HHS, Rockville, MD 20852 USA. RP Mo, AXY (reprint author), NIAID, NIH, US Dept HHS, 5601 Fishers Lane, Rockville, MD 20852 USA. EM moa@niaid.nih.gov FU NIH FX All authors are employees of NIH and are supported by NIH operating funds rather than grants or other awards. NR 42 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 9 PY 2015 VL 33 IS 25 BP 2851 EP 2857 DI 10.1016/j.vaccine.2015.04.056 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CK4JN UT WOS:000356190200001 PM 25917675 ER PT J AU Zhu, N Jacobs, DR Schreiner, PJ Launer, LJ Whitmer, RA Sidney, S Demerath, E Thomas, W Bouchard, C He, K Erus, G Battapady, H Bryan, RN AF Zhu, Na Jacobs, David R., Jr. Schreiner, Pamela J. Launer, Lenore J. Whitmer, Rachel A. Sidney, Stephen Demerath, Ellen Thomas, William Bouchard, Claude He, Ka Erus, Guray Battapady, Harsha Bryan, R. Nick TI Cardiorespiratory fitness and brain volume and white matter integrity The CARDIA Study SO NEUROLOGY LA English DT Article ID ALL-CAUSE MORTALITY; COGNITIVE FUNCTION; YOUNG-ADULTS; CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; AEROBIC FITNESS; MRI FINDINGS; RISK-FACTORS; ATROPHY AB Objective: We hypothesized that greater cardiorespiratory fitness is associated with lower odds of having unfavorable brain MRI findings. Methods: We studied 565 healthy, middle-aged, black and white men and women in the CARDIA (Coronary Artery Risk Development in Young Adults) Study. The fitness measure was symptom-limited maximal treadmill test duration (Max(dur)); brain MRI was measured 5 years later. Brain MRI measures were analyzed as means and as proportions below the 15th percentile (above the 85th percentile for white matter abnormal tissue volume). Results: Per 1-minute-higher Max(dur), the odds ratio for having less whole brain volume was 0.85 (p = 0.04) and for having low white matter integrity was 0.80 (p = 0.02), adjusted for age, race, sex, clinic, body mass index, smoking, alcohol, diet, physical activity, education, blood pressure, diabetes, total cholesterol, and lung function (plus intracranial volume for white matter integrity). No significant associations were observed between Max(dur) and abnormal tissue volume or blood flow in white matter. Findings were similar for associations with continuous brain MRI measures. Conclusions: Greater physical fitness was associated with more brain volume and greater white matter integrity measured 5 years later in middle-aged adults. C1 [Zhu, Na; Jacobs, David R., Jr.; Schreiner, Pamela J.; Demerath, Ellen] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Thomas, William] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Zhu, Na] Albert Einstein Coll Med, St Barnabas Hosp, Bronx, NY USA. [Launer, Lenore J.] NIA, Neuroepidemiol Sect, Bethesda, MD 20892 USA. [Whitmer, Rachel A.; Sidney, Stephen] Pennington Biomed Res Ctr, Kaiser Permanente Div Res, Baton Rouge, LA USA. [Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom, Baton Rouge, LA USA. [He, Ka] Indiana Univ, Sch Publ Hlth, Bloomington, IN 47405 USA. [Erus, Guray; Battapady, Harsha; Bryan, R. Nick] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Jacobs, DR (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. EM jacob004@umn.edu RI Bouchard, Claude/A-7637-2009; Meijer, Anna/K-5118-2016 FU National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Institute on Aging [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; grant for the CARDIA Fitness Study [R01 HL 078972] FX The Coronary Artery Risk Development in Young Adults (CARDIA) Study is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Institute on Aging and a grant for the CARDIA Fitness Study R01 HL 078972. NR 40 TC 8 Z9 8 U1 1 U2 7 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 JUN 9 PY 2015 VL 84 IS 23 BP 2347 EP 2353 DI 10.1212/WNL.0000000000001658 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CJ8ZO UT WOS:000355792200010 PM 25957331 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI A commentary on "A new initiative on precision medicine" SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE substance use disorders; alcohol; marijuana; cannabis; nicotine; tobacco ID CANNABIS USE C1 NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 10 TC 0 Z9 0 U1 2 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD JUN 8 PY 2015 VL 6 AR 88 DI 10.3389/fpsyt.2015.00088 PG 2 WC Psychiatry SC Psychiatry GA CV7OU UT WOS:000364464400001 PM 26106336 ER PT J AU Cifani, C Di Bonaventura, MVM Pucci, M Giusepponi, ME Romano, A Di Francesco, A Maccarrone, M D'Addario, C AF Cifani, Carlo Di Bonaventura, Maria V. Micioni Pucci, Mariangela Giusepponi, Maria E. Romano, Adele Di Francesco, Andrea Maccarrone, Mauro D'Addario, Claudio TI Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE diet induced obesity; hypothalamus; neuropeptides; gene expression; DNA methylation; high fat diet ID SPRAGUE-DAWLEY RATS; HIGH-FAT DIET; ENERGY-BALANCE; FOOD-INTAKE; BODY-WEIGHT; PPAR-GAMMA; EPIGENETIC REGULATION; ARCUATE NUCLEUS; LEPTIN; PRONE AB Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-y) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-y, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism. C1 [Cifani, Carlo; Di Bonaventura, Maria V. Micioni; Giusepponi, Maria E.] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy. [Cifani, Carlo] NIDA, NIH, Intramural Res Program, Baltimore, MD USA. [Pucci, Mariangela; Di Francesco, Andrea; D'Addario, Claudio] Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Teramo, Italy. [Romano, Adele] V Erspamer Sapienza Univ Rome, Dept Physiol & Pharmacol, Rome, Italy. [Maccarrone, Mauro] Campus Biomed Univ Rome, Ctr Integrated Res, Rome, Italy. [Maccarrone, Mauro; D'Addario, Claudio] Santa Lucia Fdn, European Ctr Brain Res CERC, Rome, Italy. RP Cifani, C (reprint author), Univ Camerino, Sch Pharm, Pharmacol Unit, Via Madonna Carceri 9, I-62032 Camerino, Italy. EM carlo.cifani@unicam.it; cdaddario@unite.it RI Pucci, Mariangela/K-6379-2016; OI Cifani, Carlo/0000-0001-6180-828X; d'addario, claudio/0000-0002-1275-098X; ROMANO, ADELE/0000-0003-3874-2627; Pucci, Mariangela/0000-0003-4657-6075; GIUSEPPONI, MARIA ELENA/0000-0002-1388-3186 FU Italian Ministry of University and Research [FIRB-RBFR12DELS, PRIN-2012JTX3KL] FX The work was supported by the Italian Ministry of University and Research under grants FIRB-RBFR12DELS to CC and CD, and PRIN-2012JTX3KL to CC. The authors declare no competing financial interests. NR 47 TC 6 Z9 6 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JUN 8 PY 2015 VL 9 AR 187 DI 10.3389/fnins.2015.00187 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CS3SU UT WOS:000361996000001 PM 26106286 ER PT J AU Kim, YJ Guzman-Hernandez, ML Wisniewski, E Balla, T AF Kim, Yeun Ju Guzman-Hernandez, Maria-Luisa Wisniewski, Eva Balla, Tamas TI Phosphatidylinositol-Phosphatidic Acid Exchange by Nir2 at ER-PM Contact Sites Maintains Phosphoinositide Signaling Competence SO DEVELOPMENTAL CELL LA English DT Article ID RETINAL-DEGENERATION-B; TRANSFER PROTEIN; ENDOPLASMIC-RETICULUM; ERYTHROCYTE-MEMBRANES; LIPID TRANSFER; INOSITOL; CELLS; DOMAINS; BRAIN; RDGB AB Sustained agonist-induced production of the second messengers InsP(3) and diacylglycerol requires steady delivery of phosphatidylinositol (PtdIns) from its site of synthesis in the ER to the plasma membrane (PM) to maintain PtdIns(4,5)P-2 levels. Similarly, phosphatidic acid (PtdOH), generated from diacylglycerol in the PM, has to reach the ER for PtdIns resynthesis. Here, we show that the Drosophila RdgB homolog, Nir2, a presumed PtdIns transfer protein, not only transfers PtdIns from the ER to the PM but also transfers PtdOH to the opposite direction at ER-PM contact sites. PtdOH delivery to the ER is impaired in Nir2-depleted cells, leading to limited PtdIns synthesis and ultimately to loss of signaling from phospholipase C-coupled receptors. These studies reveal a unique feature of Nir2, namely its ability to serve as a highly localized lipid exchanger that ensures that PtdIns synthesis is matched with PtdIns(4,5)P-2 utilization so that cells maintain their signaling competence. C1 [Kim, Yeun Ju; Guzman-Hernandez, Maria-Luisa; Wisniewski, Eva; Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov RI Wisniewski, Eva/O-9233-2015; OI Wisniewski, Eva/0000-0001-8698-6867; Balla, Tamas/0000-0002-9077-3335 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH; Hungarian American Enterprise Scholarship Fund (HAESF) FX We would like to thank Drs. John H. Brumell, Theodorus Gadella, Chris Stephan, and Nicolas Vitale for DNA constructs and Drs. Shamsad Cockcroft and Tiansen Li for PITP and Nir2 antibodies. We are also grateful for Drs. Gerald Hammond and Marko Jovic for fruitful discussions and reading the manuscript. Confocal imaging was performed at the Microscopy and Imaging Core of the National Institute of Child Health and Human Development, NIH with the kind assistance of Drs. Vincent Schram and James T. Russell. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH. E.W. was supported by a scholarship from the Hungarian American Enterprise Scholarship Fund (HAESF). NR 39 TC 33 Z9 34 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JUN 8 PY 2015 VL 33 IS 5 BP 549 EP 561 DI 10.1016/j.devcel.2015.04.028 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CK2QH UT WOS:000356055500010 PM 26028218 ER PT J AU Seder, R Reed, SG O'Hagan, D Malyala, P D'Oro, U Laera, D Abrignani, S Cerundolo, V Steinman, L Bertholet, S AF Seder, Robert Reed, Steven G. O'Hagan, Derek Malyala, Padrna D'Oro, Ugo Laera, Donatello Abrignani, Sergio Cerundolo, Vincenzo Steinman, Lawrence Bertholet, Sylvie TI Gaps in knowledge and prospects for research of adjuvanted vaccines SO VACCINE LA English DT Review DE Vaccine; Adjuvant ID RANDOMIZED CONTROLLED-TRIAL; PREVENTION; INFECTION; EFFICACY; CELLS AB A panel of researchers working in different areas of adjuvanted vaccines deliberated over the topic, "Gaps in knowledge and prospects for research of adjuvanted vaccines" at, "Enhancing Vaccine Immunity and Value" conference held in July 2014. Several vaccine challenges and applications for new adjuvant technologies were discussed. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Seder, Robert] NIAID, Cellular Immunol Sect, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98102 USA. [O'Hagan, Derek; Malyala, Padrna] Novartis Vaccines, Cambridge, MA USA. [D'Oro, Ugo; Laera, Donatello; Bertholet, Sylvie] Novartis Vaccines, Siena, Italy. [Abrignani, Sergio] Inst Nazl Genet Mol, Milan, Italy. [Cerundolo, Vincenzo] Univ Oxford, Oxford, England. [Steinman, Lawrence] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. RP Reed, SG (reprint author), Infect Dis Res Inst, Seattle, WA 98102 USA. EM sreed@idri.org OI Abrignani, Sergio/0000-0002-0794-3285 NR 14 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 8 PY 2015 VL 33 SU 2 BP B40 EP B43 DI 10.1016/j.vaccine.2015.03.057 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CK9GK UT WOS:000356548400008 PM 26022566 ER PT J AU Cole, A Wang, ZZ Coyaud, E Voisin, V Gronda, M Jitkova, Y Mattson, R Hurren, R Babovic, S Maclean, N Restall, I Wang, XM Jeyaraju, DV Sukhai, MA Prabha, S Bashir, S Ramakrishnan, A Leung, E Qia, YH Zhang, NX Combes, KR Ketela, T Lin, FS Houry, WA Aman, A Al-awar, R Zheng, W Wienholds, E Xu, CJ Dick, J Wang, JCY Moffat, J Minden, MD Eaves, CJ Bader, GD Hao, ZY Kornblau, SM Raught, B Schimmer, AD AF Cole, Alicia Wang, Zezhou Coyaud, Etienne Voisin, Veronique Gronda, Marcela Jitkova, Yulia Mattson, Rachel Hurren, Rose Babovic, Sonja Maclean, Neil Restall, Ian Wang, Xiaoming Jeyaraju, Danny V. Sukhai, Mahadeo A. Prabha, Swayam Bashir, Shaheena Ramakrishnan, Ashwin Leung, Elisa Qia, Yi Hua Zhang, Nianxian Combes, Kevin R. Ketela, Troy Lin, Fengshu Houry, Walid A. Aman, Ahmed Al-awar, Rima Zheng, Wei Wienholds, Erno Xu, Chang Jiang Dick, John Wang, Jean C. Y. Moffat, Jason Minden, Mark D. Eaves, Connie J. Bader, Gary D. Hao, Zhenyue Kornblau, Steven M. Raught, Brian Schimmer, Aaron D. TI Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia SO CANCER CELL LA English DT Article ID ADVERSE PROGNOSTIC-FACTOR; ESCHERICHIA-COLI CLPP; MULTIPLE-MYELOMA; MAMMALIAN-CELLS; HUMAN HOMOLOG; STEM-CELLS; EXPRESSION; BORTEZOMIB; LOCALIZATION; CARFILZOMIB AB From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism. C1 [Cole, Alicia; Wang, Zezhou; Coyaud, Etienne; Gronda, Marcela; Jitkova, Yulia; Mattson, Rachel; Hurren, Rose; Maclean, Neil; Restall, Ian; Wang, Xiaoming; Jeyaraju, Danny V.; Sukhai, Mahadeo A.; Prabha, Swayam; Ramakrishnan, Ashwin; Lin, Fengshu; Wienholds, Erno; Dick, John; Wang, Jean C. Y.; Minden, Mark D.; Hao, Zhenyue; Raught, Brian; Schimmer, Aaron D.] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Voisin, Veronique; Bashir, Shaheena; Xu, Chang Jiang; Bader, Gary D.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Babovic, Sonja; Eaves, Connie J.] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. [Babovic, Sonja; Eaves, Connie J.] Univ British Columbia, Vancouver, BC V5Z 1L3, Canada. [Leung, Elisa; Houry, Walid A.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Qia, Yi Hua; Combes, Kevin R.; Kornblau, Steven M.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Zhang, Nianxian] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Ketela, Troy; Moffat, Jason] Donnelly Ctr Cellular & Biomol Res, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Aman, Ahmed; Al-awar, Rima] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3, Canada. [Al-awar, Rima] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada. [Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Wienholds, Erno; Dick, John; Wang, Jean C. Y.; Minden, Mark D.; Schimmer, Aaron D.] Univ Toronto, Dept Med, Toronto, ON M5G 2C4, Canada. RP Schimmer, AD (reprint author), Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. EM aaron.schimmer@utoronto.ca RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Canadian Stem Cell Network; Leukemia and Lymphoma Society; NIH [NCI 1R01CA157456]; Canadian Institutes of Health Research; Terry Fox Research Foundation Program Project Group Grant; MaRS Innovation; Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; Princess Margaret Cancer Centre Foundation; Ministry of Long Term Health and Planning in the Province of Ontario; CIHR FX We thank Urlich Baxa (Electron Microscopy Laboratory, NCI [NIH]) for help with electron microscopy, Aisha Shamas-Din (Princess Margaret Cancer Centre) for help with preparing the manuscript, and Jill Flewelling (Princess Margaret Cancer Centre) for administrative assistance. This work was supported by the Canadian Stem Cell Network, the Leukemia and Lymphoma Society, the NIH (NCI 1R01CA157456), the Canadian Institutes of Health Research, a Terry Fox Research Foundation Program Project Group Grant (to C.J.E.), MaRS Innovation, the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario. S.B. was supported by a Vanier Scholarship award from CIHR. D.V.J. is a Fonds de recherche du Quebec - Sante (FRQS) postdoctoral scholar. A.D.S. holds the Barbara Baker Chair in Leukemia and Related Diseases. NR 36 TC 25 Z9 26 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JUN 8 PY 2015 VL 27 IS 6 BP 864 EP 876 DI 10.1016/j.ccell.2015.05.004 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CK2PN UT WOS:000356053300013 PM 26058080 ER PT J AU Troller-Renfree, SV Barker, TV Pine, DS Fox, NA AF Troller-Renfree, Sonya V. Barker, Tyson V. Pine, Daniel S. Fox, Nathan A. TI Cognitive functioning in socially anxious adults: insights from the NIH Toolbox Cognition Battery SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE social anxiety; fluid cognition; crystallized cognition; NIH Toolbox Cognition Battery; executive function ID ATTENTIONAL CONTROL-THEORY; ANXIETY SCALE; PSYCHOMETRIC PROPERTIES; TRAIT ANXIETY; PERFORMANCE; DISORDER; PHOBIA; FLUID; STRESS; BIASES AB Theory suggests that individuals with social anxiety manifest unique patterns of cognition with less efficient fluid cognition and unperturbed crystallized cognition; however, empirical support for these ideas remains inconclusive. The heterogeneity of past findings may reflect unreliability in cognitive assessments or the influence of confounding variables. The present study examined the relations among social anxiety and performance on the reliable, newly established NIH Toolbox Cognition Battery. Results indicate that high socially anxious adults performed as well as low anxious participants on all measures of fluid cognition. However, high socially anxious adults demonstrated enhanced crystallized cognitive abilities relative to a low socially anxious comparison group. C1 [Troller-Renfree, Sonya V.; Barker, Tyson V.; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Pine, Daniel S.] NIMH, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Troller-Renfree, SV (reprint author), Univ Maryland, Dept Human Dev & Quantitat Methodol, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM str@umd.edu OI Troller-Renfree, Sonya/0000-0001-9979-4696 FU National Science Foundation Graduate Research Fellowship [DGE1322106]; NIH [MH093349] FX This project was supported by a National Science Foundation Graduate Research Fellowship (DGE1322106) awarded to STR. NIH grant MH093349 was awarded to Nathan A. Fox. Thanks to Nicole Ruszkay, Riya Dhamankar, and Jill DeJames for their help with data collection. NR 37 TC 1 Z9 1 U1 2 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUN 8 PY 2015 VL 6 AR 764 DI 10.3389/fpsyg.2015.00764 PG 7 WC Psychology, Multidisciplinary SC Psychology GA CK2NE UT WOS:000356046600001 PM 26106346 ER PT J AU Miller, CM Zakrzewski, AM Robinson, DP Fuller, SJ Walker, RA Ikin, RJ Bao, SJ Grigg, ME Wiley, JS Smith, NC AF Miller, Catherine M. Zakrzewski, Alana M. Robinson, Dionne P. Fuller, Stephen J. Walker, Robert A. Ikin, Rowan J. Bao, Shisan J. Grigg, Michael E. Wiley, James S. Smith, Nicholas C. TI Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis SO PLOS ONE LA English DT Article ID NF-KAPPA-B; T-CELL RESPONSES; P38 MAP KINASE; ORAL INFECTION; INTRACELLULAR PARASITE; SMALL-INTESTINE; IFN-GAMMA; INTRAEPITHELIAL LYMPHOCYTES; CYTOKINE PRODUCTION; IL-1-BETA RELEASE AB Background Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis. Principal Findings Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of Toxoplasma gondii. This susceptibility is not dependent on the ability of P2X7R-deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NF kappa B activation in P2X7R-deficient mice. Conclusions Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation. C1 [Miller, Catherine M.] James Cook Univ, Coll Publ Hlth Med & Vet Sci, Smithfield, Qld 4878, Australia. [Zakrzewski, Alana M.; Ikin, Rowan J.] Univ Technol Sydney, Inst Biotechnol Infect Dis, Broadway, NSW 2007, Australia. [Robinson, Dionne P.; Grigg, Michael E.] NIAID, Mol Parasitol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Fuller, Stephen J.] Univ Sydney, Nepean Hosp, Sydney Med Sch, Camperdown, NSW 2006, Australia. [Walker, Robert A.; Smith, Nicholas C.] James Cook Univ, Queensland Trop Hlth Alliance Res Lab, Australian Inst Trop Hlth & Med, Smithfield, Qld 4878, Australia. [Bao, Shisan J.] Univ Sydney, Sch Med Sci, Discipline Pathol, Camperdown, NSW 2006, Australia. [Bao, Shisan J.] Univ Sydney, Bosch Inst, Camperdown, NSW 2006, Australia. [Wiley, James S.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia. RP Miller, CM (reprint author), James Cook Univ, Coll Publ Hlth Med & Vet Sci, McGregor Rd, Smithfield, Qld 4878, Australia. EM kate.miller1@jcu.edu.au RI Walker, Robert/C-3202-2013 OI Walker, Robert/0000-0003-0032-9925 FU Australian Research Council [DP0666515]; Intramural 24 Research Program of National Institutes of Health, NIAID FX Professors Smith and Wiley gratefully acknowledge the support of the Australian Research Council for funding through its Discovery Project Scheme (Project number DP0666515). This work was also supported, in part, by the Intramural 24 Research Program of the National Institutes of Health, NIAID (Dr. Michael Grigg). Dr. Grigg is a Scholar of the Canadian Institute for Advanced Research (CIFAR) Integrated Microbial Biodiversity program. These funding bodies played no part in the experimental design, collection of data, interpretation, preparation of the manuscript or the decision to publish this research. NR 61 TC 1 Z9 2 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 8 PY 2015 VL 10 IS 6 AR e0129048 DI 10.1371/journal.pone.0129048 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK1GM UT WOS:000355955300080 PM 26053862 ER PT J AU Chen, JQ Wakefield, LM Goldstein, DJ AF Chen, Jin-Qiu Wakefield, Lalage M. Goldstein, David J. TI Capillary nano-immunoassays: advancing quantitative proteomics analysis, biomarker assessment, and molecular diagnostics SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review DE Capillary nano-immunoassay; Simple western; Cell signaling; Biomarker; Proteomics; Molecular diagnostic ID ISOELECTRIC-FOCUSING IMMUNOASSAY; CELL LUNG-CANCER; PHASE PROTEIN MICROARRAYS; ACUTE MYELOID-LEUKEMIA; TECHNOLOGY INSIGHT; COLORECTAL-CANCER; BRYOSTATIN ANALOG; PROGENITOR CELLS; PROSTATE-CANCER; ANTIBODY ARRAYS AB There is an emerging demand for the use of molecular profiling to facilitate biomarker identification and development, and to stratify patients for more efficient treatment decisions with reduced adverse effects. In the past decade, great strides have been made to advance genomic, transcriptomic and proteomic approaches to address these demands. While there has been much progress with these large scale approaches, profiling at the protein level still faces challenges due to limitations in clinical sample size, poor reproducibility, unreliable quantitation, and lack of assay robustness. A novel automated capillary nano-immunoassay (CNIA) technology has been developed. This technology offers precise and accurate measurement of proteins and their post-translational modifications using either charge-based or size-based separation formats. The system not only uses ultralow nanogram levels of protein but also allows multi-analyte analysis using a parallel single-analyte format for increased sensitivity and specificity. The high sensitivity and excellent reproducibility of this technology make it particularly powerful for analysis of clinical samples. Furthermore, the system can distinguish and detect specific protein post-translational modifications that conventional Western blot and other immunoassays cannot easily capture. This review will summarize and evaluate the latest progress to optimize the CNIA system for comprehensive, quantitative protein and signaling event characterization. It will also discuss how the technology has been successfully applied in both discovery research and clinical studies, for signaling pathway dissection, proteomic biomarker assessment, targeted treatment evaluation and quantitative proteomic analysis. Lastly, a comparison of this novel system with other conventional immuno-assay platforms is performed. C1 [Chen, Jin-Qiu] NCI, Collaborat Prot Technol Resource, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Goldstein, David J.] NCI, Off Sci & Technol Resources, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, JQ (reprint author), NCI, Collaborat Prot Technol Resource, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 2140, Bethesda, MD 20892 USA. EM chenj13@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at NIH [Z1CBC 011434] FX The author thanks Drs. Peter Blumberg for critical review of the manuscript and valuable insights and advice. Also thank to Michelle A Herrmann for the contribution on developing and applying the CNIA assays in the PKC isoform and NSCLC research reviewed in this manuscript. The work was supported by the Intramural Research Program of the National Cancer Institute at NIH (Z1CBC 011434). NR 85 TC 3 Z9 3 U1 2 U2 29 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 6 PY 2015 VL 13 AR 182 DI 10.1186/s12967-015-0537-6 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CK8JZ UT WOS:000356485600001 PM 26048678 ER PT J AU Marzi, A Falzarano, D AF Marzi, Andrea Falzarano, Darryl TI An updated Ebola vaccine: immunogenic, but will it protect? SO LANCET LA English DT Editorial Material C1 [Marzi, Andrea] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Falzarano, Darryl] Univ Saskatchewan, VIDO InterVac, Saskatoon, SK S7N 5E3, Canada. RP Falzarano, D (reprint author), Univ Saskatchewan, VIDO InterVac, Saskatoon, SK S7N 5E3, Canada. EM darryl.falzarano@usask.ca NR 12 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUN 6 PY 2015 VL 385 IS 9984 BP 2229 EP 2230 DI 10.1016/S0140-6736(15)60613-4 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CK1CR UT WOS:000355943500006 PM 25817375 ER PT J AU Nicholson, SJ Nickerson, ML Dean, M Song, Y Hoyt, PR Rhee, H Kim, C Puterka, GJ AF Nicholson, Scott J. Nickerson, Michael L. Dean, Michael Song, Yan Hoyt, Peter R. Rhee, Hwanseok Kim, Changhoon Puterka, Gary J. TI The genome of Diuraphis noxia, a global aphid pest of small grains SO BMC GENOMICS LA English DT Article DE Diuraphis noxia; Russian wheat aphid; Plant-insect interactions; Phytotoxic; Aphid; Genome ID RUSSIAN WHEAT; PEA APHID; ACYRTHOSIPHON-PISUM; HEMIPTERA APHIDIDAE; DNA METHYLATION; MYZUS-PERSICAE; UNITED-STATES; BIOTYPIC DIVERSITY; PLANT-RESPONSES; GENE-EXPRESSION AB Background: The Russian wheat aphid, Diuraphis noxia Kurdjumov, is one of the most important pests of small grains throughout the temperate regions of the world. This phytotoxic aphid causes severe systemic damage symptoms in wheat, barley, and other small grains as a direct result of the salivary proteins it injects into the plant while feeding. Results: We sequenced and de novo assembled the genome of D. noxia Biotype 2, the strain most virulent to resistance genes in wheat. The assembled genomic scaffolds span 393 MB, equivalent to 93% of its 421 MB genome, and contains 19,097 genes. D. noxia has the most AT-rich insect genome sequenced to date (70.9%), with a bimodal CpG(O/E) distribution and a complete set of methylation related genes. The D. noxia genome displays a widespread, extensive reduction in the number of genes per ortholog group, including defensive, detoxification, chemosensory, and sugar transporter groups in comparison to the Acyrthosiphon pisum genome, including a 65% reduction in chemoreceptor genes. Thirty of 34 known D. noxia salivary genes were found in this assembly. These genes exhibited less homology with those salivary genes commonly expressed in insect saliva, such as glucose dehydrogenase and trehalase, yet greater conservation among genes that are expressed in D. noxia saliva but not detected in the saliva of other insects. Genes involved in insecticide activity and endosymbiont-derived genes were also found, as well as genes involved in virus transmission, although D. noxia is not a viral vector. Conclusions: This genome is the second sequenced aphid genome, and the first of a phytotoxic insect. D. noxia's reduced gene content of may reflect the influence of phytotoxic feeding in shaping the D. noxia genome, and in turn in broadening its host range. The presence of methylation-related genes, including cytosine methylation, is consistent with other parthenogenetic and polyphenic insects. The D. noxia genome will provide an important contrast to the A. pisum genome and advance functional and comparative genomics of insects and other organisms. C1 [Nicholson, Scott J.; Puterka, Gary J.] ARS, USDA, Stillwater, OK 74075 USA. [Nickerson, Michael L.; Dean, Michael] NCI, NIH, Bethesda, MD 20892 USA. [Nicholson, Scott J.; Song, Yan; Hoyt, Peter R.] Oklahoma State Univ, Dept Mol Biol & Biochem, Stillwater, OK 74078 USA. [Rhee, Hwanseok; Kim, Changhoon] Axeq Technol, Rockville, MD 20850 USA. RP Puterka, GJ (reprint author), ARS, USDA, Stillwater, OK 74075 USA. EM gary.puterka@ars.usda.gov NR 104 TC 5 Z9 5 U1 8 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 5 PY 2015 VL 16 AR 429 DI 10.1186/s12864-015-1525-1 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DA1PV UT WOS:000367568700001 PM 26044338 ER PT J AU Unni, AM Lockwood, WW Zejnullahu, K Lee-Lin, SQ Varmus, H AF Unni, Arun M. Lockwood, William W. Zejnullahu, Kreshnik Lee-Lin, Shih-Queen Varmus, Harold TI Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma SO ELIFE LA English DT Article ID NONAPOPTOTIC-CELL-DEATH; ACQUIRED-RESISTANCE; GLIOBLASTOMA CELLS; CANCER GENOMICS; GENE-MUTATIONS; HUMAN-MELANOMA; TUMOR-CELLS; ACTIVATION; INHIBITOR; PATHWAY AB Human lung adenocarcinomas (LUAD) contain mutations in EGFR in similar to 15% of cases and in KRAS in similar to 30%, yet no individual adenocarcinoma appears to carry activating mutations in both genes, a finding we have confirmed by re-analysis of data from over 600 LUAD. Here we provide evidence that co-occurrence of mutations in these two genes is deleterious. In transgenic mice programmed to express both mutant oncogenes in the lung epithelium, the resulting tumors express only one oncogene. We also show that forced expression of a second oncogene in human cancer cell lines with an endogenous mutated oncogene is deleterious. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK in the dying cells suggests that an overly active MAPK signaling pathway may mediate the phenotype. Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities. C1 [Unni, Arun M.; Lockwood, William W.; Zejnullahu, Kreshnik; Lee-Lin, Shih-Queen; Varmus, Harold] NHGRI, Canc Biol Sect, Canc Genet Branch, Bethesda, MD 20892 USA. RP Unni, AM (reprint author), NHGRI, Canc Biol Sect, Canc Genet Branch, Bethesda, MD 20892 USA. EM unni@nih.gov; wlockwood@bccrc.ca; varmus@med.cornell.edu FU National Institute of General Medical Sciences (NIGMS) Intramural Program; Canadian Institutes of Health Research FX National Institute of General Medical Sciences (NIGMS) Intramural Program Arun M Unni, William W Lockwood, Kreshnik Zejnullahu, Shih-Queen Lee-Lin; Canadian Institutes of Health Research William W Lockwood; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 52 TC 14 Z9 14 U1 1 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 5 PY 2015 VL 4 AR e06907 DI 10.7554/eLife.06907 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CL3RF UT WOS:000356867400001 PM 26047463 ER PT J AU Murphy, PM AF Murphy, Philip M. TI Viral chemokine receptors SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material ID NILE-VIRUS-INFECTION; FUNCTIONAL EXPRESSION; MIP-1 ALPHA; CLONING; RANTES; HIV-1; BETA; COFACTOR; ENTRY; RISK C1 NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov NR 14 TC 2 Z9 2 U1 1 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JUN 5 PY 2015 VL 6 AR 281 DI 10.3389/fimmu.2015.00281 PG 3 WC Immunology SC Immunology GA CL7ML UT WOS:000357156100005 PM 26097479 ER PT J AU Yoshimura, T AF Yoshimura, Teizo TI Discovery of IL-8/CXCL8 (the story from Frederick) SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material DE chemokines; chemoattractants; IL-8; MCP-1; inflammation ID THYMOCYTE-ACTIVATING FACTOR; NEUTROPHIL CHEMOTACTIC FACTOR; PURIFICATION; POLYMORPHONUCLEAR; INTERLEUKIN-1; LEUKOCYTES; CYTOKINES; MONOCYTES C1 NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Yoshimura, T (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM yoshimut@mail.nih.gov NR 16 TC 4 Z9 4 U1 1 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JUN 5 PY 2015 VL 6 AR 278 DI 10.3389/fimmu.2015.00278 PG 3 WC Immunology SC Immunology GA CL7ML UT WOS:000357156100002 PM 26097476 ER PT J AU Kadina, AP Kashemirov, BA Oertell, K Batra, VK Wilson, SH Goodman, MF McKenna, CE AF Kadina, Anastasia P. Kashemirov, Boris A. Oertell, Keriann Batra, Vinod K. Wilson, Samuel H. Goodman, Myron F. McKenna, Charles E. TI Two Scaffolds from Two Flips: (alpha,beta)/(beta,gamma) CH2/NH "Met-Im" Analogues of dTTP SO ORGANIC LETTERS LA English DT Article ID DNA-POLYMERASE-BETA; BASE EXCISION-REPAIR; ADENOSINE-TRIPHOSPHATE; TERMINAL AZIRIDINES; TRANSITION-STATE; TERNARY COMPLEX; LEAVING GROUPS; POL BETA; CANCER; ESTERS AB Novel alpha,beta-CH2 and beta,gamma-NH (1a) or alpha,beta-NH and beta,gamma-CH2 (1b) Met-Im dTTPs were synthesized via monodemethylation of triethyl-dimethyl phosphorimido-bisphosphonate synthons (4a, 4b), formed via a base-induced [1,3]-rearrangement of precursors (3a, 3b) in a reaction with dimethyl or diethyl phosphochloridate. Anomerization during final bromotrimethylsilane (BTMS) deprotection after Mitsunobu conjugation with dT was avoided by microwave conditions. 1a was 9-fold more potent in inhibiting DNA polymerase beta, attributed to an NH-group interaction with R183 in the active site. C1 [Kadina, Anastasia P.; Kashemirov, Boris A.; McKenna, Charles E.] Univ So Calif, Dept Chem, Dana & David Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA. [Oertell, Keriann; Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Dana & David Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA. [Batra, Vinod K.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP McKenna, CE (reprint author), Univ So Calif, Dept Chem, Dana & David Dornsife Coll Letters Arts & Sci, Univ Pk Campus, Los Angeles, CA 90089 USA. EM mckenna@usc.edu FU NIH [U19CA177547]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159] FX This work was supported by NIH Grant U19CA177547, and, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project numbers Z01-ES050158 and Z01-ES050159). The authors would like to thank Ms. Inch Kang for assistance in preparing the manuscript. NR 47 TC 0 Z9 0 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 EI 1523-7052 J9 ORG LETT JI Org. Lett. PD JUN 5 PY 2015 VL 17 IS 11 BP 2586 EP 2589 DI 10.1021/acs.orglett.5b00799 PG 4 WC Chemistry, Organic SC Chemistry GA CK1IY UT WOS:000355962200006 PM 25970636 ER PT J AU Nordsborg, RB Sloan, CD Shahid, H Jacquez, GM De Roos, AJ Cerhan, JR Cozen, W Severson, R Ward, MH Morton, L Raaschou-Nielsen, O Meliker, JR AF Nordsborg, Rikke Baastrup Sloan, Chantel D. Shahid, Haseeb Jacquez, Geoffrey M. De Roos, Anneclaire J. Cerhan, James R. Cozen, Wendy Severson, Richard Ward, Mary H. Morton, Lindsay Raaschou-Nielsen, Ole Meliker, Jaymie R. TI Investigation of spatio-temporal cancer clusters using residential histories in a case-control study of non-Hodgkin lymphoma in the United States SO ENVIRONMENTAL HEALTH LA English DT Article DE Non-Hodgkin lymphoma; Cancer; Spatio-temporal cluster analysis; Residential histories; Q-statistics ID DISEASE; HETEROGENEITY; POPULATIONS; LEUKEMIA; TESTS; POWER AB Background: Non-Hodgkin lymphoma (NHL) is an enigmatic disease with few known risk factors. Spatio-temporal epidemiologic analyses have the potential to reveal patterns that may give clues to new risk factors worthy of investigation. We sought to investigate clusters of NHL through space and time based on life course residential histories. Methods: We used residential histories from a population-based NHL case-control study of 1300 cases and 1044 controls with recruitment centers in Iowa, Detroit, Seattle, and Los Angeles, and diagnosed in 1998-2000. Novel methods for cluster detection allowing for residential mobility, called Q-statistics, were used to quantify nearest neighbor relationships through space and time over the life course to identify cancer clusters. Analyses were performed on all cases together and on two subgroups of NHL: Diffuse large B-cell lymphoma and follicular lymphoma. These more homogenous subgroups of cases might have a more common etiology that could potentially be detected in cluster analysis. Based on simulation studies designed to help account for multiple testing across space and through time, we required at least four significant cases nearby one another to declare a region a potential cluster, along with confirmatory analyses using spatial-only scanning windows (SaTScan). Results: Evidence of a small cluster in southeastern Oakland County, MI was suggested using residences 10-18 years prior to diagnosis, and confirmed by SaTScan in a time-slice analysis 20 years prior to diagnosis, when all cases were included in the analysis. Consistent evidence of clusters was not seen in the two histologic subgroups. Conclusions: Suggestive evidence of a small space-time cluster in southeastern Oakland County, MI was detected in this NHL case-control study in the USA. C1 [Nordsborg, Rikke Baastrup; Raaschou-Nielsen, Ole] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Sloan, Chantel D.; Meliker, Jaymie R.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Sloan, Chantel D.] Brigham Young Univ, Dept Hlth Sci, Provo, UT 84602 USA. [Shahid, Haseeb] SUNY Stony Brook, Dept Appl Math, Stony Brook, NY 11794 USA. [Jacquez, Geoffrey M.] BioMedware Inc, Ann Arbor, MI USA. [Jacquez, Geoffrey M.] SUNY Buffalo, Buffalo, NY USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med & Pathol, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Severson, Richard] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Ward, Mary H.; Morton, Lindsay] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Meliker, Jaymie R.] SUNY Stony Brook, Program Publ Hlth, Stony Brook, NY 11794 USA. RP Nordsborg, RB (reprint author), Danish Canc Soc Res Ctr, Copenhagen, Denmark. EM rikke@nordsborg.dk NR 32 TC 0 Z9 0 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JUN 5 PY 2015 VL 14 AR 48 DI 10.1186/s12940-015-0034-7 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CK4UW UT WOS:000356219800001 PM 26043768 ER PT J AU Lapkouski, M Chuenchor, W Kim, MS Gellert, M Yang, W AF Lapkouski, Mikalai Chuenchor, Watchalee Kim, Min-Sung Gellert, Martin Yang, Wei TI Assembly Pathway and Characterization of the RAG1/2-DNA Paired and Signal-end Complexes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID V(D)J RECOMBINATION; SYNAPTIC COMPLEX; SOMATIC RECOMBINATION; ACTIVE-SITE; CHAIN GENES; RAG1; CLEAVAGE; DNA; PROTEINS; SYNAPSIS AB Mammalian immune receptor diversity is established via a unique restricted set of site-specific DNA rearrangements in lymphoid cells, known as V(D)J recombination. The lymphoid-specific RAG1-RAG2 protein complex (RAG1/2) initiates this process by binding to two types of recombination signal sequences (RSS), 12RSS and 23RSS, and cleaving at the boundaries of RSS and V, D, or J gene segments, which are to be assembled into immunoglobulins and T-cell receptors. Here we dissect the ordered assembly of the RAG1/2 heterotetramer with 12RSS and 23RSS DNAs. We find that RAG1/2 binds only a single 12RSS or 23RSS and reserves the second DNA-binding site specifically for the complementary RSS, to form a paired complex that reflects the known 12/23 rule of V(D)J recombination. The assembled RAG1/2 paired complex is active in the presence of Mg2+, the physiologically relevant metal ion, in nicking and double-strand cleavage of both RSS DNAs to produce a signal-end complex. We report here the purification and initial crystallization of the RAG1/2 signal-end complex for atomic-resolution structure elucidation. Strict pairing of the 12RSS and 23RSS at the binding step, together with information from the crystal structure of RAG1/2, leads to a molecular explanation of the 12/23 rule. C1 [Lapkouski, Mikalai; Chuenchor, Watchalee; Kim, Min-Sung; Gellert, Martin; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov FU NIDDK, National Institutes of Health [DK036147, DK036167] FX This research was supported, in whole or in part, by the intramural research program of the NIDDK, National Institutes of Health (DK036147 and DK036167). NR 34 TC 2 Z9 2 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 5 PY 2015 VL 290 IS 23 BP 14618 EP 14625 DI 10.1074/jbc.M115.641787 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ8MC UT WOS:000355754600032 PM 25903130 ER PT J AU Boyd, A Almeida, JR Darrah, PA Sauce, D Seder, RA Appay, V Gorochov, G Larsen, M AF Boyd, Anders Almeida, Jorge R. Darrah, Patricia A. Sauce, Delphine Seder, Robert A. Appay, Victor Gorochov, Guy Larsen, Martin TI Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection SO PLOS ONE LA English DT Article ID ANTIGEN-SENSITIVITY; DISEASE; VIRUS AB Introduction Understanding the factors that delineate the efficacy of T cell responses towards pathogens is crucial for our ability to develop potent therapies against infectious diseases. Multidimensional evaluation of T cell functionality at the single-cell level enables exhaustive analysis of combinatorial functional properties, hence polyfunctionality. We have recently invented an algorithm that quantifies polyfunctionality, the Polyfunctionality Index (Larsen et al. PLoS One 2012). Here we demonstrate that quantitative assessment of T cell polyfunctionality correlates with T cell efficacy measured as the capacity to kill target cells in vitro and control infection in vivo. Methods We employed the polyfunctionality index on two datasets selected for their unique ability to evaluate the polyfunctional imprint on T cell efficacy. 1) HIV-specific CD8(+) T cells and 2) Leishmania major-specific CD4(+) T cells were analysed for their capacity to secrete multiple effector molecules, kill target cells and control infection. Briefly, employing the Polyfunctionality Index algorithm we determined the parameter estimates resulting in optimal correlation between T cell polyfunctionality and T cell efficacy. Results T cell polyfunctionality is correlated with T cell efficacy measured as 1) target killing (r=0.807, P<0.0001) and 2) lesion size upon challenge with Leishmania major (r=-0.50, P=0.004). Contrary to an approach relying on the Polyfunctionality Index algorithm, quantitative evaluation of T cell polyfunctionality traditionally ignores the gradual contribution of more or less polyfunctional T cells. Indeed, comparing both approaches we show that optimal description of T cell efficacy is obtained when gradually integrating all levels of polyfunctionality in accordance with the Polyfunctionality Index. Conclusions Our study presents a generalizable methodology to objectively evaluate the impact of polyfunctionality on T cell efficacy. We show that T cell polyfunctionality is a superior correlate of T cell efficacy both in vitro and in vivo as compared with response size. Therefore, future immunotherapies should aim to increase T cell polyfunctionality. C1 [Boyd, Anders] Inst Pierre Louis Epidemiol & Sante Publ, INSERM, UMR S1136, Paris, France. [Almeida, Jorge R.; Sauce, Delphine; Appay, Victor; Gorochov, Guy; Larsen, Martin] Ctr Immunol & Malad Infect CIMI Paris, INSERM, UMR S1135, Paris, France. [Darrah, Patricia A.; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gorochov, Guy; Larsen, Martin] Grp Hosp Pitie Salpetriere, AP HP, Dept Immunol, F-75634 Paris, France. [Gorochov, Guy; Larsen, Martin] Univ Paris 06, Sorbonne Univ, CR7, CIMI Paris, Paris, France. RP Larsen, M (reprint author), Ctr Immunol & Malad Infect CIMI Paris, INSERM, UMR S1135, Paris, France. EM Martin.Larsen@upmc.fr OI LARSEN, Martin/0000-0003-1375-4816 FU INSERM; University Pierre et Marie Curie EMERGENCE" program; Fondation pour l'Aide a la Recherche sur la Sclerose En Plaques; ARTHRITIS Fondation COURTIN; Agence nationale de recherche sur le Sida et les hepatites FX The study was funded by INSERM, the University Pierre et Marie Curie EMERGENCE" program (www.upmc.fr), "Fondation pour l'Aide a la Recherche sur la Sclerose En Plaques" (www.ARSEP.org) and ARTHRITIS Fondation COURTIN (http://www.fondation-arthritis.org). A.B. was awarded a post-doctoral fellowship with the "Agence nationale de recherche sur le Sida et les hepatites" (www.agence-nationale-recherche.fr). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 13 Z9 13 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 5 PY 2015 VL 10 IS 6 AR e0128714 DI 10.1371/journal.pone.0128714 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7CR UT WOS:000355652200094 PM 26046523 ER PT J AU Armstrong, JJ Mitnitski, A Andrew, MK Launer, LJ White, LR Rockwood, K AF Armstrong, Joshua J. Mitnitski, Arnold Andrew, Melissa K. Launer, Lenore J. White, Lon R. Rockwood, Kenneth TI Cumulative impact of health deficits, social vulnerabilities, and protective factors on cognitive dynamics in late life: a multistate modeling approach SO ALZHEIMERS RESEARCH & THERAPY LA English DT Article ID JAPANESE-AMERICAN MEN; OLDER-ADULTS; ALZHEIMERS-DISEASE; BRAIN ATROPHY; RISK-FACTORS; IMPAIRMENT; DEMENTIA; FRAILTY; DECLINE; ASSOCIATION AB Introduction: Many factors influence late-life cognitive changes, and evaluating their joint impact is challenging. Typical approaches focus on average decline and a small number of factors. We used multistate transition models and index variables to look at changes in cognition in relation to frailty (accumulation of health deficits), social vulnerability, and protective factors in the Honolulu-Asia Aging Study (HAAS). Methods: The HAAS is a prospective cohort study of 3,845 men of Japanese descent, aged 71 to 93 years at baseline. Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI). Baseline index variables were constructed of health deficits (frailty), social vulnerabilities, and protective factors. The chances of improvement/stability/decline in cognitive function and death were simultaneously estimated using multistate transition modeling for 3- and 6-year transitions from baseline. Results: On average, CASI scores declined by 5.3 points (standard deviation (SD) = 10.0) over 3 years and 9.5 points (SD = 13.9) over 6 years. After adjusting for education and age, baseline frailty was associated with an increased risk of cognitive decline at 3 years (beta = 0.18, 95% confidence interval (CI), 0.08 to 0.29) and 6 years (beta = 0.40, 95% CI, 0.27 to 0.54). The social vulnerability index was associated with 3-year changes (beta = 0.16, 95% CI, 0.09 to 0.23) and 6-year changes (beta = 0.14, 95% CI, 0.05 to 0.24) in CASI scores. The protective index was associated with reductions in cognitive decline over the two intervals (3-year: beta = -0.16, 95% CI, -0.24 to -0.09; 6-year: beta = -0.21, 95% CI, -0.31 to -0.11,). Conclusions: Research on cognition in late life needs to consider overall health, the accumulation of protective factors, and the dynamics of cognitive change. Index variables and multistate transition models can enhance understanding of the multifactorial nature of late-life changes in cognition. C1 [Armstrong, Joshua J.; Mitnitski, Arnold; Andrew, Melissa K.; Rockwood, Kenneth] Dalhousie Univ, Fac Med, Geriatr Med Res, Halifax, NS, Canada. [Andrew, Melissa K.; Rockwood, Kenneth] Dalhousie Univ, Dept Med, Div Geriatr Med, Halifax, NS, Canada. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [White, Lon R.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. RP Rockwood, K (reprint author), Dalhousie Univ, Fac Med, Geriatr Med Res, Halifax, NS, Canada. EM Kenneth.Rockwood@dal.ca FU Alzheimer Society of Canada; Canadian Institutes of Health Research; Dalhousie Medical Research Foundation; Intramural Research Program, National Institute on Aging FX JJA is supported by a post-doctoral fellowship award from the Alzheimer Society of Canada. AM is supported by an operating grant from the Canadian Institutes of Health Research. KR was supported by the Dalhousie Medical Research Foundation who provide career funding as the Kathryn Allen Weldon Professor of Alzheimer Research Chair. Data reported in this article were collected as part of the Honolulu-Asia Aging Study, which was partially supported by the Intramural Research Program, National Institute on Aging. NR 54 TC 4 Z9 4 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD JUN 5 PY 2015 VL 7 AR 38 DI 10.1186/s13195-015-0120-7 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CK1JZ UT WOS:000355964900001 PM 26052349 ER PT J AU Bartesaghi, A Merk, A Banerjee, S Matthies, D Wu, XW Milne, JLS Subramaniam, S AF Bartesaghi, Alberto Merk, Alan Banerjee, Soojay Matthies, Doreen Wu, Xiongwu Milne, Jacqueline L. S. Subramaniam, Sriram TI 2.2 angstrom resolution cryo-EM structure of beta-galactosidase in complex with a cell-permeant inhibitor SO SCIENCE LA English DT Article ID ATOMIC MODEL; SUBUNIT; MICROSCOPY; MECHANISM; RIBOSOME; REVEALS; VIRUS AB Cryo-electron microscopy (cryo-EM) is rapidly emerging as a powerful tool for protein structure determination at high resolution. Here we report the structure of a complex between Escherichia coli beta-galactosidase and the cell-permeant inhibitor phenylethyl beta-D-thiogalactopyranoside (PETG), determined by cryo-EM at an average resolution of similar to 2.2 angstroms (angstrom). Besides the PETG ligand, we identified densities in the map for similar to 800 water molecules and for magnesium and sodium ions. Although it is likely that continued advances in detector technology may further enhance resolution, our findings demonstrate that preparation of specimens of adequate quality and intrinsic protein flexibility, rather than imaging or image-processing technologies, now represent the major bottlenecks to routinely achieving resolutions close to 2 angstrom using single-particle cryo-EM. C1 [Bartesaghi, Alberto; Merk, Alan; Banerjee, Soojay; Matthies, Doreen; Milne, Jacqueline L. S.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wu, Xiongwu] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov FU NIH, Center for Cancer Research, National Cancer Institute; Intramural AIDS Targeted Antiviral Program FX This research was supported by funds from the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute, and the Intramural AIDS Targeted Antiviral Program. We thank R. Mueller and J. Cometa for technical assistance with electron microscopy, P. Mooney and F. Ulmer for advice and assistance with optimizing detector performance, K. Podolsky for assistance with data collection, J.-J. Fernandez for providing the code to run the TOMOCTFFIND program, and V. Falconieri for assistance in preparation of the figures and the supplementary movie. This study used the high-performance computational capabilities of the Biowulf Linux cluster at NIH (http://biowulf.nih.gov). The density map and refined atomic model have been deposited with the Electron Microscopy Data Bank (accession number EMD-2984) and the Protein Data Bank (entry code 5a1a), respectively. NR 25 TC 115 Z9 117 U1 12 U2 76 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 5 PY 2015 VL 348 IS 6239 BP 1147 EP 1151 DI 10.1126/science.aab1576 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ6FY UT WOS:000355590500051 PM 25953817 ER PT J AU Bulger, DA Conley, J Conner, SH Majumdar, G Solomon, SS AF Bulger, David A. Conley, Jermaine Conner, Spencer H. Majumdar, Gipsy Solomon, S. Solomon TI Role of PTEN in TNF alpha induced insulin resistance SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Diabetes; Insulin resistance; Hepatocytes; Obesity; Adipocyte ID TUMOR-NECROSIS-FACTOR; ADIPOSE-TISSUE; UNITED-STATES; OBESITY; EXPRESSION; SENSITIVITY; PREVALENCE; TRENDS; LIVER AB Aims/hypothesis: PTEN may play a reversible role in TNF alpha induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNF alpha, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to beta-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNF alpha treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNF alpha treatment. PTEN siRNA markedly inhibited the TNF alpha-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNF alpha-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNF alpha treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. Published by Elsevier Inc. C1 [Bulger, David A.; Conner, Spencer H.; Majumdar, Gipsy; Solomon, S. Solomon] Univ Tennessee Hlth Sci Ctr, Dept Med, Memphis, TN 38163 USA. [Bulger, David A.; Conner, Spencer H.; Majumdar, Gipsy; Solomon, S. Solomon] Univ Tennessee Hlth Sci Ctr, Dept Pharmacol, Memphis, TN 38163 USA. [Bulger, David A.; Conley, Jermaine; Conner, Spencer H.; Majumdar, Gipsy; Solomon, S. Solomon] Vet Assoc Med Ctr, Med & Res Serv, Memphis, TN 38104 USA. [Bulger, David A.] Wellcome Trust Med Res Council Inst Metab Sci, Cambridge CB2 0QQ, England. [Bulger, David A.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Solomon, SS (reprint author), VA Med Ctr, Med Serv, Res SVC 151 B120, 1030 Jefferson Ave, Memphis, TN 38104 USA. EM ssolomon@uthsc.edu FU NIH [T35-DK-07405]; past Merit Review Grants (VA) FX This research was funded by the NIH Training Grant #T35-DK-07405 and by past Merit Review Grants (VA) to Dr. Solomon. NR 19 TC 6 Z9 6 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 5 PY 2015 VL 461 IS 3 BP 533 EP 536 DI 10.1016/j.bbrc.2015.04.063 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CJ0HU UT WOS:000355157200016 PM 25918024 ER PT J AU Concheiro, M Castaneto, M Kronstrand, R Huestis, MA AF Concheiro, Marta Castaneto, Marisol Kronstrand, Robert Huestis, Marilyn A. TI Simultaneous determination of 40 novel psychoactive stimulants in urine by liquid chromatography-high resolution mass spectrometry and library matching SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE LC-HRMS; Novel psychoactive substance; Synthetic cathinones; Piperazines; Amphetamines; Urine ID DESIGNER DRUGS; SCREENING METHOD; METABOLITES; ABUSE; MS/MS; DEATHS AB The emergence of novel psychoactive substances is an ongoing challenge for analytical toxicologists. Different analogs are continuously introduced in the market to circumvent legislation and to enhance their pharmacological activity. Although detection of drugs in blood indicates recent exposure and link intoxication to the causative agent, urine is still the most preferred testing matrix in clinical and forensic settings. We developed a method for the simultaneous quantification of 8 piperazines, 4 designer amphetamines and 28 synthetic cathinones and 4 metabolites, in urine by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Data were acquired in full scan and data dependent MS2 mode. Compounds were quantified by precursor ion exact mass, and confirmed by product ion spectra library matching, taking into account product ions' exact mass and intensities. One-hundred pi, urine was subjected to solid phase cation exchange extraction (SOLA SCX). The chromatographic reverse-phase separation was achieved with gradient mobile phase of 0.1% formic acid in water and in acetonitrile in 20 min. The assay was linear from 2.5 or 5 to 500 mu g/L. Imprecision (n = 15) was <15.4%, and accuracy (n = 15) 84.2-118.5%. Extraction efficiency was 51.2-111.2%, process efficiency 57.7-104.9% and matrix effect ranged from -41.9% to 238.5% (CV < 23.3%, except MDBZP CV < 34%). Authentic urine specimens (n = 62) were analyzed with the method that provides a comprehensive confirmation for 40 new stimulant drugs with specificity and sensitivity. Published by Elsevier B.V. C1 [Concheiro, Marta; Castaneto, Marisol; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Castaneto, Marisol] Univ Maryland Baltimore Cty, Toxicol Program, Baltimore, MD 21228 USA. [Kronstrand, Robert] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden. [Kronstrand, Robert] Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Linkoping, Sweden. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, BRC, NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 21 TC 18 Z9 18 U1 5 U2 49 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 5 PY 2015 VL 1397 BP 32 EP 42 DI 10.1016/j.chroma.2015.04.002 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CI8NP UT WOS:000355029300005 PM 25931378 ER PT J AU Hultcrantz, M Lund, SH Landgren, O Samuelsson, J Goldin, LR Oddsson, A Bjorkholm, M Kristinsson, SY AF Hultcrantz, Malin Lund, Sigrun H. Landgren, Ola Samuelsson, Jan Goldin, Lynn R. Oddsson, Asmundur Bjorkholm, Magnus Kristinsson, Sigurdur Y. TI Survival in patients with familial and sporadic myeloproliferative neoplasms SO BLOOD LA English DT Letter ID ESSENTIAL THROMBOCYTHEMIA; MYELOFIBROSIS; HAPLOTYPE; MUTATIONS; SWEDEN C1 [Hultcrantz, Malin; Bjorkholm, Magnus; Kristinsson, Sigurdur Y.] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden. [Lund, Sigrun H.; Kristinsson, Sigurdur Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Lund, Sigrun H.; Kristinsson, Sigurdur Y.] Landspitali Natl Univ Hosp, Dept Hematol, Reykjavik, Iceland. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, New York, NY 10021 USA. [Samuelsson, Jan] Soder Sjukhuset, Dept Med, Div Hematol, Stockholm, Sweden. [Goldin, Lynn R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Oddsson, Asmundur] deCODE Genet, Reykjavik, Iceland. RP Hultcrantz, M (reprint author), Karolinska Univ Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM malin.hultcrantz@ki.se RI Lund, Sigrun Helga/K-9144-2015; Kristinsson, Sigurdur /M-2910-2015; OI Lund, Sigrun Helga/0000-0002-3806-2296; Kristinsson, Sigurdur /0000-0002-4964-7476; Oddsson, Asmundur/0000-0002-4606-5163 FU Intramural NIH HHS NR 10 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 4 PY 2015 VL 125 IS 23 BP 3665 EP 3666 DI 10.1182/blood-2015-04-639039 PG 2 WC Hematology SC Hematology GA CL9FK UT WOS:000357281200024 PM 26045595 ER PT J AU Johnston, JJ Lewis, KL Ng, D Singh, LN Wynter, J Brewer, C Brooks, BP Brownell, I Candotti, F Gonsalves, SG Hart, SP Kong, HH Rother, KI Sokolic, R Solomon, BD Zein, WM Cooper, DN Stenson, PD Mullikin, JC Biesecker, LG AF Johnston, Jennifer J. Lewis, Katie L. Ng, David Singh, Larry N. Wynter, Jamila Brewer, Carmen Brooks, Brian P. Brownell, Isaac Candotti, Fabio Gonsalves, Steven G. Hart, Suzanne P. Kong, Heidi H. Rother, Kristina I. Sokolic, Robert Solomon, Benjamin D. Zein, Wadih M. Cooper, David N. Stenson, Peter D. Mullikin, James C. Biesecker, Leslie G. TI Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID VARIANTS; DISEASE; PROTEIN; MEDICINE; CANCER; GENES AB Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine. C1 [Johnston, Jennifer J.; Lewis, Katie L.; Ng, David; Singh, Larry N.; Wynter, Jamila; Candotti, Fabio; Gonsalves, Steven G.; Hart, Suzanne P.; Sokolic, Robert; Solomon, Benjamin D.; Mullikin, James C.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Brewer, Carmen] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Brooks, Brian P.; Zein, Wadih M.] NEI, NIH, Bethesda, MD 20892 USA. [Brownell, Isaac; Kong, Heidi H.] NCI, NIH, Bethesda, MD 20892 USA. [Rother, Kristina I.] NIDDK, NIH, Bethesda, MD 20892 USA. [Cooper, David N.; Stenson, Peter D.] Cardiff Univ, Inst Med Genet, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Mullikin, James C.; Biesecker, Leslie G.] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU National Human Genome Research Institute; National Cancer Institute; National Eye Institute; National Institute of Deafness and Other Communication Disorders; National Institute of Diabetes and Digestive and Kidney Diseases of the NIH; BIOBASE/Qiagen; Cardiff University FX The study described here was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, the National Eye Institute, the National Institute of Deafness and Other Communication Disorders, and the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. L.G.B. is an uncompensated advisor to the Illumina Corp. and receives royalties from Genentech Corp. D.N.C. and P.D.S. acknowledge receipt of funding from BIOBASE/Qiagen through a License Agreement with Cardiff University. The authors thank Michael Collins, Julia Fekecs, Travis Hyams, Irini Manoli, and Frances Wright for support and advice. NR 19 TC 15 Z9 15 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN 4 PY 2015 VL 96 IS 6 BP 913 EP 925 DI 10.1016/j.ajhg.2015.04.013 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA CK0YH UT WOS:000355931200005 PM 26046366 ER PT J AU Schreiber, SL Kotz, JD Li, M Aube, J Austin, CP Reed, JC Rosen, H White, EL Sklar, LA Lindsley, CW Alexander, BR Bittker, JA Clemons, PA De Souza, A Foley, MA Palmer, M Shamji, AF Wawer, MJ McManus, O Wu, M Zou, BY Yu, HB Golden, JE Schoenen, FJ Simeonov, A Jadhav, A Jackson, MR Pinkerton, AB Chung, TDY Griffin, PR Cravatt, BF Hodder, PS Roush, WR Roberts, E Chung, DH Jonsson, CB Noah, JW Severson, WE Ananthan, S Edwards, B Oprea, TI Conn, PJ Hopkins, CR Wood, MR Stauffer, SR Emmitte, KA AF Schreiber, Stuart L. Kotz, Joanne D. Li, Min Aube, Jeffrey Austin, Christopher P. Reed, John C. Rosen, Hugh White, E. Lucile Sklar, Larry A. Lindsley, Craig W. Alexander, Benjamin R. Bittker, Joshua A. Clemons, Paul A. De Souza, Andrea Foley, Michael A. Palmer, Michelle Shamji, Alykhan F. Wawer, Mathias J. McManus, Owen Wu, Meng Zou, Beiyan Yu, Haibo Golden, Jennifer E. Schoenen, Frank J. Simeonov, Anton Jadhav, Ajit Jackson, Michael R. Pinkerton, Anthony B. Chung, Thomas D. Y. Griffin, Patrick R. Cravatt, Benjamin F. Hodder, Peter S. Roush, William R. Roberts, Edward Chung, Dong-Hoon Jonsson, Colleen B. Noah, James W. Severson, William E. Ananthan, Subramaniam Edwards, Bruce Oprea, Tudor I. Conn, P. Jeffrey Hopkins, Corey R. Wood, Michael R. Stauffer, Shaun R. Emmitte, Kyle A. CA NIH Mol Lib Project Team TI Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes SO CELL LA English DT Review ID PYRUVATE-KINASE; PPAR-GAMMA; GAUCHER-DISEASE; DRUG DISCOVERY; ALLOSTERIC MODULATORS; SELECTIVE INHIBITORS; ALZHEIMERS-DISEASE; S1P(4)-R AGONISTS; TARGET ENGAGEMENT; FLUID RETENTION AB Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery. C1 [Schreiber, Stuart L.; Kotz, Joanne D.; Alexander, Benjamin R.; Bittker, Joshua A.; Clemons, Paul A.; De Souza, Andrea; Foley, Michael A.; Palmer, Michelle; Shamji, Alykhan F.; Wawer, Mathias J.] Broad Inst Harvard & MIT, Probe Dev Ctr, Cambridge, MA 02142 USA. [Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Schreiber, Stuart L.] Broad Inst Harvard & MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Schreiber, Stuart L.; Kotz, Joanne D.; Clemons, Paul A.; Shamji, Alykhan F.; Wawer, Mathias J.] Broad Inst Harvard & MIT, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Bittker, Joshua A.] Broad Inst Harvard & MIT, Ctr Dev Therapeut, Cambridge, MA 02142 USA. [Alexander, Benjamin R.] Broad Inst Harvard & MIT, Med & Populat Genet, Cambridge, MA 02142 USA. [Li, Min; McManus, Owen; Wu, Meng; Zou, Beiyan; Yu, Haibo] Johns Hopkins Sch Med, Ion Channel Ctr, Baltimore, MD 21205 USA. [Aube, Jeffrey; Golden, Jennifer E.; Schoenen, Frank J.] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66045 USA. [Aube, Jeffrey] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. [Austin, Christopher P.; Simeonov, Anton; Jadhav, Ajit] NIH, NIH Chem Genom Ctr, Rockville, MD 20850 USA. [Austin, Christopher P.; Simeonov, Anton; Jadhav, Ajit] Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Reed, John C.; Jackson, Michael R.; Pinkerton, Anthony B.; Chung, Thomas D. Y.] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, La Jolla, CA 92037 USA. [Reed, John C.; Jackson, Michael R.; Pinkerton, Anthony B.; Chung, Thomas D. Y.] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, Lake Nona, FL 32827 USA. [Rosen, Hugh; Griffin, Patrick R.; Cravatt, Benjamin F.; Hodder, Peter S.; Roush, William R.; Roberts, Edward] Scripps Res Inst, Mol Screening Ctr, La Jolla, CA 92037 USA. [Rosen, Hugh; Griffin, Patrick R.; Cravatt, Benjamin F.; Hodder, Peter S.; Roush, William R.; Roberts, Edward] Scripps Res Inst, Mol Screening Ctr, Jupiter, FL 33458 USA. [Rosen, Hugh; Cravatt, Benjamin F.] Scripps Res Inst, Dept Chem Physiol, La Jolla, CA 92037 USA. [Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Roush, William R.] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA. [White, E. Lucile; Chung, Dong-Hoon; Jonsson, Colleen B.; Noah, James W.; Severson, William E.; Ananthan, Subramaniam] So Res Inst, Southern Res Specialized Biocontainment Screening, Birmingham, AL 35205 USA. [Sklar, Larry A.; Edwards, Bruce; Oprea, Tudor I.] Univ New Mexico, Ctr Mol Discovery, Albuquerque, NM 87131 USA. [Sklar, Larry A.; Edwards, Bruce] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA. [Oprea, Tudor I.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Lindsley, Craig W.; Conn, P. Jeffrey; Hopkins, Corey R.; Wood, Michael R.; Stauffer, Shaun R.; Emmitte, Kyle A.] Vanderbilt Univ, Med Ctr, Vanderbilt Specialized Chem Ctr Accelerated Probe, Nashville, TN 37232 USA. [Lindsley, Craig W.; Conn, P. Jeffrey; Hopkins, Corey R.; Wood, Michael R.; Emmitte, Kyle A.] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. RP Schreiber, SL (reprint author), Broad Inst Harvard & MIT, Probe Dev Ctr, Cambridge, MA 02142 USA. EM stuart_schreiber@harvard.edu; jkotz@broadinstitute.org RI Alexander, Benjamin/M-7471-2015; OI Alexander, Benjamin/0000-0002-0960-6119; Pillai, Ajay/0000-0002-9789-7189; Oprea, Tudor/0000-0002-6195-6976; Golden, Jennifer/0000-0002-6813-3710; Pinkerton, Anthony/0000-0003-4571-152X FU NIH [U54 MH084681-01, 1 U54 HG005033-01, U54 MH084512-01, 1 U54 HG005032-01, 1 U54 HG005034-01, U54 MH084690-01, U54 MH084691-01, 1 U54 HG005031-01, U54 MH084659-01]; Janssen; Bristol-Myers Squibb; AstraZeneca FX The authors wish to thank Matthew Boxer, Sivaraman Dandapani, Richard Y. Ebright, Juan Marugan, Andrew Phillips, Craig Thomas, Matthew Vander Heiden, and Bridget Wagner for thoughtful discussion and critical reading of the manuscript and Katie Ris-Vicari for assistance with figure design. Centers in the MLPCN were funded via the NIH grants U54 MH084681-01 (NIH Chemical Genomics Center), 1 U54 HG005033-01 (Conrad Prebys Center for Chemical Genomics), U54 MH084512-01 (The Scripps Research Institute Molecular Screening Center), 1 U54 HG005032-01 (Broad Institute Probe Development Center), 1 U54 HG005034-01 (Southern Research Specialized Biocontainment Screening Center), U54 MH084690-01 (University of New Mexico Center for Molecular Discovery), U54 MH084691-01 (Johns Hopkins School of Medicine Ion Channel Center), 1 U54 HG005031-01 (University of Kansas Specialized Chemistry Center) and U54 MH084659-01 (The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development). J.A. and F.J.S. have a financial interest in Cleave Biosciences. H.R. is a scientific founder of and consultant to Receptos, which has licensed RPC-1063. B.F.C. is a scientific founder of and advisor to Abide Therapeutics, a company that is interested in developing serine hydrolase inhibitors as therapeutic agents. L.A.S. and B.E. are scientific cofounders of Intellicyt, which sells instrumentation for high-throughput flow cytometry. All of the authors from Vanderbilt University receive funding from Janssen, Bristol-Myers Squibb, and AstraZeneca for the development of GPCR allosteric modulators for CNS disorders. NR 94 TC 26 Z9 26 U1 22 U2 90 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 4 PY 2015 VL 161 IS 6 BP 1252 EP 1265 DI 10.1016/j.cell.2015.05.023 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CK0ZR UT WOS:000355935000007 PM 26046436 ER PT J AU Zhou, TQ Lynch, RM Chen, L Acharya, P Wu, XL Doria-Rose, NA Joyce, MG Lingwood, D Soto, C Bailer, RT Ernandes, MJ Kong, R Longo, NS Louder, MK McKee, K O'Dell, S Schmidt, SD Tran, LL Yang, ZJ Druz, A Luongo, TS Moquin, S Srivatsan, S Yang, YP Zhang, BS Zheng, AQ Pancera, M Kirys, T Georgiev, IS Gindin, T Peng, HP Yang, AS Mullikin, JC Gray, MD Stamatatos, L Burton, DR Koff, WC Cohen, MS Haynes, BF Casazza, JP Connors, M Corti, D Lanzavecchia, A Sattentau, QJ Weiss, RA West, AP Bjorkman, PJ Scheid, JF Nussenzweig, MC Shapiro, L Mascola, JR Kwong, PD AF Zhou, Tongqing Lynch, Rebecca M. Chen, Lei Acharya, Priyamvada Wu, Xueling Doria-Rose, Nicole A. Joyce, M. Gordon Lingwood, Daniel Soto, Cinque Bailer, Robert T. Ernandes, Michael J. Kong, Rui Longo, Nancy S. Louder, Mark K. McKee, Krisha O'Dell, Sijy Schmidt, Stephen D. Tran, Lillian Yang, Zhongjia Druz, Aliaksandr Luongo, Timothy S. Moquin, Stephanie Srivatsan, Sanjay Yang, Yongping Zhang, Baoshan Zheng, Anqi Pancera, Marie Kirys, Tatsiana Georgiev, Ivelin S. Gindin, Tatyana Peng, Hung-Pin Yang, An-Suei Mullikin, James C. Gray, Matthew D. Stamatatos, Leonidas Burton, Dennis R. Koff, Wayne C. Cohen, Myron S. Haynes, Barton F. Casazza, Joseph P. Connors, Mark Corti, Davide Lanzavecchia, Antonio Sattentau, Quentin J. Weiss, Robin A. West, Anthony P., Jr. Bjorkman, Pamela J. Scheid, Johannes F. Nussenzweig, Michel C. Shapiro, Lawrence Mascola, John R. Kwong, Peter D. CA NISC Comparative Sequencing TI Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors SO CELL LA English DT Article ID NEUTRALIZING HIV-1 ANTIBODY; BINDING-SITE ANTIBODIES; B-CELL RECEPTORS; CRYSTAL-STRUCTURE; POTENT NEUTRALIZATION; MONOCLONAL-ANTIBODIES; CD4-BINDING SITE; RATIONAL DESIGN; ENVELOPE TRIMER; INFECTION AB The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and V-H-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by V-H-gene-restricted ontogenies. C1 [Zhou, Tongqing; Lynch, Rebecca M.; Chen, Lei; Acharya, Priyamvada; Wu, Xueling; Doria-Rose, Nicole A.; Joyce, M. Gordon; Lingwood, Daniel; Soto, Cinque; Bailer, Robert T.; Ernandes, Michael J.; Kong, Rui; Longo, Nancy S.; Louder, Mark K.; McKee, Krisha; O'Dell, Sijy; Schmidt, Stephen D.; Tran, Lillian; Yang, Zhongjia; Druz, Aliaksandr; Luongo, Timothy S.; Moquin, Stephanie; Srivatsan, Sanjay; Yang, Yongping; Zhang, Baoshan; Zheng, Anqi; Pancera, Marie; Kirys, Tatsiana; Georgiev, Ivelin S.; Casazza, Joseph P.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Zhou, Tongqing; Lynch, Rebecca M.; Chen, Lei; Acharya, Priyamvada; Wu, Xueling; Doria-Rose, Nicole A.; Joyce, M. Gordon; Lingwood, Daniel; Soto, Cinque; Bailer, Robert T.; Ernandes, Michael J.; Kong, Rui; Longo, Nancy S.; Louder, Mark K.; McKee, Krisha; O'Dell, Sijy; Schmidt, Stephen D.; Tran, Lillian; Yang, Zhongjia; Druz, Aliaksandr; Luongo, Timothy S.; Moquin, Stephanie; Srivatsan, Sanjay; Yang, Yongping; Zhang, Baoshan; Zheng, Anqi; Pancera, Marie; Kirys, Tatsiana; Georgiev, Ivelin S.; Casazza, Joseph P.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIH, Bethesda, MD 20892 USA. [Gindin, Tatyana; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Gindin, Tatyana; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA. [Peng, Hung-Pin; Yang, An-Suei] Acad Sinica, Genom Res Ctr, Taipei 11221, Taiwan. [Peng, Hung-Pin; Yang, An-Suei] Natl Yang Ming Univ, Inst Biomed Informat, Taipei 11221, Taiwan. [Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Gray, Matthew D.; Stamatatos, Leonidas] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02142 USA. [Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Microbiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Immunol, Chapel Hill, NC 27599 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Med, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Surg, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Pediat, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Human Vaccine Inst, Dept Immunol, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Ctr HIV AIDS Vaccine Immunol Immunogen Discovery, Durham, NC 27710 USA. [Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, Bethesda, MD 20892 USA. [Connors, Mark] NIH, Bethesda, MD 20892 USA. [Corti, Davide] Humabs BioMed SA, CH-6500 Bellinzona, Switzerland. [Corti, Davide; Lanzavecchia, Antonio] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland. [Sattentau, Quentin J.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RF, England. [Weiss, Robin A.] UCL, Div Infect Immun, London WC1E 6BT, England. [West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@nih.gov; pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010; Schmidt, Stephen/B-5398-2012 OI Zhou, Tongqing/0000-0002-3935-4637; FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; Division of AIDS, NIAID, National Institutes of Health [AI037526, AI072529, AI0678501, P01 AI094419, P01 AI100148, P01 AI104722, 1UM1 AI100663, UM1 AI100645]; Howard Hughes Medical Institute; Bill and Melinda Gates Foundation [38637, 1040753]; International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); UK Department for International Development (DFID); United States Agency for International Development (USAID) FX We thank members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript and B. Honig for structural biology mentorship. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panel. The authors acknowledge the contributions of the Center for HIV/AIDS Vaccine Discovery (CHAVI) Clinical Core Team. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, by the Howard Hughes Medical Institute (M.C.N. and P.J.B. are investigators), and by grants from the Division of AIDS, NIAID, National Institutes of Health (AI037526, AI072529, AI0678501, P01 AI094419, P01 AI100148, P01 AI104722, and 1UM1 AI100663 and UM1 AI100645), from the Bill and Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery Grant IDs 38637 and 1040753), and from the International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium. IAVI's work is made possible by support from many donors, including: the Bill and Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the UK Department for International Development (DFID); and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 50 TC 62 Z9 62 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUN 4 PY 2015 VL 161 IS 6 BP 1280 EP 1292 DI 10.1016/j.cell.2015.05.007 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CK0ZR UT WOS:000355935000009 PM 26004070 ER PT J AU Li, MM Gou, HF Tripathi, BK Huang, J Jiang, SL Dubois, W Waybright, T Lei, M Shi, JX Zhou, M Huang, J AF Li, Mangmang Gou, Hongfeng Tripathi, Brajendra K. Huang, Jing Jiang, Shunlin Dubois, Wendy Waybright, Tim Lei, Ming Shi, Jianxin Zhou, Ming Huang, Jing TI An Apela RNA-Containing Negative Feedback Loop Regulates p53-Mediated Apoptosis in Embryonic Stem Cells SO CELL STEM CELL LA English DT Article ID LONG NONCODING RNA; DNA-DAMAGE; MDM2-DEFICIENT MICE; NANOG EXPRESSION; P53; LETHALITY; RESCUE; TARGET; TRANSCRIPTION; PROMOTERS AB Maintaining genomic integrity is of paramount importance to embryonic stem cells (ESCs), as mutations are readily propagated to daughter cells. ESCs display hypersensitivity to DNA damage-induced apoptosis (DIA) to prevent such propagation, although the molecular mechanisms underlying this apoptotic response are unclear. Here, we report that the regulatory RNA Apela positively regulates p53-mediated DIA. Apela is highly expressed in mouse ESCs and is repressed by p53 activation, and Apela depletion compromises p53-dependent DIA. Although Apela contains a coding region, this coding ability is dispensable for Apela's role in p53-mediated DIA. Instead, Apela functions as a regulatory RNA and interacts with hnRNPL, which prevents the mitochondrial localization and activation of p53. Together, these results describe a tri-element negative feedback loop composed of p53, Apela, and hnRNPL that regulates p53-mediated DIA, and they further demonstrate that regulatory RNAs add a layer of complexity to the apoptotic response of ESCs after DNA damage. C1 [Li, Mangmang; Gou, Hongfeng; Jiang, Shunlin; Dubois, Wendy; Huang, Jing] NCI, Ctr Canc Res, Lab Canc Biol & Genet, Cancer & Stem Cell Epigenet, Bethesda, MD 20892 USA. [Tripathi, Brajendra K.] NCI, Ctr Canc Res, Cellular Oncol Lab, Signaling & Oncogenesis Sect, Bethesda, MD 20892 USA. [Huang, Jing; Lei, Ming] Univ Michigan, Howard Hughes Med Inst, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Waybright, Tim; Zhou, Ming] Frederick Natl Lab Canc Res, Canc Res Technol Program, Prot Characterizat Lab, Frederick, MD 21702 USA. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Huang, J (reprint author), NCI, Ctr Canc Res, Lab Canc Biol & Genet, Cancer & Stem Cell Epigenet, Bethesda, MD 20892 USA. EM huangj3@mail.nih.gov RI LI, MANGMANG/J-1683-2015; Huang, Jing/A-2566-2009 OI Huang, Jing/0000-0002-7163-5156 FU Office of Science and Technology at the CCR; National Cancer Institute (NCI) at the National Institutes of Health (NIH) FX We thank Douglas Lowy for reading the manuscript. This study was funded by the intramural research program and partially funded by the Office of Science and Technology Partnerships at the CCR, the National Cancer Institute (NCI) at the National Institutes of Health (NIH). The computational analyses utilized the high-performance computational capabilities of the Helix Systems at NIH (http://helix.nih.gov). NR 36 TC 6 Z9 6 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUN 4 PY 2015 VL 16 IS 6 BP 669 EP 683 DI 10.1016/j.stem.2015.04.002 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CK0YR UT WOS:000355932300015 PM 25936916 ER EF