FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Karnati, R Talla, V Peterson, K Laurie, GW AF Karnati, Roy Talla, Venu Peterson, Katherine Laurie, Gordon W. TI Lacritin and other autophagy associated proteins in ocular surface health SO EXPERIMENTAL EYE RESEARCH LA English DT Review DE Lacritin; Autophagy; Lysosomal storage disease; Eye; Dry eye; Cornea ID PROSECRETORY MITOGEN LACRITIN; LYSOSOMAL STORAGE DISORDERS; ENZYME REPLACEMENT THERAPY; CORNEAL EPITHELIAL-CELLS; OPEN-ANGLE GLAUCOMA; DRY EYE PATIENTS; METACHROMATIC LEUKODYSTROPHY; CEROID-LIPOFUSCINOSIS; DAMAGED MITOCHONDRIA; REGULATES AUTOPHAGY AB Advantage may be taken of macroautophagy ('autophagy') to promote ocular health. Autophagy continually captures aged or damaged cellular material for lysosomal degradation and recyling. When autophagic flux is chronically elevated, or alternatively deficient, health suffers. Chronic elevation of flux and stress are the consequence of inflammatory cytokines or of dry eye tears but not normal tears in vitro. Exogenous tear protein lacritin transiently accelerates flux to restore homeostasis in vitro and corneal health in vivo, and yet the monomeric active form of lacritin appears to be selectively deficient in dry eye. Tissue transglutaminase-dependent cross-linking of monomer decreases monomer quantity and monomer affinity for coreceptor syndecan-1 thereby abrogating activity. Tissue transglutaminase is elevated in dry eye. Mutation of arylsulfatase A, arylsulfatase B, ceroid-lipofuscinosis neuronal 3, mucolipin, or Niemann-Pick disease type Cl respectively underlie several diseases of apparently insufficient autophagic flux that affect the eye, including: metachromatic leukodystrophy, mucopoly-saccharidosis type VI, juvenile-onset Batten disease, mucolipidosis IV, and Niemann-Pick type C associated with myelin sheath destruction of corneal sensory and ciliary nerves and of the optic nerve; corneal clouding, ocular hypertension, glaucoma and optic nerve atrophy; accumulation of 'ceroid-lipofuscin' in surface conjunctival cells, and in ganglion and neuronal cells; decreased visual acuity and retinal dystrophy; and neurodegeneration. For some, enzyme or gene replacement, or substrate reduction, therapy is proving to be successful. Here we discuss examples of restoring ocular surface homeostasis through alteration of autophagy, with particular attention to lacritin. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Karnati, Roy] Univ Hyderabad, Sch Life Sci, Hyderabad 500134, Andhra Pradesh, India. [Talla, Venu] Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Peterson, Katherine] NEI, Sect Mol Struct & Funct Genom, Bethesda, MD 20892 USA. [Laurie, Gordon W.] Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. RP Laurie, GW (reprint author), Univ Virginia, Dept Cell Biol, UVA Hlth Syst, POB 800732, Charlottesville, VA 22908 USA. EM glaurie@virginia.edu OI Talla, Venu/0000-0002-5695-7536; Laurie, Gordon/0000-0002-5311-2650 FU NIH [R01 EY024327]; [SR/FT/LS-157/2012] FX GWL is supported by NIH R01 EY024327. RK is supported by SR/FT/LS-157/2012. The authors acknowledge the multi-institutional Lacritin Consortium for help with much of the lacritin work reviewed. NR 110 TC 1 Z9 1 U1 4 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD MAR PY 2016 VL 144 SI SI BP 4 EP 13 DI 10.1016/j.exer.2015.08.015 PG 10 WC Ophthalmology SC Ophthalmology GA DG9BI UT WOS:000372377400002 PM 26318608 ER PT J AU Mumford, SL Silver, RM Sjaarda, LA Wactawski-Wende, J Townsend, JM Lynch, AM Galai, N Lesher, LL Faraggi, D Perkins, NJ Schliep, KC Zarek, SM Schisterman, EF AF Mumford, Sunni L. Silver, Robert M. Sjaarda, Lindsey A. Wactawski-Wende, Jean Townsend, Janet M. Lynch, Anne M. Galai, Noya Lesher, Laurie L. Faraggi, David Perkins, Neil J. Schliep, Karen C. Zarek, Shvetha M. Schisterman, Enrique F. TI Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss SO HUMAN REPRODUCTION LA English DT Article DE low-dose aspirin; conception; pregnancy loss; fertility; live birth ID IN-VITRO FERTILIZATION; RECURRENT MISCARRIAGE; WOMEN; METAANALYSIS; HEPARIN; TIME; IVF AB What is the association between daily preconception-initiated low-dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses? Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses. LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses. The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses. Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach. Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% confidence interval: 0.99, 1.26). Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results. Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment. 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, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest. The trial was registered at ClinicalTrials.gov #NCT00467363. 27 April 2007. 15 June 2007. C1 [Mumford, Sunni L.; Sjaarda, Lindsey A.; Perkins, Neil J.; Schliep, Karen C.; Zarek, Shvetha M.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd 7B03, Rockville, MD 20852 USA. [Silver, Robert M.; Lesher, Laurie L.] Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Room 2B200 SOM,50 North Med Dr, Salt Lake City, UT 84132 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, 270 Farber Hall, Buffalo, NY 14214 USA. [Townsend, Janet M.] Commonwealth Med Coll, Dept Family Community & Rural Hlth, 525 East Pine St, Scranton, PA 18509 USA. [Lynch, Anne M.] Univ Colorado, Dept Obstet & Gynecol, 12700 East 19th Ave, Aurora, CO 80045 USA. [Galai, Noya; Faraggi, David] Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd 7B03, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland [HHSN267200603423, HHSN267200603424, HHSN267200603426] 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, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). NR 24 TC 2 Z9 2 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD MAR PY 2016 VL 31 IS 3 BP 657 EP 665 DI 10.1093/humrep/dev329 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DG9QN UT WOS:000372419000019 PM 26759138 ER PT J AU Bressler, SB Ayala, AR Bressler, NM Melia, M Qin, HJ Ferris, FL Flaxel, CJ Friedman, SM Glassman, AR Jampol, L Rauser, ME AF Bressler, Susan B. Ayala, Allison R. Bressler, Neil M. Melia, Michele Qin, Haijing Ferris, Frederick L., III Flaxel, Christina J. Friedman, Scott M. Glassman, Adam R. Jampol, Leem. Rauser, Michael E. CA Diabet Retinopathy Clin Res TI Persistent Macular Thickening After Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment SO JAMA OPHTHALMOLOGY LA English DT Article ID PLUS PROMPT LASER; DEFERRED LASER AB IMPORTANCE The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown. OBJECTIVE To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness >= 250 mu m on time domain optical coherence tomography) through the 24-week visit. INTERVENTIONS Four monthly intravitreous injections of ranibizumab and then as needed per protocol. MAIN OUTCOMES AND MEASURES Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 mu m and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (>= 2 line) gain or loss of visual acuity among those eyes. RESULTS The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1%(99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline. CONCLUSIONS AND RELEVANCE These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (>= 2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists. C1 [Bressler, Susan B.; Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Ayala, Allison R.; Melia, Michele; Qin, Haijing; Glassman, Adam R.] Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Flaxel, Christina J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Friedman, Scott M.] Florida Retina Consultants, Lakeland, FL USA. [Jampol, Leem.] Northwestern Univ, Sch Med, Feinberg Sch Med, Chicago, IL USA. [Rauser, Michael E.] Loma Linda Univ Hlth Care, Loma Linda, CA USA. RP Ayala, AR (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM drcrstat1@jaeb.org FU National Eye Institute [EY14231, EY23207, EY18817]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services FX This study was supported through grants EY14231, EY23207, and EY18817 from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services. NR 6 TC 7 Z9 7 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD MAR PY 2016 VL 134 IS 3 BP 278 EP 285 DI 10.1001/jamaophthalmol.2015.5346 PG 8 WC Ophthalmology SC Ophthalmology GA DH1JN UT WOS:000372540300013 PM 26746868 ER PT J AU Fair, C Cuttance, J Sharma, N Maslow, G Wiener, L Betz, C Porter, J McLaughlin, S Gilleland-Marchak, J Renwick, A Naranjo, D Jan, S Javalkar, K Ferris, M AF Fair, Cynthia Cuttance, Jessica Sharma, Niraj Maslow, Gary Wiener, Lori Betz, Cecily Porter, Jerlym McLaughlin, Suzanne Gilleland-Marchak, Jordan Renwick, Amy Naranjo, Diana Jan, Sophia Javalkar, Karina Ferris, Maria CA Int Interdisciplinary Hlth Care Tr TI International and Interdisciplinary Identification of Health Care Transition Outcomes SO JAMA PEDIATRICS LA English DT Article ID LIVER-TRANSPLANT RECIPIENTS; ADULT CARE; CHRONIC ILLNESS; SPINA-BIFIDA; YOUNG-PEOPLE; ADOLESCENTS; ADHERENCE; YOUTH; SERVICES; DELPHI AB IMPORTANCE There is a lack of agreement on what constitutes successful outcomes for the process of health care transition (HCT) among adolescent and young adults with special health care needs. OBJECTIVE To present HCT outcomes identified by a Delphi process with an interdisciplinary group of participants. DESIGN, SETTING, AND PARTICIPANTS A Delphi method involving 3 stages was deployed to refine a list of HCT outcomes. This 18-month study (from January 5, 2013, of stage 1 to July 3, 2014, of stage 3) included an initial literature search, expert interviews, and then 2 waves of a web-based survey. On this survey, 93 participants from outpatient, community-based, and primary care clinics rated the importance of the top HCT outcomes identified by the Delphi process. Analyses were performed from July 5, 2014, to December 5, 2014. EXPOSURES Health care transition outcomes of adolescents and young adults with special health care needs. MAIN OUTCOMES AND MEASURES Importance ratings of identified HCT outcomes rated on a Likert scale from 1 (not important) to 9 (very important). RESULTS The 2 waves of surveys included 117 and 93 participants as the list of outcomes was refined. Transition outcomes were refined by the 3 waves of the Delphi process, with quality of life being the highest-rated outcome with broad agreement. The 10 final outcomes identified included individual outcomes (quality of life, understanding the characteristics of conditions and complications, knowledge of medication, self-management, adherence to medication, and understanding health insurance), health services outcomes (attending medical appointments, having a medical home, and avoidance of unnecessary hospitalization), and a social outcome (having a social network). Participants indicated that different outcomes were likely needed for individuals with cognitive disabilities. CONCLUSIONS AND RELEVANCE Quality of life is an important construct relevant to HCT. Future research should identify valid measures associated with each outcome and further explore the role that quality of life plays in the HCT process. Achieving consensus is a critical step toward the development of reliable and objective comparisons of HCT outcomes across clinical conditions and care delivery locations. C1 [Fair, Cynthia] Elon Univ, Dept Human Serv Studies, CB 2337, Elon, NC 27244 USA. [Cuttance, Jessica; Javalkar, Karina; Ferris, Maria] Univ N Carolina, End Stage Kidney Dis Program, Chapel Hill, NC 27515 USA. [Sharma, Niraj] Harvard Univ, Sch Med, Brigham & Womens & Boston Childrens Hosp, Med Pediat Residency Program, Boston, MA USA. [Maslow, Gary] Duke Univ, Psychiat & Behav Sci & Pediat, Durham, NC USA. [Wiener, Lori] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Betz, Cecily] Univ So Calif, Dept Pediat, Keck Sch Med, Los Angeles, CA 90089 USA. [Porter, Jerlym] St Jude Childrens Res Hosp, Dept Psychol, 332 N Lauderdale St, Memphis, TN 38105 USA. [McLaughlin, Suzanne] Brown Univ, Internal Med Pediat, Providence, RI 02912 USA. [McLaughlin, Suzanne] Hasbro Hosp, Dept Pediat & Med, Providence, RI USA. [Gilleland-Marchak, Jordan] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Renwick, Amy] Alfred I duPont Hosp Children, Transit Care, Nemours, Wilmington, DE USA. [Naranjo, Diana] Stanford Univ, Dept Psychiat, Sch Med, Stanford, CA 94305 USA. [Jan, Sophia] Childrens Hosp Philadelphia, Div Gen Pediat, Philadelphia, PA 19104 USA. RP Fair, C (reprint author), Elon Univ, Dept Human Serv Studies, CB 2337, Elon, NC 27244 USA. EM cfair@elon.edu OI Iglesia, Enrique/0000-0003-4109-1001 NR 50 TC 6 Z9 6 U1 3 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAR PY 2016 VL 170 IS 3 BP 205 EP 211 DI 10.1001/jamapediatrics.2015.3168 PG 7 WC Pediatrics SC Pediatrics GA DG8AL UT WOS:000372304700010 PM 26619178 ER PT J AU Yeung, EH Sundaram, R Bell, EM Druschel, C Kus, C Ghassabian, A Bello, S Xie, YL Louis, GMB AF Yeung, Edwina H. Sundaram, Rajeshwari Bell, Erin M. Druschel, Charlotte Kus, Christopher Ghassabian, Akhgar Bello, Scott Xie, Yunlong Louis, Germaine M. Buck TI Examining Infertility Treatment and Early Childhood Development in the Upstate KIDS Study SO JAMA PEDIATRICS LA English DT Article ID ASSISTED REPRODUCTIVE TECHNOLOGY; AUTISM SPECTRUM DISORDERS; IN-VITRO FERTILIZATION; STAGES QUESTIONNAIRES; FERTILITY TREATMENT; CHILDREN BORN; CONCURRENT VALIDITY; PRETERM INFANTS; BIRTH COHORT; AGES AB IMPORTANCE An increasing percentage of births are conceived with assisted reproductive technology (ART) and other infertility treatment. Despite findings that such treatments may be associated with diminished gestation and birth size, scarce data exist regarding infertility treatments and children's development in the United States. OBJECTIVE To assess the use and type of infertility treatment in relation to children's development through age 36 months. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study (conducted 2008-2014) that sampled based on infertility treatment and plurality. Included in the study were infants born between 2008 and 2010 in New York state (excluding New York City) whose parents completed developmental screening instruments through 36 months of age. A total of 4824 mothers (97% of 4989) completed 1 or more developmental screening instruments for 5841 children, including 1830 conceived with infertility treatment and 2074 twins. EXPOSURES Maternal self-report of any infertility treatment was further categorized into ART and ovulation induction/intrauterine insemination. Assisted reproductive technology use was previously validated by linkage with the Society for Assisted Reproductive Technology-Clinical Outcome Reporting System. MAIN OUTCOMES AND MEASURES Five developmental domains (fine motor, gross motor, communication, personal-social functioning, and problem-solving ability), as measured by the parental completion of the Ages and Stages Questionnaires at 4, 8, 12, 18, 24, 30, and 36 months of age. Generalized linear mixed modeling techniques estimated adjusted odds ratios (aORs) and 95% CIs for use and type of infertility treatment in relation to failing a developmental domain. Data were stratified by plurality and weighted for the sampling scheme. RESULTS There were 1422 mothers (29.5%; mean [SD], age, 34.1 [5.2] years) who underwent infertility treatment. Infertility treatment was not associated with risk of their children failing any developmental domain (aOR, 1.33; 95% CI, 0.94-1.89). Assisted reproductive technology was associated with increased risk for failing any developmental domain but only when singletons and twins were evaluated together (aOR, 1.81; 95% CI, 1.21-2.72). Adjustment for birth weight further attenuated this estimate (aOR, 1.26; 95% CI, 0.82-1.93). After stratifying by plurality, type of treatment also was not significantly associated with failing any developmental domain for ovulation induction/intrauterine insemination (aOR, 1.00; 95% CI, 0.57-1.77 for singletons and aOR, 1.30; 95% CI, 0.76-2.21 for twins) or ART (aOR, 1.38; 95% CI, 0.78-2.43 for singletons and aOR, 1.58; 95% CI, 0.94-2.65 for twins). CONCLUSIONS AND RELEVANCE After considering plurality, children's development through age 3 years was similar irrespective of infertility treatment or specific type. To our knowledge, these findings are among the first to focus on non-ART treatments in the United States. C1 [Yeung, Edwina H.; Sundaram, Rajeshwari; Ghassabian, Akhgar; Xie, Yunlong; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Bell, Erin M.; Druschel, Charlotte] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY USA. [Bell, Erin M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY USA. [Druschel, Charlotte] New York State Dept Hlth, Bur Environm & Occupat Epidemiol, Ctr Environm Hlth, Albany, NY 12237 USA. [Kus, Christopher] New York State Dept Hlth, Div Family Hlth, Albany, NY 12237 USA. [Bello, Scott] CapitalCare Pediat Troy, Dev Pediat, Troy, NY USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM yeungedw@mail.nih.gov OI Ghassabian, Akhgar/0000-0001-9551-4706; Buck Louis, Germaine/0000-0002-1774-4490; Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200005C, HHSN267200700019C] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts HHSN275201200005C and HHSN267200700019C). NR 39 TC 5 Z9 5 U1 3 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAR PY 2016 VL 170 IS 3 BP 251 EP 258 DI 10.1001/jamapediatrics.2015.4164 PG 8 WC Pediatrics SC Pediatrics GA DG8AL UT WOS:000372304700016 PM 26746435 ER PT J AU Figueroa, JD Prokunina-Olsson, L Koutros, S Garcia-Closas, M Chanock, S Silverman, DT Rothman, N AF Figueroa, Jonine D. Prokunina-Olsson, Ludmila Koutros, Stella Garcia-Closas, Montserrat Chanock, Stephen Silverman, Debra T. Rothman, Nathaniel TI RE: Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms RESPONSE SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID GENOME-WIDE ASSOCIATION; METALWORKING FLUIDS; PHENOTYPES; LOCI C1 [Figueroa, Jonine D.; Prokunina-Olsson, Ludmila; Koutros, Stella; Garcia-Closas, Montserrat; Chanock, Stephen; Silverman, Debra T.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] Univ Edinburgh, Inst Genet & Mol Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland. RP Figueroa, JD (reprint author), Univ Edinburgh, Sch Med, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. EM jonine.figueroa@ed.ac.uk NR 8 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAR PY 2016 VL 108 IS 3 AR djv441 DI 10.1093/jnci/djv441 PG 1 WC Oncology SC Oncology GA DH2BP UT WOS:000372589400026 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI RE: Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-Analysis of Clinical Trials Leading to FDA Approval SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 1 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAR PY 2016 VL 108 IS 3 AR djv430 DI 10.1093/jnci/djv430 PG 2 WC Oncology SC Oncology GA DH2BP UT WOS:000372589400022 PM 26912650 ER PT J AU Zeidner, JF Karp, JE Blackford, AL Foster, MC Dees, EC Smith, G Ivy, SP Harris, P AF Zeidner, Joshua F. Karp, Judith E. Blackford, Amanda L. Foster, Matthew C. Dees, E. Claire Smith, Gary Ivy, S. Percy Harris, Pamela TI Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ACUTE MYELOCYTIC-LEUKEMIA; GEMTUZUMAB OZOGAMICIN; GROUP-B; INDUCTION; REGIMENS; MELANOMA; SAFETY; AGE AB Background: Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time. Methods: A retrospective analysis was performed on 711 adult AML patients enrolling in 45 phase I clinical trials supported by the Cancer Therapy Evaluation Program of the National Cancer Institute from 1986 to 2009. Changes in ORR and mortality rates for patients enrolled in 1986 to 1990, 1991 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009 were estimated with multivariable logistic regression models. All statistical tests were two-sided. Results: There was a statistically significant increase in AML patients enrolling in phase I clinical trials over time (1986 to 1990: n = 61; 2006 to 2009: n = 256; P = .03). The ORR for the entire cohort was 15.4% (1986 to 1990: 8.9%, 1991 to 1995: 21.1%; 1996 to 2000: 7.0%; 2001 to 2005: 10.0%; 2006 to 2009: 22.6%), and it statistically significantly improved over time (P < .001). There was a statistically significant improvement in ORRs with novel agents in combination vs single agents (ORR = 22.8% vs 4.7%, respectively, odds ratio = 5.95, 95% confidence interval = 3.22 to 11.9, P < .001). The 60-day mortality rate for the entire cohort was 22.6%, but it statistically significantly improved over time (P = .009). Conclusions: There has been an encouraging increase in AML patients enrolling in phase I clinical studies over time. The improvement in ORRs appears to be partly because of the increase in combination trials and the inclusion of previously untreated poor-risk AML. Continued enrollment of AML patients in early phase clinical trials is vital for drug development and improvement in therapeutic outcomes. C1 [Zeidner, Joshua F.; Foster, Matthew C.; Dees, E. Claire] Univ N Carolina, Lineberger Comprehens Canc Ctr, 170 Manning Dr,Phys Off Bldg,3rd Floor,CB 7305, Chapel Hill, NC 27599 USA. [Karp, Judith E.; Blackford, Amanda L.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Smith, Gary; Ivy, S. Percy; Harris, Pamela] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Zeidner, JF (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, 170 Manning Dr,Phys Off Bldg,3rd Floor,CB 7305, Chapel Hill, NC 27599 USA. EM joshua_zeidner@med.unc.edu FU National Cancer Institute FX This work was supported by the National Cancer Institute. JFZ received a 2013 Conquer Cancer Foundation Young Investigator Award, in memory of Dr. John R. Durant, and is a 2014 to 2017 Leukemia and Lymphoma Society Special Fellow in Clinical Research. NR 21 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAR PY 2016 VL 108 IS 3 AR djv335 DI 10.1093/jnci/djv335 PG 8 WC Oncology SC Oncology GA DH2BP UT WOS:000372589400004 ER PT J AU Kim, M Lee, M Kim, Y Oh, S Lee, D Yoon, B AF Kim, Minhee Lee, Minyoung Kim, Yushin Oh, Sejun Lee, Dongshin Yoon, BumChul TI Myofascial Pain Syndrome in the Elderly and Self-Exercise: A Single-Blind, Randomized, Controlled Trial SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID TRIGGER POINTS; NECK PAIN; MUSCULOSKELETAL PAIN; CLINICAL-TRIAL; MANUAL THERAPY; SOFT-TISSUE; TO-TREAT; ULTRASOUND; MANAGEMENT; MUSCLE AB Objective: This study aimed to demonstrate the effect of self-exercise with a therapeutic inflatable ball (SEIB) in elderly patients with myofascial pain syndrome. Design: Single-blind, randomized, controlled noninferiority trial. Setting: University campus. Participants: Forty elderly patients with myofascial pain syndrome completed the study. They were randomly allocated to SEIB (n = 22; mean age, 70.23 +/- 6.11 years) or ultrasound (US) therapy (n = 18; mean age, 67.99 +/- 5.64 years). Intervention: SEIB and US therapy (twice weekly for 4 consecutive weeks). Outcome measures: Visual analog scale (VAS), pressure pain threshold (PPT), and cervical lateral flexion (CLF) were measured at baseline and at 1, 2, 3, and 4 weeks. Results: The noninferiority test indicated that SEIB was not inferior to US for VAS, PPT, and CLF. Between-group comparisons showed no significant differences in the VAS (F = 2.579; p = 0.117), the PPT (F = 0.245; p = 0.624), and the CLF (F = 2.072; p = 0.159). In within-group comparisons, both groups presented significant differences in VAS (SEIB after 1 week and US after 1 week), PPT (SEIB after 3 weeks and US after 4 weeks), and CLF (SEIB after 4 weeks and US after 4 weeks) compared with baseline values. Conclusions: SEIB for 4 weeks has an effect similar to that of US for desensitizing myofascial pain and increasing joint flexibility. High accessibility and low cost would make SEIB a practical self-treatment method in elderly patients with myofascial pain syndrome. C1 [Kim, Minhee; Lee, Minyoung; Oh, Sejun; Yoon, BumChul] Korea Univ, Dept Phys Therapy, Coll Hlth Sci, Hana Hlth Sci B BLD 670,145 Anam Ro, Seoul 136701, South Korea. [Kim, Yushin] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lee, Dongshin] Eulji Univ, Dept Phys Therapy, Coll Hlth Sci, Gyeonggido, South Korea. RP Yoon, B (reprint author), Korea Univ, Dept Phys Therapy, Coll Hlth Sci, Hana Hlth Sci B BLD 670,145 Anam Ro, Seoul 136701, South Korea. EM yoonbc@korea.ac.kr FU Korea University Institute of Health Sciences Grant [K1508331] FX This research was supported by a Korea University Institute of Health Sciences Grant, (K1508331). The authors would like to thank all the participants who volunteered for this study. NR 55 TC 2 Z9 2 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 EI 1557-7708 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD MAR 1 PY 2016 VL 22 IS 3 BP 244 EP 251 DI 10.1089/acm.2015.0205 PG 8 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA DG9OG UT WOS:000372412500010 PM 26910293 ER PT J AU Wallace, GL Kenworthy, L Pugliese, CE Popal, HS White, EI Brodsky, E Martin, A AF Wallace, Gregory L. Kenworthy, Lauren Pugliese, Cara E. Popal, Haroon S. White, Emily I. Brodsky, Emily Martin, Alex TI Real-World Executive Functions in Adults with Autism Spectrum Disorder: Profiles of Impairment and Associations with Adaptive Functioning and Co-morbid Anxiety and Depression SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Adult; Executive function; Adaptive functioning; Anxiety; Depression ID MULTIPLE CASE SERIES; ASPERGER-SYNDROME; WORKING-MEMORY; DIAGNOSTIC INTERVIEW; SYMPTOMS; CHILDREN; CHILDHOOD; DEFICITS; ADOLESCENCE; PERFORMANCE AB Although executive functioning (EF) difficulties are well documented among children and adolescents with autism spectrum disorder (ASD), little is known about real-world measures of EF among adults with ASD. Therefore, this study examined parent-reported real-world EF problems among 35 adults with ASD without intellectual disability and their correlations with adaptive functioning and co-morbid anxiety and depression symptomatology. A variable EF profile was found with prominent deficits occurring in flexibility and metacognition. Flexibility problems were associated with anxiety-related symptoms while metacognition difficulties were associated with depression symptoms and impaired adaptive functioning (though the metacognition-adaptive functioning relationship was moderated by ADHD symptoms). These persistent EF problems are predictors of broader functioning and therefore remain an important treatment target among adults with ASD. C1 [Wallace, Gregory L.; Brodsky, Emily] George Washington Univ, Dept Speech & Hearing Sci, 2115 G St NW,Room 201, Washington, DC 20052 USA. [Wallace, Gregory L.; Popal, Haroon S.; White, Emily I.; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Kenworthy, Lauren; Pugliese, Cara E.] Childrens Natl Hlth Syst, Ctr Autism Spectrum Disorders, Washington, DC USA. RP Wallace, GL (reprint author), George Washington Univ, Dept Speech & Hearing Sci, 2115 G St NW,Room 201, Washington, DC 20052 USA.; Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM gwallac1@gwu.edu OI Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program at NIMH, NIH [1-ZIA-MH002920]; T32 Grant [HD046388-01A2]; NIH Combined Neuroscience Institutional Review Board [10-M-0027] FX This work was supported by the Intramural Research Program at NIMH, NIH under Grant Number 1-ZIA-MH002920. CEP was supported by a T32 Grant HD046388-01A2. Ethics approval for this study was granted by the NIH Combined Neuroscience Institutional Review Board under Protocol Number 10-M-0027. We would like to express our gratitude to the individuals and families who volunteered their time to contribute to this research. NR 49 TC 7 Z9 7 U1 19 U2 35 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD MAR PY 2016 VL 46 IS 3 BP 1071 EP 1083 DI 10.1007/s10803-015-2655-7 PG 13 WC Psychology, Developmental SC Psychology GA DG7RO UT WOS:000372281600029 PM 26572659 ER PT J AU Brugnera, E Bhandoola, A Cibotti, R Yu, Q Guinter, TI Yamashita, Y Sharrow, SO Singer, A AF Brugnera, Enrico Bhandoola, Avinash Cibotti, Richrdo Yu, Qing Guinter, Terry I. Yamashita, Yoshio Sharrow, Susan O. Singer, Alfred TI Coreceptor Reversal in the Thymus: Signaled CD4(+)8(+) Thymocytes Initially Terminate CD8 Transcription Even When Differentiating into CD8(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4/CD8 LINEAGE COMMITMENT; POSITIVE SELECTION; INTERLEUKIN-7 RECEPTOR; GENE-EXPRESSION; IN-VITRO; LYMPHOCYTES; OVEREXPRESSION; SPECIFICITY; MECHANISMS; PRECURSORS AB A central paradigm of T cell development is that CD4(+)8(+) (DP) thymocytes differentiate into CD4(+) or CD8(+) T cells in response to intrathymic signals that extinguish transcription of the inappropriate corecep tor molecule. Contrary to this prevailing paradigm, we now demonstrate that signaled DP thymocytes initially terminate CD8 transcription even when differentiating into CD8(+) T cells. Remarkably, thymocytes that have selectively terminated CD8 transcription can be signaled by IL-7 to differentiate into CD8(+) T cells by silencing CD4 transcription and reinitiating CD8 transcription, events we refer to as "coreceptor reversal." These observations significantly alter our understanding of CD8 1 T cell differentiation and lead to a new perspective ("kinetic signaling") on CD4/CD8 lineage determination in the thymus. These observations also suggest a novel mechanism by which bipotential cells throughout development can determine their appropriate cell fate. C1 [Brugnera, Enrico; Bhandoola, Avinash; Cibotti, Richrdo; Yu, Qing; Guinter, Terry I.; Sharrow, Susan O.; Singer, Alfred] NCI, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. [Yamashita, Yoshio] Oklahoma Med Res Fdn, Immunobiol Program, Oklahama City, OK 73104 USA. [Brugnera, Enrico] Univ Virgina, Beirne Carter Ctr Immunol Res, Charlottesville, VA 22908 USA. [Cibotti, Richrdo] Vaccinex LP, Rochester, NY 14620 USA. [Yamashita, Yoshio] Saga Med Sch, Dept Oral & Maxillofacial Surg, Saga 849, Japan. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. EM singera@nih.gov FU Swiss National Science Foundation FX We would like to thank Dan Littman for generously providing 004 promoter transgenic mice; Paul Kincade for anti-IL-7Ru antibodies; Larry Granger and Tony Adams for expert flow cytometry; and Remy Bosselut, Carolyn Doyle, Scot Durum, Richard Hodes, David McKean, Jennifer Punt, and Dinah Singer for critically reading the manuscript. This work was supported in part by a grant to E. B. from the Swiss National Science Foundation. NR 37 TC 0 Z9 0 U1 1 U2 1 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 MAR 1 PY 2016 VL 196 IS 5 BP 1985 EP 1997 PG 13 WC Immunology SC Immunology GA DG8LT UT WOS:000372336300002 PM 26896482 ER PT J AU Yan, M Wang, HS Sun, JF Liao, W Li, P Zhu, Y Xu, CF Joo, J Sun, Y Abbasi, S Kovalchuk, A Lv, N Leonard, WJ Morse, HC AF Yan, Ming Wang, Hongsheng Sun, Jiafang Liao, Wei Li, Peng Zhu, Yin Xu, Chengfu Joo, Jungsoo Sun, Yan Abbasi, Sadia Kovalchuk, Alexander Lv, Nonghua Leonard, Warren J. Morse, Herbert C., III TI Cutting Edge: Expression of IRF8 in Gastric Epithelial Cells Confers Protective Innate Immunity against Helicobacter pylori Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GENE; DIFFERENTIATION; MUTATION; PROGRAM; PROTEIN; MOUSE; IFIT3 AB IFN regulatory factor 8 (IRF8) is expressed in many types of blood cells and plays critical roles in cellular differentiation and function. However, the role of IRF8 in nonhematopoietic systems remains poorly understood. In this study, we provide evidence that IRF8 is a transcriptional modulator of the gastric mucosa necessary for limiting Helicobacter pylori colonization. H. pylori infection significantly upregulated expression of IRF8, which, in turn, promoted IFN-gamma expression by gastric epithelial cells. Mice deficient in IRF8 exhibited increased H. pylori colonization and aborted induction of mucosal IFN-gamma. Genome-wide analyses of IFN-gamma-treated gastric epithelial cells by chromatin immunoprecipitation sequencing and RNA sequencing led to the identification of IRF8 target genes, with many belonging to the IFN-regulated gene family that was observed previously in immune cells. Our results identify the IRF8-IFN-gamma circuit as a novel gastric innate immune mechanism in the host defense against infection with H. pylori. C1 [Yan, Ming; Xu, Chengfu; Joo, Jungsoo; Sun, Yan] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Hongsheng; Sun, Jiafang; Abbasi, Sadia; Kovalchuk, Alexander; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Liao, Wei; Li, Peng; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Liao, Wei; Li, Peng; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Zhu, Yin; Lv, Nonghua] Nanchang Univ, Affiliated Hosp 1, Dept Gastroenterol, Nanchang 330006, Peoples R China. RP Yan, M (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA.; Wang, HS; Morse, HC (reprint author), NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM yanming@mail.nih.gov; wanghongs@niaid.nih.gov; hmorse@niaid.nih.gov FU Intramural Research Programs of the National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute FX This work was supported in part by the Intramural Research Programs of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (to H.W., J.S., S.A., A.K., and H.C.M.), the National Institute of Diabetes and Digestive and Kidney Diseases (to M.Y., Y.Z., J.J., Y.S., C.X., and N.L.), and the National Heart, Lung, and Blood Institute (to W.L., P.L., and W.J.L.). NR 23 TC 1 Z9 1 U1 1 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 MAR 1 PY 2016 VL 196 IS 5 BP 1999 EP 2003 DI 10.4049/jimmunol.1500766 PG 5 WC Immunology SC Immunology GA DG8LT UT WOS:000372336300003 PM 26843324 ER PT J AU Rahman, MJ Rahir, G Dong, MB Zhao, YG Rodrigues, KB Hotta-Iwamura, C Chen, Y Guerrero, A Tarbell, KV AF Rahman, M. Jubayer Rahir, Gwendoline Dong, Matthew B. Zhao, Yongge Rodrigues, Kameron B. Hotta-Iwamura, Chie Chen, Ye Guerrero, Alan Tarbell, Kristin V. TI Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; NOD MICE; INTERFERON-ALPHA; INNATE IMMUNITY; MAP KINASE; IN-VITRO; MOUSE; DC; EXPRESSION; PATHOGENESIS AB Innate immune signals help break self-tolerance to initiate autoimmune diseases such as type 1 diabetes, but innate contributions to subsequent regulation of disease progression are less clear. Most studies have measured in vitro innate responses of GM-CSF dendritic cells (DCs) that are functionally distinct from conventional DCs (cDCs) and do not reflect in vivo DC subsets. To determine whether autoimmune NOD mice have alterations in type 1 IFN innate responsiveness, we compared cDCs from prediabetic NOD and control C57BL/6 (B6) mice stimulated in vivo with the TLR9 ligand CpG, a strong type 1 IFN inducer. In response to CpG, NOD mice produce more type 1 IFN and express higher levels of CD40, and NOD monocyte DCs make more TNF. However, the overall CpG-induced transcriptional response is muted in NOD cDCs. Of relevance the costimulatory proteins CD80/CD86, signals needed for regulatory T cell homeostasis, are upregulated less on NOD cDCs. Interestingly, NOD Rag1(-/-) mice also display a defect in CpG-induced CD86 upregulation compared with B6 Rag1(-/-), indicating this particular innate alteration precedes adaptive autoimmunity. The impaired response in NOD DCs is likely downstream of the IFN-alpha/beta receptor because DCs from NOD and B6 mice show similar CpG-induced CD86 levels when anti-IFN-alpha/beta receptor Ab is added. IFN-alpha-induced nuclear localization of activated STAT1 is markedly reduced in NOD CD11c(+) cells, consistent with lower type 1 IFN responsiveness. In conclusion, NOD DCs display altered innate responses characterized by enhanced type 1 IFN and activation of monocyte-derived DCs but diminished cDC type 1 IFN response. C1 [Rahman, M. Jubayer; Rahir, Gwendoline; Dong, Matthew B.; Zhao, Yongge; Rodrigues, Kameron B.; Hotta-Iwamura, Chie; Guerrero, Alan; Tarbell, Kristin V.] NIDDK, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Chen, Ye] NHLBI, Bioinformat & Syst Biol Core, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Tarbell, KV (reprint author), NIDDK, Immune Tolerance Sect, 10 Ctr Dr,Bldg 10,5-5940, Bethesda, MD 20892 USA. EM tarbellk@niddk.nih.gov OI Rodrigues, Kameron/0000-0002-0270-3688; Tarbell, Kristin/0000-0003-3738-379X; Rahman, M. Jubayer/0000-0002-4496-8385 FU intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; Janssen Research and Development FX This work was supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute and by a collaborative research agreement with Janssen Research and Development. NR 59 TC 2 Z9 2 U1 1 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 MAR 1 PY 2016 VL 196 IS 5 BP 2031 EP 2040 DI 10.4049/jimmunol.1501239 PG 10 WC Immunology SC Immunology GA DG8LT UT WOS:000372336300008 PM 26826238 ER PT J AU Qian, Y Jeong, JS Ye, J Dang, B Abdeladhim, M Aoki, V Hans-Filhio, G Rivitti, EA Valenzuela, JG Diaz, LA AF Qian, Ye Jeong, Joseph S. Ye, Jian Dang, Bim Abdeladhim, Maha Aoki, Valeria Hans-Filhio, Gunter Rivitti, Evandro A. Valenzuela, Jesus G. Diaz, Luis A. TI Overlapping IgG4 Responses to Self- and Environmental Antigens in Endemic Pemphigus Foliaceus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERT PANEL WORKSHOP; FOGO-SELVAGEM; AUTOIMMUNE-DISEASES; PHAGE DISPLAY; LUTZOMYIA-LONGIPALPIS; IGG4-RELATED DISEASE; MOLECULAR MIMICRY; SOMATIC MUTATIONS; BLOOD-LYMPHOCYTES; PASSIVE TRANSFER AB The etiology of human autoimmune diseases in general remains largely unknown, although the genetic and environmental interplay may be relevant. This applies to the autoimmune diseases of the skin such as the pemphigus phenotypes and others. In this group, there is an endemic form of pemphigus foliaceus (also known as fogo selvagem [FS]) in which the pathogenic IgG4 autoantibody response to the self-antigen desmoglein 1 (Dsg1) cross-reacts with the LJM11 sand fly salivary gland Ag. In this investigation, we dissected the IgG4 autoantibody repertoires used by FS patients in response to endogenous self-Dsg1 and exogenous LJM11 sand fly Ag. Based on analyses of the genetic clonal signatures of these Abs, our results indicate that there is a significant overlap between these two responses, as all identified IgG4 mAbs cross-react to both Dsg1 and LJM11 Ags. Germline H-and L-chain V gene Abs generated according to mutated cross-reactive mAbs preserved their reactivity to both Ags. Our findings suggest that both Dsg1 autoantigen and LJM11 environmental Ag could be the initial antigenic stimulants for the IgG4 autoimmune responses in FS. These results support our hypothesis that LJM11 Ag plays a substantial role in triggering the IgG4 autoantibody development in FS and provide new insights on how noninfectious environmental Ag(s) may drive the generation of autoantibodies in IgG4-related autoimmune diseases. C1 [Qian, Ye; Jeong, Joseph S.; Dang, Bim; Diaz, Luis A.] Univ N Carolina, Dept Dermatol, CB 7287, Chapel Hill, NC 27599 USA. [Ye, Jian] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Abdeladhim, Maha; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Aoki, Valeria; Rivitti, Evandro A.] Univ Sao Paulo, Dept Dermatol, BR-04038 Sao Paulo, Brazil. [Hans-Filhio, Gunter] Univ Fed Mato Grosso do Sul, Dept Dermatol, BR-79070 Campo Grande, MS, Brazil. RP Qian, Y (reprint author), Univ N Carolina, Dept Dermatol, CB 7287, Chapel Hill, NC 27599 USA. EM ye_qian@med.unc.edu RI Aoki, Valeria/H-1415-2012 FU National Institutes of Health [K01-AR056378, R01 AR067315, R01-AR32599]; Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work was supported by National Institutes of Health Grants K01-AR056378, R01 AR067315 (to Y.Q.), and R01-AR32599 (to L.A.D.) and was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 65 TC 3 Z9 3 U1 2 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 MAR 1 PY 2016 VL 196 IS 5 BP 2041 EP 2050 DI 10.4049/jimmunol.1502233 PG 10 WC Immunology SC Immunology GA DG8LT UT WOS:000372336300009 PM 26826247 ER PT J AU Prescott, J Feldmann, H AF Prescott, Joseph Feldmann, Heinz TI Humanized Mice-A Neoteric Animal Disease Model for Ebola Virus? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE humanized mouse; animal model; Ebola virus ID I INTERFERON RESPONSE; HEMORRHAGIC-FEVER; FILOVIRUS INFECTION; DENDRITIC CELLS; PATHOGENESIS; MOUSE; TRANSMISSION; MEN C1 [Prescott, Joseph; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Feldmann, H (reprint author), NIAID, Rocky Mt Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov FU Intramural NIH HHS NR 32 TC 0 Z9 0 U1 1 U2 3 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 MAR 1 PY 2016 VL 213 IS 5 BP 691 EP 693 DI 10.1093/infdis/jiv539 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG9XY UT WOS:000372438300002 PM 26582953 ER PT J AU Viboud, C Simonsen, L Fuentes, R Flores, J Miller, MA Chowell, G AF Viboud, Cecile Simonsen, Lone Fuentes, Rodrigo Flores, Jose Miller, Mark A. Chowell, Gerardo TI Global Mortality Impact of the 1957-1959 Influenza Pandemic SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE mortality rates; pandemic influenza; historical studies; vital statistics; severity; models; global disease burden; development indicators; health indicators; pandemic planning ID EXCESS MORTALITY; UNITED-STATES; AGE; EPIDEMIC; WAVE; INFECTION; ENGLAND; CITY; SEX AB Background. Quantitative estimates of the global burden of the 1957 influenza pandemic are lacking. Here we fill this gap by modeling historical mortality statistics. Methods. We used annual rates of age-and cause-specific deaths to estimate pandemic-related mortality in excess of background levels in 39 countries in Europe, the Asia-Pacific region, and the Americas. We modeled the relationship between excess mortality and development indicators to extrapolate the global burden of the pandemic. Results. The pandemic-associated excess respiratory mortality rate was 1.9/10 000 population (95% confidence interval [CI], 1.2-2.6 cases/10 000 population) on average during 1957-1959. Excess mortality rates varied 70-fold across countries; Europe and Latin America experienced the lowest and highest rates, respectively. Excess mortality was delayed by 1-2 years in 18 countries (46%). Increases in the mortality rate relative to baseline were greatest in school-aged children and young adults, with no evidence that elderly population was spared from excess mortality. Development indicators were moderate predictors of excess mortality, explaining 35%-77% of the variance. Overall, we attribute 1.1 million excess deaths (95% CI, .7 million-1.5 million excess deaths) globally to the 1957-1959 pandemic. Conclusions. The global mortality rate of the 1957-1959 influenza pandemic was moderate relative to that of the 1918 pandemic but was approximately 10-fold greater than that of the 2009 pandemic. The impact of the pandemic on mortality was delayed in several countries, pointing to a window of opportunity for vaccination in a future pandemic. C1 [Viboud, Cecile; Simonsen, Lone; Miller, Mark A.; Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Washington, DC USA. [Flores, Jose] Univ S Dakota, Dept Math Sci, Vermillion, SD 57069 USA. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, DK-1168 Copenhagen, Denmark. [Fuentes, Rodrigo] Univ Chile, Minist Salud, Dept Epidemiol, Santiago, Chile. [Flores, Jose] Univ Chile, Natl Ctr Environm, Biodivers Labs, Santiago, Chile. RP Viboud, C (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 FU International Influenza Unit, Office of Global Affairs, Office of the Secretary of the Department of Health and Human Services; RAPIDD Program, Science and Technology Directorate, Department of Homeland Security; Lundbeck Foundation, Denmark; Marie Sklodowska-Curie Senior Fellowship [H2020-MSCA-IF-2014, 6594] FX This work was supported by the International Influenza Unit, Office of Global Affairs, Office of the Secretary of the Department of Health and Human Services; the RAPIDD Program, Science and Technology Directorate, Department of Homeland Security (to L. S.); the Lundbeck Foundation, Denmark (visiting scientist award to L. S.); and a Marie Sklodowska-Curie Senior Fellowship (award H2020-MSCA-IF-2014 to L. S.; project no. 6594). NR 24 TC 2 Z9 2 U1 4 U2 8 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 MAR 1 PY 2016 VL 213 IS 5 BP 738 EP 745 DI 10.1093/infdis/jiv534 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG9XY UT WOS:000372438300008 PM 26908781 ER PT J AU Anuradha, R Munisankar, S Dolla, C Kumaran, P Nutman, TB Babu, S AF Anuradha, Rajamanickam Munisankar, Saravanan Dolla, Chandrakumar Kumaran, Paul Nutman, Thomas B. Babu, Subash TI Modulation of CD4(+) and CD8(+) T-Cell Function by Interleukin 19 and Interleukin 24 During Filarial Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE filarial infections; T cells; cytokines; IL-19; IL-24; IL-10 ID HUMAN LYMPHATIC FILARIASIS; IL-10 FAMILY; CYTOKINES; IL-20; INFLAMMATION; EXPANSION; MEMBERS AB Interleukin 19 (IL-19) and interleukin 24 (IL-24) are cytokines that are highly expressed in filarial infections. To study the role of IL-19 and IL-24 in regulating T-cell responses, we examined the frequency of T-helper type 1 (Th1)/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, Th22/Tc22, and Tr1 cells in 26 filariae-infected individuals stimulated with filarial antigen following IL-19 or IL-24 neutralization. IL-19 or IL-24 neutralization resulted in significantly enhanced frequencies of Th1/Tc1 and/or Th17/Tc17 cells and significantly reduced frequencies of Th2/Tc2, Tr1, and/or Th9/Tc9 cells. Thus, we demonstrate that IL-19 and IL-24 are associated with the modulation of T-cell responses in filarial infections. C1 [Anuradha, Rajamanickam; Munisankar, Saravanan; Babu, Subash] NIRT, NIH, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Dolla, Chandrakumar; Kumaran, Paul] NIRT, Madras, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Babu, S (reprint author), NIH NIRT ICER, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 14 TC 0 Z9 0 U1 0 U2 2 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 MAR 1 PY 2016 VL 213 IS 5 BP 811 EP 815 DI 10.1093/infdis/jiv497 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG9XY UT WOS:000372438300019 PM 26486636 ER PT J AU Bianchi, MLE Leoncini, E Masciullo, M Modoni, A Gadalla, SM Massa, R Rastelli, E Terracciano, C Antonini, G Bucci, E Petrucci, A Costanzi, S Santoro, M Boccia, S Silvestri, G AF Bianchi, Maria Laura Ester Leoncini, Emanuele Masciullo, Marcella Modoni, Anna Gadalla, Shahinaz M. Massa, Roberto Rastelli, Emanuele Terracciano, Chiara Antonini, Giovanni Bucci, Elisabetta Petrucci, Antonio Costanzi, Sandro Santoro, Massimo Boccia, Stefania Silvestri, Gabriella TI Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors SO JOURNAL OF NEUROLOGY LA English DT Article DE Myotonic dystrophy type 1; Tumor; Cancer; Thyroid disease; Risk factors ID MYOTONIC-DYSTROPHY TYPE-1; MULTIPLE PILOMATRICOMAS; INSULIN-RECEPTOR; CANCER AB Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6 %), thyroid (21.0 %), ovary (10.5 %), and breast (10.5 %). Uterine fibroid was the most common benign tumor (37.6 %) in women, while pilomatricoma was the most common in men (28.6 %). Age at enrollment (OR = 1.02, 95 % CI 1.00-1.05), and female gender (OR = 5.71, 95 % CI 2.90-11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95 % CI 1.35-19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation. C1 [Bianchi, Maria Laura Ester; Modoni, Anna; Silvestri, Gabriella] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, Largo F Vito 1, I-00168 Rome, Italy. [Leoncini, Emanuele; Boccia, Stefania] UCSC, Sect Hyg, Inst Publ Hlth, Rome, Italy. [Masciullo, Marcella] IRCSS Fdn Santa Lucia, Rome, Italy. [Gadalla, Shahinaz M.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Massa, Roberto; Rastelli, Emanuele; Terracciano, Chiara] Univ Roma Tor Vergata, Dept Syst Med Neurol, Rome, Italy. [Antonini, Giovanni; Bucci, Elisabetta] Univ Roma La Sapienza, Dept Neurosci Mental Hlth & Sensory Organs NESMOS, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Petrucci, Antonio] Azienda Osped San Camillo Forlanini, Unita Operat Complessa Neurol & Neurofisiopatol, Rome, Italy. [Costanzi, Sandro] S Camillo Forlanini Hosp, Ctr Neuromuscular & Neurol Rare Dis, Unit Med Genet, Rome, Italy. [Santoro, Massimo] Fdn Don Carlo Gnocchi Onlus, Milan, Italy. RP Silvestri, G (reprint author), Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, Largo F Vito 1, I-00168 Rome, Italy. EM gsilvestri@rm.unicatt.it RI Massa, Roberto/I-7223-2012; Masciullo, Marcella/J-9144-2016; Santoro, Massimo/P-6575-2014; OI Massa, Roberto/0000-0001-7523-6956; Masciullo, Marcella/0000-0003-1368-7692; Santoro, Massimo/0000-0002-3037-2775; SILVESTRI, Gabriella/0000-0002-1950-1468 FU Fondazione Veronesi; National Cancer Institute, Bethesda, MA FX The work of Dr. Emanuele Leoncini was supported by Fondazione Veronesi. Dr. Shahinaz Gadalla is supported by the intramural program of the National Cancer Institute, Bethesda, MA. NR 30 TC 4 Z9 5 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD MAR PY 2016 VL 263 IS 3 BP 492 EP 498 DI 10.1007/s00415-015-8006-y PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DG9WD UT WOS:000372433600011 PM 26739382 ER PT J AU Bianchi, MLE Leoncini, E Masciullo, M Modoni, A Gadalla, SM Massa, R Botta, A Rastelli, E Terracciano, C Antonini, G Bucci, E Petrucci, A Costanzi, S Santoro, M Boccia, S Silvestri, G AF Bianchi, Maria Laura Ester Leoncini, Emanuele Masciullo, Marcella Modoni, Anna Gadalla, Shahinaz M. Massa, Roberto Botta, Annalisa Rastelli, Emanuele Terracciano, Chiara Antonini, Giovanni Bucci, Elisabetta Petrucci, Antonio Costanzi, Sandro Santoro, Massimo Boccia, Stefania Silvestri, Gabriella TI Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors (vol 263, pg 492, 2016) SO JOURNAL OF NEUROLOGY LA English DT Correction C1 [Bianchi, Maria Laura Ester; Modoni, Anna; Silvestri, Gabriella] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, Largo F Vito 1, I-00168 Rome, Italy. [Leoncini, Emanuele; Boccia, Stefania] UCSC, Sect Hyg, Inst Publ Hlth, Rome, Italy. [Masciullo, Marcella] IRCSS Fdn Santa Lucia, Rome, Italy. [Gadalla, Shahinaz M.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Massa, Roberto; Rastelli, Emanuele; Terracciano, Chiara] Univ Roma Tor Vergata, Dept Syst Med Neurol, Rome, Italy. [Antonini, Giovanni; Bucci, Elisabetta] Univ Roma La Sapienza, Dept Neurosci Mental Hlth & Sensory Organs NESMOS, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Petrucci, Antonio] Azienda Osped San Camillo Forlanini, Unita Operat Complessa Neurol & Neurofisiopatol, Rome, Italy. [Costanzi, Sandro] S Camillo Forlanini Hosp, Ctr Neuromuscular & Neurol Rare Dis, Unit Med Genet, Rome, Italy. [Santoro, Massimo] Fdn Don Carlo Gnocchi Onlus, Milan, Italy. [Botta, Annalisa] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy. RP Silvestri, G (reprint author), Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, Largo F Vito 1, I-00168 Rome, Italy. EM gsilvestri@rm.unicatt.it RI Masciullo, Marcella/J-9144-2016; Santoro, Massimo/P-6575-2014 OI Masciullo, Marcella/0000-0003-1368-7692; Santoro, Massimo/0000-0002-3037-2775 NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD MAR PY 2016 VL 263 IS 3 BP 499 EP 499 DI 10.1007/s00415-016-8068-5 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DG9WD UT WOS:000372433600012 PM 26914929 ER PT J AU Pokrovskaya, ID Aronova, MA Kamykowski, JA Prince, AA Hoyne, JD Calco, GN Kuo, BC He, Q Leapman, RD Storrie, B AF Pokrovskaya, I. D. Aronova, M. A. Kamykowski, J. A. Prince, A. A. Hoyne, J. D. Calco, G. N. Kuo, B. C. He, Q. Leapman, R. D. Storrie, B. TI STEM tomography reveals that the canalicular system and -granules remain separate compartments during early secretion stages in blood platelets SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE blood platelets; cytoplasmic granules; electron microscope tomography; hemostasis; platelet activation ID ALPHA-GRANULES; ELECTRON TOMOGRAPHY; FREEZE-SUBSTITUTION; PROTEINS; PATHWAY; RELEASE; ULTRASTRUCTURE; ANGIOGENESIS; EXOCYTOSIS; FIXATION AB How platelets organize their -granule cargo and use their canalicular system remains controversial. Past structural studies were limited due to small sampling volumes or decreased resolution. Our analyses revealed homogeneous granules and a closed canalicular system that opened on activation. Understanding how platelets alter their membranes during activation and secretion elucidates hemostasis. Summary Background Platelets survey the vasculature for damage and, in response, activate and release a wide range of proteins from their -granules. Alpha-granules may be biochemically and structurally heterogeneous; however, other studies suggest that they may be more homogeneous with the observed variation reflecting granule dynamics rather than fundamental differences. Objectives Our aim was to address how the structural organization of -granules supports their dynamics. Methods To preserve the native state, we prepared platelets by high-pressure freezing and freeze-substitution; and to image nearly entire cells, we recorded tomographic data in the scanning transmission electron microscope (STEM). Results and Conclusions In resting platelets, we observed a morphologically homogeneous -granule population that displayed little variation in overall matrix electron density in freeze-substituted preparations (i.e., macro-homogeneity). In resting platelets, the incidence of tubular granule extensions was low, similar to 4%, but this increased by > 10-fold during early steps in platelet secretion. Using STEM, we observed that the initially decondensing -granules and the canalicular system remained as separate membrane domains. Decondensing -granules were found to fuse heterotypically with the plasma membrane via long, tubular connections or homotypically with each other. The frequency of canalicular system fusion with the plasma membrane also increased by about three-fold. Our results validate the utility of freeze-substitution and STEM tomography for characterizing platelet granule secretion and suggest a model in which fusion of platelet -granules with the plasma membrane occurs via long tubular connections that may provide a spatially limited access route for the timed release of -granule proteins. C1 [Pokrovskaya, I. D.; Kamykowski, J. A.; Prince, A. A.; Storrie, B.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Aronova, M. A.; Hoyne, J. D.; Calco, G. N.; Kuo, B. C.; He, Q.; Leapman, R. D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Storrie, B (reprint author), Univ Arkansas Med Sci, Dept Physiol & Biophys, Slot 505,4301 W Markham St, Little Rock, AR 72205 USA. EM storriebrian@uams.edu FU NIH [R01 HL119393]; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX We gratefully acknowledge the technical contributions of Laura MacDonald to this research and the constructive comments of Laura MacDonald and Sidney W. Whiteheart of the University of Kentucky on the manuscript. Research in the Storrie laboratory was supported by NIH grant R01 HL119393. Research in the Leapman laboratory was supported by the intramural program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 36 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD MAR PY 2016 VL 14 IS 3 BP 572 EP 584 DI 10.1111/jth.13225 PG 13 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DH1DR UT WOS:000372525100019 PM 26663480 ER PT J AU Fassiotto, M Hamel, EO Ku, MW Correll, S Grewal, D Lavori, P Periyakoil, VJ Reiss, A Sandborg, C Walton, G Winkleby, M Valantine, H AF Fassiotto, Magali Hamel, Elizabeth Otto Ku, Manwai Correll, Shelley Grewal, Daisy Lavori, Philip Periyakoil, V. J. Reiss, Allan Sandborg, Christy Walton, Gregory Winkleby, Marilyn Valantine, Hannah TI Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty SO JOURNAL OF WOMENS HEALTH LA English DT Article ID MATH PERFORMANCE; NEGATIVE STEREOTYPES; GENDER-DIFFERENCES; POSSIBLE SELVES; IDENTITY; ADVANCEMENT; SENSITIVITY; EXPERIENCE; REJECTION; PROGRESS AB Background: Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine. Methods: Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty. Results: 174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42). Conclusions: Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine. C1 [Fassiotto, Magali] Stanford Univ, Off Fac Dev & Div, Sch Med, 1265 Welch Rd,Suite X100, Stanford, CA 94305 USA. [Lavori, Philip] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Periyakoil, V. J.; Winkleby, Marilyn; Valantine, Hannah] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Reiss, Allan] Stanford Univ, Dept Psychiat & Behav Med, Sch Med, Stanford, CA 94305 USA. [Sandborg, Christy] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Hamel, Elizabeth Otto] Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA. [Correll, Shelley] Stanford Univ, Dept Sociol, Stanford, CA 94305 USA. [Grewal, Daisy] Stanford Univ, Off Vice Provost Undergrad Educ, Stanford, CA 94305 USA. [Walton, Gregory] Stanford Univ, Dept Psychol, Stanford, CA USA. [Ku, Manwai] Apple Inc, Cupertino, CA USA. [Valantine, Hannah] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Fassiotto, M (reprint author), Stanford Univ, Off Fac Dev & Div, Sch Med, 1265 Welch Rd,Suite X100, Stanford, CA 94305 USA. EM magali.fassiotto@stanford.edu FU National Institutes of Health FX This work was funded by a National Institutes of Health Pathfinder Award to Promote Diversity in the Scientific Workforce. Stanford University School of Medicine's IRB reviewed and approved the study protocol, IRB-19272. NR 46 TC 2 Z9 2 U1 10 U2 17 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD MAR 1 PY 2016 VL 25 IS 3 BP 292 EP 298 DI 10.1089/jwh.2015.5380 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DG6DU UT WOS:000372173200014 PM 26555562 ER PT J AU Schwartz, SR Kumwenda, N Kumwenda, J Chen, S Mofenson, LM Taylor, AW Fowler, MG Taha, TE AF Schwartz, Sheree R. Kumwenda, Newton Kumwenda, Johnstone Chen, Shu Mofenson, Lynne M. Taylor, Allan W. Fowler, Mary Glenn Taha, Taha E. TI Maternal Highly Active Antiretroviral Therapy and Child HIV-Free Survival in Malawi, 2004-2009 SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE HIV-1; Prevention of mother-to-child transmission; Highly active antiretroviral therapy; Child survival; Breastfeeding ID DAR-ES-SALAAM; TRANSMISSION; WOMEN; MORTALITY; PROPHYLAXIS; PREVENTION; TANZANIA; TRIAL; DRUGS; PREGNANCY AB Objectives Highly active antiretroviral therapy (HAART) provision to eligible HIV-infected pregnant and post-partum women is critical for optimizing maternal health. We assessed the impact of maternal HAART on HIV-free survival of breastfed infants in Malawi. Methods The post-exposure prophylaxis of infants-Malawi trial (2004-2009) enrolled mothers/infants during labor or immediately postpartum to evaluate 14-week extended infant antiretroviral prophylaxis for preventing HIV transmission through breastfeeding. Mothers meeting national HAART guidelines were referred for therapy. Child HIV-free survival-survival without HIV infection-was compared by maternal HAART status. Results Overall, 3022 mother-infant pairs contributed 4214 infant/person-years (PY) at-risk for HIV infection or death, with 532 events (incidence 12.6/100 PY, 95 % confidence interval [CI] 11.6-13.7). During follow-up, 349 mothers were HAART initiated; 581 remained HAART naive with CD4 cell counts <250 cells/mm(3), and 2092 were never HAART-eligible. By 3 months, 11 % of infants with HAART naive mothers (CD4 < 250) were infected with HIV or died versus 7 % of infants of HAART-initiated mothers and 4 % of infants of HAART-ineligible mothers. Maternal HAART was associated with a 46 % reduction in infant HIV infection or death as compared to infants with HAART naive mothers (CD4 < 250) (adjusted hazards ratio 0.54, 95 % CI 0.36-0.81). Among HIV-exposed, uninfected infants, breastfeeding, but not HAART, was significantly associated with decreased child mortality. Conclusions HIV infection and mortality are high during the first 3 months post-partum in infants of mothers with advanced HIV, and rapid maternal HAART initiation can significantly improve HIV-related infant outcomes. C1 [Schwartz, Sheree R.; Kumwenda, Newton; Chen, Shu; Taha, Taha E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,E7139, Baltimore, MD 21205 USA. [Kumwenda, Johnstone] Univ Malawi, Coll Med, Dept Med, Blantyre, Malawi. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Taylor, Allan W.] Ctr Dis Control & Prevent, Natl Ctr HIV Viral Hepatitis STD & TB Prevent, Div HIV AIDS Prevent, Epidemiol Branch, Atlanta, GA USA. [Fowler, Mary Glenn] Johns Hopkins Med Sch, Dept Pathol, Baltimore, MD USA. RP Schwartz, SR (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,E7139, Baltimore, MD 21205 USA. EM sschwartz@jhu.edu; ttaha1@jhu.edu FU Centers for Disease Control and Prevention [5 U50 PS022061-05, U50/CC0222061]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by a Cooperative Agreement (Grant number 5 U50 PS022061-05 and award # U50/CC0222061) from the Centers for Disease Control and Prevention and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 24 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD MAR PY 2016 VL 20 IS 3 BP 542 EP 549 DI 10.1007/s10995-015-1852-5 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG6BW UT WOS:000372168200006 PM 26525557 ER PT J AU Huggins, CJ Mayekar, MK Martin, N Saylor, KL Gonit, M Jailwala, P Kasoji, M Haines, DC Quinones, OA Johnson, PF AF Huggins, Christopher J. Mayekar, Manasi K. Martin, Nancy Saylor, Karen L. Gonit, Mesfin Jailwala, Parthav Kasoji, Manjula Haines, Diana C. Quinones, Octavio A. Johnson, Peter F. TI C/EBP gamma Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; TRANSCRIPTIONAL INHIBITORY PROTEIN; BRONCHIAL EPITHELIAL-CELLS; AMINO-ACID RESPONSE; ER-STRESS; OXIDATIVE STRESS; BINDING-PROTEIN; GENE-EXPRESSION; TARGETED DISRUPTION AB The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBP gamma:ATF4 heterodimers, but not C/EBP beta:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBP gamma and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBP beta and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg(-/-) mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBP gamma-deficient new-borns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant N-acetylcysteine. Cebpg(-/-) mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBP gamma as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. C1 [Huggins, Christopher J.; Mayekar, Manasi K.; Martin, Nancy; Gonit, Mesfin; Johnson, Peter F.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Saylor, Karen L.] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Jailwala, Parthav; Kasoji, Manjula] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD USA. [Haines, Diana C.] Leidos Biomed Res Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Quinones, Octavio A.] DMS Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Johnson, PF (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. EM johnsope@mail.nih.gov FU HHS \ NIH \ National Cancer Institute (NCI) [HHSN261200800001E] FX HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to Christopher J. Huggins, Manasi K. Mayekar, Nancy Martin, Karen L. Saylor, Mesfin Gonit, Parthav Jailwala, Manjula Kasoji, Diana C. Haines, Octavio A. Quinones, and Peter F. Johnson. HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to Diana C. Haines under grant number contract no. HHSN261200800001E. NR 67 TC 1 Z9 1 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2016 VL 36 IS 5 BP 693 EP 713 DI 10.1128/MCB.00911-15 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IY UT WOS:000372328600004 ER PT J AU He, B Cruz-Topete, D Oakley, RH Xiao, X Cidlowski, JA AF He, Bo Cruz-Topete, Diana Oakley, Robert H. Xiao, Xiao Cidlowski, John A. TI Human Glucocorticoid Receptor beta Regulates Gluconeogenesis and Inflammation in Mouse Liver SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GENE-THERAPY VECTORS; ADENOASSOCIATED VIRUS; TRANSCRIPTIONAL ACTIVITY; IMMUNE-RESPONSES; EXPRESSION; ISOFORM; MECHANISMS; DISEASE; CELLS; INHIBITION AB While in vitro studies have demonstrated that a glucocorticoid receptor (GR) splice isoform, beta-isoform of human GR (hGR beta), acts as a dominant-negative inhibitor of the classic hGR alpha and confers glucocorticoid resistance, the in vivo function of hGR beta is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGR beta in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGR beta significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGR beta antagonized GR alpha's function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGR beta did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGR beta regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGR beta binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGR beta. Finally, our array data demonstrate that hGR beta regulates unique components of liver gene expression in vivo by both GR alpha-dependent and GR alpha-independent mechanisms. C1 [He, Bo; Cruz-Topete, Diana; Oakley, Robert H.; Cidlowski, John A.] NIEHS, Signal Transduct Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Xiao, Xiao] Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC USA. RP Cidlowski, JA (reprint author), NIEHS, Signal Transduct Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH Intramural Research Program FX NIH Intramural Research Program provided funding to John A. Cidlowski. NR 35 TC 1 Z9 1 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2016 VL 36 IS 5 BP 714 EP 730 DI 10.1128/MCB.00908-15 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IY UT WOS:000372328600005 PM 26711253 ER PT J AU Pedersen, SM Chan, WP Jattani, RP Mackie, DS Pomerantz, JL AF Pedersen, Sarah M. Chan, Waipan Jattani, Rakhi P. Mackie, deMauri S. Pomerantz, Joel L. TI Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; RESPONSIVE INHIBITORY DOMAIN; COMBINED IMMUNODEFICIENCY; INDUCED PHOSPHORYLATION; KINASE-BETA; ACTIVATION; CARMA1; MUTATIONS; BCL10; COMPLEX AB NF-kappa B activation downstream of antigen receptor engagement is a highly regulated event required for lymphocyte activation during the adaptive immune response. The pathway is often dysregulated in lymphoma, leading to constitutive NF-kappa B activity that supports the aberrant proliferation of transformed lymphocytes. To identify novel regulators of antigen receptor signaling to NF-kappa B, we developed bioluminescence resonance energy transfer-based interaction cloning (BRIC), a screening strategy that can detect protein-protein interactions in live mammalian cells in a high-throughput manner. Using this strategy, we identified the RING finger protein RNF181 as an interactor of CARD11, a key signaling scaffold in the antigen receptor pathway. We present evidence that RNF181 functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-kappa B downstream of CARD11. The levels of the obligate signaling protein Bcl10 are reduced by RNF181 even prior to signaling, and Bcl10 can serve as a substrate for RNF181 E3 ligase activity in vitro. Furthermore, RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-kappa B for growth and survival in culture. Our results define a new regulatory checkpoint that can modulate the output of CARD11 signaling to NF-kappa B in both normal and transformed lymphocytes. C1 [Pomerantz, Joel L.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD USA. [Chan, Waipan] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Pomerantz, JL (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. EM joel.pomerantz@jhmi.edu OI Pomerantz, Joel L./0000-0002-5030-1018 FU HHS \ NIH \ National Cancer Institute (NCI) [RO1CA177600, F31CA171532]; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R21AI118606] FX HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to Sarah Pedersen, Rakhi Jattani, deMauri Mackie, and Joel Pomerantz under grant number RO1CA177600. HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to deMauri Mackie under grant number F31CA171532. HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Sarah Pedersen, Rakhi Jattani, deMauri Mackie, and Joel Pomerantz under grant number R21AI118606. NR 45 TC 3 Z9 4 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2016 VL 36 IS 5 BP 794 EP 808 DI 10.1128/MCB.00876-15 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IY UT WOS:000372328600011 PM 26711259 ER PT J AU Ortiz, AM Klase, ZA DiNapoli, SR Vujkovic-Cvijin, I Carmack, K Perkins, MR Calantone, N Vinton, CL Riddick, NE Gallagher, J Klatt, NR McCune, JM Estes, JD Paiardini, M Brenchley, JM AF Ortiz, A. M. Klase, Z. A. DiNapoli, S. R. Vujkovic-Cvijin, I. Carmack, K. Perkins, M. R. Calantone, N. Vinton, C. L. Riddick, N. E. Gallagher, J. Klatt, N. R. McCune, J. M. Estes, J. D. Paiardini, M. Brenchley, J. M. TI IL-21 and probiotic therapy improve Th17 frequencies, microbial translocation, and microbiome in ARV-treated, SIV-infected macaques SO MUCOSAL IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; HIV-INFECTION; IMMUNE ACTIVATION; ANTIRETROVIRAL THERAPY; LENTIVIRAL INFECTIONS; VIRAL REPLICATION; PIGTAIL MACAQUES; RHESUS MACAQUES; T(H)17 CELLS; TGF-BETA AB Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4(+) T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals. C1 [Ortiz, A. M.; Klase, Z. A.; DiNapoli, S. R.; Carmack, K.; Perkins, M. R.; Calantone, N.; Vinton, C. L.; Riddick, N. E.; Gallagher, J.; Klatt, N. R.; Brenchley, J. M.] NIAID, Program Tissue Immun & Repair, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ortiz, A. M.; Klase, Z. A.; DiNapoli, S. R.; Carmack, K.; Perkins, M. R.; Calantone, N.; Vinton, C. L.; Riddick, N. E.; Gallagher, J.; Klatt, N. R.; Brenchley, J. M.] NIAID, Immunopathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Klase, Z. A.] Univ Sci, Dept Biol Sci, Philadelphia, PA USA. [Vujkovic-Cvijin, I.; McCune, J. M.] Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA USA. [Klatt, N. R.] Univ Washington, Dept Pharmaceut, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Estes, J. D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, FrederickNat Lab Canc Res, Frederick, MD USA. [Paiardini, M.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Div Microbiol & Immunol,Yerkes Natl Primate Res C, Atlanta, GA 30322 USA. RP Brenchley, JM (reprint author), NIAID, Program Tissue Immun & Repair, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Brenchley, JM (reprint author), NIAID, Immunopathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@niaid.nih.gov OI DiNapoli, Sarah/0000-0002-3675-9030; Vujkovic-Cvijin, Ivan/0000-0002-8611-4900 FU Division of Intramural Research/NIAID/NIH; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank F. Villinger (Emory University) for providing the IL-21; D. Hazuda (Gilead), M. Miller (Merck), and J. Lifson (NCI) for providing the ARVs; C. de Simon (Sigma Tau Pharmaceuticals) for providing the VSL#3; H. Cronise, J. Swerczek, and R. Herbert for veterinary assistance; and the NIAID LMM-Core for assessing viral loads. Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E to JDE. The content of this publication does not necessarily reflect the views or policies of DHHS, or does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 46 TC 14 Z9 14 U1 3 U2 7 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 MAR PY 2016 VL 9 IS 2 BP 458 EP 467 DI 10.1038/mi.2015.75 PG 10 WC Immunology SC Immunology GA DG9TD UT WOS:000372425800014 PM 26286233 ER PT J AU Drummond, RA Dambuza, IM Vautier, S Taylor, JA Reid, DM Bain, CC Underhill, DM Masopust, D Kaplan, DH Brown, GD AF Drummond, R. A. Dambuza, I. M. Vautier, S. Taylor, J. A. Reid, D. M. Bain, C. C. Underhill, D. M. Masopust, D. Kaplan, D. H. Brown, G. D. TI CD4(+) T-cell survival in the GI tract requires dectin-1 during fungal infection SO MUCOSAL IMMUNOLOGY LA English DT Article ID CD103(+) DENDRITIC CELLS; BETA-GLUCAN RECEPTOR; CANDIDA-ALBICANS; HOST-DEFENSE; RECOGNITION; HOMEOSTASIS; IMMUNITY; SUBSETS; COLONIZATION; EXPRESSION AB Dectin-1 is an innate antifungal C-type lectin receptor necessary for protective antifungal immunity. We recently discovered that Dectin-1 is involved in controlling fungal infections of the gastrointestinal (GI) tract, but how this C-type lectin receptor mediates these activities is unknown. Here, we show that Dectin-1 is essential for driving fungal-specific CD4(+) T-cell responses in the GI tract. Loss of Dectin-1 resulted in abrogated dendritic cell responses in the mesenteric lymph nodes (mLNs) and defective T-cell co-stimulation, causing substantial increases in CD4(+) T-cell apoptosis and reductions in the cellularity of GI-associated lymphoid tissues. CD8(+) T-cell responses were unaffected by Dectin-1 deficiency. These functions of Dectin-1 have significant implications for our understanding of intestinal immunity and susceptibility to fungal infections. C1 [Drummond, R. A.; Dambuza, I. M.; Vautier, S.; Taylor, J. A.; Reid, D. M.; Brown, G. D.] Univ Aberdeen, Inst Med Sci, Aberdeen Fungal Grp, Aberdeen, Scotland. [Bain, C. C.] Univ Glasgow, Inst Infect Immun & Inflammat, Coll Vet Med & Life Sci, Glasgow G12 8QQ, Lanark, Scotland. [Underhill, D. M.] Cedars Sinai Med Ctr, Div Immunol, Inflammatory Bowel & Immunobiol Res Inst, Los Angeles, CA 90048 USA. [Masopust, D.] Univ Minnesota, Sch Med, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. [Kaplan, D. H.] Univ Minnesota, Dept Dermatol, Ctr Immunol, Minneapolis, MN 55455 USA. [Drummond, R. A.; Vautier, S.] NIH, Fungal Pathogenesis Unit RAD, Lab Mucosal Immunol, Bldg 10, Bethesda, MD 20892 USA. RP Brown, GD (reprint author), Univ Aberdeen, Inst Med Sci, Aberdeen Fungal Grp, Aberdeen, Scotland. EM gordon.brown@abdn.ac.uk OI Drummond, Rebecca/0000-0001-5424-7074 FU Medical Research Council; Wellcome Trust [086558, 102705, 97377]; University of Aberdeen FX We thank the Medical Research Council, the Wellcome Trust (086558, 102705, 97377) and the University of Aberdeen for funding. We thank Doreen Cantrell for useful comments, and acknowledge Medical Research Facility staff for care of the animals used in this study. NR 37 TC 2 Z9 2 U1 2 U2 3 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 MAR PY 2016 VL 9 IS 2 BP 492 EP 502 DI 10.1038/mi.2015.79 PG 11 WC Immunology SC Immunology GA DG9TD UT WOS:000372425800017 PM 26349660 ER PT J AU Turfkruyer, M Verhasselt, V AF Turfkruyer, M. Verhasselt, V. TI Response to "Disparity between vitamin A-induced Th1-dependent oral tolerance in newborn mice and vitamin A-induced atopic sensitization in Guinean girls" SO MUCOSAL IMMUNOLOGY LA English DT Letter C1 [Turfkruyer, M.] NIAID, Food Allergy Res Unit, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Turfkruyer, M.; Verhasselt, V.] Univ Nice Sophia Antipolis, Immune Tolerance Team TIM EA6302, F-06189 Nice, France. [Verhasselt, V.] Worldwide Univ Network, Int Inflammat In FLAME Network, Nice, France. RP Verhasselt, V (reprint author), Univ Nice Sophia Antipolis, Immune Tolerance Team TIM EA6302, F-06189 Nice, France.; Verhasselt, V (reprint author), Worldwide Univ Network, Int Inflammat In FLAME Network, Nice, France. EM verhasselt@unice.fr NR 7 TC 0 Z9 0 U1 1 U2 5 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 MAR PY 2016 VL 9 IS 2 BP 565 EP 565 DI 10.1038/mi.2016.3 PG 1 WC Immunology SC Immunology GA DG9TD UT WOS:000372425800024 PM 26860819 ER PT J AU Backonja, U Louis, GMB Lauver, DR AF Backonja, Uba Louis, Germaine M. Buck Lauver, Diane R. TI Overall Adiposity, Adipose Tissue Distribution, and Endometriosis A Systematic Review SO NURSING RESEARCH LA English DT Review DE endometriosis; adiposity; body size; systematic review ID PERITONEAL-FLUID LEPTIN; BODY-FAT DISTRIBUTION; PELVIC ENDOMETRIOSIS; RETROGRADE MENSTRUATION; MASS INDEX; WOMEN; BIOMARKERS; METAANALYSIS; ADIPONECTIN; OBESITY AB Background Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops-some of the physiological actions of adipose tissue differ depending on tissue amount and location and are related to proposed mechanisms of endometriosis development. Objectives The aim of this study was to review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. Methods We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Results Of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Discussion Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis and delineate potential etiological mechanisms underlying endometriosis. C1 [Backonja, Uba] Univ Washington, Sch Med, Dept Biomed Informat & Med Educ, Box 358047, Seattle, WA 98109 USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Off Director, Rockville, MD USA. [Lauver, Diane R.] Univ Wisconsin, Sch Nursing, Madison, WI 53706 USA. RP Backonja, U (reprint author), Univ Washington, Sch Med, Dept Biomed Informat & Med Educ, Box 358047, Seattle, WA 98109 USA. EM backonja@uw.edu OI Buck Louis, Germaine/0000-0002-1774-4490 FU NINR/NIH; NIH, National Library of Medicine Biomedical and Health Informatics Training Program at the University of Washington [T15LM007442] FX Dr. Backonja was funded through the NINR/NIH Graduate Partnership Program during the literature review and initial writing of the manuscript. She is currently funded by the NIH, National Library of Medicine Biomedical and Health Informatics Training Program at the University of Washington (Grant No. T15LM007442). NR 84 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2016 VL 65 IS 2 BP 151 EP 166 DI 10.1097/NNR.0000000000000146 PG 16 WC Nursing SC Nursing GA DG6RZ UT WOS:000372215100004 PM 26938364 ER PT J AU Nadarajah, S Buchholz, S Wiegand, D Berger, A AF Nadarajah, Sheeba Buchholz, Susan Wiegand, Debra Berger, Ann TI Barriers and Facilitators of Cardiac Recovery in Cardiac Rehabilitation Patients SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Nadarajah, Sheeba] Bowie State Univ, Bowie, MD USA. [Buchholz, Susan] Rush Univ, Coll Nursing, Chicago, IL USA. [Wiegand, Debra] Univ Maryland, Bethesda, MD USA. [Berger, Ann] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2016 VL 65 IS 2 BP E66 EP E66 PG 1 WC Nursing SC Nursing GA DG6SA UT WOS:000372215200180 ER PT J AU Tuthill, E Cusson, R McGrath, J AF Tuthill, Emily Cusson, Regina McGrath, Jacqueline TI Exclusive Breastfeeding Promotion Among HIV-Infected Women in South Africa: An IMB-Model Based Pilot Intervention SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Tuthill, Emily] NIH, Bethesda, MD USA. [Cusson, Regina; McGrath, Jacqueline] Univ Connecticut, Storrs, CT USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2016 VL 65 IS 2 BP E67 EP E67 PG 1 WC Nursing SC Nursing GA DG6SA UT WOS:000372215200183 ER PT J AU Weaver, KR Melkus, GD Henderson, WA AF Weaver, Kristen R. Melkus, Gail D'Eramo Henderson, Wendy A. TI Allostatic Load in IBS SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Weaver, Kristen R.; Henderson, Wendy A.] NINR, Bethesda, MD 20892 USA. [Melkus, Gail D'Eramo] NYU, New York, NY 10003 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2016 VL 65 IS 2 BP E53 EP E54 PG 2 WC Nursing SC Nursing GA DG6SA UT WOS:000372215200147 ER PT J AU Burris, AM Ballew, BJ Kentosh, JB Turner, CE Norton, SA Giri, N Alter, BP Nellan, A Gamper, C Hartman, KR Savage, SA AF Burris, Ashley M. Ballew, Bari J. Kentosh, Joshua B. Turner, Clesson E. Norton, Scott A. Giri, Neelam Alter, Blanche P. Nellan, Anandani Gamper, Christopher Hartman, Kip R. Savage, Sharon A. CA NCI DCEG Canc Genomics NCI DCEG Canc Sequencing TI Hoyeraal-Hreidarsson Syndrome due to PARN Mutations: Fourteen Years of Follow-Up SO PEDIATRIC NEUROLOGY LA English DT Article DE dyskeratosis congenita; Hoyeraal-Hreidarsson syndrome; telomere; PARN; microcephaly; CNS calcification ID BONE-MARROW FAILURE; POLY(A)-SPECIFIC RIBONUCLEASE PARN; TELOMERE BIOLOGY DISORDERS; DYSKERATOSIS-CONGENITA; COMBINED IMMUNODEFICIENCY; GERMLINE MUTATION; PROTEIN TPP1; CANCER; VARIANTS; LENGTH AB BACKGROUND: Hoyeraal-Hreidarsson syndrome is a dyskeratosis congenita related telomere biology disorder that presents in infancy with intrauterine growth retardation, immunodeficiency, and cerebellar hypoplasia in addition to the triad of nail dysplasia, skin pigmentation, and oral leukoplakia. Individuals with Hoyeraal-Hreidarsson syndrome often develop bone marrow failure in early childhood. Germline mutations in DKC1, TERT, TINF2, RTEL1, ACD, or PARN cause about 60% of individuals with Hoyeraal-Hreidarsson syndrome. PATIENT DESCRIPTION: We describe 14 years of follow-up of an individual with Hoyeraal-Hreidarsson syndrome who initially presented as an infant with intrauterine growth retardation, microcephaly, and central nervous system calcifications. He was diagnosed with Hoyeraal-Hreidarsson syndrome at age 6 years and had a complicated medical history including severe developmental delay, cerebellar hypoplasia, esophageal and urethral stenosis, hip avascular necrosis, immunodeficiency, and bone marrow failure evolving to myelodysplastic syndrome requiring hematopoietic cell transplantation at age 14 years. He had progressive skin pigmentation, oral leukoplakia, and nail dysplasia leading to anonychia. Whole exome sequencing identified novel biallelic variants in PARN. CONCLUSIONS: This patient illustrates that the constellation of intrauterine growth retardation, central nervous system calcifications, and cerebellar hypoplasia, esophageal or urethral stenosis, and cytopenias, in the absence of congenital infection, may be due to Hoyeraal-Hreidarsson syndrome. Early diagnosis of Hoyeraal-Hreidarsson syndrome is important to optimize medical management and provide genetic counseling. C1 [Burris, Ashley M.] San Antonio Mil Med Ctr, San Antonio, TX USA. [Ballew, Bari J.; Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.; NCI DCEG Canc Sequencing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kentosh, Joshua B.; Turner, Clesson E.; Hartman, Kip R.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Norton, Scott A.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [NCI DCEG Canc Genomics] NCI Frederick, Canc Genom Res Lab, Leidos Biomed Res, Rockville, MD USA. [Nellan, Anandani; Gamper, Christopher] Johns Hopkins Univ, Dept Oncol, Div Pediat Oncol, Baltimore, MD USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E456,MSC 9772, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Tobias, Geoffrey/M-4135-2016 OI Tobias, Geoffrey/0000-0002-2878-8253 FU Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH FX Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH NR 30 TC 1 Z9 1 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAR PY 2016 VL 56 BP 62 EP 68 DI 10.1016/j.pediatrneurol.2015.12.005 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DH3JN UT WOS:000372683400014 PM 26810774 ER PT J AU Goey, AKL Figg, WD AF Goey, Andrew K. L. Figg, William D. TI UGT genotyping in belinostat dosing SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Belinostat; UGT1A1; Polymorphisms; Pharmacogenomics; Pharmacokinetics; Pharmacodynamics ID UDP-GLUCURONOSYLTRANSFERASE 1A1; IRINOTECAN-INDUCED NEUTROPENIA; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; GILBERTS-SYNDROME; PHASE-I; INDUCED HYPERBILIRUBINEMIA; GENETIC-VARIANTS; NEONATAL HYPERBILIRUBINEMIA; UGT1A1-ASTERISK-28 GENOTYPE AB Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1*28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1*60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1*28 and *60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy. Published by Elsevier Ltd. C1 [Goey, Andrew K. L.; Figg, William D.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, CCR, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM andrew.goey@nih.gov; figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Dr. Cindy H. Chau for critically reviewing the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. NR 67 TC 2 Z9 2 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD MAR PY 2016 VL 105 BP 22 EP 27 DI 10.1016/j.phrs.2016.01.002 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG9CE UT WOS:000372379600003 PM 26773202 ER PT J AU Reshma, RS Sreelatha, KH Somasundaram, V Kumar, SS Nadhan, R Nair, RS Srinivas, P AF Reshma, R. S. Sreelatha, K. H. Somasundaram, Veena Kumar, Satheesh S. Nadhan, Revathy Nair, Rakesh Sathish Srinivas, Priya TI Plumbagin, a naphthaquinone derivative induces apoptosis in BRCA 1/2 defective castrate resistant prostate cancer cells as well as prostate cancer stem-like cells SO PHARMACOLOGICAL RESEARCH LA English DT Article DE Plumbagin; Prostate cancer; BRCA1/2; Cancer stem cells ID NF-KAPPA-B; PROTHYMOSIN-ALPHA; CYCLE ARREST; IN-VIVO; GROWTH; PATHWAY; PROGRESSION; MODULATION; EXPRESSION; OVARIAN AB Eventhough the role of BRCA1/2 in hereditary prostatic cancer is being unleashed at a rapid rate; their optimal clinical management remains undefined. Cancer stem cells are thought to be responsible for cancer chemoresistance and relapse, thus they represent a significant concern for cancer prognosis and therapy. In this study, we have analyzed the effect of Plumbagin (PB) and structurally related naphthaquinones on BRCA1/2 silenced prostate cancer cells and the ability of PB to target stem cells. Our cell proliferation studies showed that both PC-3 and DU145 cells were more sensitive to PB, though all the compounds induced mitochondrial potential loss, DNA fragmentation and morphological changes which are indicative of apoptosis. Both BRCA1/2 siRNA transfected PC-3 and DU145 cells exhibited increased sensitivity to PB. Gene expression profiling post PB treatment in BRCA1/2 silenced cells revealed that PB has a putative role in tumor suppression in BRCA defective cancers. Using flow cytometric analysis we have proved that PB has the putative ability to directly target CSCs. Overall studies suggest that PB's antitumour mechanisms holds promise for novel therapeutic approaches against BRCA mutated cancers as well as CSCs. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Reshma, R. S.; Sreelatha, K. H.; Somasundaram, Veena; Kumar, Satheesh S.; Nadhan, Revathy; Nair, Rakesh Sathish; Srinivas, Priya] Rajiv Gandhi Ctr Biotechnol, Canc Res Program, Thiruvananthapuram, Kerala, India. [Somasundaram, Veena] NCI, Ctr Canc Res, Bldg 567,Room 254, Frederick, MD 21702 USA. [Nair, Rakesh Sathish] Dept Surg, 840 South Wood St, Chicago, IL 60612 USA. [Nair, Rakesh Sathish] Univ Illinois, Sch Med, 840 South Wood St, Chicago, IL 60612 USA. RP Srinivas, P (reprint author), Rajiv Gandhi Ctr Biotechnol, Canc Res Program, Thiruvananthapuram, Kerala, India. EM priyasrinivas@rgcb.res.in FU Board of Research in Nuclear Sciences (BRNS) Department of Atomic Energy, Govt. of India [2009/37/5/BRNS/1213, 37(1)/14/16/2014]; Indian Council of Medical Research (ICMR) [3/2/2/215/2013/NCD-III (OPA-29483), 53/20/2012]; Rajiv Gandhi Centre for Biotechnology; Kerala State Council for Science Technology and Environment [016/SRSHS/2011/CSTE]; Council for Scientific and Industrial Research (CSIR), Govt. of India; University Grants Commission (UGC), Govt. of India; BRNS; ICMR FX We thank Dr. Asoke Banerji, Professor, Amrita School of Biotechnology, Kerala, India, for the generous gift of 1,4-NQ, This work was supported by Board of Research in Nuclear Sciences (BRNS) Department of Atomic Energy, Govt. of India (BRNS Project No. 2009/37/5/BRNS/1213 and No.37(1)/14/16/2014) and Indian Council of Medical Research (ICMR) ICMR Project No. 3/2/2/215/2013/NCD-III (OPA-29483 & No.53/20/2012). The authors also acknowledge financial support from intramural grant, Rajiv Gandhi Centre for Biotechnology, Kerala State Council for Science Technology and Environment (No.016/SRSHS/2011/CSTE) to PS. R.R.S acknowledges research fellowship from BRNS and ICMR and S.K.H acknowledges Senior Research Fellowship from ICMR. The authors also acknowledge the research fellowship from the Council for Scientific and Industrial Research (CSIR), Govt. of India to V.S., R.N and R.S. and from the University Grants Commission (UGC), Govt. of India to S.K.S. NR 50 TC 2 Z9 2 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD MAR PY 2016 VL 105 BP 134 EP 145 DI 10.1016/j.phrs.2016.01.012 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG9CE UT WOS:000372379600014 PM 26808083 ER PT J AU Bayik, D Gursel, I Klinman, DM AF Bayik, Defne Gursel, Ihsan Klinman, Dennis M. TI Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides SO PHARMACOLOGICAL RESEARCH LA English DT Review DE CpG oligonucleotide; IRF8; IRF5; Dendritic cell; TLR9 ID STIMULATORY CPG OLIGONUCLEOTIDES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DENDRITIC CELL ACTIVATION; INDUCED IMMUNE ACTIVATION; TOLL-LIKE RECEPTORS; REGULATORY T-CELLS; SUPPRESSIVE OLIGODEOXYNUCLEOTIDES; INHIBITORY OLIGONUCLEOTIDES; BACTERIAL-DNA; IN-VITRO AB Synthetic oligodeoxynucleotides that can down-regulate cellular elements of the immune system have been developed and are being widely studied in preclinical models. These agents vary in sequence, mechanism of action, and cellular target(s) but share the ability to suppress a plethora of inflammatory responses. This work reviews the types of immunosuppressive oligodeoxynucleotide (Sup ODN) and compares their therapeutic activity against diseases characterized by pathologic levels of immune stimulation ranging from autoimmunity to septic shock to cancer (see graphical abstract). The mechanism(s) underlying the efficacy of Sup ODN and the influence size, sequence and nucleotide backbone on function are considered. Published by Elsevier Ltd. C1 [Bayik, Defne; Klinman, Dennis M.] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. [Bayik, Defne; Gursel, Ihsan] Bilkent Univ, Mol Biol & Genet Dept, Therapeut ODN Res Lab, TR-06800 Ankara, Turkey. RP Klinman, DM (reprint author), Frederick Natl Lab Canc Res, Bldg 567 Rm 205, Frederick, MD 21702 USA.; Gursel, I (reprint author), Bilkent Univ, Fac Sci, Biotherapeut ODN Res Lab, TR-06800 Ankara, Turkey. EM ihsangursel@bilkent.edu.tr; klinmand@mail.nih.gov FU Intramural Research Program of National Cancer Institute of National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 106 TC 2 Z9 2 U1 3 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD MAR PY 2016 VL 105 BP 216 EP 225 DI 10.1016/j.phrs.2015.11.010 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG9CE UT WOS:000372379600023 PM 26779666 ER PT J AU Adesanya, MR Bailey, W Belcher, DC Beltran, M Branch, T Brand, MK Craft, EM Donahue, AH Dye, BA Thornton-Evans, G Garcia, I Hyman, F Joskow, R Lester, AM Makrides, NS Manski, RJ Mehegan, M Mouden, LD Nelson, D Norris, L O'Hara, J Cherry-Peppers, G Ricks, TL Rollins, R AF Adesanya, Margo R. Bailey, William Belcher, Donald C. Beltran, Marco Branch, Tracy Brand, Marcia K. Craft, Edwin M. Donahue, Agnes H. Dye, Bruce A. Thornton-Evans, Gina Garcia, Isabel Hyman, Frederick Joskow, Renee Lester, Arlene M. Makrides, Nicholas S. Manski, Richard J. Mehegan, Marian Mouden, Lynn Douglas Nelson, Danielle Norris, Laurie O'Hara, Jessica Cherry-Peppers, Gail Ricks, Timothy L. Rollins, Rochelle CA US Dept Hlth Human Serv TI US Department of Health and Human Services Oral Health Strategic Framework, 2014-2017 SO PUBLIC HEALTH REPORTS LA English DT Editorial Material ID DENTAL-CARE; CARIES C1 [Adesanya, Margo R.] Natl Inst Dent & Craniofacial Res, NIH, Off Sci Policy & Anal, Rockville, MD USA. [Bailey, William] Ctr Dis Control & Prevent, Atlanta, GA USA. [Belcher, Donald C.] US Coast Guard, Qual & Performance Improvement, Washington, DC USA. [Beltran, Marco; Rollins, Rochelle] Adm Children & Families, Washington, DC USA. [Branch, Tracy; Lester, Arlene M.] OS Off Minor Hlth, Washington, DC USA. [Brand, Marcia K.; Joskow, Renee] Hlth Resources & Serv Adm, Rockville, MD USA. [Craft, Edwin M.] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Donahue, Agnes H.] OS Off Assistant Secretary Hlth, OASH Intergovt Affairs RHA, Washington, DC USA. [Dye, Bruce A.] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Thornton-Evans, Gina] Ctr Dis Control & Prevent, Div Oral Hlth, Atlanta, GA USA. [Garcia, Isabel] Natl Inst Dent & Craniofacial Res, NIH, Rockville, MD USA. [Hyman, Frederick] US FDA, Ctr Drug Evaluat & Res, Div Dermatol & Dent Prod, Silver Spring, MD USA. [Makrides, Nicholas S.] Fed Bur Prisons, Washington, DC USA. [Manski, Richard J.] Agcy Healthcare Res & Qual, Rockville, MD USA. [Mehegan, Marian] Off Assistant Secretary Hlth, Off Womens Hlth, Washington, DC USA. [Mouden, Lynn Douglas] Ctr Medicare & Medicaid Serv, Div Qual Evaluat & Hlth Outcomes, Children & Adults Hlth Programs Grp, Washington, DC USA. [Nelson, Danielle] Adm Community Living, Washington, DC USA. [Norris, Laurie] Ctr Medicare & Medicaid Serv, Oral Hlth Initiat, Div Qual Evaluat & Hlth Outcomes, Washington, DC USA. [O'Hara, Jessica] Off Secretary, Off Assistant Secretary Planning & Evaluat, Washington, DC USA. [Cherry-Peppers, Gail] US FDA, Ctr Tobacco Prod, Off Sci, Silver Spring, MD USA. [Ricks, Timothy L.] Indian Hlth Serv, Nashville Area Off Publ Hlth, Nashville, TN USA. RP Adesanya, MR (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Off Sci Policy & Anal, Rockville, MD USA. NR 56 TC 0 Z9 0 U1 2 U2 2 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 MAR-APR PY 2016 VL 131 IS 2 BP 242 EP 257 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG9HH UT WOS:000372392900007 ER PT J AU Panchision, DM AF Panchision, David M. TI Concise Review: Progress and Challenges in Using Human Stem Cells for Biological and Therapeutics Discovery: Neuropsychiatric Disorders SO STEM CELLS LA English DT Review DE Induced pluripotent stem cells; Induced neuronal cells; Schizophrenia; Bipolar disorder; Autism spectrum disorders; Genetics; Drug discovery ID FRAGILE-X-SYNDROME; AUTISM SPECTRUM DISORDERS; INNERVATING MOTOR-NEURONS; IPSC-DERIVED NEURONS; HUMAN SOMATIC-CELLS; HUMAN FIBROBLASTS; RETT-SYNDROME; HUMAN BRAIN; BIPOLAR DISORDER; DIRECTED DIFFERENTIATION AB In facing the daunting challenge of using human embryonic and induced pluripotent stem cells to study complex neural circuit disorders such as schizophrenia, mood and anxiety disorders, and autism spectrum disorders, a 2012 National Institute of Mental Health workshop produced a set of recommendations to advance basic research and engage industry in cell-based studies of neuropsychiatric disorders. This review describes progress in meeting these recommendations, including the development of novel tools, strides in recapitulating relevant cell and tissue types, insights into the genetic basis of these disorders that permit integration of risk-associated gene regulatory networks with cell/circuit phenotypes, and promising findings of patient-control differences using cell-based assays. However, numerous challenges are still being addressed, requiring further technological development, approaches to resolve disease heterogeneity, and collaborative structures for investigators of different disciplines. Additionally, since data obtained so far is on small sample sizes, replication in larger sample sets is needed. A number of individual success stories point to a path forward in developing assays to translate discovery science to therapeutics development. C1 [Panchision, David M.] NIMH, Div Neurosci & Basic Behav Sci, 6001 Execut Blvd,MSC 9641, Bethesda, MD 20892 USA. RP Panchision, DM (reprint author), NIMH, Div Neurosci & Basic Behav Sci, 6001 Execut Blvd,MSC 9641, Bethesda, MD 20892 USA. EM panchisiond@mail.nih.gov FU National Institute of Mental Health FX I thank Margaret Grabb, Douglas Meinecke, and Lois Winsky at NIMH and Kristen Fabre at NCATS for thoughtful advice and Sergiu Pasca for the use of primary data images. Support for and clearance of this manuscript was provided by the National Institute of Mental Health. The views expressed do not necessarily represent the views of the NIMH, the National Institutes of Health, the Department of Health and Human Services, or the United States Government. NR 149 TC 2 Z9 2 U1 6 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD MAR PY 2016 VL 34 IS 3 BP 523 EP 536 DI 10.1002/stem.2295 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DH1NU UT WOS:000372552600001 PM 26840228 ER PT J AU Xie, ZH Chan, EC Druey, KM AF Xie, Zhihui Chan, Eunice C. Druey, Kirk M. TI R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity SO AAPS JOURNAL LA English DT Review DE G proteins; immune system; inflammation; RGS proteins ID T-LYMPHOCYTE MIGRATION; MULTIPLE-SCLEROSIS; COUPLED RECEPTOR; GENE-EXPRESSION; B-LYMPHOCYTES; DIFFERENTIAL EXPRESSION; NEGATIVE REGULATOR; CELL-ACTIVATION; DENDRITIC CELLS; DRUG DISCOVERY AB G protein-coupled receptors (GPCRs) have important functions in both innate and adaptive immunity, with the capacity to bridge interactions between the two arms of the host responses to pathogens through direct recognition of secreted microbial products or the by-products of host cells damaged by pathogen exposure. In the mid-1990s, a large group of intracellular proteins was discovered, the regulator of G protein signaling (RGS) family, whose main, but not exclusive, function appears to be to constrain the intensity and duration of GPCR signaling. The R4/B subfamily-the focus of this review-includes RGS1-5, 8, 13, 16, 18, and 21, which are the smallest RGS proteins in size, with the exception of RGS3. Prominent roles in the trafficking of B and T lymphocytes and macrophages have been described for RGS1, RGS13, and RGS16, while RGS18 appears to control platelet and osteoclast functions. Additional G protein independent functions of RGS13 have been uncovered in gene expression in B lymphocytes and mast cell-mediated allergic reactions. In this review, we discuss potential physiological roles of this RGS protein subfamily, primarily in leukocytes having central roles in immune and inflammatory responses. We also discuss approaches to target RGS proteins therapeutically, which represents a virtually untapped strategy to combat exaggerated immune responses leading to inflammation. C1 [Xie, Zhihui; Chan, Eunice C.; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 50 South Dr Room 4154, Bethesda, MD 20892 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 50 South Dr Room 4154, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 117 TC 3 Z9 3 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2016 VL 18 IS 2 BP 294 EP 304 DI 10.1208/s12248-015-9847-0 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG3NV UT WOS:000371977400003 PM 26597290 ER PT J AU Diao, XX Scheidweiler, KB Wohlfarth, A Pang, SK Kronstrand, R Huestis, MA AF Diao, Xingxing Scheidweiler, Karl B. Wohlfarth, Ariane Pang, Shaokun Kronstrand, Robert Huestis, Marilyn A. TI In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22 SO AAPS JOURNAL LA English DT Article DE FDU-PB-22; FUB-PB-22; hepatocyte metabolism; high-resolution mass spectrometry; synthetic cannabinoid ID RESOLUTION MASS-SPECTROMETRY; HUMAN HEPATOCYTES; ILLEGAL PRODUCTS; 5-FLUORO ANALOG; DRUG DISCOVERY; DESIGNER DRUGS; HUMAN URINE; IDENTIFICATION; PHARMACOLOGY; 3-N-BUTYLPHTHALIDE AB In 2014, FDU-PB-22 and FUB-PB-22, two novel synthetic cannabinoids, were detected in herbal blends in Japan, Russia, and Germany and were quickly added to their scheduled drugs list. Unfortunately, no human metabolism data are currently available, making it challenging to confirm their intake. The present study aims to identify appropriate analytical markers by investigating FDU-PB-22 and FUB-PB-22 metabolism in human hepatocytes and confirm the results in authentic urine specimens. For metabolic stability, 1 mu M FDU-PB-22 and FUB-PB-22 was incubated with human liver microsomes for up to 1 h; for metabolite profiling, 10 mu M was incubated with human hepatocytes for 3 h. Two authentic urine specimens from FDU-PB-22 and FUB-PB-22 positive cases were analyzed after beta-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Both FDU-PB-22 and FUB-PB-22 were rapidly metabolized in HLM with half-lives of 12.4 and 11.5 min, respectively. In human hepatocyte samples, we identified seven metabolites for both compounds, generated by ester hydrolysis and further hydroxylation and/or glucuronidation. After ester hydrolysis, FDU-PB-22 and FUB-PB-22 yielded the samemetabolite M7, fluorobenzylindole-3-carboxylic acid (FBI-COOH). M7 and M6 (hydroxylated FBI-COOH) were the major metabolites. In authentic urine specimens after beta-glucuronidase hydrolysis, M6 and M7 also were the predominant metabolites. Based on our study, we recommend M6 (hydroxylated FBI-COOH) and M7 (FBI-COOH) as suitable urinary markers for documenting FDU-PB-22 and/or FUB-PB-22 intake. C1 [Diao, Xingxing; Scheidweiler, Karl B.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Chem & Drug Metab, IRP, NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. [Wohlfarth, Ariane; Kronstrand, Robert] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden. [Wohlfarth, Ariane; Kronstrand, Robert] Linkoping Univ, Dept Drug Res, S-58185 Linkoping, Sweden. [Pang, Shaokun] SCIEX Ltd, Redwood City, CA 94404 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Chem & Drug Metab, IRP, 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 is supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. FDU-PB-22 and FUB-PB-22 were generously donated by the US Drug Enforcement Administration. Molecular Discovery kindly provided the MetaSite software. NR 38 TC 8 Z9 8 U1 6 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2016 VL 18 IS 2 BP 455 EP 464 DI 10.1208/s12248-016-9867-4 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG3NV UT WOS:000371977400019 PM 26810398 ER PT J AU Dutta, N Helton, SG Schwandt, M Zhu, X Momenan, R Lohoff, FW AF Dutta, Nisha Helton, Sarah G. Schwandt, Melanie Zhu, Xi Momenan, Reza Lohoff, Falk W. TI Genetic Variation in the Vesicular Monoamine Transporter 1 (VMAT1/SLC18A1) Gene and Alcohol Withdrawal Severity SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Withdrawal; Presynaptic Monoamine Transporter; Genetics; VMAT1 ID DELIRIUM-TREMENS; POLYMORPHISMS; ASSOCIATION; DEPENDENCE; AMPHETAMINE; SYMPTOMS; KNOCKOUT; SEIZURES; SYSTEM AB BackgroundAlcohol withdrawal (AW) can be a serious consequence of alcohol dependence and consists of various neurochemical adaptations in the brain. One such neuroadaptation occurs in the monoamine neurotransmitter system. Recently, a functional variant in the presynaptic vesicular monoamine transporter gene (VMAT1/SLC18A1Thr136Ilers1390938) was found to significantly increase transport of monoamines into synaptic vesicles invitro. We hypothesize that the alteration of magnitude of monoamine release contributes to severity of AW symptoms. MethodsAlcohol-dependent individuals (n=609; European American n=340; African American n=216; other n=53) were administered the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) questionnaire at the time of inpatient admission. Patients were subsequently genotyped for 12 single nucleotide polymorphism (SNP) markers in VMAT1. Association analyses were conducted on the combined sample and separated by ethnicity. ResultsSingle marker association tests revealed a significant association between 3 VMAT1 markers and CIWA-Ar scores in the EA sample. The minor alleles of rs1390938 (A) and rs952859 (C) were significantly associated with lower CIWA-Ar scores (p=0.0006; p=0.0007), whereas the minor allele of rs3779672 (G) was significantly associated with higher scores (p=0.006). Additionally, these 3 SNPs were found in a haplotype block that was significantly associated with lower CIWA-Ar scores after haplotype analyses were run (p=0.009). ConclusionsThis study shows that genetic variants in VMAT1, including the functional SNP rs1390938, contribute to the severity of AW in patients of European descent. Our data show for the first time a role of presynaptic neurotransmitter release in AW severity. This finding could contribute to identifying patients at risk for severe AW and shed light into the pathophysiology of AW and its treatment. C1 [Dutta, Nisha; Helton, Sarah G.; Schwandt, Melanie; Lohoff, Falk W.] NIAAA, Sect Clin Genom & Expt Therapeut, NIH, 10 Ctr Dr,10CRC-2-2352, Bethesda, MD 20892 USA. [Zhu, Xi; Momenan, Reza] NIAAA, Sect Brain & Electrophys & Imaging, NIH, Bethesda, MD 20892 USA. RP Lohoff, FW (reprint author), NIAAA, Sect Clin Genom & Expt Therapeut, NIH, 10 Ctr Dr,10CRC-2-2352, Bethesda, MD 20892 USA. EM falk.lohoff@nih.gov RI Schwandt, Melanie/L-9866-2016; Lohoff, Falk/M-7951-2016 FU intramural research funding from National Institute on Alcohol Abuse and Alcoholism FX The study was supported by intramural research funding from the National Institute on Alcohol Abuse and Alcoholism. NR 40 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2016 VL 40 IS 3 BP 474 EP 481 DI 10.1111/acer.12991 PG 8 WC Substance Abuse SC Substance Abuse GA DG4EC UT WOS:000372023000005 PM 26876819 ER PT J AU Yokoyama, A Brooks, PJ Yokoyama, T Mizukami, T Matsui, T Kimura, M Matsushita, S Higuchi, S Maruyama, K AF Yokoyama, Akira Brooks, Philip J. Yokoyama, Tetsuji Mizukami, Takeshi Matsui, Toshifumi Kimura, Mitsuru Matsushita, Sachio Higuchi, Susumu Maruyama, Katsuya TI Blood Leukocyte Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Acetaldehyde; Alcohol Dehydrogenase; Alcoholic; Aldehyde Dehydrogenase; Leukocyte; White Blood Cell ID FOLATE-DEFICIENCY; LIVER-DISEASE; BONE-MARROW; ACETALDEHYDE; ETHANOL; METABOLISM; RISK; MICE; GRANULOCYTES; INFLAMMATION AB BackgroundRoughly 40% of East Asians have inactive aldehyde dehydrogenase-2 (ALDH2) encoded by the ALDH2*2 allele, and 90% have highly active alcohol dehydrogenase-1B (ADH1B) encoded by the ADH1B*2 allele. Macrocytosis and macrocytic anemia in alcoholics have been associated with ADH1B and ALDH2gene variants which increase acetaldehyde (AcH) levels. MethodsWe investigated the relationship between ADH1B*2, ALDH2*2, and leukocyte counts of Japanese alcoholic men (N=1,661). ResultsAfter adjusting for age, drinking habits, smoking habits, body mass index, presence of liver cirrhosis, and serum levels of C-reactive protein, we found that total and differential leukocyte counts were lower in the presence of the ALDH2*1/*2 genotype (vs. ALDH2*1/*1 genotype). ALDH2*2/*2 carriers were not found in our study population. Leukocyte, granulocyte, and monocyte counts were also lower in the presence of ADH1B*2 (vs. ADH1B*1/*1 genotype), but the lymphocyte count was higher. The ALDH2*1/*2 genotype was associated with leukocytopenia (<4,000/l; adjusted odds ratio [95% confidence interval]=1.89 [1.27 to 2.80]), granulocytopenia (<2,000/l; 1.86 [1.22 to 2.82]), monocytopenia (<250/l; 2.22 [1.49 to 3.29]), and lymphocytopenia (<1,000/l; 1.93 [1.32 to 2.83]). In contrast, the ADH1B*2 had the opposite effect on lymphocytopenia (0.65 [0.46 to 0.93]). Considering genotype effects under conditions of immune stimulation, we observed suppressive effects of ADH1B*2 allele on leukocytosis (9,000/l; 0.69 [0.50 to 0.97]), granulocytosis (6,500/l; 0.66 [0.47 to 0.93]), and monocytosis (750/l; 0.56 [0.39 to 0.79]). The ADH1B*2 plus ALDH2*1/*2 combination had the greatest suppressive effects on the leukocyte, granulocyte, and monocyte counts. ConclusionsThe total and differential blood leukocyte counts of Japanese alcoholics were strongly affected by their ADH1B and ALDH2 gene variants. High AcH exposure levels probably play a critical role in the suppression of blood leukocyte counts in alcoholics. C1 [Yokoyama, Akira; Mizukami, Takeshi; Matsui, Toshifumi; Kimura, Mitsuru; Matsushita, Sachio; Higuchi, Susumu; Maruyama, Katsuya] Natl Hosp Org, Kurihama Med & Addict Ctr, Kanagawa, Japan. [Brooks, Philip J.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Yokoyama, Tetsuji] Natl Inst Publ Hlth, Dept Hlth Promot, Saitama, Japan. [Matsui, Toshifumi] Kyorin Univ Hosp, Dept Geriatr Med, Tokyo, Japan. [Brooks, Philip J.] NIH, Natl Ctr Adv Translat Sci, Div Clin Innovat, Bldg 10, Bethesda, MD 20892 USA. RP Yokoyama, A (reprint author), Natl Hosp Org, Kurihama Med & Addict Ctr, Clin Res Unit, 5-3-1 Nobi, Yokosuka, Kanagawa 2390841, Japan. EM a_yokoyama@kurihama1.hosp.go.jp NR 49 TC 1 Z9 1 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2016 VL 40 IS 3 BP 507 EP 517 DI 10.1111/acer.12983 PG 11 WC Substance Abuse SC Substance Abuse GA DG4EC UT WOS:000372023000009 PM 26917006 ER PT J AU Komori, M Lin, YC Cortese, I Blake, A Ohayon, J Cherup, J Maric, D Kosa, P Wu, TX Bielekova, B AF Komori, Mika Lin, Yen Chih Cortese, Irene Blake, Andrew Ohayon, Joan Cherup, Jamie Maric, Dragan Kosa, Peter Wu, Tianxia Bielekova, Bibiana TI Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID CEREBROSPINAL-FLUID; PHASE-I; B-CELLS; MONOCLONAL-ANTIBODY; LYMPHOMA; TRIAL; THERAPY; NEURODEGENERATION; INFLAMMATION; IDEC-C2B8 AB Objective: Inaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low-Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction? MethodsPatients aged 18-65years were randomly assigned to rituximab or placebo. Protocol-stipulated interim analysis quantified the efficacy of B-cell depletion. ResultsThe efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B-cell-related CSF biomarkers (sCD21 and B-cell activating factor) changed only in the active-treatment arm. While CSF B cells were killed robustly (median -79.71%, P=0.0176), B cells in CNS tissue were depleted inadequately (similar to-10-20%, P<0.0001). Consequently, the T-cell-specific CSF biomarker sCD27 decreased slightly (-10.97%, P=0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56(dim) NK cells contribute to decreased efficacy of rituximab in the CNS. InterpretationBiomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS-inflammation targeting monoclonal antibodies. C1 [Komori, Mika; Lin, Yen Chih; Blake, Andrew; Cherup, Jamie; Kosa, Peter; Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cortese, Irene; Ohayon, Joan] NINDS, Neuroimmunol Clin, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Clin Neurosci Program, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bielekova, Bibiana] NIH, NIH Ctr Human Immunol CHI, Bldg 10, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Branch NIB, NIH, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov NR 33 TC 10 Z9 10 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD MAR PY 2016 VL 3 IS 3 BP 166 EP 179 DI 10.1002/acn3.293 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DG2WS UT WOS:000371931900002 PM 27042677 ER PT J AU Postnikov, YV Bustin, M AF Postnikov, Yuri V. Bustin, Michael TI Functional interplay between histone H1 and HMG proteins in chromatin SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE Histone H1; HMG proteins; Chromatin ID MOBILITY-GROUP PROTEINS; GROUP CHROMOSOMAL-PROTEINS; 4-WAY JUNCTION DNA; RNA-POLYMERASE-II; LINKER HISTONES; LIVING CELLS; DYNAMIC INTERACTION; BINDING PROTEINS; TRANSCRIPTION; NUCLEOSOMES AB The dynamic interaction of nucleosome binding proteins with their chromatin targets is an important element in regulating the structure and function of chromatin. Histone H1 variants and High Mobility Group (HMG) proteins are ubiquitously expressed in all vertebrate cells, bind dynamically to chromatin, and are known to affect chromatin condensation and the ability of regulatory factors to access their genomic binding sites. Here, we review the studies that focus on the interactions between H1 and HMGs and highlight the functional consequences of the interplay between these architectural chromatin binding proteins. H-1 and HMG proteins are mobile molecules that bind to nucleosomes as members of a dynamic protein network. All HMGs compete with H1 for chromatin binding sites, in a dose dependent fashion, but each HMG family has specific effects on the interaction of H1 with chromatin. The interplay between H1 and HMGs affects chromatin organization and plays a role in epigenetic regulation. Published by Elsevier B.V. C1 [Postnikov, Yuri V.; Bustin, Michael] NIH, Prot Sect, Lab Metab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Postnikov, YV (reprint author), NIH, Bldg 37 Room 3122,37 Convent Dr, Bethesda, MD 20892 USA. EM PostnikY@mail.nih.gov RI Bustin, Michael/G-6155-2015 FU CCR, NCI, NIH [ZIA BC011154, ZIA BC004496] FX The literature on H1 and HMGs is relatively large and we could not acknowledge and quote all the pertinent references. We do apologize to the authors which we did not quote. This research was supported by project #s ZIA BC011154 and ZIA BC004496 from the Intramural Research Programs of the CCR, NCI, NIH. NR 82 TC 5 Z9 5 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAR PY 2016 VL 1859 IS 3 SI SI BP 462 EP 467 DI 10.1016/j.bbagrm.2015.10.006 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DG2ZS UT WOS:000371939900006 PM 26455954 ER PT J AU Bat, T Bat, BE El-Moghraby, A Patel, S Feng, XM Dunbar, CE Sarac, E AF Bat, Taha Bat, Betul E. El-Moghraby, Ahmed Patel, Samir Feng, Xingmin Dunbar, Cynthia E. Sarac, Erdal TI Thrombopoietic status of patients on haemodialysis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE thrombopoietin; immature platelet fraction; absolute immature platelet number; haemodialysis; IL1A (IL1) ID BONE-MARROW; THROMBOCYTOPENIA; MEMBRANES AB Thrombocytopenia is a potential dialysis-related treatment complication. Developments in bio-compatible dialyser membranes have decreased the occurrence of thrombocytopenia. We investigated whether thrombopoiesis is impaired in haemodialysis patients by measuring the thrombopoietin level and absolute immature platelet number (AIPN) in the blood of patients undergoing haemodialysis. Samples were collected from the dialysis tubing pre- and post- haemodialysis in a cohort of 45 well-characterized haemodialysis patients. Thrombopoietin levels and AIPN increased following haemodialysis, despite no change in platelet count. Observed increase in release of immature platelets from the bone marrow following haemodialysis indicates possible complement activation secondary to interaction between blood constituents and the dialysis membrane. C1 [Bat, Taha; Bat, Betul E.; El-Moghraby, Ahmed; Patel, Samir; Sarac, Erdal] Northeastern Ohio Med Univ NEOMED, Western Reserve Hlth Educ, Youngstown, OH 44504 USA. [Feng, Xingmin; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Bat, T (reprint author), Northeastern Ohio Med Univ NEOMED, Western Reserve Hlth Educ, Internal Med, 500 Gypsy Lane, Youngstown, OH 44504 USA. EM md.tbat@gmail.com OI Patel, Samir/0000-0002-4471-2996 FU Division of Intramural Research, National Heart, Lung, and Blood Institute FX We would like to thank Martha Pallant, of the Department of Laboratory Medicine at Northside Medical Center for her expertise and assistance with this study and Dr. Neal S Young, Hematology Branch, NHLBI, for supporting these studies. This work was supported in part by the Division of Intramural Research, National Heart, Lung, and Blood Institute. NR 14 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2016 VL 172 IS 6 BP 954 EP 957 DI 10.1111/bjh.13918 PG 4 WC Hematology SC Hematology GA DG7NA UT WOS:000372269800013 PM 26887628 ER PT J AU Drahos, J Schwameis, K Orzolek, LD Hao, HP Birner, P Taylor, PR Pfeiffer, RM Schoppmann, SF Cook, MB AF Drahos, Jennifer Schwameis, Katrin Orzolek, Linda D. Hao, Haiping Birner, Peter Taylor, Phillip R. Pfeiffer, Ruth M. Schoppmann, Sebastian F. Cook, Michael B. TI MicroRNA Profiles of Barrett's Esophagus and Esophageal Adenocarcinoma: Differences in Glandular Non-native Epithelium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HIGH-GRADE DYSPLASIA; DOWN-REGULATION; NASOPHARYNGEAL CARCINOMA; GASTRIC-CARCINOMA; TUMOR-SUPPRESSOR; BREAST-CANCER; EXPRESSION; TARGETS; PROGRESSION AB Background: The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus. Methods: In a case-control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using Nano-String miRNA v2. We tested differences in detection by case group using the chi(2) test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E-05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation. Results: We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with > 5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case-control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity. Conclusion: This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma. C1 [Drahos, Jennifer; Taylor, Phillip R.; Pfeiffer, Ruth M.; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, DDHS, Bethesda, MD 20892 USA. [Schwameis, Katrin; Birner, Peter; Schoppmann, Sebastian F.] Med Univ Vienna, Upper GI Serv, CCC GET Unit, Dept Surg, Vienna, Austria. [Orzolek, Linda D.; Hao, Haiping] Johns Hopkins Med Inst, Deep Sequencing & Microarray Core, Baltimore, MD USA. RP Drahos, J (reprint author), NCI, 9609 Med Ctr Dr,Rm 7E 226,MSC 9774, Bethesda, MD 20892 USA. EM jennifer.drahos@nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural Program of NCI at NIH; Department of Health and Human Services FX This work was supported by the Intramural Program of the NCI at the NIH and the Department of Health and Human Services. NR 58 TC 1 Z9 1 U1 2 U2 5 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 MAR PY 2016 VL 25 IS 3 BP 429 EP 437 DI 10.1158/1055-9965.EPI-15-0161 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6EA UT WOS:000372173900001 PM 26604271 ER PT J AU Winham, SJ Pirie, A Chen, YA Larson, MC Fogarty, ZC Earp, MA Anton-Culver, H Bandera, EV Cramer, D Doherty, JA Goodman, MT Gronwald, J Karlan, BY Kjaer, SK Levine, DA Menon, U Ness, RB Pearce, CL Pejovic, T Rossing, MA Wentzensen, N Bean, YT Bisogna, M Brinton, LA Carney, ME Cunningham, JM Cybulski, C Defazio, A Dicks, EM Edwards, RP Gayther, SA Gentry-Maharaj, A Gore, M Iversen, ES Jensen, A Johnatty, SE Lester, J Lin, HY Lissowska, J Lubinski, J Menkiszak, J Modugno, F Moysich, KB Orlow, I Pike, MC Ramus, SJ Song, HL Terry, KL Thompson, PJ Tyrer, JP van den Berg, DJ Vierkant, RA Vitonis, AF Walsh, C Wilkens, LR Wu, AH Yang, H Ziogas, A Berchuck, A Chenevix-Trench, G Schildkraut, JM Permuth-Wey, J Phelan, CM Pharoah, PDP Fridley, BL Sellers, TA Goode, EL AF Winham, Stacey J. Pirie, Ailith Chen, Yian Ann Larson, Melissa C. Fogarty, Zachary C. Earp, Madalene A. Anton-Culver, Hoda Bandera, Elisa V. Cramer, Daniel Doherty, Jennifer A. Goodman, Marc T. Gronwald, Jacek Karlan, Beth Y. Kjaer, Susanne K. Levine, Douglas A. Menon, Usha Ness, Roberta B. Pearce, Celeste L. Pejovic, Tanja Rossing, Mary Anne Wentzensen, Nicolas Bean, Yukie T. Bisogna, Maria Brinton, Louise A. Carney, Michael E. Cunningham, Julie M. Cybulski, Cezary Defazio, Anna Dicks, Ed M. Edwards, Robert P. Gayther, Simon A. Gentry-Maharaj, Aleksandra Gore, Martin Iversen, Edwin S. Jensen, Allan Johnatty, Sharon E. Lester, Jenny Lin, Hui-Yi Lissowska, Jolanta Lubinski, Jan Menkiszak, Janusz Modugno, Francesmary Moysich, Kirsten B. Orlow, Irene Pike, Malcolm C. Ramus, Susan J. Song, Honglin Terry, Kathryn L. Thompson, Pamela J. Tyrer, Jonathan P. van den Berg, David J. Vierkant, Robert A. Vitonis, Allison F. Walsh, Christine Wilkens, Lynne R. Wu, Anna H. Yang, Hannah Ziogas, Argyrios Berchuck, Andrew Chenevix-Trench, Georgia Schildkraut, Joellen M. Permuth-Wey, Jennifer Phelan, Catherine M. Pharoah, Paul D. P. Fridley, Brooke L. Sellers, Thomas A. Goode, Ellen L. CA Australian Ovarian Canc Study Grp TI Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; BREAST-CANCER; MUTATION CARRIERS; COMMON VARIANTS; RARE VARIANTS; BRCA1; WOMEN; AUTOPHAGY; DISEASES AB Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independent-EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (P-meta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (P-meta = 1.1E-6; P-corrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. C1 [Winham, Stacey J.; Larson, Melissa C.; Fogarty, Zachary C.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Pirie, Ailith] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Chen, Yian Ann; Lin, Hui-Yi; Permuth-Wey, Jennifer; Phelan, Catherine M.; Sellers, Thomas A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Earp, Madalene A.; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Bandera, Elisa V.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Cramer, Daniel; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cramer, Daniel; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. [Cramer, Daniel; Terry, Kathryn L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Lebanon, NH USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Gronwald, Jacek; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Karlan, Beth Y.; Lester, Jenny; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kjaer, Susanne K.; Jensen, Allan] Danish Canc Soc, Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark. [Kjaer, Susanne K.] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Levine, Douglas A.; Bisogna, Maria] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Dept Womens Canc, Gynaecol Canc Res Ctr, London, England. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Pearce, Celeste L.; Gayther, Simon A.; Pike, Malcolm C.; Ramus, Susan J.; van den Berg, David J.; Wu, Anna H.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Pejovic, Tanja; Bean, Yukie T.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja; Bean, Yukie T.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Wentzensen, Nicolas; Brinton, Louise A.; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Carney, Michael E.] Univ Hawaii, John A Burns Sch Med, Dept Obstet & Gynecol, Honolulu, HI 96822 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN 55905 USA. [Cybulski, Cezary] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Defazio, Anna] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia. [Defazio, Anna; Chenevix-Trench, Georgia] Univ Sydney, Westmead Millennium Inst, Ctr Canc Res, Sydney, NSW 2006, Australia. [Dicks, Ed M.; Song, Honglin; Tyrer, Jonathan P.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Sch Med, Div Gynecol Oncol, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Johnatty, Sharon E.; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Surg Gynecol & Gynecol Oncol Adults & Adoles, Szczecin, Poland. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Dept Epidemiol, Irvine, CA 92717 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Div, Herston, Qld, Australia. [Chenevix-Trench, Georgia; Australian Ovarian Canc Study Grp] Peter MacCallum Canc Inst, 481 Little Lonsdale St, Melbourne, Vic 3000, Australia. [Schildkraut, Joellen M.] Univ Virginia, Publ Hlth Serv, Charlottesville, VA USA. [Fridley, Brooke L.] Univ Kansas, Ctr Canc, Kansas IDeA Network Biomed Res Excellence Bioinfo, Kansas City, KS USA. RP Goode, EL (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. EM egoode@mayo.edu RI Menkiszak, Janusz/I-4036-2014; Johnatty, Sharon/R-8890-2016; Gronwald, Jacek/A-4576-2017; OI Johnatty, Sharon/0000-0002-7888-1966; Gronwald, Jacek/0000-0002-3643-2871; Ramus, Susan/0000-0003-0005-7798; Winham, Stacey/0000-0002-8492-9102; Ewing, Ailith/0000-0002-2272-1277 FU NIH Office of Research on Women's Health (Building Interdisciplinary Careers in Women's Health award) [K12HD065987]; Genetic Associations and Mechanisms in Oncology (GAME-ON); NCI Cancer Post-GWAS Initiative [U19-CA148112]; NHMRC; University of Sydney Cancer Research Fund; Cancer Institute NSW through Sydney West Translational Cancer Research Centre; NIH [R01 CA-149429]; Medical Research Council Studentship; Eve Appeal; Oak Foundation; AUS: U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; National Health & Medical Research Council of Australia [199600, 400281]; Cancer Council of New South Wales; Cancer Councils of Victoria; Cancer Councils of Queensland; Cancer Councils of South Australia; Cancer Councils of Tasmania; Cancer Foundation of Western Australia; HAW: NIH [R01-CA58598, N01-CN-55424, N01-PC-67001]; HOP: US Army Medical Research and Material Command [DAMD17-02-1-0669]; NCI [K07-CA080668, R01-CA95023, R01-CA126841]; NIH/National Center for Research Resources/General Clinical Research Center [M01-RR000056]; LAX: American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; NCI, Bethesda, MD [R01-CA61107]; Danish Cancer Society, Copenhagen, Denmark [94 222 52]; Mermaid I project; MAC and MAY: NIH [R01-CA122443, P30-CA15083, P50-CA136393]; NCO: Department of Defense [DAMD17-02-1-0666]; NEC: NIH [R01-CA54419, P50-CA105009]; Department of Defense [W81XWH-10-1-02802]; NJO: NCI [NIH-K07 CA095666, NIH-K22-CA138563, P30-CA072720]; Cancer Institute of New Jersey; ORE: OHSU Foundation; POC: Pomeranian Medical University; RMH: Cancer Research UK; Royal Marsden Hospital; SEA: Cancer Research UK [C490/A10119 C490/A10124]; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy; Eve Appeal (The Oak Foundation); National Institute for Health Research University College London Hospitals Biomedical Research Centre; California Cancer Research Program [0001389V-20170, 2II0200]; [P50-CA159981]; [USC: P01-CA17054]; [P30-CA14089]; [R01-CA61132]; [N01-PC67010]; [N01-CN025403]; [R03-CA113148]; [R03-CA115195] FX This work was supported by grants from the NIH Office of Research on Women's Health (Building Interdisciplinary Careers in Women's Health award K12HD065987; to S.J. Winham) and Genetic Associations and Mechanisms in Oncology (GAME-ON), an NCI Cancer Post-GWAS Initiative (U19-CA148112; to T.A. Sellers). G. Chenevix-Trench is supported by Fellowships from NHMRC. A. deFazio is supported by the University of Sydney Cancer Research Fund and the Cancer Institute NSW through the Sydney West Translational Cancer Research Centre. C.M. Phelan is funded in part by NIH R01 CA-149429. A. Pirie is funding in part by a Medical Research Council Studentship. A. Gentry-Maharaj is supported by Eve Appeal and the Oak Foundation. In addition, the individual study sites were supported by: AUS: U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729; to G. Chenevix-Trench), National Health & Medical Research Council of Australia (199600 and 400281; to G. Chenevix-Trench), Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia. DOV: Funding for this study was provided by U19-CA148112 (to T. Sellers); HAW: NIH (R01-CA58598, N01-CN-55424, and N01-PC-67001; to M.T. Goodman); HOP: US Army Medical Research and Material Command DAMD17-02-1-0669 (to F. Modugno); NCI K07-CA080668, R01-CA95023, R01-CA126841 (to F. Modugno); P50-CA159981 (to F. Modugno); NIH/National Center for Research Resources/General Clinical Research Center grant M01-RR000056 (to F. Modugno); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN; to B.Y. Karlan) and the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000124 (to B. Y. Karlan); MAL: funding for this study was provided by research grant R01-CA61107 from the NCI, Bethesda, MD (to S.K. Kjaer and A. Jensen); research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark (to S.K. Kjaer and A. Jensen); and the Mermaid I project (to S.K. Kjaer and A. Jenesn); MAC and MAY: NIH (R01-CA122443, P30-CA15083, P50-CA136393; to E.L. Goode); NCO: Department of Defense (DAMD17-02-1-0666; to J.M. Schildkraut); NEC: NIH R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802 (to K.L. Terry); NJO: NCI (NIH-K07 CA095666, NIH-K22-CA138563, and P30-CA072720; to E.V. Bandera) and the Cancer Institute of New Jersey (to E.V. Bandera); ORE: OHSU Foundation (to T. Pejovic); POC: Pomeranian Medical University (to J. Gronwald); RMH: Cancer Research UK (no grant number is available), Royal Marsden Hospital (to P.D. Pharoah); SEA: Cancer Research UK (C490/A10119 C490/A10124; to P.D. Pharoah); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to U. Menon and S.A. Gayther). USC: P01-CA17054, P30-CA14089, R01-CA61132, N01-PC67010, N01-CN025403 (to M.C. Pike), R03-CA113148, R03-CA115195 (to C.L. Pearce), and California Cancer Research Program (0001389V-20170, 2II0200; to A. Wu); POL: Intramural Research Program of the NCI. NR 38 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 BP 446 EP 454 DI 10.1158/1055-9965.EPI-15-0240 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6EA UT WOS:000372173900003 PM 26747452 ER PT J AU Murtola, TJ Gurel, B Umbehr, M Lucia, MS Thompson, IM Goodman, PJ Kristal, AR Parnes, HL Lippman, SM Sutcliffe, S Peskoe, SB Barber, JR Drake, CG Nelson, WG De Marzo, AM Platz, EA AF Murtola, Teemu J. Gurel, Bora Umbehr, Martin Lucia, M. Scott Thompson, Ian M., Jr. Goodman, Phyllis J. Kristal, Alan R. Parnes, Howard L. Lippman, Scott M. Sutcliffe, Siobhan Peskoe, Sarah B. Barber, John R. Drake, Charles G. Nelson, William G. De Marzo, Angelo M. Platz, Elizabeth A. TI Inflammation in Benign Prostate Tissue and Prostate Cancer in the Finasteride Arm of the Prostate Cancer Prevention Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SYSTEM AB Background: A previous analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT) reported 82% overall prevalence of intraprostatic inflammation and identified a link between inflammation and higher-grade prostate cancer and serum PSA. Here, we studied these associations in the PCPT finasteride arm. Methods: Prostate cancer cases (N = 197) detected either on a clinically indicated biopsy or on protocol-directed end-of-study biopsy, and frequency-matched controls (N = 248) with no cancer on an end-of-study biopsy were sampled from the finasteride arm. Inflammation in benign prostate tissue was visually assessed using digital images of hematoxylin and eosin-stained sections. Logistic regression was used for statistical analysis. Results: In the finasteride arm, 91.6% of prostate cancer cases and 92.4% of controls had at least one biopsy core with inflammation in benign areas (P < 0.001 for difference compared with placebo arm). Overall, the odds of prostate cancer did not differ by prevalence [ OR, 0.90; 95% confidence interval (CI), 0.44-1.84] or extent (P trend = 0.68) of inflammation. Inflammation was not associated with higher-grade disease (prevalence: OR, 1.07; 95% CI, 0.43-2.69). Furthermore, mean PSA concentration did not differ by the prevalence or extent of inflammation in either cases or controls. Conclusion: The prevalence of intraprostatic inflammation was higher in the finasteride than placebo arm of the PCPT, with no association with higher-grade prostate cancer. C1 [Murtola, Teemu J.] Univ Tampere, Sch Med, Dept Urol, FIN-33101 Tampere, Finland. [Murtola, Teemu J.] Univ Tampere, Tampere Univ Hosp, FIN-33101 Tampere, Finland. [Murtola, Teemu J.; Umbehr, Martin; Peskoe, Sarah B.; Barber, John R.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gurel, Bora] Kocaeli Univ, Dept Pathol, Sch Med, Kocaeli, Turkey. [Umbehr, Martin] Univ Zurich, Univ Hosp, Dept Urol, Zurich, Switzerland. [Lucia, M. Scott] Univ Colorado, Denver Sch Med, Dept Pathol, Aurora, CO USA. [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Goodman, Phyllis J.; Kristal, Alan R.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Goodman, Phyllis J.; Kristal, Alan R.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Parnes, Howard L.] NCI, Div Canc Prevent, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Sutcliffe, Siobhan] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Sutcliffe, Siobhan] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Drake, Charles G.] Johns Hopkins Univ, Sch Med, Dept Immunol, Baltimore, MD 21205 USA. [Drake, Charles G.; Nelson, William G.; De Marzo, Angelo M.; Platz, Elizabeth A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Drake, Charles G.; Nelson, William G.; De Marzo, Angelo M.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Drake, Charles G.; Nelson, William G.; De Marzo, Angelo M.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [De Marzo, Angelo M.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Platz, EA (reprint author), Johns Hopkins Univ, Sch Publ Hlth, Room E6132,615 North Wolfe St, Baltimore, MD 21205 USA.; De Marzo, AM (reprint author), Johns Hopkins Sch Med, Dept Pathol, 1650 Orleans St, Baltimore, MD 21231 USA. EM ademarz@jhmi.edu; eplatz1@jhu.edu FU Public Health Service grants from NCI [P01 CA108964, P50 CA58236, U10 CA37429, UM1 CA182883] FX This work was funded by Public Health Service grants P01 CA108964 (to I.M. Thompson Jr; Project 4, to E.A. Platz) and P50 CA58236 (to W.G. Nelson) from the NCI. The PCPT is funded by Public Health Service grants U10 CA37429 (to C.D. Blanke) and UM1 CA182883 (to I.M. Thompson Jr and C.M. Tangen) from the NCI. NR 11 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 BP 463 EP 469 DI 10.1158/1055-9965.EPI-15-0987 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6EA UT WOS:000372173900005 PM 26715424 ER PT J AU Pine, SR Mechanic, LE Enewold, L Bowman, ED Ryan, BM Cote, ML Wenzlaff, AS Loffredo, CA Olivo-Marston, S Chaturvedi, A Caporaso, NE Schwartz, AG Harris, CC AF Pine, Sharon R. Mechanic, Leah E. Enewold, Lindsey Bowman, Elise D. Ryan, Brid M. Cote, Michele L. Wenzlaff, Angela S. Loffredo, Christopher A. Olivo-Marston, Susan Chaturvedi, Anil Caporaso, Neil E. Schwartz, Ann G. Harris, Curtis C. TI Differential Serum Cytokine Levels and Risk of Lung Cancer Between African and European Americans SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID C-REACTIVE PROTEIN; GENE POLYMORPHISMS; INTERLEUKIN-6; INFLAMMATION; TRANSCRIPTION; DISPARITIES; FREQUENCIES; CLASSIFIER; EXPRESSION; MORTALITY AB Background: African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. Methods: Differences in 10 serum cytokine levels, IL1 beta, IL4, IL5, IL6, IL8, IL10, IL12, granulocyte macrophage colony-stimulating factor, IFN gamma, and TNF alpha, between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the Wayne State University Karmanos Cancer Institute case-control study. Results: Six cytokines, IL4, IL5, IL8, IL10, IFN gamma, and TNF alpha, were significantly higher among European-American as compared with African-American controls. Elevated IL6 and IL8 levels were associated with lung cancer among both races in all three studies. Elevated IL1b, IL10, and TNFa levels were associated with lung cancer only among African Americans. The association between elevated TNFa levels and lung cancer among European Americans was significant after adjustment for additional factors. Conclusions: Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. C1 [Pine, Sharon R.; Mechanic, Leah E.; Bowman, Elise D.; Ryan, Brid M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Pine, Sharon R.] Rutgers State Univ, Robert Wood Johnson Med Sch, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Mechanic, Leah E.] NCI, Epidemiol & Genom Res Program, Host Factors Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Enewold, Lindsey] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Enewold, Lindsey] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Cote, Michele L.; Wenzlaff, Angela S.; Schwartz, Ann G.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Loffredo, Christopher A.] Georgetown Univ, Canc Genet & Epidemiol Program, Oncol & Biostat, Washington, DC USA. [Olivo-Marston, Susan] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Chaturvedi, Anil] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA.; Pine, SR (reprint author), Rutgers State Univ, 195 Little Albany St, New Brunswick, NJ 08903 USA. EM pinesr@cinj.rutgers.edu; curtis_harris@nih.gov RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural Research Program of NIH, NCI, Center for Cancer Research; Prevent Cancer Foundation; NIH [R01CA060691, N01-PC35145, P30CA22453, K07CA125203] FX This study was supported by Intramural Research Program of the NIH, NCI, Center for Cancer Research (to C.C. Harris); Prevent Cancer Foundation (to S.R. Pine); NIH grant R01CA060691, NIH contracts N01-PC35145 and P30CA22453 (to A.G. Schwartz); and NIH grant K07CA125203 (to M.L. Cote). NR 42 TC 3 Z9 3 U1 1 U2 1 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 MAR PY 2016 VL 25 IS 3 BP 488 EP 497 DI 10.1158/1055-9965.EPI-15-0378 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DG6EA UT WOS:000372173900008 PM 26711330 ER PT J AU Mathews, S Feng, DC Maricic, I Ju, C Kumar, V Gao, B AF Mathews, Stephanie Feng, Dechun Maricic, Igor Ju, Cynthia Kumar, Vipin Gao, Bin TI Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE alcoholic hepatitis; CD1d; inflammation; liver ID NECROSIS-FACTOR-ALPHA; NKT CELLS; THERAPEUTIC TARGETS; DISEASE; MICE; PATHOGENESIS; INFLAMMATION; OSTEOPONTIN; PROGRESS; BIOLOGY AB Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T (iNKT) cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice (CD1d- and J alpha 18-deficient mice) were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone. iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines (e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin) involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CD1d blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease. C1 [Mathews, Stephanie; Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Maricic, Igor; Kumar, Vipin] Torrey Pines Inst Mol Studies, Lab Autoimmun, San Diego, CA USA. [Ju, Cynthia] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci & Integrated Im, Anschutz Med Campus, Aurora, CO USA. RP Gao, B (reprint author), NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Feng, Dechun/Q-5962-2016 FU intramural program of NIAAA, NIH [U01AA021723, R01 AA020864, R01 CA100660] FX This work was supported by the intramural program of NIAAA, NIH (BG), U01AA021723 (to CJ and BG) and R01 AA020864 & R01 CA100660 (VK). NR 39 TC 6 Z9 6 U1 1 U2 1 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD MAR PY 2016 VL 13 IS 2 BP 206 EP 216 DI 10.1038/cmi.2015.06 PG 11 WC Immunology SC Immunology GA DG3VC UT WOS:000371997600008 PM 25661730 ER PT J AU Foppa, M Arora, G Gona, P Ashrafi, A Salton, CJ Yeon, SB Blease, SJ Levy, D O'Donnell, CJ Manning, WJ Chuang, ML AF Foppa, Murilo Arora, Garima Gona, Philimon Ashrafi, Arman Salton, Carol J. Yeon, Susan B. Blease, Susan J. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. Chuang, Michael L. TI Right Ventricular Volumes and Systolic Function by Cardiac Magnetic Resonance and the Impact of Sex, Age, and Obesity in a Longitudinally Followed Cohort Free of Pulmonary and Cardiovascular Disease The Framingham Heart Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE cardiac MRI; cardiac volume; epidemiology; right ventricle; systolic function ID EJECTION FRACTION; REFERENCE VALUES; BODY-SIZE; ATHEROSCLEROSIS; DIMENSIONS; CARDIOLOGY; COMMITTEE; SURVIVAL; FAILURE; MRI AB Background Cardiac magnetic resonance is uniquely well suited for noninvasive imaging of the right ventricle. We sought to define normal cardiac magnetic resonance reference values and to identify the main determinants of right ventricular (RV) volumes and systolic function using a modern imaging sequence in a community-dwelling, longitudinally followed cohort free of clinical cardiovascular and pulmonary disease. Methods and Results The Framingham Heart Study Offspring cohort has been followed since 1971. We scanned 1794 Offspring cohort members using steady-state free precession cardiac magnetic resonance and identified a reference group of 1336 adults (649 years, 576 men) free of prevalent cardiovascular and pulmonary disease. RV trabeculations and papillary muscles were considered cavity volume. Men had greater RV volumes and cardiac output before and after indexation to body size (all P<0.001). Women had higher RV ejection fraction than men (68 +/- 6% versus 64 +/- 7%; P<0.0001). RV volumes and cardiac output decreased with advancing age. There was an increase in raw and height-indexed RV measurements with increasing body mass index, but this trend was weakly inverted after indexation of RV volumes to body surface area. Sex, age, height, body mass index, and heart rate account for most of the variability in RV volumes and function in this community-dwelling population. Conclusions We report sex-specific normative values for RV measurements among principally middle-aged and older adults. RV ejection fraction is greater in women. RV volumes increase with body size, are greater in men, and are smaller in older people. Body surface area seems to be appropriate for indexation of cardiac magnetic resonance-derived RV volumes. C1 [Foppa, Murilo; Ashrafi, Arman; Salton, Carol J.; Manning, Warren J.; Chuang, Michael L.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Foppa, Murilo] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Arora, Garima; Levy, Daniel] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Gona, Philimon; Blease, Susan J.; Levy, Daniel; O'Donnell, Christopher J.; Chuang, Michael L.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Gona, Philimon] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Yeon, Susan B.] Wolters Kluwer Hlth, UpToDate, Waltham, MA USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA USA. [O'Donnell, Christopher J.; Manning, Warren J.] Harvard Univ, Sch Med, Boston, MA USA. RP Manning, WJ (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. EM wmanning@bidmc.harvard.edu FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institutes of Health [RO1 HL70279]; Ministry of Education, Brazil (Coordination for the Improvement of Higher Education Personnel, CAPES) [9601-11-2] FX This study was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and a grant from the National Institutes of Health (RO1 HL70279). Dr Foppa was supported in part by the Ministry of Education, Brazil (Coordination for the Improvement of Higher Education Personnel, CAPES No. 9601-11-2). NR 22 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2016 VL 9 IS 3 AR e003810 DI 10.1161/CIRCIMAGING.115.003810 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DG3OZ UT WOS:000371980700001 PM 26962126 ER PT J AU Iantorno, M Hays, AG Schar, M Krishnaswamy, R Soleimanifard, S Steinberg, A Stuber, M Gerstenblith, G Weiss, RG AF Iantorno, Micaela Hays, Allison G. Schar, Michael Krishnaswamy, Rupa Soleimanifard, Sahar Steinberg, Angela Stuber, Matthias Gerstenblith, Gary Weiss, Robert G. TI Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE atherosclerosis; coronary artery disease; endothelium; magnetic resonance imaging; vasodilation ID ARTERY-DISEASE; NITRIC-OXIDE; DEPENDENT VASODILATION; HANDGRIP EXERCISE; VENOUS GRAFTS; ACETYLCHOLINE; DYSFUNCTION; HUMANS; ATHEROSCLEROSIS; METAANALYSIS AB Background Normal endothelial function is a measure of vascular health and dysfunction is a predictor of coronary events. Nitric oxide-mediated coronary artery endothelial function, as assessed by vasomotor reactivity during isometric handgrip exercise (IHE), was recently quantified noninvasively with magnetic resonance imaging (MRI). Because the internal mammary artery (IMA) is often visualized during coronary MRI, we propose the strategy of simultaneously assessing systemic and coronary endothelial function noninvasively by MRI during IHE. Methods and Results Changes in cross-sectional area and blood flow in the right coronary artery and the IMA in 25 patients with coronary artery disease and 26 healthy subjects during IHE were assessed using 3T MRI. In 8 healthy subjects, a nitric oxide synthase inhibitor was infused to evaluate the role of nitric oxide in the IMA-IHE response. Interobserver IMA-IHE reproducibility was good for cross-sectional area (R=0.91) and blood flow (R=0.91). In healthy subjects, cross-sectional area and blood flow of the IMA increased during IHE, and these responses were significantly attenuated by monomethyl-l-arginine (P<0.01 versus placebo). In patients with coronary artery disease, the right coronary artery did not dilate with IHE, and dilation of the IMA was less than that of the healthy subjects (P=0.01). The blood flow responses of both the right coronary artery and IMA to IHE were also significantly reduced in patients with coronary artery disease. Conclusions MRI-detected IMA responses to IHE primarily reflect nitric oxide-dependent endothelial function and are reproducible and reduced in patients with coronary artery disease. Endothelial function in both coronary and systemic (IMA) arteries can now be measured noninvasively with the same imaging technique and promises novel insights into systemic and local factors affecting vascular health. C1 [Iantorno, Micaela; Hays, Allison G.; Krishnaswamy, Rupa; Steinberg, Angela; Gerstenblith, Gary; Weiss, Robert G.] Johns Hopkins Univ, Dept Med, Div Cardiol, Blalock 544,600N Wolfe St, Baltimore, MD 21287 USA. [Schar, Michael; Soleimanifard, Sahar; Stuber, Matthias; Weiss, Robert G.] Johns Hopkins Univ, Div Magnet Resonance Res, Dept Radiol, Baltimore, MD 21287 USA. [Soleimanifard, Sahar] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21287 USA. [Iantorno, Micaela] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Stuber, Matthias] Univ Lausanne, CHU Vaudois, Dept Radiol, Ctr Biomed Imaging CIBM, Lausanne, Switzerland. RP Weiss, RG (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, Blalock 544,600N Wolfe St, Baltimore, MD 21287 USA. EM rweiss@jhmi.edu RI Schar, Michael/C-8087-2015 FU National Institutes of Health [HL120905, HL125059, HL61912]; American Heart Association [11SDG5200004]; Swiss National Science Foundation [320030-143923]; PJ Schafer Award; Clarence Doodeman Endowment of Johns Hopkins FX This work was supported by the National Institutes of Health (HL120905, HL125059, HL61912), the American Heart Association (11SDG5200004), the Swiss National Science Foundation Grant 320030-143923, the PJ Schafer Award, and the Clarence Doodeman Endowment of Johns Hopkins. NR 32 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2016 VL 9 IS 3 AR e003954 DI 10.1161/CIRCIMAGING.115.003954 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DG3PI UT WOS:000371981600001 PM 26919997 ER PT J AU Korach, K Arao, Y Hamilton, KJ Coons, L Hewitt, SC AF Korach, Kenneth Arao, Y. Hamilton, K. J. Coons, L. Hewitt, S. C. TI Genetically modified mouse models to dissect the physiological roles of ER alpha's functional domains SO CLINICAL ENDOCRINOLOGY LA English DT Meeting Abstract CT Annual Scientific Meeting of the Endocrine-Society-of-Australia CY AUG 23-26, 2015 CL Adelaide, AUSTRALIA SP Endocrine Soc Australia C1 [Korach, Kenneth; Arao, Y.; Hamilton, K. J.; Coons, L.; Hewitt, S. C.] NIEHS, NIH, Chapel Hill, NC 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 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAR PY 2016 VL 84 SU 1 SI SI MA 60 BP 7 EP 7 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DG8CQ UT WOS:000372310400021 ER PT J AU Talbot, GH Powers, JH Hoffmann, SC AF Talbot, George H. Powers, John H. Hoffmann, Steven C. CA Fdn Natl Inst Hlth CABP-ABSSSI & H TI Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE antibacterial drug development; noninferiority trial design; early clinical response; patient-reported outcome; PRO ID COMMUNITY-ACQUIRED PNEUMONIA; SKIN-STRUCTURE INFECTIONS; ACUTE BACTERIAL SKIN; TASK-FORCE AB One important component in determining the benefits and harms of medical interventions is the use of well-defined and reliable outcome assessments as endpoints in clinical trials. Improving endpoints can better define patient benefits, allowing more accurate assessment of drug efficacy and more informed benefit-vs-risk decisions; another potential plus is facilitating efficient trial design. Since our first report in 2012, 2 Foundation for the National Institutes of Health Biomarkers ConsortiumProject Teams have continued to develop outcome assessments for potential uses as endpoints in registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. In addition, the teams have initiated similar work in the indications of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. This report provides an update on progress to date in these 4 diseases. C1 [Talbot, George H.] Talbot Advisors LLC, POB 2121, Anna Maria, FL 34216 USA. [Powers, John H.] George Washington Univ, Sch Med, Washington, DC USA. [Powers, John H.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Hoffmann, Steven C.] Fdn Natl Inst Hlth, Biomarkers Consortium, Bethesda, MD USA. RP Talbot, GH (reprint author), Talbot Advisors LLC, POB 2121, Anna Maria, FL 34216 USA. EM ghtalbot@gmail.com OI Wunderink, Richard/0000-0002-8527-4195 FU Actelion; Basilea; Bayer; Cubist (now Merck); Medicines Company; Merck; Nabriva; Roche; Tetraphase FX The work of the HABP-VABP Project Team was supported by financial contributions from Actelion, Basilea, Bayer, Cubist (now Merck), The Medicines Company, Merck, Nabriva, Roche, and Tetraphase. Clinical trial data were generously contributed in-kind by Antoni Torres, MD (University of Barcelona, Spain), Pfizer Inc, Shionogi Pharmaceuticals, and Theravance Inc. The CABP-ABSSSI Project Team members and the sponsors that provided in-kind clinical trial data and/or generous financial support were acknowledged in our 2012 publication. NR 19 TC 6 Z9 6 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 MAR 1 PY 2016 VL 62 IS 5 BP 603 EP 607 DI 10.1093/cid/civ927 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XK UT WOS:000371715600018 PM 26668337 ER PT J AU McGuire, JF Orr, SP Wu, MS Lewin, AB Small, BJ Phares, V Murphy, TK Wilhelm, S Pine, DS Geller, D Storch, EA AF McGuire, Joseph F. Orr, Scott P. Wu, Monica S. Lewin, Adam B. Small, Brent J. Phares, Vicky Murphy, Tanya K. Wilhelm, Sabine Pine, Daniel S. Geller, Daniel Storch, Eric A. TI FEAR CONDITIONING AND EXTINCTION IN YOUTH WITH OBSESSIVE-COMPULSIVE DISORDER SO DEPRESSION AND ANXIETY LA English DT Article DE fear conditioning; extinction; skin conductance; inhibitory learning; obsessive-compulsive disorder; children ID COGNITIVE-BEHAVIORAL THERAPY; ANXIETY DISORDERS; FUNCTIONAL IMPAIRMENT; TREATMENT RESPONSE; BIAS MODIFICATION; CHILD VERSION; ADOLESCENTS; PREDICTORS; ADULTS; RELIABILITY AB BackgroundFear acquisition and extinction are central constructs in the cognitive-behavioral model of obsessive-compulsive disorder (OCD), which underlies exposure-based cognitive-behavioral therapy (CBT). Youth with OCD may have impairments in fear acquisition and extinction that carry treatment implications. We examined these processes using a differential conditioning procedure. MethodsForty-one youth (19 OCD, 22 community comparisons) completed a battery of clinical interviews, rating scales, and a differential conditioning task that included habituation, acquisition, and extinction phases. Skin conductance response (SCR) served as the primary dependent measure. ResultsDuring habituation, no difference between groups was observed. During acquisition, differential fear conditioning was observed across participants as evidenced by larger SCRs to the CS+ compared to CS-; there were no between-group differences. Across participants, the number and frequency of OCD symptoms and anxiety severity was associated with greater reactivity to stimuli during acquisition. During extinction, a three-way interaction and follow-up tests revealed that youth with OCD showed a different pattern of SCR extinction compared to the community comparison group. ConclusionsYouth with OCD exhibit a different pattern of fear extinction relative to community comparisons. This may be attributed to impaired inhibitory learning and contingency awareness in extinction. Findings suggest the potential benefit of utilizing inhibitory-learning principles in CBT for youth with OCD, and/or augmentative retraining interventions prior to CBT to reduce threat bias and improve contingency detection. C1 [McGuire, Joseph F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Pl,48-228B, Los Angeles, CA 90095 USA. [Orr, Scott P.; Wilhelm, Sabine; Geller, Daniel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Wu, Monica S.; Lewin, Adam B.; Phares, Vicky; Storch, Eric A.] Univ S Florida, Dept Psychol, Tampa, FL 33620 USA. [Wu, Monica S.; Lewin, Adam B.; Murphy, Tanya K.; Storch, Eric A.] Univ S Florida, Dept Pediat, Tampa, FL 33620 USA. [Lewin, Adam B.; Murphy, Tanya K.; Storch, Eric A.] Univ S Florida, Dept Psychiat & Behav Neurosci, Tampa, FL USA. [Lewin, Adam B.; Murphy, Tanya K.; Storch, Eric A.] Univ S Florida, All Childrens Hosp, Johns Hopkins Med, St Petersburg, FL 33701 USA. [Small, Brent J.] Univ S Florida, Sch Aging Studies, Tampa, FL USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Rockville, MD 20857 USA. [Storch, Eric A.] Rogers Behav Hlth Tampa Bay, Tampa, FL USA. [Storch, Eric A.] Univ S Florida, Dept Hlth Policy & Management, Tampa, FL USA. RP McGuire, JF (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Pl,48-228B, Los Angeles, CA 90095 USA. EM jfmcguire@mednet.ucla.edu FU National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) [R01MH093381-02S1]; NIMH Intramural Research Program FX Contract grant sponsor: Support for this article comes in part from the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) as a research supplement to promote diversity in health-related research (R01MH093381-02S1). Dr. Pine is supported by the NIMH Intramural Research Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or NIH. NR 54 TC 4 Z9 4 U1 6 U2 10 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 MAR PY 2016 VL 33 IS 3 BP 229 EP 237 DI 10.1002/da.22468 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DG6FY UT WOS:000372179800007 PM 26799264 ER PT J AU Wlodawer, A AF Wlodawer, Alexander TI Introducing Structural Snapshots SO FEBS JOURNAL LA English DT Editorial Material C1 [Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. EM wlodawer@camfebs.co.uk NR 2 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD MAR PY 2016 VL 283 IS 5 BP 815 EP 815 DI 10.1111/febs.13583 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DG3XX UT WOS:000372005600004 PM 26524689 ER PT J AU Santesso, N Mustafa, RA Schunemann, HJ Arbyn, M Blumenthal, PD Cain, J Chirenje, M Denny, L De Vuyst, H Eckert, LO Forhan, SE Franco, EL Gage, JC Garcia, F Herrero, R Jeronimo, J Lu, ER Luciani, S Quek, SC Sankaranarayanan, R Tsu, V Broutet, N AF Santesso, Nancy Mustafa, Reem A. Schuenemann, Holger J. Arbyn, Marc Blumenthal, Paul D. Cain, Joanna Chirenje, Michael Denny, Lynette De Vuyst, Hugo Eckert, Linda O'Neal Forhan, Sara E. Franco, Eduardo L. Gage, Julia C. Garcia, Francisco Herrero, Rolando Jeronimo, Jose Lu, Enriquito R. Luciani, Silvana Quek, Swee Chong Sankaranarayanan, Rengaswamy Tsu, Vivien Broutet, Nathalie CA Guideline Support Grp TI World Health Organization Guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Editorial Material DE Cervical cancer; Cervical intraepithelial neoplasia; Guidelines; Recommendations; Screen; Treat ID HUMAN-PAPILLOMAVIRUS INFECTION; WOMENS PREFERENCES; GRADE; MANAGEMENT; INDIA AB Background: It is estimated that 1%-2% of women develop cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) annually worldwide. The prevalence among women living with HIV is higher, at 10%. If left untreated, CIN 2-3 can progress to cervical cancer. WHO has previously published guidelines for strategies to screen and treat pre-cancerous cervical lesions and for treatment of histologically confirmed CIN 2-3. Methods: Guidelines were developed using the WHO Handbook for Guideline Development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. A multidisciplinary guideline panel was created. Systematic reviews of randomized controlled trials and observational studies were conducted. Evidence tables and Evidence to Recommendations Tables were prepared and presented to the panel. Results: There are nine recommendations for screen-and-treat strategies to prevent cervical cancer, including the HPV test, cytology, and visual inspection with acetic acid. There are seven for treatment of CIN with cryotherapy, loop electrosurgical excision procedure, and cold knife conization. Conclusion: Recommendations have been produced on the basis of the best available evidence. However, high-quality evidence was not available. Such evidence is needed, in particular for screen-and-treat strategies that are relevant to low- and middle-income countries. (C) 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. C1 [Santesso, Nancy; Mustafa, Reem A.; Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Room 2C16,1280 Main St West, Hamilton, ON L8S 4K1, Canada. [Mustafa, Reem A.] Univ Missouri, Dept Internal Med, Kansas City, MO 64110 USA. [Mustafa, Reem A.] Univ Missouri, Dept Nephrol, Kansas City, MO 64110 USA. [Mustafa, Reem A.] Univ Missouri, Dept Biomed & Hlth Informat, Kansas City, MO 64110 USA. [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Blumenthal, Paul D.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Cain, Joanna] Univ Massachusetts, Sch Med, Worcester, MA USA. [Chirenje, Michael] Univ Zimbabwe, Harare, Zimbabwe. [Denny, Lynette] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Denny, Lynette] Groote Schuur Hosp, ZA-7925 Cape Town, South Africa. [De Vuyst, Hugo; Herrero, Rolando; Sankaranarayanan, Rengaswamy] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Eckert, Linda O'Neal] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Forhan, Sara E.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Franco, Eduardo L.] McGill Univ, Montreal, PQ, Canada. [Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Garcia, Francisco] Amer Canc Soc, Tucson, AZ USA. [Jeronimo, Jose; Tsu, Vivien] PATH, Seattle, WA USA. [Lu, Enriquito R.] Jhpiego, Baltimore, MD USA. [Luciani, Silvana] Canc Prevent & Control PAHO, Washington, DC USA. [Quek, Swee Chong] KK Womens & Childrens Hosp, Singapore, Singapore. [Broutet, Nathalie] WHO, Reprod Hlth & Res, CH-1211 Geneva, Switzerland. RP Schunemann, HJ (reprint author), McMaster Univ, Dept Clin Epidemiol & Biostat, Room 2C16,1280 Main St West, Hamilton, ON L8S 4K1, Canada. OI Franco, Eduardo/0000-0002-4409-8084 FU World Health Organization [001] NR 22 TC 7 Z9 8 U1 1 U2 5 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 MAR PY 2016 VL 132 IS 3 BP 252 EP 258 DI 10.1016/j.ijgo.2015.07.038 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DG3AO UT WOS:000371942100002 PM 26868062 ER PT J AU Mitson-Salazar, A Yin, YZ Wansley, DL Young, M Bolan, H Arceo, S Ho, N Koh, C Milner, JD Stone, KD Wank, SA Prussin, C AF Mitson-Salazar, Alyssa Yin, Yuzhi Wansley, Daniel L. Young, Michael Bolan, Hyejeong Arceo, Sarah Ho, Nancy Koh, Christopher Milner, Joshua D. Stone, Kelly D. Wank, Stephen A. Prussin, Calman TI Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Atopic dermatitis; eosinophilic inflammation; eosinophilic gastrointestinal disease; IL-5; hematopoietic prostaglandin D synthase; chemoattractant receptor-homologous molecule expressed on T(H)2 cells; T(H)2; CD4; CD161; CD294 ID CHEMOKINE RECEPTOR EXPRESSION; INNATE LYMPHOID-CELLS; THYMIC STROMAL LYMPHOPOIETIN; HELPER TYPE-2 CELLS; HUMAN TH2 CELLS; CD4(+) T-CELLS; CYTOKINE PRODUCTION; ATOPIC-DERMATITIS; UP-REGULATION; CUTTING EDGE AB Background: IL-5 1 pathogenic effector T(H)2 (peT(H)2) cells are a T(H)2 cell subpopulation with enhanced proinflammatory function that has largely been characterized in murine models of allergic inflammation. Objective: We sought to identify phenotype markers for human peT(H)2 cells and characterize their function in patients with allergic eosinophilic inflammatory diseases. Methods: Patients with eosinophilic gastrointestinal disease (EGID), patients with atopic dermatitis (AD), and nonatopic healthy control (NA) subjects were enrolled. peT(H)2 and conventional T(H)2 (cT(H)2) cell phenotype, function, and cytokine production were analyzed by using flow cytometry. Confirmatory gene expression was measured by using quantitative RT-PCR. Prostaglandin D-2 levels were measured with ELISA. Gut T(H)2 cells were obtained by means of esophagogastroduodenoscopy. Results: peT(H)2 cells were identified as chemoattractant receptor-homologous molecule expressed onT(H)2 cells-positive (CRT(H)2(+)), hematopoietic prostaglandin D synthase-positive CD161 hi CD4 T cells. peT(H)2 cells expressed significantly greater IL-5 and IL-13 than did hematopoietic prostaglandin D synthase-negative and CD161 2 cT(H)2 cells. peT(H)2 cells were highly correlated with blood eosinophilia (r = 0.78-0.98) and were present in 30- to 40-fold greater numbers in subjects with EGID and those with AD versus NA subjects. Relative to cT(H)2 cells, peT(H)2 cells preferentially expressed receptors for thymic stromal lymphopoietin, IL-25, and IL-33 and demonstrated greater responsiveness to these innate pro-T(H)2 cytokines. peT(H)2 but not cT(H)2 cells produced prostaglandin D-2. In patients with EGID and those with AD, peT(H)2 cells expressed gut-and skin-homing receptors, respectively. There were significantly greater numbers of peT(H)2 cells in gut tissue from patients with EGID versus NA subjects. Conclusion: peT(H)2 cells are the primary functional proinflammatory human T(H)2 cell subpopulation underlying allergic eosinophilic inflammation. The unambiguous phenotypic identification of human peT(H)2 cells provides a powerful tool to track these cells in future pathogenesis studies and clinical trials. C1 [Mitson-Salazar, Alyssa; Yin, Yuzhi; Wansley, Daniel L.; Bolan, Hyejeong; Arceo, Sarah; Milner, Joshua D.; Stone, Kelly D.; Prussin, Calman] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Young, Michael] Frederick Natl Lab Canc Res, Clin Res Directorate CMRP, Leidos Biomed Res, Frederick, MD USA. [Ho, Nancy; Koh, Christopher; Wank, Stephen A.] NIDDK, Gastroenterol Sect, NIH, Frederick, MD USA. RP Prussin, C (reprint author), 10 Ctr Dr,MSC 181, Bethesda, MD 20892 USA. EM calmanp@gmail.com FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research, National Institutes of Health [1ZIAAI000993] FX Supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research, National Institutes of Health, project 1ZIAAI000993. NR 51 TC 6 Z9 6 U1 2 U2 5 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 MAR PY 2016 VL 137 IS 3 BP 907 EP + DI 10.1016/j.jaci.2015.08.007 PG 21 WC Allergy; Immunology SC Allergy; Immunology GA DG2LB UT WOS:000371897500035 PM 26431580 ER PT J AU Ku, CL Lin, CH Chang, SW Chu, CC Chan, JFW Kong, XF Lee, CH Rosen, EA Ding, JY Lee, WI Bustamante, J Witte, T Shih, HP Kuo, CY Chetchotisakd, P Kiertiburanakul, S Suputtamongkol, Y Yuen, KY Casanova, JL Holland, SM Doffinger, R Browne, SK Chi, CY AF Ku, Cheng-Lung Lin, Chia-Hao Chang, Su-Wei Chu, Chen-Chung Chan, Jasper F. W. Kong, Xiao-Fei Lee, Chen-Hsiang Rosen, Emily A. Ding, Jing-Ya Lee, Wen-I. Bustamante, Jacinta Witte, Torsten Shih, Han-Po Kuo, Chen-Yen Chetchotisakd, Ploenchan Kiertiburanakul, Sasisopin Suputtamongkol, Yupin Yuen, Kwok-Yung Casanova, Jean-Laurent Holland, Steven M. Doffinger, Rainer Browne, Sarah K. Chi, Chih-Yu TI Anti-IFN-gamma autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID NONTUBERCULOUS MYCOBACTERIAL INFECTIONS C1 [Ku, Cheng-Lung; Lin, Chia-Hao; Ding, Jing-Ya; Shih, Han-Po; Kuo, Chen-Yen] Chang Gung Univ, Grad Inst Clin Med Sci, Lab Human Immunol & Infect Dis, Taoyuan, Taiwan. [Ku, Cheng-Lung; Chi, Chih-Yu] China Med Univ, Grad Inst Clin Med Sci, Taichung, Taiwan. [Ku, Cheng-Lung] Chang Gung Mem Hosp, Chang Gung Immunol Consortium, Taoyuan, Taiwan. [Ku, Cheng-Lung] Chang Gung Univ, Taoyuan, Taiwan. [Chang, Su-Wei] Chang Gung Univ, Clin Informat & Med Stat Res Ctr, Taoyuan, Taiwan. [Chan, Jasper F. W.; Yuen, Kwok-Yung] Univ Hong Kong, Queen Mary Hosp, Carol Yu Ctr Infect, Key Lab Emerging Infect Dis,Dept Microbiol, Hong Kong, Hong Kong, Peoples R China. [Kong, Xiao-Fei; Bustamante, Jacinta; Casanova, Jean-Laurent] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA. [Lee, Chen-Hsiang] Kaohsiung Chang Gung Mem Hosp, Dept Internal Med, Div Infect Dis, Kaohsiung, Taiwan. [Lee, Chen-Hsiang] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Rosen, Emily A.; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lee, Wen-I.] Chang Gung Mem Hosp, Div Allergy Immunol & Rheumatol, Dept Pediat, Taoyuan, Taiwan. [Bustamante, Jacinta; Casanova, Jean-Laurent] INSERM, U1163, Lab Human Genet Infect Dis, Necker Branch, Paris, France. [Bustamante, Jacinta; Casanova, Jean-Laurent] Paris Descartes Univ, Imagine Inst, Paris, France. [Witte, Torsten] Med Sch Hanover, Clin Immunol & Rheumatol, Hannover, NH, Germany. [Kuo, Chen-Yen] Chang Gung Mem Hosp Linkou, Dept Pediat, Taoyuan, Taiwan. [Chetchotisakd, Ploenchan] Khon Kaen Univ, Srinagarind Hosp, Khon Kaen, Thailand. [Kiertiburanakul, Sasisopin] Ramathibodi Hosp, Fac Med, Bangkok, Thailand. [Suputtamongkol, Yupin] Mahidol Univ, Fac Med, Siriraj Hosp, Div Infect Dis & Trop Med,Dept Med, Bangkok 10700, Thailand. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY USA. [Casanova, Jean-Laurent] Necker Hosp Sick Children, AP HP, Pediat Immunohematol Unit, Paris, France. [Doffinger, Rainer] Addenbrookes Hosp, Dept Clin Biochem & Immunol, Cambridge, England. [Doffinger, Rainer] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England. [Chi, Chih-Yu] China Med Univ Hosp, Dept Internal Med, Div Infect Dis, Taichung, Taiwan. [Chu, Chen-Chung] Mackay Mem Hosp, Dept Med Res, Immunogenet Lab, Taipei, Taiwan. RP Ku, CL (reprint author), Chang Gung Univ, Grad Inst Clin Med Sci, Lab Human Immunol & Infect Dis, Taoyuan, Taiwan.; Ku, CL (reprint author), China Med Univ, Grad Inst Clin Med Sci, Taichung, Taiwan.; Ku, CL (reprint author), Chang Gung Mem Hosp, Chang Gung Immunol Consortium, Taoyuan, Taiwan.; Ku, CL (reprint author), Chang Gung Univ, Taoyuan, Taiwan. EM clku@mail.cgu.edu.tw NR 9 TC 4 Z9 4 U1 2 U2 5 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 MAR PY 2016 VL 137 IS 3 BP 945 EP 948 DI 10.1016/j.jaci.2015.09.018 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA DG2LB UT WOS:000371897500045 PM 26522403 ER PT J AU Dassanayake, RP Orru, CD Hughson, AG Caughey, B Graca, T Zhuang, DY Madsen-Bouterse, SA Knowles, DP Schneider, DA AF Dassanayake, Rohana P. Orru, Christina D. Hughson, Andrew G. Caughey, Byron Graca, Telmo Zhuang, Dongyue Madsen-Bouterse, Sally A. Knowles, Donald P. Schneider, David A. TI Sensitive and specific detection of classical scrapie prions in the brains of goats by real-time quaking-induced conversion SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID EXPERIMENTALLY CHALLENGED GOATS; CREUTZFELDT-JAKOB-DISEASE; NATURAL SCRAPIE; IMMUNOHISTOCHEMICAL DETECTION; SEEDED CONVERSION; CAPRINE SCRAPIE; LYMPHOID-TISSUE; SHEEP SCRAPIE; RECTAL MUCOSA; PROTEIN GENE AB Real-time quaking-induced conversion (RT-QuIC) is a rapid, specific and highly sensitive prion seeding activity detection assay that uses recombinant prion protein (rPrP(Sen)) to detect subinfectious levels of the abnormal isoforms of the prion protein (PrPSc). Although RT-QuIC has been successfully used to detect PrPSc in various tissues from humans and animals, including sheep, tissues from goats infected with classical scrapie have not yet been tested. Therefore, the aims of the present study were to (1) evaluate whether prion seeding activity could be detected in the brain tissues of goats with scrapie using RT-QuIC, (2) optimize reaction conditions to improve scrapie detection in goats, and (3) compare the performance of RT-QuIC for the detection of PrPSc with the more commonly used ELISA and Western blot assays. We further optimized RT-QuIC conditions for sensitive and specific detection of goat scrapie seeding activity in brain tissue from clinical animals. When used with 200 mM sodium chloride, both full-length sheep rPrP(Sen) substrates (PrP genotypes A(136)R(154)Q(171) and V(136)R(154)Q(171)) provided good discrimination between scrapie-infected and normal goat brain samples at 10(-3) dilution within 15 h. Our findings indicate that RT-QuIC was at least 10 000-fold more sensitive than ELISA and Western blot assays for the detection of scrapie seeding activity in goat brain samples. In addition to PRNP WT samples, positive RT-QuIC reactions were also observed with three PRNP polymorphic goat brain samples (G/S127, I/M142 and H/R143) tested. Taken together, these findings demonstrate that RT-QuIC sensitively detects prion seeding activity in classical scrapie-infected goat brain samples. C1 [Dassanayake, Rohana P.; Graca, Telmo; Madsen-Bouterse, Sally A.; Knowles, Donald P.; Schneider, David A.] Washington State Univ, Coll Vet Med, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. [Orru, Christina D.; Hughson, Andrew G.; Caughey, Byron] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Graca, Telmo] Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. [Zhuang, Dongyue; Knowles, Donald P.; Schneider, David A.] ARS, Anim Dis Res Unit, USDA, Pullman, WA 99164 USA. RP Dassanayake, RP (reprint author), Washington State Univ, Coll Vet Med, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. EM rohana1@vetmed.wsu.edu FU US Department of Agriculture Agricultural Research Service [CRIS 2090-32000-030-00D]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This study was funded by the US Department of Agriculture Agricultural Research Service (CRIS 2090-32000-030-00D) and also in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. We thank Katherine O'Rourke (Washington State University) for critical reading of the manuscript. The authors would also like to thank Linda Hamburg, Lori Fuller, Laetisha O'Rourke, Deborah Wolheter, Jan Luft, Karel Emma and Desiree Lesiak for technical assistance. Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. NR 37 TC 3 Z9 3 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2016 VL 97 BP 803 EP 812 DI 10.1099/jgv.0.000367 PN 3 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA DG8KP UT WOS:000372333000027 PM 26653410 ER PT J AU Qi, R Joo, HS Sharma-Kuinkel, B Berlon, NR Park, L Fu, CL Messina, JA Thaden, JT Yan, Q Ruffin, F Maskarinec, S Warren, B Chu, VH Fortes, CQ Giannitsioti, E Durante-Mangoni, E Kanafani, ZA Otto, M Fowler, VG AF Qi, Robert Joo, Hwang-Soo Sharma-Kuinkel, Batu Berlon, Nicholas R. Park, Lawrence Fu, Chih-Lung Messina, Julia A. Thaden, Joshua T. Yan, Qin Ruffin, Felicia Maskarinec, Stacey Warren, Bobby Chu, Vivian H. Fortes, Claudio Q. Giannitsioti, Efthymia Durante-Mangoni, Emanuele Kanafani, Zeina A. Otto, Michael Fowler, Vance G., Jr. TI Increased in vitro phenol-soluble modulin production is associated with soft tissue infection source in clinical isolates of methicillin-susceptible Staphylococcus aureus SO JOURNAL OF INFECTION LA English DT Article DE Phenol-soluble modulin; Methicillin-susceptible Staphylococcus aureus; Skin and soft tissue infection; Pneumonia; Endocarditis ID VIRULENCE DETERMINANTS; RABBIT MODEL; ENDOCARDITIS; RESISTANT; SKIN; PATHOGENESIS; VANCOMYCIN; TELAVANCIN; DIAGNOSIS; PEPTIDES AB Background: Phenol-soluble modulins (PSM) are amphipathic proteins produced by Staphylococcus aureus that promote virulence, inflammatory response, and biofilm formation. We previously showed that MRSA isolates from soft tissue infection (SSTI) produced significantly higher levels of PSM than MRSA isolates from hospital-acquired pneumonia (HAP) or infective endocarditis (IE). In this investigation, we sought to validate this finding in methicillin-susceptible S. aureus (MSSA) isolates. Methods: MSSA isolates (n = 162) from patients with SSTI, HAP, and IE were matched 1: 1: 1 based on geographic origin of the infection to form 54 triplets (North America n = 27, Europe n = 25, Australia n = 2). All isolates underwent spa typing and were classified using eGenomics. In vitro PSM production was quantified by high-performance liquid chromatography/mass spectrometry. Fischer's Exact Test and the Kruskal-Wallis test were used for statistical analysis. Results: Spa1 was more common in SSTI (14.81% SSTI, 3.70% HAP, 1.85% IE) (p < 0.03). Spa2 was more common in HAP (0% SSTI, 12.96% HAP, 3.70% IE) (p < 0.01). Levels of PSM alpha 1-4 all differed significantly among the three clinical groups, with SSTI isolates producing the highest levels and IE producing the lowest levels of PSMa1-4. Spa1 isolates produced significantly more delta-toxin (p < 0.03) than non-Spa1 isolates. No associations between PSM levels and clinical outcome of SSTI, HAP, or IE were identified. Conclusion: Production of PSMa1-4 is highest in SSTI MSSA isolates, supporting the hypothesis that these peptides are important for SSTI pathogenesis. These findings are similar to those described in MRSA, and demonstrate that associations between PSM levels and type of infection are independent of the methicillin-resistance status of the isolate. (C) 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved. C1 [Qi, Robert; Sharma-Kuinkel, Batu; Berlon, Nicholas R.; Park, Lawrence; Messina, Julia A.; Thaden, Joshua T.; Yan, Qin; Ruffin, Felicia; Maskarinec, Stacey; Warren, Bobby; Chu, Vivian H.; Fowler, Vance G., Jr.] Duke Univ, Div Infect Dis, Dept Med, Med Ctr, Box 102359 Med Ctr, Durham, NC 27710 USA. [Joo, Hwang-Soo; Fu, Chih-Lung; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Bacteriol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Messina, Julia A.; Fowler, Vance G., Jr.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Fortes, Claudio Q.] Hosp Univ Clementino Fraga Filho UFRJ, Rio De Janeiro, Brazil. [Giannitsioti, Efthymia] Attikon Univ, Gen Hosp, Athens, Greece. [Durante-Mangoni, Emanuele] Univ Naples 2, Dept Cardiothorac Sci, Internal Med Sect, Monaldi Hosp, Naples, Italy. [Durante-Mangoni, Emanuele] Univ Naples 2, Monaldi Hosp, Div Infect & Transplant Med, Naples, Italy. [Kanafani, Zeina A.] Amer Univ Beirut, Med Ctr, Dept Internal Med, Div Infect Dis, Beirut, Lebanon. RP Fowler, VG (reprint author), Duke Univ, Div Infect Dis, Dept Med, Med Ctr, Box 102359 Med Ctr, Durham, NC 27710 USA. EM fowle003@mc.duke.edu OI Qi, Robert/0000-0001-6445-7331; Otto, Michael/0000-0002-2222-4115 FU National Institute of Health [R01-AI068804, K24-AI093969]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; Duke University School of Medicine Eugene A. Stead Student Research Scholarship FX This work was supported by the Duke University School of Medicine Eugene A. Stead Student Research Scholarship [to RQ], grants provided by the National Institute of Health [R01-AI068804 and K24-AI093969 to VGF], and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases [to MO]. NR 30 TC 3 Z9 3 U1 1 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 EI 1532-2742 J9 J INFECTION JI J. Infect. PD MAR PY 2016 VL 72 IS 3 BP 302 EP 308 DI 10.1016/j.jinf.2015.11.002 PG 7 WC Infectious Diseases SC Infectious Diseases GA DG2XW UT WOS:000371935100004 PM 26778460 ER PT J AU Aberra, T Joshi, A Lerman, J Rodante, J Silverman, J Aridi, T Chen, M Playford, M Mehta, N AF Aberra, T. Joshi, A. Lerman, J. Rodante, J. Silverman, J. Aridi, T. Chen, M. Playford, M. Mehta, N. TI COMORBID DEPRESSION OR ANXIETY IS ASSOCIATED WITH AORTIC VASCULAR INFLAMMATION AND CORONARY HEART DISEASE BEYOND TRADITIONAL CARDIOVASCULAR RISK FACTORS IN PSORIASIS SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research (AFMR) CY APR 13, 2016 CL Washington, DC SP Amer Federat Med Res C1 [Aberra, T.; Joshi, A.; Lerman, J.; Rodante, J.; Silverman, J.; Aridi, T.; Chen, M.; Playford, M.; Mehta, N.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2016 VL 64 IS 3 MA MP11 BP 809 EP 809 DI 10.1136/jim-2016-000080.23 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DG6GE UT WOS:000372180700030 ER PT J AU Joshi, A Shukla, P Aberra, TM Lerman, JB Natarajan, B Ng, Q Silverman, J Rodante, J Mehta, NN AF Joshi, A. Shukla, P. Aberra, T. M. Lerman, J. B. Natarajan, B. Ng, Q. Silverman, J. Rodante, J. Mehta, N. N. TI VASCULAR INFLAMMATION AND AORTIC WALL CHARACTERISTICS MODULATE FOLLOWING LIFESTYLE CHANGES IN PSORIASIS PATIENTS AT 1 YEAR FOLLOW UP SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research (AFMR) CY APR 13, 2016 CL Washington, DC SP Amer Federat Med Res C1 [Joshi, A.; Shukla, P.; Aberra, T. M.; Lerman, J. B.; Natarajan, B.; Ng, Q.; Silverman, J.; Rodante, J.; Mehta, N. N.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2016 VL 64 IS 3 MA 23 BP 816 EP 816 DI 10.1136/jim-2016-000080.39 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DG6GE UT WOS:000372180700044 ER PT J AU Kabbany, MT Joshi, AA Ahlman, M Rodante, J Lerman, JB Aberra, T Silverman, J Dahiya, A Bluemke, DA Playford, MP Mehta, NN AF Kabbany, M. T. Joshi, A. A. Ahlman, M. Rodante, J. Lerman, J. B. Aberra, T. Silverman, J. Dahiya, A. Bluemke, D. A. Playford, M. P. Mehta, N. N. TI DETERMINANTS OF VASCULAR INFLAMMATION BY 18-FLUORODEOXYGLUCOSE PET/MRI: FINDINGS FROM THE PSORIASIS, ATHEROSCLEROSIS AND CARDIOMETABOLIC DISEASE INITIATIVE SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research (AFMR) CY APR 13, 2016 CL Washington, DC SP Amer Federat Med Res C1 [Kabbany, M. T.; Joshi, A. A.; Ahlman, M.; Rodante, J.; Lerman, J. B.; Aberra, T.; Silverman, J.; Dahiya, A.; Bluemke, D. A.; Playford, M. P.; Mehta, N. N.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2016 VL 64 IS 3 MA 21 DI 10.1136/jim-2016-000080.37 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DG6GE UT WOS:000372180700043 ER PT J AU Lerman, JB Joshi, AA Rodante, J Aberra, T Kabbany, MT Salahuddin, TF Ng, Q Silverman, J Chen, MY Mehta, NN AF Lerman, J. B. Joshi, A. A. Rodante, J. Aberra, T. Kabbany, M. T. Salahuddin, T. F. Ng, Q. Silverman, J. Chen, M. Y. Mehta, N. N. TI IMPROVEMENT IN PSORIASIS SKIN DISEASE SEVERITY IS ASSOCIATED WITH REDUCTION OF CORONARY PLAQUE BURDEN SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research (AFMR) CY APR 13, 2016 CL Washington, DC SP Amer Federat Med Res C1 [Lerman, J. B.; Joshi, A. A.; Rodante, J.; Aberra, T.; Kabbany, M. T.; Salahuddin, T. F.; Ng, Q.; Silverman, J.; Chen, M. Y.; Mehta, N. N.] NHLBI, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2016 VL 64 IS 3 MA 18 DI 10.1136/jim-2016-000080.34 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DG6GE UT WOS:000372180700041 ER PT J AU Li, LZ Chen, KQ Xiang, Y Yoshimura, T Su, SB Zhu, JW Bian, XW Wang, JM AF Li, Liangzhu Chen, Keqiang Xiang, Yi Yoshimura, Teizo Su, Shaobo Zhu, Jianwei Bian, Xiu-wu Wang, Ji Ming TI New development in studies of formyl-peptide receptors: critical roles in host defense SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE leukocytes; trafficking; inflammation; immunity; cancer ID N-FORMYLPEPTIDE RECEPTOR; HUMAN GLIOBLASTOMA CELLS; LISTERIA-MONOCYTOGENES; CHEMOATTRACTANT RECEPTOR; BONE-MARROW; IN-VIVO; NEUTROPHIL MIGRATION; MOUSE NEUTROPHILS; IMMUNE-RESPONSES; 2 FPR2 AB Formyl-peptide receptors are a family of 7 transmembrane domain, Gi-protein-coupled receptors that possess multiple functions in many pathophysiologic processes because of their expression in a variety of cell types and their capacity to interact with a variety of structurally diverse, chemotactic ligands. Accumulating evidence demonstrates that formyl-peptide receptors are critical mediators of myeloid cell trafficking in the sequential chemotaxis signal relays in microbial infection, inflammation, and immune responses. Formylpeptide receptors are also involved in the development and progression of cancer. In addition, one of the formylpeptide receptor family members, Fpr2, is expressed by normal mouse-colon epithelial cells, mediates cell responses to microbial chemotactic agonists, participates in mucosal development and repair, and protects against inflammation-associated tumorigenesis. These novel discoveries greatly expanded the current understanding of the role of formyl-peptide receptors in host defense and as potential molecular targets for the development of therapeutics. C1 [Li, Liangzhu; Zhu, Jianwei] Shanghai Jiao Tong Univ, Sch Pharm, Minist Educ, Engn Res Ctr Cell & Therapeut Antibody, Shanghai 200030, Peoples R China. [Li, Liangzhu; Chen, Keqiang; Yoshimura, Teizo; Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Chen, Keqiang; Su, Shaobo] Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200092, Peoples R China. [Xiang, Yi] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Pulm Med, Sch Med, Shanghai 200030, Peoples R China. [Bian, Xiu-wu; Wang, Ji Ming] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China. [Bian, Xiu-wu; Wang, Ji Ming] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China. [Bian, Xiu-wu] Collaborat Innovat Ctr Canc Med, 651 Dongfeng East Rd, Guangzhou, Guangdong, Peoples R China. RP Wang, JM (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA.; Bian, XW (reprint author), Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China.; Bian, XW (reprint author), Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China.; Bian, XW (reprint author), Collaborat Innovat Ctr Canc Med, 651 Dongfeng East Rd, Guangzhou, Guangdong, Peoples R China. EM bianxiuwu@263.net; wangji@mail.nih.gov RI Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU U.S. National Institutes of Health (NIH) National Cancer Institute (NCI) [HHSN261200800001E]; Intramural Research Program of NCI, NIH; Starting Foundation for New Teachers of Shanghai Jiao Tong University, Shanghai, China [14X100040016]; National Natural Science Foundation of China [81470073, 31170861, 81101771, 81473127, 81230062] FX This project was funded in part with federal funds from the U.S. National Institutes of Health (NIH) National Cancer Institute (NCI), under Contract No. HHSN261200800001E, and also in part by the Intramural Research Program of NCI, NIH. Additional sources of support were The Starting Foundation for New Teachers of Shanghai Jiao Tong University, Shanghai, China (Grant 14X100040016 to L.L.); the National Natural Science Foundation of China (Grant 81470073 to L.L., Grant 31170861 to S.S., Grant 81101771 to Y.X., Grant 81473127 to J.Z., and Grant 81230062 to X.B.). The authors thank Dr.J.J. Oppenheim for critically reviewing the manuscript, Ms. C. Lamb and Ms. S. Livingstone for secretarial assistance. NR 117 TC 5 Z9 6 U1 1 U2 9 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 MAR PY 2016 VL 99 IS 3 BP 425 EP 435 DI 10.1189/jlb.2RI0815-354RR PG 11 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DG2IO UT WOS:000371890800005 PM 26701131 ER PT J AU Zhang, LJ Bell, BA Yu, MZ Chan, CC Peachey, NS Fung, J Zhang, XM Caspi, RR Lin, F AF Zhang, Lingjun Bell, Brent A. Yu, Minzhong Chan, Chi-Chao Peachey, Neal S. Fung, John Zhang, Xiaoming Caspi, Rachel R. Lin, Feng TI Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE T cell; regulation; retinal inflammation; mouse model; innate immunity ID OPTICAL COHERENCE TOMOGRAPHY; SCANNING LASER OPHTHALMOSCOPY; T-CELL ALLOIMMUNITY; RETINAL DEGENERATION; DENDRITIC CELLS; INNATE IMMUNITY; IN-VIVO; MOUSE; UVEORETINITIS; MICE AB Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated autoimmune diseases such as autoimmune uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of autoimmune uveitis remains elusive and controversial. We induced experimental autoimmune uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental autoimmune uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental autoimmune uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with autoimmune uveitis. C1 [Zhang, Lingjun; Zhang, Xiaoming] Tianjin Med Univ, Eye Res Inst, Ctr Eye, Tianjin, Peoples R China. [Zhang, Lingjun; Lin, Feng] Cleveland Clin, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA. [Bell, Brent A.; Yu, Minzhong; Peachey, Neal S.] Cleveland Clin, Dept Ophthalm Res, Cole Eye Inst, Cleveland, OH 44195 USA. [Fung, John] Cleveland Clin, Inst Digest Dis, Cleveland, OH 44195 USA. [Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lin, F (reprint author), Cleveland Clin, Dept Immuno NE60, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA.; Zhang, XM (reprint author), Tianjin Med Univ, Eye Res Inst, Tianjin, Peoples R China. EM xzhang08@tmu.edu.cn; linf2@ccf.org FU U.S. National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR061564]; National Institute of Diabetes and Digestive and Kidney Diseases [DK10358]; Foundation Fighting Blindness; Research to Prevent Blindness; Wolf Family Foundation; Llura and Gordon Gund Foundation; China National Natural Science Foundation [8142800018] FX This work was supported in part by U.S. National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant AR061564) and National Institute of Diabetes and Digestive and Kidney Diseases (Grant DK10358), and the Foundation Fighting Blindness, Research to Prevent Blindness, the Wolf Family Foundation, and the Llura and Gordon Gund Foundation. L.Z. was supported in part by China National Natural Science Foundation Grant 8142800018. We thank Catherine Doller from Visual Sciences Research Center at Case Western Reserve University (EY11373) for histology and Christine Kassuba from Cleveland Clinic for help with manuscript preparation. NR 48 TC 1 Z9 2 U1 1 U2 1 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 MAR PY 2016 VL 99 IS 3 BP 447 EP 454 DI 10.1189/jlb.3A0415-157R PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DG2IO UT WOS:000371890800007 PM 26394814 ER PT J AU Solaymani-Mohammadi, S Lakhdari, O Minev, I Shenouda, S Frey, BF Billeskov, R Singer, SM Berzofsky, JA Eckmann, L Kagnoff, MF AF Solaymani-Mohammadi, Shahram Lakhdari, Omar Minev, Ivelina Shenouda, Steve Frey, Blake F. Billeskov, Rolf Singer, Steven M. Berzofsky, Jay A. Eckmann, Lars Kagnoff, Martin F. TI Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Citrobacter rodentium; granzyme B; perforin; attaching/effacing bacteria; PD-1 ID CITROBACTER-RODENTIUM INFECTION; BACTERIAL PATHOGENS; DENDRITIC CELLS; NK CELLS; PD-1; DEFENSE; EXPRESSION; IMMUNITY; MICE; CYTOTOXICITY AB The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wildtype but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function. C1 [Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Kagnoff, Martin F.] Univ Calif San Diego, Lab Mucosal Immunol, La Jolla, CA 92093 USA. [Eckmann, Lars] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Solaymani-Mohammadi, Shahram; Frey, Blake F.; Billeskov, Rolf; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 41,Room D702, Bethesda, MD 20892 USA. [Singer, Steven M.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Singer, Steven M.] Georgetown Univ, Ctr Infect Dis, Washington, DC USA. RP Solaymani-Mohammadi, S (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 41,Room D702, Bethesda, MD 20892 USA. EM shahram.sm@nih.gov OI Billeskov, Rolf/0000-0003-4533-7304 FU U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [DK35108]; NIH National Institute of Allergy and Infectious Diseases [AI 094492]; NIH National Cancer Institute Intramural Research Program of Center for Cancer Research [Z01-C04020] FX This work was supported by the U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grant DK35108 (M.F.K), the NIH National Institute of Allergy and Infectious Diseases Grant AI 094492 (S.M.S), and by the NIH National Cancer Institute Intramural Research Program of the Center for Cancer Research (Project Z01-C04020; J.A.B). We are grateful to Dr. T. Honjo, Department of Immunology and Genomic Medicine, Kyoto University, Japan, and Dr. W.R. Green, the Geisel School of Medicine at Dartmouth for providing PD-1-/- mice. We thank E. Hanson, L. Hall, K. McKinnon, and L. Pasquet for technical assistance and C. McAllister and K. Vu for advice during the course of these studies. NR 37 TC 2 Z9 2 U1 0 U2 0 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 MAR PY 2016 VL 99 IS 3 BP 475 EP 482 DI 10.1189/jlb.4A0115-003RR PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DG2IO UT WOS:000371890800010 PM 26467188 ER PT J AU Li, HM Hiroi, T Zhang, YQ Shi, A Chen, GB De, S Metter, EJ Wood, WH Sharov, A Milner, JD Becker, KG Zhan, M Weng, NP AF Li, Hoi Ming Hiroi, Toyoko Zhang, Yongqing Shi, Alvin Chen, Guobing De, Supriyo Metter, E. Jeffrey Wood, William H., III Sharov, Alexei Milner, Joshua D. Becker, Kevin G. Zhan, Ming Weng, Nan-ping TI TCR beta repertoire of CD4(+) and CD8(+) T cells is distinct in richness, distribution, and CDR3 amino acid composition SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Human; TCR diversity; supervised learning; RACE; RNAseq ID PROTEIN-SEQUENCE; CLASS-I; DIVERSITY; SELECTION; NAIVE; RECOGNITION; REVEALS; MACHINE; NUMBER; AGE AB The TCR repertoire serves as a reservoir of TCRs for recognizing all potential pathogens. Two major types of T cells, CD4(+) and CD8(+), that use the same genetic elements and process to generate a functional TCR differ in their recognition of peptide bound to MHC class II and I, respectively. However, it is currently unclear to what extent the TCR repertoire of CD4(+) and CD8(+) T cells is different. Here, we report a comparative analysis of the TCR beta repertoires of CD4(+) and CD8(+) T cells by use of a 59 rapid amplification of cDNA ends-PCR-sequencing method. We found that TCRb richness of CD4(+) T cells ranges from 1.2 to 9.8 x 10(4) and is approximately 5 times greater, on average, than that of CD8(+) T cells in each study subject. Furthermore, there was little overlap in TCR beta sequences between CD4(+) (0.3%) and CD8(+) (1.3%) T cells. Further analysis showed that CD4(+) and CD8(+) T cells exhibited distinct preferences for certain amino acids in the CDR3, and this was confirmed further by a support vector machine classifier, suggesting that there are distinct and discernible differences between TCRb CDR3 in CD4(+) and CD8(+) T cells. Finally, we identified 5-12% of the unique TCR beta s that share an identical CDR3 with different variable genes. Together, our findings reveal the distinct features of the TCRb repertoire between CD4(+) and CD8(+) T cells and could potentially be used to evaluate the competency of T cell immunity. C1 [Li, Hoi Ming; Hiroi, Toyoko; Shi, Alvin; Chen, Guobing; Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Sharov, Alexei] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing; De, Supriyo; Wood, William H., III; Becker, Kevin G.] NIA, Lab Gene Express & Genom, NIH, Baltimore, MD 21224 USA. [Zhan, Ming] NIA, Bioinformat Units, NIH, Baltimore, MD 21224 USA. [Metter, E. Jeffrey] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Baltimore, MD USA. [Shi, Alvin] MIT, Computat & Syst Biol Grad Program, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Weng, NP (reprint author), NIA, Lab Mol Biol & Immunol, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM wengn@mail.nih.gov RI Chen, Guobing/D-9572-2012 OI Chen, Guobing/0000-0002-2401-6168 FU Intramural Research Program of the U.S. National Institutes of Health National Institute on Aging (NIA) FX This research was supported by the Intramural Research Program of the U.S. National Institutes of Health National Institute on Aging (NIA). The authors thank Ranjan Sen for critically reviewing the manuscript, Dr. Luigi Ferrucci for his support in studying the Baltimore Longitudinal Study of Aging participants, and NIA Clinical Core Lab for collecting blood samples. NR 36 TC 2 Z9 2 U1 2 U2 4 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 MAR PY 2016 VL 99 IS 3 BP 505 EP 513 DI 10.1189/jlb.6A0215-071RR PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DG2IO UT WOS:000371890800013 PM 26394815 ER PT J AU Perna, FM Coa, K Troiano, RP Lawman, HG Wang, CY Li, Y Moser, RP Ciccolo, JT Comstock, BA Kraemer, WJ AF Perna, Frank M. Coa, Kisha Troiano, Richard P. Lawman, Hannah G. Wang, Chia-Yih Li, Yan Moser, Richard P. Ciccolo, Joseph T. Comstock, Brett A. Kraemer, William J. TI MUSCULAR GRIP STRENGTH ESTIMATES OF THE US POPULATION FROM THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY 2011-2012 SO JOURNAL OF STRENGTH AND CONDITIONING RESEARCH LA English DT Article DE NHANES; fitness; youth; adults ID BODY-COMPOSITION; OLDER-ADULTS; MUSCLE MASS; MUSCULOSKELETAL FITNESS; HANDGRIP STRENGTH; MORTALITY; CHILDREN; ADOLESCENTS; RESISTANCE; WEIGHT AB Perna, FM, Coa, K, Troiano, RP, Lawman, HG, Wang, C-Y, Li, Y, Moser, RP, Ciccolo, JT, Comstock, BA, and Kraemer, WJ. Muscular grip strength estimates of the U.S. population from the National Health and Nutrition Examination Survey 2011-12. J Strength Cond Res 30(3): 867-874, 2016The purposes of this study were to use the National Health and Nutrition Examination Study (2011-12) data to determine nationally representative combined handgrip strength ranges and percentile information by sex and age group, examine trends in strength across age by sex, and to determine the relative proportion of children and adults falling into established health benefit zones (HBZ). Results indicate that mean strength was greater among men than women and increased linearly for children and in a quadratic fashion among adults for both sexes. Grip strength peaked in the 30- to 39-year age group for both men (216.4 lbs) and women (136.5 lbs) with subsequent age groups showing gradual decline, p < 0.0001. Relative and absolute increases in grip strength were greater for men than for women, but relative decrease from peak strength was less among women than men. Although absolute strength was greater among men than women, HBZ data indicated that a higher percentage of men than women overall and at each age group fell into the needs improvement zone, with differences particularly pronounced during adolescence and older adulthood. These data provide the first nationally representative population estimates of combined handgrip strength and percentile information from childhood through senescence and suggest consideration of HBZ information in conjunction with grip strength to improve surveillance data interpretation and intervention planning. C1 [Perna, Frank M.; Coa, Kisha; Troiano, Richard P.; Moser, Richard P.] NCI, Bethesda, MD 20892 USA. [Lawman, Hannah G.; Wang, Chia-Yih] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Li, Yan] Univ Maryland, Silver Spring, MD USA. [Ciccolo, Joseph T.] Columbia Univ, Teachers Coll, Dept Biobehav Sci, New York, NY 10027 USA. [Comstock, Brett A.] Univ S Dakota, Dept Kinesiol & Sport Sci, Vermillion, SD 57069 USA. [Kraemer, William J.] Ohio State Univ, Dept Human Sci, Columbus, OH 43210 USA. RP Perna, FM (reprint author), NCI, Bethesda, MD 20892 USA. EM pernafm@mail.nih.gov NR 35 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1064-8011 EI 1533-4287 J9 J STRENGTH COND RES JI J. Strength Cond. Res. PD MAR PY 2016 VL 30 IS 3 BP 867 EP 874 DI 10.1519/JSC.0000000000001104 PG 8 WC Sport Sciences SC Sport Sciences GA DG1MF UT WOS:000371831500034 PM 26196662 ER PT J AU Tempero, M AF Tempero, Margaret TI Promising the Moon! SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, Med, San Francisco, CA USA. [Tempero, Margaret] ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] AACR ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] Mayo Clin, Pancreas SPOREs, Rochester, MN 55905 USA. [Tempero, Margaret] UAB Minnesota, Minneapolis, MN 55401 USA. [Tempero, Margaret] Univ Arizona, GI SPORE, Tucson, AZ 85721 USA. [Tempero, Margaret] Lustgarten Fdn, Bethpage, NY 66873 USA. [Tempero, Margaret] Pancreat Canc Act Network, Manhattan Beach, CA 90266 USA. [Tempero, Margaret] V Fdn, Cary, NC 27513 USA. [Tempero, Margaret] Alberta Canada Canc Board, Edmonton, AB, Canada. [Tempero, Margaret] EORTC, Brussels, Belgium. [Tempero, Margaret] US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE 68198 USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, Med, San Francisco, CA USA.; Tempero, M (reprint author), ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), AACR ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA.; Tempero, M (reprint author), Mayo Clin, Pancreas SPOREs, Rochester, MN 55905 USA.; Tempero, M (reprint author), UAB Minnesota, Minneapolis, MN 55401 USA.; Tempero, M (reprint author), Univ Arizona, GI SPORE, Tucson, AZ 85721 USA.; Tempero, M (reprint author), Lustgarten Fdn, Bethpage, NY 66873 USA.; Tempero, M (reprint author), Pancreat Canc Act Network, Manhattan Beach, CA 90266 USA.; Tempero, M (reprint author), V Fdn, Cary, NC 27513 USA.; Tempero, M (reprint author), Alberta Canada Canc Board, Edmonton, AB, Canada.; Tempero, M (reprint author), EORTC, Brussels, Belgium.; Tempero, M (reprint author), US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA.; Tempero, M (reprint author), UNMC Eppley Canc Ctr, Omaha, NE 68198 USA.; Tempero, M (reprint author), UCSF, Div Med Oncol, San Francisco, CA 94143 USA.; Tempero, M (reprint author), UCSF Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. NR 0 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 MAR PY 2016 VL 14 IS 3 BP 237 EP 237 PG 1 WC Oncology SC Oncology GA DG3VF UT WOS:000371997900003 PM 26957609 ER PT J AU Bindewald, E Afonin, KA Viard, M Zakrevsky, P Kim, T Shapiro, BA AF Bindewald, Eckart Afonin, Kirin A. Viard, Mathias Zakrevsky, Paul Kim, Taejin Shapiro, Bruce A. TI Multistrand Structure Prediction of Nucleic Acid Assemblies and Design of RNA Switches SO NANO LETTERS LA English DT Article DE RNA switch; RNA/DNA hybrid; RNA interference; Dicer; secondary structure ID TISSUE GROWTH-FACTOR; SECONDARY STRUCTURE PREDICTION; THERMODYNAMIC PARAMETERS; INCLUDING PSEUDOKNOTS; SPLIT FUNCTIONALITIES; PARTITION-FUNCTION; BREAST-CANCER; DNA HYBRIDS; IN-SILICO; CELLS AB RNA is an attractive material for the creation of molecular logic gates that release programmed functionalities only in the presence of specific molecular interaction partners. Here we present HyperFold, a multistrand RNA/DNA structure prediction approach for predicting nucleic acid complexes that can contain pseudoknots. We show that HyperFold also performs competitively compared to other published folding algorithms. We performed a large variety of RNA/DNA hybrid reassociation experiments for different concentrations, DNA toehold lengths, and G+C content and find that the observed tendencies for reassociation correspond well to computational predictions. Importantly, we apply this method to the design and experimental verification of a two-stranded RNA molecular switch that upon binding to a single-stranded RNA toehold disease-marker trigger mRNA changes its conformation releasing an shRNA-like Dicer substrate structure. To demonstrate the concept, connective tissue growth factor (CTGF) mRNA and enhanced green fluorescent protein (eGFP) mRNA were chosen as trigger and target sequences, respectively. In vitro experiments confirm the formation of an RNA switch and demonstrate that the functional unit is being released when the trigger RNA interacts with the switch toehold. The designed RNA switch is shown to be functional in MDA-MB-231 breast cancer cells. Several other switches were also designed and tested. We conclude that this approach has considerable potential because, in principle, it allows the release of an siRNA designed against a gene that differs from the gene that is utilized as a biomarker for a disease state. C1 [Bindewald, Eckart; Viard, Mathias] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Afonin, Kirin A.; Zakrevsky, Paul; Kim, Taejin; Shapiro, Bruce A.] Natl Canc Inst, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Afonin, Kirin A.] Univ N Carolina, Dept Chem, 9201 Univ City Blvd, Charlotte, NC 28223 USA. RP Shapiro, BA (reprint author), Natl Canc Inst, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU Federal funds from Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Computational support by the NCI Advanced Biomedical Computing Center (ABCC) as well as the NIH Helix/Biowulf facility is highly appreciated. This work has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 52 TC 6 Z9 6 U1 9 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD MAR PY 2016 VL 16 IS 3 BP 1726 EP 1735 DI 10.1021/acs.nanolett.5b04651 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DG3CE UT WOS:000371946300032 PM 26926528 ER PT J AU Afonin, KA Viard, M Tedbury, P Bindewald, E Parlea, L Howington, M Valdman, M Johns-Boehme, A Brainerd, C Freed, EO Shapiro, BA AF Afonin, Kirill A. Viard, Mathias Tedbury, Philip Bindewald, Eckart Parlea, Lorena Howington, Marshall Valdman, Melissa Johns-Boehme, Alizah Brainerd, Cara Freed, Eric O. Shapiro, Bruce A. TI The Use of Minimal RNA Toeholds to Trigger the Activation of Multiple Functionalities SO NANO LETTERS LA English DT Article DE RNA nanotechnology; RNA nanoparticles; RNA interference; RNA-DNA hybrid reassociation ID IN-SILICO; SPLIT FUNCTIONALITIES; PROTEIN COMPLEXES; EMERGING FIELD; DNA HYBRIDS; PRNA 3WJ; NANOPARTICLES; DELIVERY; NANOTECHNOLOGY; INTERFERENCE AB Current work reports the use of single-stranded RNA toeholds of different lengths to promote the reassociation of various RNA-DNA hybrids, which results in activation of multiple split functionalities inside human cells. The process of reassociation is analyzed and followed with a novel computational multistrand secondary structure prediction algorithm and various experiments. All of our previously designed RNA/DNA nanoparticles employed single stranded DNA toeholds to initiate reassociation. The use of RNA toeholds is advantageous because of the simpler design rules, the shorter toeholds, and the smaller size of the resulting nanoparticles (by up to 120 nucleotides per particle) compared to the same hybrid nanoparticles with single-stranded DNA toeholds. Moreover, the cotranscriptional assemblies result in higher yields for hybrid nanopartides with ssRNA toeholds. C1 [Afonin, Kirill A.; Viard, Mathias; Parlea, Lorena; Johns-Boehme, Alizah; Brainerd, Cara; Shapiro, Bruce A.] Natl Canc Inst, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Afonin, Kirill A.; Howington, Marshall; Valdman, Melissa] Univ N Carolina, Dept Chem, 9201 Univ City Blvd, Charlotte, NC 28223 USA. [Viard, Mathias; Bindewald, Eckart] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Tedbury, Philip; Freed, Eric O.] Natl Canc Inst, Ctr Canc Res, HIV Dynam & Replicat Program, Frederick, MD 21702 USA. RP Afonin, KA; Shapiro, BA (reprint author), Natl Canc Inst, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA.; Afonin, KA (reprint author), Univ N Carolina, Dept Chem, 9201 Univ City Blvd, Charlotte, NC 28223 USA. EM kafonin@uncc.edu; shapirbr@mail.nih.gov OI Tedbury, Philip/0000-0001-8151-4967 FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; UNC Charlotte; Intramural Research Program of National Institutes of Health, Center for Cancer Research FX This publication was funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract HHSN261200800001E and by the start-up funds provided by UNC Charlotte to KAA. This research was additionally supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research. 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. HIV-Ig was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Catalog #3957 HIV-IG from NABI and NHLBI). NR 49 TC 5 Z9 5 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD MAR PY 2016 VL 16 IS 3 BP 1746 EP 1753 DI 10.1021/acs.nanolett.5b04676 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DG3CE UT WOS:000371946300035 PM 26926382 ER PT J AU Serr, I Furst, RW Achenbach, P Scherm, MG Gokmen, F Haupt, F Sedlmeier, EM Knopff, A Shultz, L Willis, RA Ziegler, AG Daniel, C AF Serr, Isabelle Fuerst, Rainer W. Achenbach, Peter Scherm, Martin G. Goekmen, Fuesun Haupt, Florian Sedlmeier, Eva-Maria Knopff, Annette Shultz, Leonard Willis, Richard A. Ziegler, Anette-Gabriele Daniel, Carolin TI Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice SO NATURE COMMUNICATIONS LA English DT Article ID REGULATORY T-CELLS; CLASS-II MHC; IN-VIVO; NOD MICE; MICRONEEDLE PATCHES; IMMUNE-RESPONSES; HIGH-RISK; INSULIN; ANTIGEN; TOLERANCE AB Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing beta-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4(+)T cells and demonstrate efficient human insulin-specific Foxp3(+)Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2R alpha and TIGIT and can efficiently suppress effector T cells. Such Foxp3(+)Treg-induction does not trigger any effector Tcells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3(+)Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D. C1 [Serr, Isabelle; Scherm, Martin G.; Goekmen, Fuesun; Daniel, Carolin] Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, Diabet Res Inst, Independent Young Investigator Grp Immune Toleran, Heidemannstr 1, D-80939 Munich, Germany. [Serr, Isabelle; Fuerst, Rainer W.; Achenbach, Peter; Scherm, Martin G.; Goekmen, Fuesun; Haupt, Florian; Sedlmeier, Eva-Maria; Knopff, Annette; Ziegler, Anette-Gabriele; Daniel, Carolin] Deutsch Zentrum Diabet Forsch, Ingolstadter Landstr 1, D-85764 Munich, Germany. [Fuerst, Rainer W.; Achenbach, Peter; Haupt, Florian; Sedlmeier, Eva-Maria; Knopff, Annette; Ziegler, Anette-Gabriele] Tech Univ Munich, Diabet Res Inst, Klinikum Rechts Isar, Helmholtz Diabet Ctr,Helmholtz Zentrum Munchen, Heidemannstr 1, D-80939 Munich, Germany. [Shultz, Leonard] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Willis, Richard A.] NIH, Emory Vaccine Ctr, Tetramer Core Facil, 201 Dowman Dr, Atlanta, GA 30322 USA. RP Daniel, C (reprint author), Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, Diabet Res Inst, Independent Young Investigator Grp Immune Toleran, Heidemannstr 1, D-80939 Munich, Germany.; Daniel, C (reprint author), Deutsch Zentrum Diabet Forsch, Ingolstadter Landstr 1, D-85764 Munich, Germany. EM carolin.daniel@helmholtz-muenchen.de FU Junior Research Group at Helmholtz Zentrum Munchen; Deutsche Forschungsgemeinschaft [CRC1054]; Juvenile Diabetes Research Foundation [JDRF 2-SRA-2014-161-Q-R, JDRF 17-2012-16, JDRF 6-2012-20]; Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus) - Federal Ministry of Education and Research [FKZ 01GI0805-07, FKZ 01GI0805]; German Center for Diabetes Research (DZD); National Institutes of Health [U01 DK089572]; Helmsley Charitable Trust grant [2012PG-T1D018] FX We thank Katharina Warncke for providing umbilical cord blood samples from the Immune Diab Risk Study (IDR); Ruth Chmiel, Melanie Bunk and Susanne Hummel for blood sample collection and patient follow-up; and M. H. Tschop for critical reading of the manuscript. C.D. is supported by a Junior Research Group at Helmholtz Zentrum Munchen. C.D. received support through an associated membership in the CRC1054 of the Deutsche Forschungsgemeinschaft. The work was supported by grants from the Juvenile Diabetes Research Foundation (JDRF 2-SRA-2014-161-Q-R (C.D., A.-G.Z.), JDRF 17-2012-16 (A.-G.Z.), JDRF 6-2012-20 (A.-G.Z.)), the Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus), funded by the Federal Ministry of Education and Research (FKZ 01GI0805-07, FKZ 01GI0805) and the German Center for Diabetes Research (DZD). L.S. was supported by National Institutes of Health grants U01 DK089572 and the Helmsley Charitable Trust grant 2012PG-T1D018. NR 70 TC 7 Z9 8 U1 9 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10991 DI 10.1038/ncomms10991 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG6IY UT WOS:000372189000001 PM 26975663 ER PT J AU Wang, QY Sawyer, IA Sung, MH Sturgill, D Shevtsov, SP Pegoraro, G Hakim, O Baek, S Hager, GL Dundr, M AF Wang, Qiuyan Sawyer, Iain A. Sung, Myong-Hee Sturgill, David Shevtsov, Sergey P. Pegoraro, Gianluca Hakim, Ofir Baek, Songjoon Hager, Gordon L. Dundr, Miroslav TI Cajal bodies are linked to genome conformation SO NATURE COMMUNICATIONS LA English DT Article ID RNA-POLYMERASE-II; SMALL NUCLEAR-RNA; HISTONE MESSENGER-RNAS; GENE-EXPRESSION; COILED BODIES; HUMAN-CELLS; INTEGRATOR COMPLEX; SUMO ISOPEPTIDASE; NONCODING RNAS; IN-VIVO AB The mechanisms underlying nuclear body (NB) formation and their contribution to genome function are unknown. Here we examined the non-random positioning of Cajal bodies (CBs), major NBs involved in spliceosomal snRNP assembly and their role in genome organization. CBs are predominantly located at the periphery of chromosome territories at a multi-chromosome interface. Genome-wide chromosome conformation capture analysis (4C-seq) using CB-interacting loci revealed that CB-associated regions are enriched with highly expressed histone genes and U small nuclear or nucleolar RNA (sn/snoRNA) loci that form intra-and inter-chromosomal clusters. In particular, we observed a number of CB-dependent gene-positioning events on chromosome 1. RNAi-mediated disassembly of CBs disrupts the CB-targeting gene clusters and suppresses the expression of U sn/snoRNA and histone genes. This loss of spliceosomal snRNP production results in increased splicing noise, even in CB-distal regions. Therefore, we conclude that CBs contribute to genome organization with global effects on gene expression and RNA splicing fidelity. C1 [Wang, Qiuyan; Sawyer, Iain A.; Shevtsov, Sergey P.; Dundr, Miroslav] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol, N Chicago, IL 60064 USA. [Wang, Qiuyan; Sawyer, Iain A.; Sung, Myong-Hee; Sturgill, David; Pegoraro, Gianluca; Hakim, Ofir; Baek, Songjoon; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pegoraro, Gianluca] NCI, High Throughput Imaging Facil HiTIF, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Qiuyan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning 530021, Guangxi, Peoples R China. [Hakim, Ofir] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel. RP Dundr, M (reprint author), Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol, N Chicago, IL 60064 USA.; Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM hagerg@dce41.nci.nih.gov; mirek.dundr@rosalindfranklin.edu OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Intramural Research Program of NIH; NIGMS [NIH R01GM090156] FX We are particularly grateful to T. Misteli for helpful discussions. We thank T. Misteli and S. Oberdoerffer for critical reading of the manuscript. Analysis of high throughput sequencing data was partly performed on the NIH supercomputing cluster Biowulf. This research is supported by the Intramural Research Program of NIH (M.-H.S., S.B., S.P.S., G.P., G.L.H.) and NIH R01GM090156 from NIGMS (M.D.). NR 75 TC 6 Z9 6 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10966 DI 10.1038/ncomms10966 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0GW UT WOS:000372462100001 PM 26997247 ER PT J AU Abunimer, AN Salazar, J Noursi, DP Abu-Asab, MS AF Abunimer, Ayman N. Salazar, Jose Noursi, David P. Abu-Asab, Mones S. TI A Systems Biology Interpretation of Array Comparative Genomic Hybridization (aCGH) Data through Phylogenetics SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID CGH DATA; EXPRESSION; MEDICINE; OMICS AB Array Comparative Genomic Hybridization (aCGH) is a rapid screening technique to detect gene deletions and duplications, providing an overview of chromosomal aberrations throughout the entire genome of a tumor, without the need for cell culturing. However, the heterogeneity of aCGH data obfuscates existing methods of data analysis. Analysis of aCGH data from a systems biology perspective or in the context of total aberrations is largely absent in the published literature. We present here a novel alternative to the functional analysis of aCGH data using the phylogenetic paradigm that is well-suited to high dimensional datasets of heterogeneous nature, but has not been widely adapted to aCGH data. Maximum parsimony phylogenetic analysis sorts out genetic data through the simplest presentation of the data on a cladogram, a graphical evolutionary tree, thus providing a powerful and efficient method for aCGH data analysis. For example, the cladogram models the multiphasic changes in the cancer genome and identifies shared early mutations in the disease progression, providing a simple yet powerful means of aCGH data interpretation. As such, applying maximum parsimony phylogenetic analysis to aCGH results allows for the differentiation between drivers and passenger genes aberrations in cancer specimens. In addition to offering a novel methodology to analyze aCGH results, we present here a crucial software suite that we wrote to carry out the analysis. In a broader context, we wish to underscore that phylogenetic analysis of aCGH data is a non-parametric method that circumvents the pitfalls and frustrations of standard analytical techniques that rely on parametric statistics. Organizing the data in a cladogram as explained in this research article provides insights into the disease common aberrations, as well as the disease subtypes and their shared aberrations (the synapomorphies) of each subtype. Hence, we report the method and make the software suite publicly and freely available at http://software.phylomcs.com so that researchers can test alternative and innovative approaches to the analysis of aCGH data. C1 [Abunimer, Ayman N.] Virginia Tech Carilion Sch Med & Res Inst, Roanoke, VA USA. [Salazar, Jose] MIT, Elect Engn & Comp Sci Dept, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Noursi, David P.] Univ Chicago, Coll, Chicago, IL 60637 USA. [Abu-Asab, Mones S.] NEI, NIH, Bethesda, MD 20892 USA. RP Abu-Asab, MS (reprint author), NEI, Pathol Lab, NIH, Bldg 10,Room 2A10, Bethesda, MD 20892 USA. EM mones@mail.nih.gov FU National Institutes of Health FX The authors thank Dr. Hassan Brim of Howard University College of Medicine for the opportunity to analyze the data. The research presented here was partially supported by the intramural program of the National Institutes of Health. NR 25 TC 1 Z9 1 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 EI 1557-8100 J9 OMICS JI OMICS PD MAR 1 PY 2016 VL 20 IS 3 BP 169 EP 179 DI 10.1089/omi.2015.0184 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DG6HX UT WOS:000372186000004 PM 26983023 ER PT J AU Mahanty, S AF Mahanty, S. TI Host-parasite interactions and the immunobiology of cestodes SO PARASITE IMMUNOLOGY LA English DT Editorial Material DE Cestodes; immunology; pathogenesis; cellular responses; immunodiagnosis; vaccines; parasite molecules ID TAENIA-SOLIUM C1 [Mahanty, S.] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Mahanty, S (reprint author), 4 Ctr Dr,Room 424, Bethesda, MD 20892 USA. EM smahanty@niaid.nih.gov OI Mahanty, Siddhartha/0000-0003-1068-0524 NR 15 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0141-9838 EI 1365-3024 J9 PARASITE IMMUNOL JI Parasite Immunol. PD MAR PY 2016 VL 38 IS 3 SI SI BP 121 EP 123 DI 10.1111/pim.12309 PG 3 WC Immunology; Parasitology SC Immunology; Parasitology GA DG7LA UT WOS:000372264600001 PM 26864711 ER PT J AU Bezrukov, SM Nestorovich, EM AF Bezrukov, Sergey M. Nestorovich, Ekaterina M. TI Inhibiting bacterial toxins by channel blockage SO PATHOGENS AND DISEASE LA English DT Review DE rational drug design; structure-based drug discovery; channel-blocking antitoxins; single molecule/protein interaction; multivalent interactions; physical forces of efficient blockage ID BOTULINUM C2 TOXIN; PERFRINGENS EPSILON-TOXIN; SYMMETRICAL TETRAALKYLAMMONIUM IONS; PHOSPHOLIPID-BILAYER MEMBRANES; ANTHRAX LETHAL TOXIN; RESISTANT STAPHYLOCOCCUS-AUREUS; BETA-CYCLODEXTRIN DERIVATIVES; ACTIVATED POTASSIUM CHANNELS; SMALL-MOLECULE INHIBITORS; VOLTAGE-DEPENDENT BLOCK AB Emergent rational drug design techniques explore individual properties of target biomolecules, small and macromolecule drug candidates, and the physical forces governing their interactions. In this minireview, we focus on the single-molecule biophysical studies of channel-forming bacterial toxins that suggest new approaches for their inhibition. We discuss several examples of blockage of bacterial pore-forming and AB-type toxins by the tailor-made compounds. In the concluding remarks, the most effective rationally designed pore-blocking antitoxins are compared with the small-molecule inhibitors of ion-selective channels of neurophysiology. C1 [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Nestorovich, Ekaterina M.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. RP Nestorovich, EM (reprint author), Catholic Univ Amer, Dept Biol, McCort Ward, 620 Michigan Ave N-E, Washington, DC 20064 USA. EM nestorovich@cua.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; NIAID of the NIH [1R15AI099897-01A1] FX SMB research is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. EMN research is supported by NIAID of the NIH under award number 1R15AI099897-01A1. NR 120 TC 1 Z9 1 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD MAR PY 2016 VL 74 IS 2 AR UNSP ftv113 DI 10.1093/femspd/ftv113 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG2VY UT WOS:000371929200002 ER PT J AU Chew, M Xie, J Klein, R Klein, B Cotch, MF Redline, S Wong, TY Cheung, N AF Chew, Merwyn Xie, Jing Klein, Ronald Klein, Barbara Cotch, Mary Frances Redline, Susan Wong, Tien Yin Cheung, Ning TI Sleep apnea and retinal signs in cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis SO SLEEP AND BREATHING LA English DT Article DE Cardiovascular disease; Retinopathy; Retinal vascular caliber; Retinal imaging; Microcirculation; Sleep apnea ID CORONARY-HEART-DISEASE; MICROVASCULAR ABNORMALITIES; VESSEL DIAMETERS; RISK; ASSOCIATION; WOMEN; COMMUNITIES; ARTERIOLAR; CALIBER; MEN AB Purpose The aim of the study was to examine the relationship between sleep apnea, retinal vascular caliber and retinopathy, and their impact on cardiovascular disease (CVD) risk. Methods A multi-ethnic cohort of 5,803 participants was examined based on standardized grading of retinal vascular caliber and retinopathy from digital fundus photographs, self-reported physician-diagnosed sleep apnea (PDSA), and incident cardiovascular events. Results In women, PDSA was associated with narrower arterioles (regression coefficient [beta] -5.76; 95 % confidence Interval [CI] -8.51, -3.02) after adjusting for cardio-metabolic risk factors. The incident rate ratio (IRR) of CVD was also associated with narrower arterioles (IRR for highest versus lowest tertile 1.91; 95 % CI 1.08, 3.38). In men, PDSA was not associated with arteriolar caliber. However, incident CVD was associated with narrower arterioles (IRR 1.67; 95 % CI 1.10, 2.52), wider venules (IRR 1.71; 95 % CI 1.13, 2.59) and PDSA (IRR 2.03, 95 % CI 1.17, 3.51). The IRR of CVD in men with PDSA increased minimally to 2.06 (95 % CI 1.18, 3.56) after adjustment for retinal arteriolar and venular caliber. Combining women and men, the IRR of CVD was 3.41 (95 % CI 1.79, 6.50) in those with both PDSA and narrower retinal arterioles. Conclusions Sleep apnea was associated with narrower retinal arterioles in women but not in men. However, sleep apnea was also associated with incident CVD in men. These suggest potential gender differences in susceptibility to microvascular disease in association with sleep apnea. C1 [Chew, Merwyn; Wong, Tien Yin; Cheung, Ning] Singapore Natl Eye Ctr, Singapore Eye Res Inst, 11 Third Hosp Ave, Singapore 168751, Singapore. [Chew, Merwyn; Wong, Tien Yin] Natl Univ Singapore, Dept Ophthalmol, Yong Loo Lin Sch Med, Singapore 117548, Singapore. [Xie, Jing; Wong, Tien Yin; Cheung, Ning] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Klein, Ronald; Klein, Barbara] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Chew, Merwyn; Wong, Tien Yin] Natl Univ Hlth Syst, Dept Ophthalmol, Singapore, Singapore. RP Chew, M (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, 11 Third Hosp Ave, Singapore 168751, Singapore.; Chew, M (reprint author), Natl Univ Singapore, Dept Ophthalmol, Yong Loo Lin Sch Med, Singapore 117548, Singapore.; Chew, M (reprint author), Natl Univ Hlth Syst, Dept Ophthalmol, Singapore, Singapore. EM merwynchew@gmail.com OI Cotch, Mary Frances/0000-0002-2046-4350 FU National Heart, Lung and Blood Institute [NHLBI T32 HL076132]; National Institute of Health [HL69979-03]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95167] 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-95167, and a grant NHLBI T32 HL076132 from the National Heart, Lung and Blood Institute. Additional support was provided by National Institute of Health grant HL69979-03 (Klein R, Wong TY). NR 30 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1520-9512 EI 1522-1709 J9 SLEEP BREATH JI Sleep Breath. PD MAR PY 2016 VL 20 IS 1 BP 15 EP 23 DI 10.1007/s11325-015-1177-z PG 9 WC Clinical Neurology; Respiratory System SC Neurosciences & Neurology; Respiratory System GA DG5ZJ UT WOS:000372160800003 PM 25903075 ER PT J AU Ritchie, DL Gibson, SV Abee, CR Kreil, TR Ironside, JW Brown, P AF Ritchie, Diane L. Gibson, Susan V. Abee, Christian R. Kreil, Thomas R. Ironside, James W. Brown, Paul TI Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study SO TRANSFUSION LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; SPONGIFORM ENCEPHALOPATHY; NERVOUS-SYSTEM; TISSUE SAMPLES; VARIANT; PROTEIN; TRANSFUSION; ACCUMULATION; UK; APPENDIX AB BACKGROUNDFour secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease. STUDY DESIGN AND METHODSWhole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion. RESULTSNo clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrPTSE in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Straussler-Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months. CONCLUSIONBlood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period. C1 [Ritchie, Diane L.; Ironside, James W.] Univ Edinburgh, Western Gen Hosp, Natl CJD Res & Surveillance Unit, Ctr Clin Brain Sci, Edinburgh EH46 7EA, Midlothian, Scotland. [Gibson, Susan V.] Univ S Alabama, Coll Med, Mobile, AL USA. [Abee, Christian R.] Univ Texas MD Anderson Canc Ctr, Bastrop, TX USA. [Kreil, Thomas R.] Baxalta, Global Pathogen Safety, Vienna, Austria. [Kreil, Thomas R.] Baxter BioSci, Vienna, Austria. [Brown, Paul] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Ritchie, DL (reprint author), Univ Edinburgh, Sch Clin Sci, Natl CJD Res & Surveillance Unit, Western Gen Hosp, Edinburgh EH46 7EA, Midlothian, Scotland. EM diane.ritchie@ed.ac.uk OI Ironside, James/0000-0001-5869-2108 FU Department of Health, England; Scottish Government FX The NCJDRSU is supported by the Department of Health, England, and the Scottish Government. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. NR 33 TC 0 Z9 0 U1 1 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 MAR PY 2016 VL 56 IS 3 BP 712 EP 721 DI 10.1111/trf.13422 PG 10 WC Hematology SC Hematology GA DG7SH UT WOS:000372283500025 PM 26594017 ER PT J AU Chen, Q Srivastava, K Ardinski, SC Lam, K Huvard, MJ Schmid, P Flegel, WA AF Chen, Qing Srivastava, Kshitij Ardinski, Stefanie C. Lam, Kevin Huvard, Michael J. Schmid, Pirmin Flegel, Willy A. TI Full-length nucleotide sequences of 30 common SLC44A2 alleles encoding human neutrophil antigen-3 SO TRANSFUSION LA English DT Article ID ACUTE LUNG INJURY; ALLOANTIGEN GENOTYPE FREQUENCIES; TRANSPORTER-LIKE PROTEIN-2; BLOOD-DONORS; GENETIC-VARIATION; INNER-EAR; HNA-3; ALLOANTIBODIES; POPULATIONS; ANTIBODIES AB BACKGROUNDHuman neutrophil antigen-3a (HNA-3a) alloantibodies can cause severe transfusion-related acute lung injury. The frequencies of the single-nucleotide polymorphisms (SNPs) indicative of the two clinically relevant HNA-3a/b antigens are known in many populations. In this study, we determined the full-length nucleotide sequence of common SLC44A2 alleles encoding the choline transporter-like protein-2 that harbors HNA-3a/b antigens. STUDY DESIGN AND METHODSA method was devised to determine the full-length coding sequence (CDS) and adjacent intron sequences from genomic DNA by eight polymerase chain reaction amplifications covering all 22 SLC44A2 exons. Samples from 200 African American, 96 Caucasian, two Hispanic, and four Asian blood donors were analyzed. We developed a decision tree to determine alleles (confirmed haplotypes) from the genotype data. RESULTSA total of 10 SNPs were detected in the SLC44A2 CDS. The noncoding sequences harbored an additional 28 SNPs (one in the 5-untranslated region [UTR]; 23 in the introns; and four in the 3-UTR). No SNP indicative of a nonfunctional allele was detected. The nucleotide sequences for 30 SLC44A2 alleles (haplotypes) were confirmed. There may be 66 haplotypes among the 604 chromosomes screened. CONCLUSIONSWe found 38 SNPs, including one novel SNP, in 8192 nucleotides covering the CDS of the SLC44A2 gene among 302 blood donors. Population frequencies of these SNPs were established for African Americans and Caucasians. Because alleles encoding HNA-3b are more common than non-functional SLC44A2 alleles, we confirmed our previous postulate that African American donors are less likely to form HNA-3a antibodies compared to Caucasians. C1 [Chen, Qing; Srivastava, Kshitij; Ardinski, Stefanie C.; Lam, Kevin; Huvard, Michael J.; Schmid, Pirmin; Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Chen, Qing] Jiangsu Prov Blood Ctr, Nanjing, Jiangsu, Peoples R China. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM waf@nih.gov FU grant "Jiangsu Health International Exchange Program"; Jiangsu Province Medical Elite Program [RC2011088]; National Natural Science Foundation of China [81101734]; NIH Clinical Center FX QC was supported by a grant "Jiangsu Health International Exchange Program," by Grant RC2011088 from the Jiangsu Province Medical Elite Program and by Grant 81101734 from the National Natural Science Foundation of China. Part of the study was performed at NIH in 2012 by QC as Visiting Senior Research Scientist, by SA in partial fulfillment of her study of molecular medicine (University of Ulm), and by KL as part of his Summer Internship program. This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 43 TC 3 Z9 3 U1 3 U2 7 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 MAR PY 2016 VL 56 IS 3 BP 729 EP 736 DI 10.1111/trf.13300 PG 8 WC Hematology SC Hematology GA DG7SH UT WOS:000372283500027 PM 26437811 ER PT J AU Chen, Q Srivastava, K Liu, Z Xiao, JY Huang, CY Sun, J Li, M Flegel, WA AF Chen, Qing Srivastava, Kshitij Liu, Zhong Xiao, Jianyu Huang, Chengyin Sun, Jun Li, Min Flegel, Willy Albert TI Genotype frequency of human neutrophil antigen-3 polymorphisms in the Yi, Han, and Tibetan populations of China SO TRANSFUSION LA English DT Article ID ACUTE LUNG INJURY; BLOOD-DONORS; GENE-FREQUENCIES; ALLOANTIGENS; ALLOANTIBODIES; HNA-3; TRALI; 5B AB BACKGROUNDHuman neutrophil antigen-3 (HNA-3) alloantibodies can cause fatal transfusion-related acute lung injury (TRALI). Most frequencies of SLC44A2 alleles encoding the HNA-3a/b antigens have been established in Han individuals by polymerase chain reaction with sequence-specific priming (PCR-SSP). We sequenced SLC44A2 gene fragments and determined allele frequencies in three ethnicities of China. STUDY DESIGN AND METHODSGenomic DNA was extracted from 448 samples of 100 blood donors of Yi ethnicity in Xichang, Liangshan; 248 Han in Nanjing, Jiangsu; and 100 Tibetan in Lhasa, Tibet. A PCR-SSP was applied to determine the phase of two single-nucleotide polymorphisms (SNPs); SLC44A2 haplotypes were constructed. RESULTSIn the 567 nucleotides of the SLC44A2 gene covered by our sequencing approach in Han individuals, we detected the known 331-44G>A (rs12972963) and 461G>A (rs2288904) polymorphisms. In the 243 nucleotides sequenced in Yi and Tibetan populations, we detected the known 461G>A and 503-15T>C (rs1560711) polymorphisms. A PCR-SSP for the common HNA-3a/b SNP was 100% concordant. The frequencies of the HNA-3a allele were 0.58, 0.66, and 0.69 in Yi, Han (Nanjing), and Tibetan, respectively (0.42, 0.34, and 0.31 for HNA-3b). CONCLUSIONSThe Yi population of China had the highest frequency of blood donors at risk of harboring anti-HNA-3a compared to any population studied so far. We confirmed that the underlying SLC44A2*2 allele is more common in China than in any European or African populations. C1 [Chen, Qing; Xiao, Jianyu; Huang, Chengyin; Sun, Jun] Jiangsu Prov Blood Ctr, Nanjing, Jiangsu, Peoples R China. [Chen, Qing] Soochow Univ, Suzhou, Jiangsu, Peoples R China. [Liu, Zhong] Chinese Acad Med Sci, Inst Blood Transfus, Chengdu, Sichuan, Peoples R China. [Liu, Zhong] Peking Union Med Coll, Chengdu, Sichuan, Peoples R China. [Li, Min] Chinese Acad Med Sci, Inst Dermatol, Nanjing, Jiangsu, Peoples R China. [Li, Min] Peking Union Med Coll, Nanjing, Jiangsu, Peoples R China. [Li, Min] Jiangsu Key Lab Mol Biol Skin Dis & STIs, Nanjing, Jiangsu, Peoples R China. [Srivastava, Kshitij; Flegel, Willy Albert] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM waf@nih.gov FU Jiangsu Province Social Development Program [BE2015717]; Jiangsu Province Medical Elite Program [RC2011088]; Jiangsu Health International Exchange Program; National Natural Science Foundation of China [81101734]; NIH Clinical Center FX This research was supported by the Jiangsu Province Social Development Program (BE2015717), Jiangsu Province Medical Elite Program (RC2011088), the Jiangsu Health International Exchange Program, the National Natural Science Foundation of China (81101734), and the Intramural Research Program of the NIH Clinical Center. NR 35 TC 1 Z9 1 U1 2 U2 4 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 MAR PY 2016 VL 56 IS 3 BP 737 EP 742 DI 10.1111/trf.13413 PG 6 WC Hematology SC Hematology GA DG7SH UT WOS:000372283500028 PM 26593331 ER PT J AU Hurwitz, JL Penkert, RR Xu, BS Fan, YP Partridge, JF Maul, RW Gearhart, PJ AF Hurwitz, Julia L. Penkert, Rhiannon R. Xu, Beisi Fan, Yiping Partridge, Janet F. Maul, Robert W. Gearhart, Patricia J. TI Hotspots for Vitamin-Steroid-Thyroid Hormone Response Elements Within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination SO VIRAL IMMUNOLOGY LA English DT Article ID RNA-POLYMERASE-II; RETINOID-X-RECEPTOR; A-DEFICIENT MICE; SOMATIC HYPERMUTATION; RESPIRATORY-TRACT; NUCLEAR RECEPTORS; VIRUS-VACCINE; IGA RESPONSE; ACID; DNA AB Vitamin A deficiencies are common throughout the world and have a significant negative influence on immune protection against viral infections. Mouse models demonstrate that the production of IgA, a first line of defense against viruses at mucosal sites, is inhibited in the context of vitamin A deficiency. In vitro, the addition of vitamin A to activated B cells can enhance IgA expression, but downregulate IgE. Previous reports have demonstrated that vitamin A modifies cytokine patterns, and in so doing may influence antibody isotype expression by an indirect mechanism. However, we have now discovered hundreds of potential response elements among S, S, and S switch sites within immunoglobulin heavy chain loci. These hotspots appear in both mouse and human loci and include targets for vitamin receptors and related proteins (e.g., estrogen receptors) in the nuclear receptor superfamily. Full response elements with direct repeats are relatively infrequent or absent in S regions although half-sites are present. Based on these results, we pose a hypothesis that nuclear receptors have a direct effect on the immunoglobulin heavy chain class switch recombination event. We propose that vitamin A may alter S site accessibility to activation-induced deaminase and nonhomologous end-joining machinery, thereby influencing the isotype switch, antibody production, and protection against viral infections at mucosal sites. C1 [Hurwitz, Julia L.; Penkert, Rhiannon R.] St Jude Childrens Res Hosp, Dept Infect Dis, 262 Danny Thomas Pl, Memphis, TN 38105 USA. [Xu, Beisi; Fan, Yiping] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA. [Partridge, Janet F.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Hurwitz, Julia L.] Univ Tennessee, Hlth Sci Ctr, Dept Microbiol Immunol & Biochem, Memphis, TN USA. [Maul, Robert W.; Gearhart, Patricia J.] NIA, NIH, Baltimore, MD 21224 USA. RP Hurwitz, JL (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM julia.hurwitz@stjude.org RI Xu, Beisi/C-8560-2009 OI Xu, Beisi/0000-0003-0099-858X FU NIH NIAID [R01 AI088729]; NCI [P30 CA21765]; American Lebanese Syrian Associated Charities (ALSAC); Intramural Research Program of the NIH, National Institute on Aging FX The research was funded in part by NIH NIAID R01 AI088729, NCI P30 CA21765, the American Lebanese Syrian Associated Charities (ALSAC), and the Intramural Research Program of the NIH, National Institute on Aging. NR 45 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0882-8245 EI 1557-8976 J9 VIRAL IMMUNOL JI Viral Immunol. PD MAR 1 PY 2016 VL 29 IS 2 BP 132 EP 136 DI 10.1089/vim.2015.0104 PG 5 WC Immunology; Virology SC Immunology; Virology GA DG2AM UT WOS:000371868600008 PM 26741514 ER PT J AU Kerridge, BT Saha, TD Hasin, DS AF Kerridge, Bradley T. Saha, Tulshi D. Hasin, Deborah S. TI Armed Conflict, Substance Use and HIV: A Global Analysis SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Substance use; Conflict; Partial least squares structural equation modeling; Terrorism; Refugees; Disasters ID SUB-SAHARAN AFRICA; PUBLIC-HEALTH; ALCOHOL-USE; COMPLEX EMERGENCIES; WAR; PREVENTION; HIV/AIDS; SETTINGS; PEOPLE; COMBAT AB Armed conflict is frequently assumed to be a contributor to the global HIV epidemic, but existing evidence is sparse. We examined the relationship between armed conflict between 2002 and 2008 and HIV disability life years (DALYs) in 2010 among WHO Member States. Using partial least squares analysis we also examined moderation of the armed conflict-HIV link by two susceptibility constructs (background risk, substance use) and one vulnerability mediator (numbers of refugees, people on ART, and total HIV spending). Background risk directly impacted HIV DALYs (p < 0.05), substance use moderated the conflict-HIV relationship (p < 0.01). The vulnerability construct mediated the conflict-HIV association (p < 0.01). Findings underscore the need to align HIV prevention/intervention efforts with pre-existing HIV burden and reduce the impact of natural disasters on the populace in conflict-affected states. Integration of substance prevention/harm reduction programs within national HIV responses, attention to most-at-risk populations and increased surveillance/treatment of drug resistant HIV and TB is warranted. C1 [Kerridge, Bradley T.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Saha, Tulshi D.] NIAAA, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane,Room 3077, Rockville, MD 20852 USA. [Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, Mailman Sch Publ Hlth,New York State Psychiat Ins, New York, NY 10032 USA. RP Kerridge, BT (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. EM bradleykerridge@gmail.com OI Kerridge, Bradley/0000-0003-0459-9439 FU National Institute on Drug Abuse, National Institutes of Health [5F32DA0364431]; National Institute on Alcohol Abuse and Alcoholism [K05AA014223]; New York State Psychiatric Institute FX This research was supported by the National Institute on Drug Abuse, National Institutes of Health (5F32DA0364431: Dr. Kerridge), the National Institute on Alcohol Abuse and Alcoholism (K05AA014223: Dr. Hasin), and the New York State Psychiatric Institute (Dr. Hasin). NR 76 TC 0 Z9 0 U1 1 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAR PY 2016 VL 20 IS 3 BP 473 EP 483 DI 10.1007/s10461-015-1161-4 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DF8JA UT WOS:000371602700001 PM 26286341 ER PT J AU Rentsch, C Tate, JP Akgun, KM Crystal, S Wang, KH Greysen, SR Wang, EA Bryant, KJ Fiellin, DA Justice, AC Rimland, D AF Rentsch, Christopher Tate, Janet P. Akguen, Kathleen M. Crystal, Stephen Wang, Karen H. Greysen, S. Ryan Wang, Emily A. Bryant, Kendall J. Fiellin, David A. Justice, Amy C. Rimland, David TI Alcohol-Related Diagnoses and All-Cause Hospitalization Among HIV-Infected and Uninfected Patients: A Longitudinal Analysis of United States Veterans from 1997 to 2011 SO AIDS AND BEHAVIOR LA English DT Article DE Inpatient care; HIV; Substance abuse; Clinical epidemiology; Aging ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH-CARE UTILIZATION; ANTIRETROVIRAL THERAPY; SERVICES UTILIZATION; USE DISORDERS; COHORT; RISK; METAANALYSIS; INDIVIDUALS; ADULTS AB Individuals with HIV infection are living substantially longer on antiretroviral therapy, but hospitalization rates continue to be relatively high. We do not know how overall or diagnosis-specific hospitalization rates compare between HIV-infected and uninfected individuals or what conditions may drive hospitalization trends. Hospitalization rates among United States Veterans were calculated and stratified by HIV serostatus and principal diagnosis disease category. Because alcohol-related diagnoses (ARD) appeared to have a disproportional effect, we further stratified our calculations by ARD history. A multivariable Cox proportional hazards model was fitted to assess the relative risk of hospitalization controlling for demographic and other comorbidity variables. From 1997 to 2011, 46,428 HIV-infected and 93,997 uninfected patients were followed for 1,497,536 person-years. Overall hospitalization rates decreased among HIV-infected and uninfected patients. However, cardiovascular and renal insufficiency admissions increased for all groups while gastrointestinal and liver, endocrine, neurologic, and non-AIDS cancer admissions increased among those with an alcohol-related diagnosis. After multivariable adjustment, HIV-infected individuals with an ARD had the highest risk of hospitalization (hazard ratio 3.24, 95 % CI 3.00, 3.49) compared to those free of HIV infection and without an ARD. Still, HIV alone also conferred increased risk (HR 2.08, 95 % CI 2.04, 2.13). While decreasing overall, risk of all-cause hospitalization remains higher among HIV-infected than uninfected individuals and is strongly influenced by the presence of an ARD. C1 [Rentsch, Christopher; Rimland, David] Atlanta VA Med Ctr, Infect Dis, Decatur, GA USA. [Rentsch, Christopher; Tate, Janet P.; Akguen, Kathleen M.; Wang, Karen H.; Justice, Amy C.] VA Connecticut Healthcare Syst, Res, West Haven, CT USA. [Rentsch, Christopher; Tate, Janet P.; Akguen, Kathleen M.; Wang, Karen H.; Wang, Emily A.; Fiellin, David A.; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Crystal, Stephen] Rutgers State Univ, Sch Social Work, New Brunswick, NJ 08903 USA. [Greysen, S. Ryan] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Bryant, Kendall J.] NIAAA, NIH, Bethesda, MD USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. RP Rentsch, C (reprint author), VA Connecticut Healthcare Syst, Res, West Haven, CT USA. EM christopher.rentsch@va.gov OI Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502 FU National Institutes of Health: AHRQ [R01-HS018372]; NIAAA [U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566-completed]; NHLBI [R01-HL095136, R01-HL090342]; NIAID [U01-A1069918]; NIMH [P30-MH062294]; NIDA [R01DA035616]; NCI [R01 CA173754]; Veterans Health Administration Office of Research and Development [VA REA 08-266, V1CDA2012-20]; Office of Academic Affiliations; Department of Veterans Affairs, Veterans Health Administration; Office of Research and Development FX This work was supported by the National Institutes of Health: AHRQ [R01-HS018372], NIAAA [U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566-completed], NHLBI [R01-HL095136; R01-HL090342], NIAID [U01-A1069918], NIMH [P30-MH062294], NIDA [R01DA035616], NCI [R01 CA173754] and the Veterans Health Administration Office of Research and Development [VA REA 08-266, VA IRR Merit Award, VISN 1 Career Development Award [V1CDA2012-20]] and Office of Academic Affiliations [Medical Informatics Fellowship]. This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development. We must disclaim that the views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 51 TC 5 Z9 5 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAR PY 2016 VL 20 IS 3 BP 555 EP 564 DI 10.1007/s10461-015-1025-y PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DF8JA UT WOS:000371602700007 PM 25711299 ER PT J AU Rentsch, C Tate, JP Akgun, KM Crystal, S Wang, KH Greysen, SR Wang, EA Bryant, KJ Fiellin, DA Justice, AC Rimland, D AF Rentsch, Christopher Tate, Janet P. Akgun, Kathleen M. Crystal, Stephen Wang, Karen H. Greysen, S. Ryan Wang, Emily A. Bryant, Kendall J. Fiellin, David A. Justice, Amy C. Rimland, David TI Alcohol-Related Diagnoses and All-Cause Hospitalization Among HIV-Infected and Uninfected Patients: A Longitudinal Analysis of United States Veterans from 1997 to 2011 (vol 20, pg 555, 2016) SO AIDS AND BEHAVIOR LA English DT Correction C1 [Rentsch, Christopher; Rimland, David] Atlanta VA Med Ctr, Infect Dis, Decatur, GA USA. [Rentsch, Christopher; Tate, Janet P.; Akgun, Kathleen M.; Wang, Karen H.; Justice, Amy C.] VA Connecticut Healthcare Syst, Res, West Haven, CT USA. [Rentsch, Christopher; Tate, Janet P.; Akgun, Kathleen M.; Wang, Karen H.; Wang, Emily A.; Fiellin, David A.; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Crystal, Stephen] Rutgers State Univ, Sch Social Work, New Brunswick, NJ 08903 USA. [Greysen, S. Ryan] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Bryant, Kendall J.] NIAAA, NIH, Bethesda, MD USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. RP Rentsch, C (reprint author), Atlanta VA Med Ctr, Infect Dis, Decatur, GA USA.; Rentsch, C (reprint author), VA Connecticut Healthcare Syst, Res, West Haven, CT USA.; Rentsch, C (reprint author), Yale Univ, Sch Med, New Haven, CT USA. EM christopher.rentsch@va.gov FU AHRQ HHS [R01 HS018372]; NCI NIH HHS [R01 CA173754]; NHLBI NIH HHS [R01 HL095136, R01 HL090342]; NIAAA NIH HHS [U24 AA022007, U24 AA022001, U01 AA020790, U01 AA020795, U01 AA020799, U10 AA013566, U01 AA013566, U13 AA022864, U24 AA020794]; NIDA NIH HHS [R01 DA035616]; NIMH NIH HHS [P30 MH062294] NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAR PY 2016 VL 20 IS 3 BP 565 EP 565 DI 10.1007/s10461-015-1072-4 PG 1 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DF8JA UT WOS:000371602700008 PM 25972072 ER PT J AU Braithwaite, RS Fang, YX Tate, J Mentor, SM Bryant, KJ Fiellin, DA Justice, AC AF Braithwaite, R. Scott Fang, Yixin Tate, Janet Mentor, Sherry M. Bryant, Kendall J. Fiellin, David A. Justice, Amy C. TI Do Alcohol Misuse, Smoking, and Depression Vary Concordantly or Sequentially? A Longitudinal Study of HIV-Infected and Matched Uninfected Veterans in Care SO AIDS AND BEHAVIOR LA English DT Article DE Alcohol use; Aging; Temporal analysis; Depression; HIV; Smoking; Veterans ID NATIONAL-COMORBIDITY-SURVEY; UNITED-STATES; MENTAL-DISORDERS; AGING COHORT; HEALTH; ASSOCIATION; CONSUMPTION; DRINKING; ABUSE; RATES AB We analyzed temporal patterns of alcohol misuse, smoking, and depression among veterans in care to determine whether these conditions vary concordantly or sequentially. Using the Veterans Aging Cohort Study, harmful alcohol use (AUDIT-C a parts per thousand yen 4), current smoking, and depression (PHQ-9 a parts per thousand yen 8), were measured. In regression analyses, predictors included each outcome condition at baseline, the other two conditions in the same survey, the other two conditions in the immediately preceding survey, number of years since enrollment, and HIV status. We found that current smoking and depression were more common among HIV infected individuals. Harmful alcohol use was more common among uninfected individuals. Temporal analyses suggested a concurrent pattern: each condition was associated with the other two conditions (p < 0.03, OR 1.12-1.66) as well as with the prior presence of the same condition (p < 0.0001; OR 6.38-22.02). Smoking was associated with prior depression after controlling for current depression (OR 1.16; p = 0.003). In conclusion, alcohol misuse, smoking, and depression were temporally concordant and persistent, raising the question of whether they constitute a common syndrome in HIV infected patients and others with chronic diseases. C1 [Braithwaite, R. Scott; Fang, Yixin; Mentor, Sherry M.] NYU, Dept Populat Hlth, Sch Med, 227 East 30th St,Floor 6 Room 615, New York, NY 10016 USA. [Tate, Janet; Fiellin, David A.; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Bryant, Kendall J.] NIAAA, NIH, Bethesda, MD USA. RP Braithwaite, RS (reprint author), NYU, Dept Populat Hlth, Sch Med, 227 East 30th St,Floor 6 Room 615, New York, NY 10016 USA. EM Scott.Braithwaite@nyumc.org OI Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502; Fang, Yixin/0000-0003-0104-9140 FU National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health [U24AA022007] FX Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number U24AA022007. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 25 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAR PY 2016 VL 20 IS 3 BP 566 EP 572 DI 10.1007/s10461-015-1117-8 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DF8JA UT WOS:000371602700009 PM 26187007 ER PT J AU Zhu, YY Olsen, SF Mendola, P Yeung, EH Vaag, A Bowers, K Liu, AY Bao, W Li, SS Madsen, C Grunnet, LG Granstrom, C Hansen, S Martin, K Chavarro, JE Hu, FB Langhoff-Roos, J Damm, P Zhang, CL AF Zhu, Yeyi Olsen, Sjurdur F. Mendola, Pauline Yeung, Edwina H. Vaag, Allan Bowers, Katherine Liu, Aiyi Bao, Wei Li, Shanshan Madsen, Camilla Grunnet, Louise G. Granstrom, Charlotta Hansen, Susanne Martin, Kelly Chavarro, Jorge E. Hu, Frank B. Langhoff-Roos, Jens Damm, Peter Zhang, Cuilin TI Growth and obesity through the first 7 y of life in association with levels of maternal glycemia during pregnancy: a prospective cohort study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE childhood obesity; fasting plasma glucose; gestational diabetes; intrauterine exposure; macrosomia; prepregnancy obesity ID GESTATIONAL DIABETES-MELLITUS; CHILDHOOD OBESITY; GLUCOSE-TOLERANCE; OUTCOME HAPO; HYPERGLYCEMIA; CHILDREN; MOTHERS; OVERWEIGHT; WOMEN; RISK AB Background: Given the long-term adverse sequelae of childhood obesity, identification of early life factors related to fetal growth and childhood obesity is warranted. Investigation on growth and obesity in early life in association with intrauterine exposure to maternal hyperglycemia, a common metabolic pregnancy complication, is of public health significance and clinical implications. Objective: We investigated the association of fasting plasma glucose (FPG) concentrations during pregnancy with offspring growth and risk of overweight/obesity through age 7 y, after adjustment for confounders, including maternal prepregnancy obesity status. Design: FPG concentrations at 28 gestational weeks (IQR: 22-32 wk) were extracted from medical records for 661 pregnancies complicated by gestational diabetes mellitus in the Danish National Birth Cohort (1996-2002). Offspring's ponderal index was derived from birth weight and length; age- and sex-specific body mass index (BMI) z scores at 5 mo, 12 mo, and 7 y were calculated based on WHO reference data. Relations between FPG and offspring growth and obesity were assessed by linear and Poisson regression with robust standard errors, adjusting for maternal prepregnancy BMI and sociodemographic and perinatal factors. Results: At birth, maternal FPG during pregnancy was significantly associated with offspring ponderal index (beta = 0.46; 95% CI: 0.14, 0.78 per 1-mmol/L increase) and risk of macrosomia (birth weight >4000 g) (RR = 1.21; 95% CI: 1.07, 1.38 per 1-mmol/L increase),. At 7 y, higher maternal FPG concentrations were significantly associated with increased BMI z scores (beta = 0.20; 95% CI: 0.04, 0.36) and elevated risk of overweight/obesity (RR = 1.21; 95% CI: 1.01, 1.50). Additional adjustment for birth weight and childhood lifestyle factors did not appreciably alter results. No associations were observed at 5 or 12 mo. Conclusion: Among women with gestational diabetes mellitus, maternal FPG concentrations during pregnancy were significantly and positively associated with offspring birth size and overweight/obesity risk at 7 y, adjusting for maternal prepregnancy BMI. C1 [Zhu, Yeyi; Mendola, Pauline; Yeung, Edwina H.; Bowers, Katherine; Liu, Aiyi; Bao, Wei; Li, Shanshan; Martin, Kelly; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Olsen, Sjurdur F.; Granstrom, Charlotta; Hansen, Susanne] Staten Serum Inst, Dept Epidemiol Res, Ctr Fetal Programming, Copenhagen, Denmark. [Vaag, Allan; Madsen, Camilla; Grunnet, Louise G.] Univ Copenhagen Hosp, Rigshosp, Dept Endocrinol, DK-2100 Copenhagen, Denmark. [Langhoff-Roos, Jens] Univ Copenhagen Hosp, Rigshosp, Dept Obstet, DK-2100 Copenhagen, Denmark. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Damm, Peter] Univ Copenhagen, Rigshosp, Inst Clin Med, Dept Obstet,Fac Hlth & Med Sci,Ctr Pregnant Women, DK-2100 Copenhagen, Denmark. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. EM zhangcu@mail.nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Yeung, Edwina/0000-0002-3851-2613; Liu, Aiyi/0000-0002-6618-5082 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HHSN275201000020C]; Danish Research Council [09-067124, 09-075611] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (HHSN275201000020C). The Danish National Birth Cohort is supported by grants 09-067124 (Center for Fetal Programming) and 09-075611 from the Danish Research Council. NR 41 TC 2 Z9 2 U1 1 U2 4 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 MAR PY 2016 VL 103 IS 3 BP 794 EP 800 DI 10.3945/ajcn.115.121780 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DF8ZO UT WOS:000371650200016 PM 26817507 ER PT J AU Mumford, SL Chavarro, JE Zhang, CL Perkins, NJ Sjaarda, LA Pollack, AZ Schliep, KC Michels, KA Zarek, SM Plowden, TC Radin, RG Messer, LC Frankel, RA Wactawski-Wende, J AF Mumford, Sunni L. Chavarro, Jorge E. Zhang, Cuilin Perkins, Neil J. Sjaarda, Lindsey A. Pollack, Anna Z. Schliep, Karen C. Michels, Kara A. Zarek, Shvetha M. Plowden, Torie C. Radin, Rose G. Messer, Lynne C. Frankel, Robyn A. Wactawski-Wende, Jean TI Dietary fat intake and reproductive hormone concentrations and ovulation in regularly menstruating women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary fats; estradiol; menstrual cycle; ovulation; testosterone ID HIGH-FIBER DIET; SERUM ESTROGEN CONCENTRATIONS; FOOD FREQUENCY QUESTIONNAIRE; POLYCYSTIC-OVARY-SYNDROME; PREMENOPAUSAL WOMEN; FERTILITY MONITOR; PHYSICAL-ACTIVITY; BREAST-CANCER; ACID; CYCLE AB Background: Emerging evidence suggests potential links between some dietary fatty acids and improved fertility, because specific fatty acids may affect prostaglandin synthesis and steroidogenesis. Objective: The objective of this exploratory study was to evaluate associations between total and specific types of dietary fat intake and 1) hormone concentrations and 2) the risk of sporadic anovulation in a cohort of 259 regularly menstruating women in the Bio-Cycle Study. Design: Endogenous reproductive hormones were measured up to 8 times/cycle for up to 2 cycles, with visits scheduled with the use of fertility monitors. Dietary intake was assessed with up to four 24-h recalls/cycle. Linear mixed models and generalized linear models were used to evaluate the associations between dietary fatty acids and both reproductive hormone concentrations and ovulatory status. All models were adjusted for total energy intake, age, body mass index, and race. Results: Relative to the lowest levels of percentage of energy from total fat, the highest tertile was associated with increased total and free testosterone concentrations (total: percentage change of 4.0%; 95% CI: 0.7%, 7.3%; free: percentage change of 4.1%; 95% CI: 0.5%, 7.7%). In particular, the percentage of energy from polyunsaturated fatty acids (PUFAs) in the highest tertile was associated with increases in total and free testosterone (total: percentage change of 3.7%; 95% CI: 0.6%, 6.8%; free: percentage change of 4.0%; 95% CI: 0.5%, 7.5%). The PUFA docosapentaenoic acid (22:5n-3) was not significantly associated with testosterone concentrations (P-trend = 0.86 in energy substitution models) but was associated with increased progesterone and a reduced risk of anovulation (highest tertile compared with the lowest tertile: RR: 0.42; 95% CI: 0.18, 0.95). Fat intakes were not associated with other reproductive hormone concentrations. Conclusions: These results indicate that total fat intake, and PUFA intake in particular, is associated with very small increases in testosterone concentrations in healthy women and that increased docosapentaenoic acid was associated with a lower risk of anovulation. C1 [Mumford, Sunni L.; Zhang, Cuilin; Perkins, Neil J.; Sjaarda, Lindsey A.; Schliep, Karen C.; Michels, Kara A.; Zarek, Shvetha M.; Plowden, Torie C.; Radin, Rose G.; Frankel, Robyn A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Zarek, Shvetha M.; Plowden, Torie C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Chavarro, Jorge E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Pollack, Anna Z.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Messer, Lynne C.] Portland State Univ, Sch Community Hlth, Portland, OR 97207 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HHSN275200403394C, HHSN275201100002I, HHSN27500001]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH [P30-DK46200] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (contracts HHSN275200403394C and HHSN275201100002I and Task 1 HHSN27500001); JEC was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, grant P30-DK46200. NR 47 TC 1 Z9 1 U1 2 U2 9 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 MAR PY 2016 VL 103 IS 3 BP 868 EP 877 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DF8ZO UT WOS:000371650200024 PM 26843151 ER PT J AU Agarwal, SK Wruck, L Quibrera, M Matsushita, K Loehr, LR Chang, PP Rosamond, WD Wright, J Heiss, G Coresh, J AF Agarwal, Sunil K. Wruck, Lisa Quibrera, Miguel Matsushita, Kunihiro Loehr, Laura R. Chang, Patricia P. Rosamond, Wayne D. Wright, Jacqueline Heiss, Gerardo Coresh, Josef TI Temporal Trends in Hospitalization for Acute Decompensated Heart Failure in the United States, 1998-2011 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE acute decompensated heart failure; adjudicated heart failure; community surveillance; hospitalizations; International Classification of Diseases codes; national inpatient sample; secular trends; United States ID ATHEROSCLEROSIS RISK; CLASSIFICATION; COMMUNITIES; VALIDATION; UPDATE; RATES AB Estimates of the numbers and rates of acute decompensated heart failure (ADHF) hospitalization are central to understanding health-care utilization and efforts to improve patient care. We comprehensively estimated the frequency, rate, and trends of ADHF hospitalization in the United States. Based on Atherosclerosis Risk in Communities (ARIC) Study surveillance adjudicating 12,450 eligible hospitalizations during 2005-2010, we developed prediction models for ADHF separately for 3 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 428 discharge diagnosis groups: 428 primary, 428 nonprimary, or 428 absent. We applied the models to data from the National Inpatient Sample (11.5 million hospitalizations of persons aged a parts per thousand yen55 years with eligible ICD-9-CM codes), an all-payer, 20% probability sample of US community hospitals. The average estimated number of ADHF hospitalizations per year was 1.76 million (428 primary, 0.80 million; 428 nonprimary, 0.83 million; 428 absent, 0.13 million). During 1998-2004, the rate of ADHF hospitalization increased by 2.0%/year (95% confidence interval (CI): 1.8, 2.5) versus a 1.4%/year (95% CI: 0.8, 2.1) increase in code 428 primary hospitalizations (P < 0.001). In contrast, during 2005-2011, numbers of ADHF hospitalizations were stable (-0.5%/year; 95% CI: -1.4, 0.3), while the numbers of 428-primary hospitalizations decreased by -1.5%/year (95% CI: -2.2, -0.8) (P for contrast = 0.03). In conclusion, the estimated number of hospitalizations with ADHF is approximately 2 times higher than the number of hospitalizations with ICD-9-CM code 428 in the primary position. The trend increased more steeply prior to 2005 and was relatively flat after 2005. C1 [Agarwal, Sunil K.; Matsushita, Kunihiro; Coresh, Josef] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Agarwal, Sunil K.; Matsushita, Kunihiro; Coresh, Josef] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Wruck, Lisa; Quibrera, Miguel] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Loehr, Laura R.; Rosamond, Wayne D.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Sch Global Publ Hlth, Chapel Hill, NC USA. [Loehr, Laura R.; Chang, Patricia P.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Wright, Jacqueline] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 2020 E Monument St,Room B-321, Baltimore, MD 21287 USA. EM sunilagarwal1@gmail.com FU National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, T32HL007024] FX The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. S. K. A. was supported by Cardiovascular Epidemiology Training Grant T32HL007024 from the National Heart, Lung, and Blood Institute ( Principal Investigator: Prof. Josef Coresh). NR 20 TC 3 Z9 4 U1 0 U2 0 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 MAR 1 PY 2016 VL 183 IS 5 BP 462 EP 470 DI 10.1093/aje/kwv455 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DF9NU UT WOS:000371688800022 PM 26895710 ER PT J AU Chen, SF Huang, JF Zhao, Q Chen, J Jaquish, CE He, J Lu, XF Yang, XL Gu, CC Hixson, JE Liu, FC Rice, TK Cao, J Chen, JC Gu, DF AF Chen, Shufeng Huang, Jianfeng Zhao, Qi Chen, Jing Jaquish, Cashell E. He, Jiang Lu, Xiangfeng Yang, Xueli Gu, Charles C. Hixson, James E. Liu, Fangchao Rice, Treva K. Cao, Jie Chen, Jichun Gu, Dongfeng TI Associations Between Genetic Variants of the Natriuretic Peptide System and Blood Pressure Response to Dietary Sodium Intervention: The GenSalt Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure response; dietary intervention; genetic association; natriuretic peptide ID GENOME-WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; COMMON VARIANTS; INCIDENT HYPERTENSION; ISCHEMIC-STROKE; URINARY SODIUM; SALT INTAKE; RECEPTOR; CHINESE; RISK AB BACKGROUND The aim of this study was to comprehensively test the association of genetic variants in the natriuretic peptide (NP) system with blood pressure (BP) response to dietary sodium intervention in a Chinese population. METHODS We conducted a 7-day low-sodium intervention followed by a 7-day high-sodium intervention among 1,906 participants in rural China. BP measurements were obtained at baseline and each dietary intervention using a random-zero sphygmomanometer. Linear mixed-effect models were used to assess the associations of 48 single-nucleotide polymorphisms (SNPs) in 6 genes of NP system with BP response to dietary sodium intervention. RESULTS SNP rs5063 in the NPPA gene and SNP rs2077386 in the NPPC gene exhibited significant associations with BP response to low-sodium dietary intervention under recessive genetic model. For rs5063, absolute mean arterial pressure responses (95% confidence interval) to the low-sodium intervention were 1.31 (-1.08, 3.70) mm Hg for TT genotype and -3.74 (-4.01, -3.46) mm Hg for CC or TC genotype, respectively (P = 4.1 x 10(-5)). Individuals with at least one copy of the C allele of rs2077386 had significantly reduction in systolic BP during the low-sodium intervention compared to those with genotype GG with responses of -5.48 (-5.83, -5.14) vs. -2.76 (-3.52, -2.00) mm Hg, respectively (P = 1.9 x 10(-13)). CONCLUSIONS These novel findings suggested that genetic variants of NP system may contribute to the variation of BP response to sodium intervention in Chinese population. Certainly, replication of these results in other populations and further functional studies are warranted to clarify their role in the regulation of BP and hypertension. C1 [Chen, Shufeng; Huang, Jianfeng; Lu, Xiangfeng; Yang, Xueli; Liu, Fangchao; Cao, Jie; Chen, Jichun; Gu, Dongfeng] Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China. [Chen, Shufeng; Huang, Jianfeng; Lu, Xiangfeng; Yang, Xueli; Liu, Fangchao; Cao, Jie; Chen, Jichun; Gu, Dongfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Zhao, Qi; Chen, Jing; He, Jiang] Tulane Univ, Sch Publ Hlth, Dept Epidemiol, New Orleans, LA USA. [Jaquish, Cashell E.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gu, Charles C.; Rice, Treva K.] Washington Univ, Sch Med, St Louis, MO USA. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. RP Chen, SF (reprint author), Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.; Chen, SF (reprint author), Peking Union Med Coll, Beijing 100021, Peoples R China. EM shufengchen2001@163.com FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA [U01HL072507, R01HL087263, R01HL090682]; High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China [2012AA02A516]; Beijing Natural Science Foundation, China [7132205] FX The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by a cooperative agreement project grant (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. This study is also funded by a research grant (2012AA02A516) from the High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China. S.C. is a scholar supported by Beijing Natural Science Foundation (7132205), China. NR 40 TC 0 Z9 0 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAR PY 2016 VL 29 IS 3 BP 397 EP 404 DI 10.1093/ajh/hpv129 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DF9OD UT WOS:000371689800016 PM 26224401 ER PT J AU Traboulsee, A Simon, JH Stone, L Fisher, E Jones, DE Malhotra, A Newsome, SD Oh, J Reich, DS Richert, N Rammohan, K Khan, O Radue, EW Ford, C Halper, J Li, D AF Traboulsee, A. Simon, J. H. Stone, L. Fisher, E. Jones, D. E. Malhotra, A. Newsome, S. D. Oh, J. Reich, D. S. Richert, N. Rammohan, K. Khan, O. Radue, E. -W. Ford, C. Halper, J. Li, D. TI Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; SPINAL-CORD LESIONS; MCDONALD CRITERIA; INTERFERON-BETA; TRIAL; ABNORMALITIES; DISABILITY; ATROPHY; RISK; LOAD AB This is a comprehensive group of guidelines for imaging patients with demyelinating disease, from an international group of neurologists and radiologists. Suggestions for MR imaging protocols are given for the brain, for surveillance imaging for progressive multifocal leukoencephalopathy, for spinal cord imaging, and for the orbit. Recommendations are also given for what type of material should be included in the report. SUMMARY: An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available. C1 [Traboulsee, A.] Univ British Columbia, Dept Med Neurol, Vancouver, BC V5Z 1M9, Canada. [Simon, J. H.] Portland VA Res Fdn, Portland, OR USA. [Simon, J. H.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Stone, L.] Cleveland Clin, Mellen Ctr MS Treatment & Res, Cleveland, OH 44106 USA. [Fisher, E.] Cleveland Clin, Dept Biomed Engn, Cleveland, OH 44106 USA. [Jones, D. E.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Malhotra, A.] Yale Univ, Dept Radiol & Biomed Imaging, New Haven, CT USA. [Newsome, S. D.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Oh, J.] Univ Toronto, St Michaels Hosp, Toronto, ON, Canada. [Reich, D. S.] NINDS, Translat Neuroradiol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Richert, N.] Biogen Idec Inc, Cambridge, MA USA. [Rammohan, K.] Univ Miami, Multiple Sclerosis Ctr, Miami, FL USA. [Khan, O.] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Radue, E. -W.] Univ Basel Hosp, Dept Radiol, CH-4031 Basel, Switzerland. [Ford, C.] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Halper, J.] Consortium Multiple Sclerosis Ctr, Hackensack, NJ USA. [Li, D.] Univ British Columbia, Dept Radiol, Vancouver, BC, Canada. RP Traboulsee, A (reprint author), Univ British Columbia, Dept Med Neurol, UBC Hosp, 2211 Wesbrook Mall,Room s199, Vancouver, BC V6T 2B5, Canada. EM t.traboulsee@ubc.ca RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU Consortium of Multiple Sclerosis Centers FX Organizational support and funding for the meetings were provided by the Consortium of Multiple Sclerosis Centers (www.mscare.org). NR 46 TC 15 Z9 15 U1 3 U2 8 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD MAR PY 2016 VL 37 IS 3 BP 394 EP 401 DI 10.3174/ajnr.A4539 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DF8TG UT WOS:000371631500008 PM 26564433 ER PT J AU Feldblum, JT Wroblewski, EE Rudicell, RS Li, YY Hahn, BH Pusey, AE Gilby, IC AF Feldblum, Joseph T. Wroblewski, Emily E. Rudicell, Rebecca S. Li, Yingying Hahn, Beatrice H. Pusey, Anne E. Gilby, Ian C. TI Alternative reproductive tactics among male chimpanzees in Gombe National Park, Tanzania SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Physical-Anthropologists CY APR 13-16, 2016 CL Atlanta, GA SP Amer Assoc Phys Anthropologists C1 [Feldblum, Joseph T.; Pusey, Anne E.] Duke Univ, Dept Evolutionary Anthropol, Durham, NC 27706 USA. [Wroblewski, Emily E.] Stanford Univ, Sch Med, Dept Struct Biol, Stanford, CA 94305 USA. [Rudicell, Rebecca S.] NIH, Vaccine Res Ctr, Bethesda, MD USA. [Rudicell, Rebecca S.] Sanofi, Rockville, MD USA. [Li, Yingying; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Li, Yingying; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Gilby, Ian C.] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 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 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2016 VL 159 SU 62 BP 142 EP 142 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA DF3OW UT WOS:000371255201136 ER PT J AU Sherry, S Xiao, CL Slotta, D Rodarmer, K Feolo, M Kimelman, M Godynskiy, G O'Sullivan, C Yaschenko, E AF Sherry, Stephen Xiao, Chunlin Slotta, Douglas Rodarmer, Kurt Feolo, Mike Kimelman, Michael Godynskiy, Georgiy O'Sullivan, Chris Yaschenko, Eugene TI Simplified access to human genomic evidence for clinical variants with new NCBI services SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 85th Annual Meeting of the American-Association-of-Physical-Anthropologists CY APR 13-16, 2016 CL Atlanta, GA SP Amer Assoc Phys Anthropologists C1 [Sherry, Stephen; Xiao, Chunlin; Slotta, Douglas; Rodarmer, Kurt; Feolo, Mike; Kimelman, Michael; Godynskiy, Georgiy; O'Sullivan, Chris; Yaschenko, Eugene] NIH, NCBI, 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 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2016 VL 159 SU 62 BP 289 EP 290 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA DF3OW UT WOS:000371255202220 ER PT J AU Berg, CD AF Berg, Christine D. TI Just Say No! Smoking Abstinence Works SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID LUNG; MORTALITY C1 [Berg, Christine D.] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA. [Berg, Christine D.] NCI, Div Canc Epidemiol & Prevent, Bethesda, MD 20892 USA. RP Berg, CD (reprint author), Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.; Berg, CD (reprint author), NCI, Div Canc Epidemiol & Prevent, Bethesda, MD 20892 USA. NR 12 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 MAR 1 PY 2016 VL 193 IS 5 BP 476 EP 477 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DG0KI UT WOS:000371753300004 PM 26930428 ER PT J AU Du Toit, J Miller, F AF Du Toit, Jessica Miller, Franklin TI THE ETHICS OF CONTINUED LIFE-SUSTAINING TREATMENT FOR THOSE DIAGNOSED AS BRAIN-DEAD SO BIOETHICS LA English DT Article DE brain death; life-sustaining treatment; Jahi McMath; futility; scarce resource allocation ID RATIONALE AB Given the long-standing controversy about whether the brain-dead should be considered alive in an irreversible coma or dead despite displaying apparent signs of life, the ethical and policy issues posed when family members insist on continued treatment are not as simple as commentators have claimed. In this article, we consider the kind of policy that should be adopted to manage a family's insistence that their brain-dead loved one continues to receive supportive care. We argue that while it would be ethically inappropriate to continue to devote scarce acute care resources to such patients in a hospital setting, it may not be ethically inappropriate for patients to receive these resources in certain other settings. Thus, if a family insists on continuing to care for their brain-dead loved at their home, we should not, from a policy perspective, interfere with the family's wishes. We also argue that healthcare professionals should make some effort to facilitate the transfer of brain-dead patients to these other settings when families insist on continued treatment despite being informed about the lack of any potential for recovery of consciousness. Our arguments are strengthened by the fact that patients in a persistent vegetative state, who, when correctly diagnosed, also have no potential for recovery of consciousness, are routinely transferred from hospitals to nursing homes or long-term care facilities where they continue to be ventilated, tube fed and to receive other supportive care. We also briefly explore the question of who should be responsible for the costs of such treatment at the long-term care facility. C1 [Du Toit, Jessica; Miller, Franklin] NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. [Miller, Franklin] Weill Cornell Med Coll, Med Eth Med, New York, NY 10065 USA. RP Miller, F (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA.; Miller, F (reprint author), Weill Cornell Med Coll, Med Eth Med, New York, NY 10065 USA. EM fmiller@cc.nih.gov NR 22 TC 1 Z9 1 U1 0 U2 5 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 MAR PY 2016 VL 30 IS 3 BP 151 EP 158 DI 10.1111/bioe.12178 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DF6SS UT WOS:000371487500003 PM 26183857 ER PT J AU Blehm, BH Devine, A Staunton, JR Tanner, K AF Blehm, Benjamin H. Devine, Alexus Staunton, Jack R. Tanner, Kandice TI In vivo tissue has non-linear rheological behavior distinct from 3D biomimetic hydrogels, as determined by AMOTIV microscopy SO BIOMATERIALS LA English DT Article DE Microrheology; Optical traps; Biomaterials; Tissue mechanics; Hydrogels; Zebrafish ID 3-DIMENSIONAL CULTURE MODELS; SINGLE KINESIN MOLECULES; MECHANICAL-PROPERTIES; BASEMENT-MEMBRANE; OPTICAL TWEEZERS; FORCE MICROSCOPY; CELL; MICRORHEOLOGY; CANCER; ZEBRAFISH AB Variation in matrix elasticity has been shown to determine cell fate in both differentiation and development of malignant phenotype. The tissue microenvironment provides complex biochemical and biophysical signals in part due to the architectural heterogeneities found in extracellular matrices (ECMs). Three dimensional cell cultures can partially mimic in vivo tissue architecture, but to truly understand the role of viscoelasticity on cell fate, we must first determine in vivo tissue mechanical properties to improve in vitro models. We employed Active Microrheology by Optical Trapping In Vivo (AMOTIV), using in situ calibration to measure in vivo zebrafish tissue mechanics. Previously used trap calibration methods overestimate complex moduli by 2-20 fold compared to AMOTIV. Applying differential microscale stresses and strains showed that hyaluronic acid (HA) gels display semi-flexible polymer behavior, while laminin-rich ECM hydrogels display flexible polymer behavior. In contrast, zebrafish tissues displayed different moduli at different stresses, with higher power law exponents at lower stresses, indicating that living tissue has greater stress dependence than the 3D hydrogels examined. To our knowledge, this work is the first vertebrate tissue rheological characterization performed in vivo. Our fundamental observations are important for the development and refinement of in vitro platforms. Published by Elsevier Ltd. C1 [Blehm, Benjamin H.; Devine, Alexus; Staunton, Jack R.; Tanner, Kandice] NIH, Cell Biol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Tanner, K (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2132, Bethesda, MD 20892 USA. EM kandice.tanner@nih.gov FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute FX This effort was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. We thank Benjamin Feldman of the National Institute of Child Health and Human Development and Eric Glasgow of Georgetown University, for helpful discussions and assistance with zebrafish husbandry. We also thank George Leiman for critical reading of this manuscript. We thank Ross Lake for help with histology. We also thank Daniel Blair, and Xinran Zhang of Georgetown University for assistance with bulk rheometry. NR 61 TC 2 Z9 2 U1 9 U2 28 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 MAR PY 2016 VL 83 BP 66 EP 78 DI 10.1016/j.biomaterials.2015.12.019 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DF9AD UT WOS:000371651700006 PM 26773661 ER PT J AU Tao, Y Gao, H Ackerman, B Guo, W Saffen, D Shugart, YY AF Tao, Yu Gao, Hui Ackerman, Benjamin Guo, Wei Saffen, David Shugart, Yin Yao TI Evidence for contribution of common genetic variants within chromosome 8p21.2-8p21.1 to restricted and repetitive behaviors in autism spectrum disorders SO BMC GENOMICS LA English DT Article DE Restricted and Repetitive Behaviors (RRB); Genome-Wide Association Study; Autism Spectrum Disorders (ASD); Autism Diagnostic Interview-Revised (ADI-R) ID GENOME-WIDE LINKAGE; PERVASIVE DEVELOPMENTAL DISORDERS; DIAGNOSTIC INTERVIEW; ASSOCIATION; RISK; SCHIZOPHRENIA; EXPRESSION; LOCI; SCAN; IDENTIFICATION AB Background: Restricted and Repetitive Behaviors (RRB), one of the core symptom categories for Autism Spectrum Disorders (ASD), comprises heterogeneous groups of behaviors. Previous research indicates that there are two or more factors (subcategories) within the RRB domain. In an effort to identify common variants associated with RRB, we have carried out a genome-wide association study (GWAS) using the Autism Genetic Resource Exchange (AGRE) dataset (n = 1,335, all ASD probands of European ancestry) for each identified RRB subcategory, while allowing for comparisons of associated single nucleotide polymorphisms (SNPs) with associated SNPs in the same set of probands analyzed using all the RRB subcategories as phenotypes in a multivariate linear mixed model. The top ranked SNPs were then explored in an independent dataset. Results: Using principal component analysis of item scores obtained from Autism Diagnostic Interview-Revised (ADI-R), two distinct subcategories within Restricted and Repetitive Behaviors were identified: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS). Quantitative RSM and IS scores were subsequently used as phenotypes in a GWAS using the AGRE ASD cohort. Although no associated SNPs with genome-wide significance (P < 5.0E-08) were detected when RSM or IS were analyzed independently, three SNPs approached genome-wide significance when RSM and IS were considered together using multivariate association analysis. These included the top IS-associated SNP, rs62503729 (P-value = 6.48E-08), which is located within chromosome 8p21.2-8p21.1, a locus previously linked to schizophrenia. Notably, all of the most significantly associated SNPs are located in close proximity to STMN4 and PTK2B, genes previously shown to function in neuron development. In addition, several of the top-ranked SNPs showed correlations with STMN4 mRNA expression in adult CEU (Caucasian and European descent) human prefrontal cortex. However, the association signals within chromosome 8p21.2-8p21.1 failed to replicate in an independent sample of 2,588 ASD probands; the insufficient sample size and between-study heterogeneity are possible explanations for the non-replication. Conclusions: Our analysis indicates that RRB in ASD can be represented by two distinct subcategories: RSM and IS. Subsequent univariate and multivariate genome-wide association studies of these RRB subcategories enabled the detection of associated SNPs at 8p21.2-8p21.1. Although these results did not replicate in an independent ASD dataset, genomic features of this region and pathway analysis suggest that common variants in 8p21.2-8p21.1 may contribute to RRB, particularly IS. Together, these observations warrant future studies to elucidate the possible contributions of common variants in 8p21.2-8p21.1 to the etiology of RSM and IS in ASD. C1 [Ackerman, Benjamin; Guo, Wei; Shugart, Yin Yao] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Tao, Yu; Gao, Hui; Saffen, David] Fudan Univ, Sch Basic Med Sci, Dept Cellular & Genet Med, 130Dongan Rd, Shanghai 200032, Peoples R China. [Ackerman, Benjamin] Johns Hopkins Univ, Baltimore, MD USA. RP Shugart, YY (reprint author), NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM kay1yao@mail.nih.gov FU Intramural Research Program, National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [MH002930-05]; National Basic Research 973 Program of China [2010CB529601] FX We are grateful to the families at the participating SFARI Simplex Collection (SSC) sites and to the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study (https://ordering.base.sfari.org/browsecollection/archive[sfaricollectio nv91]/ui:view()) by applying at https://base.sfari.org. The authors gratefully acknowledge the support of the Intramural Research Program, National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH, grant number MH002930-05) and the National Basic Research 973 Program of China (2010CB529601). NR 83 TC 1 Z9 1 U1 2 U2 11 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 MAR 1 PY 2016 VL 17 AR 163 DI 10.1186/s12864-016-2475-y PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DF8GF UT WOS:000371594700003 PM 26931105 ER PT J AU Duzel, E van Praag, H Sendtner, M AF Duzel, Emrah van Praag, Henriette Sendtner, Michael TI Can physical exercise in old age improve memory and hippocampal function? SO BRAIN LA English DT Article DE hippocampus; exercise; cerebral blood flow; Alzheimer's disease; memory ID GROWTH-FACTOR-I; ADULT DENTATE GYRUS; SPORADIC ALZHEIMERS-DISEASE; RANDOMIZED-CONTROLLED-TRIAL; MILD COGNITIVE IMPAIRMENT; MEDIAL TEMPORAL-LOBE; A-BETA OLIGOMERS; BODY-MASS INDEX; PATTERN SEPARATION; AEROBIC EXERCISE AB Physical activity can offer protection against cognitive decline and neurodegenerative diseases, but whether it slows the trajectory of normal ageing or boosts plasticity above and beyond preservation of function is unclear. Duzel et al. examine the evidence that exercise improves hippocampal plasticity in ageing and discuss avenues for future research.Physical activity can offer protection against cognitive decline and neurodegenerative diseases, but whether it slows the trajectory of normal ageing or boosts plasticity above and beyond preservation of function is unclear. Duzel et al. examine the evidence that exercise improves hippocampal plasticity in ageing and discuss avenues for future research.Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer's disease. While the long-term health-promoting and protective effects of exercise are encouraging, it's potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry-brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer's disease pathology, vascular and metabolic risk factors and genetic variability. C1 [Duzel, Emrah] Univ Magdeburg, Inst Cognit Neurol & Dementia Res, Leipziger Str 44, D-39120 Magdeburg, Germany. [Duzel, Emrah] German Ctr Neurodegenerat Dis DZNE, Magdeburg Site,Leipziger Str 44, D-39120 Magdeburg, Germany. [Duzel, Emrah] UCL, Inst Cognit Neurosci, 17 Queen Sq, London, England. [van Praag, Henriette] NIA, Neuroplast & Behav Unit, Lab Neurosci, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Sendtner, Michael] Univ Wurzburg, Inst Clin Neurobiol, Versbacher Str 5, D-97078 Wurzburg, Germany. RP Duzel, E (reprint author), German Ctr Neurodegenerat Dis DZNE, Magdeburg Site,Leipziger Str 44, D-39120 Magdeburg, Germany. EM emrah.duezel@dzne.de RI van Praag, Henriette/F-3939-2015; Sendtner, Michael/J-1542-2012 OI van Praag, Henriette/0000-0002-5727-434X; Sendtner, Michael/0000-0002-4737-2974 FU National Institute on Aging, Intramural Research Program (DFG) [TRR58, A09]; BMBF through the EnergI consortium; Deutsche Forschungs-Gemeinschaft [SFB 779 TP A7] FX This work was supported in part by the National Institute on Aging, Intramural Research Program (DFG, TRR58, A09) and the BMBF through the EnergI consortium and the Deutsche Forschungs-Gemeinschaft (SFB 779 TP A7). NR 146 TC 8 Z9 8 U1 14 U2 48 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD MAR 1 PY 2016 VL 139 BP 662 EP 673 DI 10.1093/brain/awv407 PN 3 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DF9PX UT WOS:000371694600013 PM 26912638 ER PT J AU Wang, X Zhang, Y Peng, Y Hutchinson, MR Rice, KC Yin, H Watkins, LR AF Wang, X. Zhang, Y. Peng, Y. Hutchinson, M. R. Rice, K. C. Yin, H. Watkins, L. R. TI Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID NEUROPATHIC PAIN; NITRIC-OXIDE; BINDING-SITE; SPINAL-CORD; ACTIVATION; NALOXONE; CELLS; TLR4; TRIF; LIPOPOLYSACCHARIDE AB Background and PurposeThe toll-like receptor TLR4 is involved in neuropathic pain and in drug reward and reinforcement. The opioid inactive isomers (+)-naltrexone and (+)-naloxone act as TLR4 antagonists, reversing neuropathic pain and reducing opioid and cocaine reward and reinforcement. However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexone and (+)-naloxone on TLR4 signalling. Experimental ApproachBV-2 mouse microglial cell line, primary rat microglia and primary rat peritoneal macrophages were treated with LPS and TLR4 signalling inhibitors. Effects were measured using Western blotting, luciferase reporter assays, fluorescence microscopy and ELISA Key Results(+)-Naltrexone and (+)-naloxone were equi-potent inhibitors of the LPS-induced TLR4 downstream signalling and induction of the pro-inflammatory factors NO and TNF-. Similarly, (+)-naltrexone or (+)-naloxone inhibited production of reactive oxygen species and increased microglial phagocytosis, induced by LPS. However, (+)-naltrexone and (+)-naloxone did not directly inhibit the increased production of IL-1, induced by LPS. The drug interaction of (+)-naloxone and (+)-naltrexone was additive. (+)-Naltrexone or (+)-naloxone inhibited LPS-induced activation of IFN regulatory factor 3 and production of IFN-. However, they did not inhibit TLR4 signalling via the activation of either NF-B, p38 or JNK in these cellular models. Conclusions and Implications(+)-Naltrexone and (+)-naloxone were TRIF-IFN regulatory factor 3 axis-biased TLR4 antagonists. They blocked TLR4 downstream signalling leading to NO, TNF- and reactive oxygen species. This pattern may explain, at least in part, the in vivo therapeutic effects of (+)-naltrexone and (+)-naloxone. C1 [Wang, X.] Chinese Acad Sci, Changchun Inst Appl Chem, Biol Chem Lab, Changchun 130022, Jilin, Peoples R China. [Wang, X.] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China. [Zhang, Y.; Watkins, L. R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Zhang, Y.; Watkins, L. R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Peng, Y.; Yin, H.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Peng, Y.; Yin, H.] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Hutchinson, M. R.] Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA 5005, Australia. [Rice, K. C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, K. C.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Wang, X (reprint author), Chinese Acad Sci, Changchun Inst Appl Chem, Biol Chem Lab, Changchun 130022, Jilin, Peoples R China. EM xiaohui.wang@ciac.ac.cn OI Hutchinson, Mark/0000-0003-2154-5950; YIN, HANG/0000-0002-9762-4818 FU National Institutes of Health [R01DE021966, R01GM101279, R01GM103843]; Australian Research Council Research Fellowship [DP110100297]; National Natural Science Foundation of China [21543013]; Open Funding of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMKF201502]; intramural research programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; 100 Talents Program of Chinese Academy of Sciences FX We thank the National Institutes of Health (R01DE021966 to L. R. W.; R01GM101279 and R01GM103843 to H. Y.) for financial support. M. R. H. is the recipient of an Australian Research Council Research Fellowship (DP110100297). X. W. was supported by the starting-up funding for the candidate of 100 Talents Program of Chinese Academy of Sciences, National Natural Science Foundation of China (no. 21543013) and the Open Funding of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMKF201502). Some part of this work was supported by the intramural research programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 58 TC 7 Z9 8 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAR PY 2016 VL 173 IS 5 BP 856 EP 869 DI 10.1111/bph.13394 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DF9JM UT WOS:000371677000006 PM 26603732 ER PT J AU Kang, XZ Liu, HL Onaitis, MW Liu, ZS Owzar, K Han, YH Su, L Wei, YY Hung, RJ Brhane, Y McLaughlin, J Brennan, P Bickeboller, H Rosenberger, A Houlston, RS Caporaso, N Landi, MT Heinrich, J Risch, A Wu, XF Ye, YQ Christiani, DC Amos, CI Wei, QY AF Kang, Xiaozheng Liu, Hongliang Onaitis, Mark W. Liu, Zhensheng Owzar, Kouros Han, Younghun Su, Li Wei, Yongyue Hung, Rayjean J. Brhane, Yonathan McLaughlin, John Brennan, Paul Bickeboeller, Heike Rosenberger, Albert Houlston, Richard S. Caporaso, Neil Landi, Maria Teresa Heinrich, Joachim Risch, Angela Wu, Xifeng Ye, Yuanqing Christiani, David C. Amos, Christopher I. Wei, Qingyi CA Transdisciplinary Res Canc Lung TI Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14 463 cases and 44 188 controls SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCUS; DISEASE; AMPLIFICATION; ABNORMALITIES; VITILIGO; VARIANTS; CELLS; VISUALIZATION; INSTABILITY AB After combining the summary results of SNPs in 106 centrosomal genes from eight published lung cancer GWASs, we found that two potential functional SNPs (rs151606 and rs12212247) in FGFR1OP were significantly associated with lung cancer risk.Centrosome abnormalities are often observed in premalignant lesions and in situ tumors and have been associated with aneuploidy and tumor development. We investigated the associations of 9354 single-nucleotide polymorphisms (SNPs) in 106 centrosomal genes with lung cancer risk by first using the summary data from six published genome-wide association studies (GWASs) of the Transdisciplinary Research in Cancer of the Lung (TRICL) (12 160 cases and 16 838 controls) and then conducted in silico replication in two additional independent lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26 380 controls). A total of 44 significant SNPs with false discovery rate (FDR) a parts per thousand currency sign 0.05 were mapped to one novel gene FGFR1OP and two previously reported genes (TUBB and BRCA2). After combined the results from TRICL with those from Harvard and deCODE, the most significant association (P (combined) = 8.032x10(-6)) was with rs151606 within FGFR1OP. The rs151606 T > G was associated with an increased risk of lung cancer [odds ratio (OR) = 1.10, 95% confidence interval (95% CI) = 1.05-1.14]. Another significant tagSNP rs12212247 T > C (P (combined) = 9.589x10(-6)) was associated with a decreased risk of lung cancer (OR = 0.93, 95% CI = 0.90-0.96). Further in silico functional analyzes revealed that rs151606 might affect transcriptional regulation and result in decreased FGFR1OP expression (P (trend) = 0.022). The findings shed some new light on the role of centrosome abnormalities in the susceptibility to lung carcinogenesis. C1 [Kang, Xiaozheng; Liu, Hongliang; Onaitis, Mark W.; Liu, Zhensheng; Owzar, Kouros; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, 905 S LaSalle St, Durham, NC 27710 USA. [Kang, Xiaozheng; Onaitis, Mark W.] Duke Univ, Med Ctr, Div Cardiovasc & Thorac Surg, Dept Surg, 905 S LaSalle St, Durham, NC 27710 USA. [Kang, Xiaozheng] Peking Univ, Canc Hosp & Inst, Minist Educ,Dept Thorac Surg 1, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China. [Liu, Hongliang; Liu, Zhensheng; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Owzar, Kouros] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Han, Younghun; Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Community & Family Med, Hanover, NH 03755 USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Hung, Rayjean J.; Brhane, Yonathan] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON M5T 3L9, Canada. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, 150 Cours Albert Thomas, F-69372 Lyon, France. [Bickeboeller, Heike; Rosenberger, Albert] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Caporaso, Neil; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Heinrich, Joachim] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, A-5020 Salzburg, Austria. [Wu, Xifeng; Ye, Yuanqing] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Wei, QY (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, 905 S LaSalle St, Durham, NC 27710 USA.; Wei, QY (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. EM qingyi.wei@duke.edu RI Hung, Rayjean/A-7439-2013; Risch, Angela/H-2669-2013; OI Risch, Angela/0000-0002-8026-5505; Houlston, Richard/0000-0002-5268-0242 FU Duke Cancer Institute as part of the P30 Cancer Center Support Grant [NIH CA014236]; Duke Cancer Institute, Duke University Medical Center FX As Duke Cancer Institute members, Q.W., M.W.O., and K.O. acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (NIH CA014236). Q.W. was also supported by a start-up fund from Duke Cancer Institute, Duke University Medical Center. NR 61 TC 1 Z9 1 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2016 VL 37 IS 3 BP 280 EP 289 DI 10.1093/carcin/bgw014 PG 10 WC Oncology SC Oncology GA DF9QP UT WOS:000371696400006 PM 26905588 ER PT J AU Ma, JF Yang, F Mahida, SN Zhao, L Chen, XM Zhang, ML Sun, ZJ Yao, Y Zhang, YX Zheng, GY Dong, J Feng, MJ Zhang, R Sun, J Li, S Wang, QS Cao, HQ Benjamin, EJ Ellinor, PT Li, YG Tian, XL AF Ma, Ji-Fang Yang, Fan Mahida, Saagar N. Zhao, Ling Chen, Xiaomin Zhang, Micheal L. Sun, Zhijun Yao, Yan Zhang, Yi-Xin Zheng, Gu-Yan Dong, Jie Feng, Ming-Jun Zhang, Rui Sun, Jian Li, Shuo Wang, Qun-Shan Cao, Huiqing Benjamin, Emelia J. Ellinor, Patrick T. Li, Yi-Gang Tian, Xiao-Li TI TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians SO CARDIOVASCULAR RESEARCH LA English DT Article DE Atrial fibrillation; TBX5; ANP; Connexin; Mutation ID HOLT-ORAM-SYNDROME; CARDIAC CONDUCTION SYSTEM; TRANSCRIPTION FACTOR TBX5; NATRIURETIC-PEPTIDE; COMMON VARIANTS; RISK-FACTORS; PR INTERVAL; CONNEXIN40; GENE; POLYMORPHISMS AB Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-alpha (MHC-alpha) and myosin light chain-2 alpha (MLC-2 alpha). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (Delta Asp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects. Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40. C1 [Ma, Ji-Fang; Zhang, Rui; Sun, Jian; Li, Shuo; Wang, Qun-Shan; Li, Yi-Gang] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Cardiol, Shanghai 200092, Peoples R China. [Yang, Fan; Zhao, Ling; Zhang, Yi-Xin; Zheng, Gu-Yan; Dong, Jie; Cao, Huiqing; Tian, Xiao-Li] Peking Univ, Dept Human Populat Genet, 5 Yiheyuan Rd, Beijing 100871, Peoples R China. [Yang, Fan; Zhao, Ling; Zhang, Yi-Xin; Zheng, Gu-Yan; Dong, Jie; Cao, Huiqing; Tian, Xiao-Li] Peking Univ, Beijing Key Lab Cardiometabol Mol Med, IMM, 5 Yiheyuan Rd, Beijing 100871, Peoples R China. [Mahida, Saagar N.; Zhang, Micheal L.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Chen, Xiaomin; Feng, Ming-Jun] Ningbo Univ, Ningbo Hosp 1, Key Lab, 59 Liuting St, Ningbo 315010, Peoples R China. [Chen, Xiaomin; Feng, Ming-Jun] Ningbo Univ, Ningbo Hosp 1, Ctr Cardiovasc, 59 Liuting St, Ningbo 315010, Peoples R China. [Sun, Zhijun] Peoples Liberat Army Gen Hosp, Cardiovasc Dept, 28 Fuxing Rd, Beijing 100853, Peoples R China. [Yao, Yan] Capital Med Univ, Beijing Inst Heart Lung & Blood Vessel Dis, Beijing Anzhen Hosp, Dept Cardiol, Beijing, Peoples R China. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02215 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Li, YG (reprint author), Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Cardiol, Shanghai 200092, Peoples R China.; Tian, XL (reprint author), Peking Univ, Dept Human Populat Genet, 5 Yiheyuan Rd, Beijing 100871, Peoples R China.; Tian, XL (reprint author), Peking Univ, Beijing Key Lab Cardiometabol Mol Med, IMM, 5 Yiheyuan Rd, Beijing 100871, Peoples R China. EM drliyigang@outlook.com; tianxiaoli@pku.edu.cn FU National Basic Research Program of China (973 program) [2013CB530700, 2007CB512100]; National Science Foundation of China [31221002, 81070154, 81270258]; Shanghai Excellent Academic Leaders Project [10xd1402800]; National Institutes of Health [1RO1HL104156, 1K24HL105780, 1RO1HL092577]; American Heart Association [13EIA14220013] FX This study was supported by grants from the National Basic Research Program of China (973 program) (2013CB530700 and 2007CB512100 to X.L.T.), the National Science Foundation of China (31221002 to X.L.T., no. 81070154 and No. 81270258 to Y.G.L.), the Shanghai Excellent Academic Leaders Project (grant number 10xd1402800 to Y.G.L.), the National Institutes of Health to P.T.E. (1RO1HL104156 and 1K24HL105780 to P.T.E., 1RO1HL092577 to P.T.E. and E.J.B.), and the American Heart Association (13EIA14220013 to P.T.E.). NR 50 TC 4 Z9 4 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2016 VL 109 IS 3 BP 442 EP 450 DI 10.1093/cvr/cvw003 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF7ER UT WOS:000371521100013 PM 26762269 ER PT J AU Chertow, DS Palmore, TN Masur, H AF Chertow, Daniel S. Palmore, Tara N. Masur, Henry TI Critical Care Medicine After the 2014-2015 Ebola Outbreak: Are We Ready If It Happens Again? Foreword SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID INFECTION-CONTROL; VIRUS DISEASE; MERS; MANAGEMENT; SARS C1 [Chertow, Daniel S.; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Palmore, Tara N.] NIH, Hosp Epidemiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Chertow, DS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NR 16 TC 0 Z9 0 U1 4 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2016 VL 44 IS 3 BP 457 EP 459 DI 10.1097/CCM.0000000000001590 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA DF7HM UT WOS:000371528700001 PM 26901541 ER PT J AU Zhu, ZQ Liu, W Gotlieb, V AF Zhu, Ziqiang Liu, Wei Gotlieb, Vladimir TI The rapidly evolving therapies for advanced melanoma-Towards immunotherapy, molecular targeted therapy, and beyond SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE Advanced melanoma; Immunotherapy; Targeted therapy ID CHIMERIC ANTIGEN RECEPTOR; BRAF-MUTANT MELANOMA; PHASE-III TRIAL; METASTATIC MALIGNANT-MELANOMA; IPILIMUMAB PLUS DACARBAZINE; ADOPTIVE CELL TRANSFER; OPEN-LABEL; MEK INHIBITION; T-CELLS; CANCER-IMMUNOTHERAPY AB The incidence of melanoma in both males and females continues to rise during the past 40 years despite the stable or declining trends for most cancer types. Due to the tremendous advance in immunobiology and molecular biology, breakthroughs in both immunotherapies and molecular targeted therapies have recently revolutionized the standard of care for patients with advanced melanoma. In 2011, US Food and Drug Administration (FDA) approved ipilimumab, an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody for metastatic melanoma therapy. Since then, novel drugs including antibodies to programmed cell death 1 (PD-1) such as pembrolizumab and nivolumab (both approved in 2014), selective BRAF inhibitors such as vemurafenib (approved in 2011), dabrafenib (approved in 2013); and MEK inhibitor trametinib (approved in 2013), have greatly extended the potential of immunotherapy and molecular targeted therapy for advanced melanoma. All of which have been demonstrated a significant increase in overall survival rate, and long-term benefits in multiple large clinical trials. Several new agents and novel therapies are currently under phase III clinical trials with the hope of being approved in the near future. We already entered a golden era in oncology that are providing significant survival improvement. In the meantime, new challenges for clinicians also started to emerge. In this review, we presented the existing evidence for the newest treatments for advanced melanoma, including CTLA-4, PD-1/PD-L1 checkpoint inhibitors and BRAF, MEK inhibitors. We also discussed the strengths, limitations and challenges of using these novel therapies, and potential solutions as well as highlighted the areas requiring further research. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Zhu, Ziqiang] Brookdale Univ Hosp & Med Ctr, Dept Internal Med, One Brookdale Plaza, Brooklyn, NY 11212 USA. [Liu, Wei] NCI, Metab & Canc Susceptibil Sect, NIH, Frederick, MD 21702 USA. [Gotlieb, Vladimir] Brookdale Univ Hosp & Med Ctr, Div Hematol Oncol, One Brookdale Plaza, Brooklyn, NY 11212 USA. RP Zhu, ZQ (reprint author), Brookdale Univ Hosp & Med Ctr, Dept Internal Med, One Brookdale Plaza, Brooklyn, NY 11212 USA. EM zhuz2013@gmail.com NR 124 TC 10 Z9 10 U1 4 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 EI 1879-0461 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD MAR PY 2016 VL 99 BP 91 EP 99 DI 10.1016/j.critrevonc.2015.12.002 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA DG2YW UT WOS:000371937700008 PM 26708040 ER PT J AU Frankl, JA Thearle, MS Desmarais, C Bogardus, C Krakoff, J AF Frankl, Joseph A. Thearle, Marie S. Desmarais, Cindy Bogardus, Clifton Krakoff, Jonathan TI T-cell receptor repertoire variation may be associated with type 2 diabetes mellitus in humans SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE autoimmunity; human; Pima Indians; survival analysis; T-cell receptor; type 2 diabetes mellitus ID PIMA-INDIANS; INSULIN-RESISTANCE; BETA-CHAINS; OBESITY; DIVERSITY; IDENTIFICATION; PATHOGENESIS; INDIVIDUALS; ANTIBODIES; SECRETION AB BackgroundRecent work in Pima Indians, a population with high rates of obesity and type 2 diabetes mellitus (T2DM), demonstrated that human leukocyte antigen haplotype DRB1*02 carriers have an increased acute insulin response and decreased risk for the development of T2DM, implicating loss of self-tolerance in the pathogenesis of T2DM. Advances in genomic sequencing have made T-cell receptor repertoire analysis a practical mode of investigation. MethodsHigh-throughput sequencing of T-cell receptor complementarity-determining region 3 was carried out in male Pima Indians with normal glucose regulation (n=11; age=318years; %fat=30.28.7%) and the protective DRB1*02 haplotype versus those with T2DM without DRB1*02 (n=7; age=34 +/- 8years; %fat=31.2 +/- 4.7%). Findings were partially replicated in another cohort by assessing the predictive ability of T-cell receptor variation on risk of T2DM in Pima Indian men (n=27; age=28.9 +/- 7.1years; %fat=28.8 +/- 7.1%) and women (n=20; age=29 +/- 7.0years; %fat=37.1 +/- 6.8%) with baseline normal glucose regulation but without the protective haplotype who were invited to follow-up examinations as frequently as every 2years where diabetes status was assessed by a 75-g oral glucose tolerance test. Of these subjects, 13 developed diabetes. ResultsT-cell receptor complementarity-determining region 3 length was shorter in those with T2DM, and a one-nucleotide decrease in complementarity-determining region 3 length was associated with a nearly threefold increase in risk for future diabetes. The frequency of one variable gene, TRBV7-8, was higher in those with T2DM. A 1% increase in TRBV7-8 frequency was associated with a greater than threefold increase in diabetes risk. ConclusionsThese results indicate that T-cell autoimmunity may be an important component in progression to T2DM in Pima Indians. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Frankl, Joseph A.; Thearle, Marie S.; Bogardus, Clifton; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ USA. [Desmarais, Cindy] Adapt Biotechnol, Seattle, WA USA. RP Krakoff, J (reprint author), Phoenix Indian Med Ctr, 5th Floor,4212 N 16th St, Phoenix, AZ 85016 USA. EM jkrakoff@mail.nih.gov OI Frankl, Joseph/0000-0002-0156-3150 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 40 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-7560 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD MAR PY 2016 VL 32 IS 3 BP 297 EP 307 DI 10.1002/dmrr.2720 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DG1LK UT WOS:000371829400008 PM 26408818 ER PT J AU Gadalla, SM Pfeiffer, RM Kristinsson, SY Bjorkholm, M Landgren, O Greene, MH AF Gadalla, S. M. Pfeiffer, R. M. Kristinsson, S. Y. Bjorkholm, M. Landgren, O. Greene, M. H. TI Brain tumors in patients with myotonic dystrophy: a population-based study SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE brain; cancer; incidence; mortality; myotonic dystrophy; neoplasms ID NERVOUS-SYSTEM TUMORS; WHITE-MATTER; CTG REPEAT; MUSCULAR-DYSTROPHY; MALIGNANT-MELANOMA; DYSPLASTIC NEVI; CANCER-RISK; TYPE-1; EXPANSION; GENE AB Background and purposePatients with myotonic dystrophy (DM) are at high risk of brain cancer. This study describes the spectrum of brain neoplasms in DM patients. MethodsData from 1119 DM patients identified from the National Swedish Patient Register between 1987 and 2007 were linked to the National Cancer and the Cause of Death Registers. Standardized incidence ratios (SIRs) and cumulative incidence to quantify the relative and absolute risks of brain neoplasms were calculated and the Kaplan-Meier estimator was used for survival analysis. Patient follow-up started at birth or the age at the start of Swedish cancer registration (1 January 1958) and ended at the age of brain neoplasm diagnosis, death or on 31 December 2007. ResultsTwenty patients developed brain neoplasm during follow-up {median age 53, range 2-76 years, accounting for a five-fold excess risk of brain tumors during the patient lifetime [SIR = 5.4, 95% confidence interval (CI) 3.4-8.1, P = 1 x 10(-5)]}. Astrocytoma was the most common histological subtype (n = 16, 80%), and almost all cases (n = 19) developed after age 20. No statistically significant differences in gender-specific risks (SIR in men 6.3 and in women 3.8, P-heterogeneity 0.46) were observed. After accounting for competing mortality related to DM, the cumulative incidence of brain neoplasms reached 2.9% (95% CI 1.8%-4.7%) by age 70. Five-year survival after brain tumor diagnosis was 52% (95%CI 29%-75%) overall (number at risk 8) and 34% (95% CI 26%-47%) for malignant neoplasms (number at risk 5). ConclusionDespite the high relative risk of DM-related brain tumors, the absolute risk is modest. Nonetheless, careful evaluation of DM patients with new central nervous system symptoms is warranted. C1 [Gadalla, S. M.; Greene, M. H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Pfeiffer, R. M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Kristinsson, S. Y.; Bjorkholm, M.] Karolinska Univ Hosp Solna, Dept Med, Div Hematol, Stockholm, Sweden. [Kristinsson, S. Y.; Bjorkholm, M.] Karolinska Inst, Stockholm, Sweden. [Kristinsson, S. Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Kristinsson, S. Y.] Landspitali Natl Univ Hosp, Dept Hematol, Reykjavik, Iceland. [Landgren, O.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Gadalla, SM (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM gadallas@mail.nih.gov FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; National Cancer Institute, USA [N02CP31003-3] FX This work was supported by the Swedish Cancer Society, Stockholm County Council, the Karolinska Institutet Foundations, and the Intramural Research Program of the National Cancer Institute, USA (contract N02CP31003-3). NR 36 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2016 VL 23 IS 3 BP 542 EP 547 DI 10.1111/ene.12886 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DF5XV UT WOS:000371427200021 PM 26508558 ER PT J AU Liberini, CG Boyle, CN Cifani, C Venniro, M Hope, BT Lutz, TA AF Liberini, Claudia G. Boyle, Christina N. Cifani, Carlo Venniro, Marco Hope, Bruce T. Lutz, Thomas A. TI Amylin receptor components and the leptin receptor are co-expressed in single rat area postrema neurons SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE calcitonin receptor; laser capture microdissection; receptor activity-modifying protein 1; receptor activity-modifying protein 2; receptor activity-modifying protein 3 ID ACTIVITY-MODIFYING PROTEINS; VITRO AUTORADIOGRAPHIC LOCALIZATION; VENTRAL TEGMENTAL AREA; GENE-RELATED PEPTIDE; DIET-INDUCED OBESITY; CALCITONIN-RECEPTOR; FOOD-INTAKE; CIRCUMVENTRICULAR ORGANS; ENERGY HOMEOSTASIS; BRAIN AB Amylin is a pancreatic -cell hormone that acts as a satiating signal to inhibit food intake by binding to amylin receptors (AMYs) and activating a specific neuronal population in the area postrema (AP). AMYs are heterodimers that include a calcitonin receptor (CTR) subunit [CTR isoform a or b (CTRa or CTRb)] and a member of the receptor activity-modifying proteins (RAMPs). Here, we used single-cell quantitative polymerase chain reaction to assess co-expression of AMY subunits in AP neurons from rats that were injected with amylin or vehicle. Because amylin interacts synergistically with the adipokine leptin to reduce body weight, we also assessed the co-expression of AMY and the leptin receptor isoform b (LepRb) in amylin-activated AP neurons. Single cells were collected from Wistar rats and from transgenic Fos-GFP rats that express green fluorescent protein (GFP) under the control of the Fos promoter. We found that the mRNAs of CTRa, RAMP1, RAMP2 and RAMP3 were all co-expressed in single AP neurons. Moreover, most of the CTRa+ cells co-expressed more than one of the RAMPs. Amylin down-regulated RAMP1 and RAMP3 but not CTR mRNAs in AMY+ neurons, suggesting a possible negative feedback mechanism of amylin at its own primary receptors. Interestingly, amylin up-regulated RAMP2 mRNA. We also found that a high percentage of single cells that co-expressed all components of a functional AMY expressed LepRb mRNA. Thus, single AP cells expressed both AMY and LepRb, which formed a population of first-order neurons that presumably can be directly activated by amylin and, at least in part, also by leptin. C1 [Liberini, Claudia G.; Boyle, Christina N.; Lutz, Thomas A.] Univ Zurich UZH, Vetsuisse Fac, Inst Vet Physiol, Winterthurerstr 260, CH-8057 Zurich, Switzerland. [Liberini, Claudia G.; Lutz, Thomas A.] Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, Zurich, Switzerland. [Liberini, Claudia G.] Univ Zurich, Vetsuisse Fac, Zurich Ctr Clin Studies, Zurich, Switzerland. [Cifani, Carlo] Univ Camerino, Pharmacol Unit, Sch Pharm, I-62032 Camerino, Italy. [Cifani, Carlo; Venniro, Marco; Hope, Bruce T.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Boyle, CN (reprint author), Univ Zurich UZH, Vetsuisse Fac, Inst Vet Physiol, Winterthurerstr 260, CH-8057 Zurich, Switzerland. EM boyle@vetphys.uzh.ch RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU Swiss National Science Foundation; Center for Integrative Human Physiology of the University of Zurich; Italian Ministry of University; [FIRB-RBFR12DELS] FX This work was supported by the Swiss National Science Foundation and the Center for Integrative Human Physiology of the University of Zurich. The laboratory stay of C.C. in NIDA/NIH was supported by Italian Ministry of University and Research Grant FIRB-RBFR12DELS to C.C. The authors gratefully acknowledge the Center for Clinical Studies, the Center for Microscopy and Image Analysis (University of Zurich, Zurich, Switzerland) and Dr Savina Adamo for technical support. NR 45 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAR PY 2016 VL 43 IS 5 BP 653 EP 661 DI 10.1111/ejn.13163 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DG2PN UT WOS:000371909800006 PM 26750109 ER PT J AU Chuang, K Nguyen, E Sergeev, Y Badea, TC AF Chuang, Katherine Nguyen, Eileen Sergeev, Yuri Badea, Tudor C. TI Novel Heterotypic Rox Sites for Combinatorial Dre Recombination Strategies SO G3-GENES GENOMES GENETICS LA English DT Article DE site specific recombination; Cre recombination; Dre recombinase; gene targeting ID CRE-MEDIATED RECOMBINATION; LOXP SPACER REGION; DNA RECOMBINATION; MAMMALIAN-CELLS; VECTORS; SYSTEM; MULTIPLE; BACTERIOPHAGE-P1; SPECIFICITY; EXPRESSION AB Site-specific recombinases (SSRs) such as Cre are widely used in gene targeting and genetic approaches for cell labeling and manipulation. They mediate DNA strand exchange between two DNA molecules at dedicated recognition sites. Precise understanding of the Cre recombination mechanism, including the role of individual base pairs in its loxP target site, guided the generation of mutant lox sites that specifically recombine with themselves but not with the wild type loxP. This has led to the development of a variety of combinatorial Cre-dependent genetic strategies, such as multicolor reporters, irreversible inversions, or recombination-mediated cassette exchange. Dre, a Cre-related phage integrase that recognizes roxP sites, does not cross-react with the Cre-loxP system, but has similar recombination efficiency. We have previously described intersectional genetic strategies combining Dre and Cre. We now report a mutagenesis screen aimed at identifying roxP base pairs critical for self-recognition. We describe several rox variant sites that are incompatible with roxP, but are able to efficiently recombine with themselves in either purified systems or bacterial and eukaryotic tissue culture systems. These newly identified rox sites are not recognized by Cre, thus enabling potential combinatorial strategies involving Cre, Dre, and target loci including multiple loxP and roxP variants. C1 [Chuang, Katherine; Nguyen, Eileen; Sergeev, Yuri; Badea, Tudor C.] NEI, Retinal Circuits Dev & Genet Unit, NIH, Bethesda, MD 20892 USA. RP Badea, TC (reprint author), N NRL DIR NEI, Retinal Circuits Dev & Genet Unit, NIH, Bldg 6,Room 331B,6 Ctr Dr, Bethesda, MD 20892 USA. EM badeatc@mail.nih.gov FU National Eye Institute (National Institutes of Health, Bethesda) FX The authors acknowledge Michael Cashel for helpful discussions and suggestions, and providing the pGB2 vector; Beverly Wu for constructing and testing the pAAVPTPY vector; and Edward Giniger, Harold Burgess, Kathryn Tabor, and Chi-Hon Lee for critical reading of the manuscript and insightful comments. Funding provided to T.B. and Y.S. by intramural funds of the National Eye Institute (National Institutes of Health, Bethesda). NR 39 TC 0 Z9 0 U1 1 U2 2 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD MAR 1 PY 2016 VL 6 IS 3 BP 559 EP 571 DI 10.1534/g3.115.025841 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DG1MA UT WOS:000371831000007 ER PT J AU Miller, JG Liu, Y Williams, CW Smith, HE O'Connell, KF AF Miller, Jacqueline G. Liu, Yan Williams, Christopher W. Smith, Harold E. O'Connell, Kevin F. TI The E2F-DP1 Transcription Factor Complex Regulates Centriole Duplication in Caenorhabditis elegans SO G3-GENES GENOMES GENETICS LA English DT Article DE centriole duplication; C. elegans; transcriptional regulation; E2F/DP1; SAS-6 ID PLK4-RELATED KINASE ZYG-1; C-ELEGANS; CENTROSOME DUPLICATION; HUMAN-CELLS; PROTEIN SPD-2; LIN-35 RB; PLK4; RECRUITMENT; BIOGENESIS; CEP152 AB Centrioles play critical roles in the organization of microtubule-based structures, from the mitotic spindle to cilia and flagella. In order to properly execute their various functions, centrioles are subjected to stringent copy number control. Central to this control mechanism is a precise duplication event that takes place during S phase of the cell cycle and involves the assembly of a single daughter centriole in association with each mother centriole. Recent studies have revealed that posttranslational control of the master regulator Plk4/ZYG-1 kinase and its downstream effector SAS-6 is key to ensuring production of a single daughter centriole. In contrast, relatively little is known about how centriole duplication is regulated at a transcriptional level. Here we show that the transcription factor complex EFL-1-DPL-1 both positively and negatively controls centriole duplication in the Caenorhabditis elegans embryo. Specifically, we find that down regulation of EFL-1-DPL-1 can restore centriole duplication in a zyg-1 hypomorphic mutant and that suppression of the zyg-1 mutant phenotype is accompanied by an increase in SAS-6 protein levels. Further, we find evidence that EFL-1-DPL-1 promotes the transcription of zyg-1 and other centriole duplication genes. Our results provide evidence that in a single tissue type, EFL-1-DPL-1 sets the balance between positive and negative regulators of centriole assembly and thus may be part of a homeostatic mechanism that governs centriole assembly. C1 [Miller, Jacqueline G.; Liu, Yan; Williams, Christopher W.; O'Connell, Kevin F.] NIDDK, Lab Biochem & Genet, NIH, 8 Ctr Dr,Room 2A07, Bethesda, MD 20892 USA. [Smith, Harold E.] NIDDK, Genom Core, NIH, Bethesda, MD 20892 USA. RP O'Connell, KF (reprint author), NIDDK, Lab Biochem & Genet, NIH, 8 Ctr Dr,Room 2A07, Bethesda, MD 20892 USA. EM kevino@mail.nih.gov FU National Institutes of Health Office of Research Infrastructure Programs [P40 OD010440]; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Valerie Reinke for generously providing the DPL-1-GFP-expressing C. elegans strain and Andy Golden for some of the CRISPR reagents. We also thank Geraldine Seydoux and Alex Paix for sharing protocols for CRISPR technology. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 83 TC 1 Z9 1 U1 0 U2 1 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD MAR 1 PY 2016 VL 6 IS 3 BP 709 EP 720 DI 10.1534/g3.115.025577 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DG1MA UT WOS:000371831000020 PM 26772748 ER PT J AU Petersen, T Townsend, K Gordon, LA Sidharthan, S Silk, R Nelson, A Gross, C Calderon, M Proschan, M Osinusi, A Polis, MA Masur, H Kottilil, S Kohli, A AF Petersen, Tess Townsend, Kerry Gordon, Lori A. Sidharthan, Sreetha Silk, Rachel Nelson, Amy Gross, Chloe Calderon, Monica Proschan, Michael Osinusi, Anu Polis, Michael A. Masur, Henry Kottilil, Shyam Kohli, Anita TI High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study SO HEPATOLOGY INTERNATIONAL LA English DT Article DE HCV; DAA; Adherence; MEMS ID HEPATITIS-C VIRUS; GENOTYPE 1; TREATMENT-NAIVE; LEDIPASVIR; SOFOSBUVIR; RIBAVIRIN; COMBINATION; MEDICATION; INFECTION; CIRRHOSIS AB As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described. Medication adherence was measured in 60 HCV, genotype-1, treatment-na < ve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report. Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report. Adherence to short courses of DAA therapy with 1-3 pills a day was excellent in an urban population with multiple risk factors for non-adherence. C1 [Petersen, Tess; Sidharthan, Sreetha; Silk, Rachel; Masur, Henry; Kohli, Anita] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Townsend, Kerry; Osinusi, Anu; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gordon, Lori A.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Gordon, Lori A.] Xavier Univ Louisiana, New Orleans, LA USA. [Silk, Rachel; Nelson, Amy; Gross, Chloe; Osinusi, Anu; Kottilil, Shyam] Univ Maryland, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA. [Gross, Chloe; Calderon, Monica; Kohli, Anita] SAIC Frederick Inc, Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program,Frederick Natl Lab Ca, Frederick, MD USA. [Calderon, Monica] US FDA, Silver Spring, MD USA. [Proschan, Michael] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Osinusi, Anu] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Kohli, Anita] Creighton Univ, St Josephs Hosp, Div Hepatol, Phoenix, AZ USA. [Kohli, Anita] Creighton Univ, Med Ctr, Sch Med, Phoenix, AZ USA. [Kottilil, Shyam] Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, N222,725 West Lombard St,Room S222, Baltimore, MD 21201 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA.; Kottilil, S (reprint author), Univ Maryland, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA.; Kottilil, S (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, N222,725 West Lombard St,Room S222, Baltimore, MD 21201 USA. EM SKottilil@ihv.umaryland.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases; NIH; Gilead Sciences FX The 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. ClinicalTrials.gov no. NCT01805882. The research was supported in part by the National Institute of Allergy and Infectious Diseases. Study medications were provided by Gilead Sciences, Inc., and the study was partially funded by a Collaborate Research and Development Agreement between NIH and Gilead Sciences. The study involves human subjects, and all subjects signed informed consent approved by the NIAID IRB. We would like to acknowledge the contributions of Colleen Kotb, NP, Colleen Hadigan, MD, and Senora Mitchell for their clinic support. NR 31 TC 5 Z9 5 U1 3 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-0533 EI 1936-0541 J9 HEPATOL INT JI Hepatol. Int. PD MAR PY 2016 VL 10 IS 2 BP 310 EP 319 DI 10.1007/s12072-015-9680-7 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG0YM UT WOS:000371792100010 PM 26612014 ER PT J AU Joyce, E Chung, C Badloe, S Odutayo, K Desai, A Givertz, MM Nohria, A Lakdawala, NK Stewart, GC Young, M Weintraub, J Stevenson, LW Lewis, EF AF Joyce, Emer Chung, Christine Badloe, Sabrina Odutayo, Kayode Desai, Akshay Givertz, Michael M. Nohria, Anju Lakdawala, Neal K. Stewart, Garrick C. Young, Michelle Weintraub, Joanne Stevenson, Lynne W. Lewis, Eldrin F. TI Variable Contribution of Heart Failure to Quality of Life in Ambulatory Heart Failure With Reduced, Better, or Preserved Ejection Fraction SO JACC-HEART FAILURE LA English DT Article DE better left; heart failure; left ventricular ejection fraction; quality of life ID EUROPEAN ASSOCIATION; ECHOCARDIOGRAPHIC-ASSESSMENT; AMERICAN SOCIETY; RECOMMENDATIONS; DYSFUNCTION; PREDICTOR; ADULTS AB OBJECTIVES The relative contribution of heart failure (HF) compared with other medical and nonmedical factors on diminished quality of life (QOL) across subtypes with reduced, better, and preserved left ventricular ejection fraction (LVEF) in a large ambulatory HF population was evaluated. BACKGROUND Dominant factors influencing limited QOL in patients with HF have not been investigated. METHODS Before routine HF clinic visits, 726 patients with ambulatory HF (mean age 56 +/- 15 years, 37% women) completed a 1-page questionnaire that assessed QOL and relative contributions of HF compared with other medical and nonmedical factors to their QOL limitations. Visual analogue scales were used to assess overall QOL, breathing, and energy level. Results were compared across reduced (57%), preserved (16%) and better (improvement in LVEF >= 50%) (19%) subtypes. RESULTS Just under one-half of patients (48%) rated QOL as limited dominantly by HF, 19% rated HF and medical problems as equally limiting, 18% cited medical problems as dominant, and 15% cited nonmedical factors. Patients with HF with better LVEF had the highest overall QOL score and less dyspnea burden than those with HF with preserved EF. Independent correlates of HF-dominated diminished QOL were prior cardiac surgery, worse New York Heart Association functional class, renin-angiotensin-aldosterone antagonism, use of diuretic agents;lower body mass index, lower LVEF, and tack of arthritis or history of cancer. CONCLUSIONS Fewer than one-half of patients with ambulatory HF rated HF as the greatest limitation to their QOL, suggesting that this important outcome will be difficult to affect by HF-targeted therapies alone, particularly in those with higher LVEFs and comorbidities. Patients with HF with better LVEF represent a distinct subtype with better overall QOL. (J Am Coll Cardiol HF 2016;4:184-93) (C) 2016 by the American College of Cardiology Foundation. C1 Brigham & Womens Hosp, Ctr Adv Heart Dis, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Joyce, Emer] NHLBI, Heart Failure Network, Bethesda, MD USA. RP Lewis, EF (reprint author), Brigham & Womens Hosp, Ctr Adv Heart Dis, 75 Francis St, Boston, MA 02115 USA. EM eflewis@partners.org NR 29 TC 3 Z9 3 U1 3 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD MAR PY 2016 VL 4 IS 3 BP 184 EP 193 DI 10.1016/j.jchf.2015.12.011 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF9AC UT WOS:000371651600003 PM 26874379 ER PT J AU Morgand, M Bouvin-Pley, M Plantier, JC Moreau, A Alessandri, E Simon, F Pace, CS Pancera, M Ho, DD Poignard, P Bjorkman, PJ Mouquet, H Nussenzweig, MC Kwong, PD Baty, D Chames, P Braibant, M Barin, F AF Morgand, Marion Bouvin-Pley, Melanie Plantier, Jean-Christophe Moreau, Alain Alessandri, Elodie Simon, Francois Pace, Craig S. Pancera, Marie Ho, David D. Poignard, Pascal Bjorkman, Pamela J. Mouquet, Hugo Nussenzweig, Michel C. Kwong, Peter D. Baty, Daniel Chames, Patrick Braibant, Martine Barin, Francis TI V1/V2 Neutralizing Epitope is Conserved in Divergent Non-M Groups of HIV-1 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; diversity; antibodies; epitopes; neutralization ID IMMUNODEFICIENCY-VIRUS TYPE-1; GROUP-O; MONOCLONAL-ANTIBODIES; GP41-GP120 INTERFACE; DEPENDENT EPITOPE; POTENT; VACCINE; DOMAIN; GP120; BROAD AB Background: Highly potent broadly neutralizing monoclonal antibodies (bNAbs) have been obtained from individuals infected by HIV-1 group M variants. We analyzed the cross-group neutralization potency of these bNAbs toward non-M primary isolates (PI). Material and Methods: The sensitivity to neutralization was analyzed in a neutralization assay using TZM-bl cells. Twenty-three bNAbs were used, including reagents targeting the CD4-binding site, the N160 glycan-V1/V2 site, the N332 glycan-V3 site, the membrane proximal external region of gp41, and complex epitopes spanning both env subunits. Two bispecific antibodies that combine the inhibitory activity of an anti-CD4 with that of PG9 or PG16 bNAbs were included in the study (PG9-iMab and PG16-iMab). Results: Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O PIs, 1 group N PI, and the group P PI were neutralized by PG9 and/or PG16 or PGT145 at low concentrations (0.04-9.39 mu g/mL). None of the non-M PIs was neutralized by the bNAbs targeting other regions at the highest concentration tested, except 10E8 that neutralized weakly 2 group N PIs and 35O22 that neutralized 1 group O PI. The bispecific bNAbs neutralized very efficiently all the non-M PIs with IC50 below 1 mu g/mL, except 2 group O strains. Conclusion: The N160 glycan-V1/V2 site is the most conserved neutralizing site within the 4 groups of HIV-1. This makes it an interesting target for the development of HIV vaccine immunogens. The corresponding bNAbs may be useful for immunotherapeutic strategies in patients infected by non-M variants. C1 [Morgand, Marion; Bouvin-Pley, Melanie; Moreau, Alain; Braibant, Martine; Barin, Francis] Univ Tours, INSERM, U966, Tours, France. [Plantier, Jean-Christophe; Alessandri, Elodie] Univ Rouen, Rouen, France. [Plantier, Jean-Christophe; Alessandri, Elodie] CHU Charles Nicolle, Rouen, France. [Simon, Francois] Hop St Louis, Virol Lab, Paris, France. [Pace, Craig S.; Ho, David D.] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, 1230 York Ave, New York, NY 10021 USA. [Pancera, Marie; Kwong, Peter D.] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Bjorkman, Pamela J.] CALTECH, Pasadena, CA 91125 USA. [Mouquet, Hugo] Inst Pasteur, Dept Immunol, Lab Humoral Response Pathogens, F-75724 Paris, France. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Baty, Daniel; Chames, Patrick] INSERM, CRCM, U1068, F-13258 Marseille, France. [Baty, Daniel; Chames, Patrick] Inst J Paoli I Calmettes, Marseille, France. [Baty, Daniel; Chames, Patrick] CNRS, UMR7258, Marseille, France. [Baty, Daniel; Chames, Patrick] AMU, UM105, Marseille, France. [Barin, Francis] CHU Bretonneau, Ctr Natl Reference VIH, Lab Bacteriol Virol, 2 Bd Tonnelle, F-37044 Tours, France. RP Barin, F (reprint author), CHU Bretonneau, CNR VIH, Virol Lab, 2 Bd Tonnelle, F-37044 Tours, France. EM fbarin@med.univ-tours.fr RI poignard, pascal/N-6678-2013; Chames, Patrick/R-1800-2016; OI Chames, Patrick/0000-0002-6104-6286; Baty, Daniel/0000-0001-8443-4444; PLANTIER, Jean-Christophe/0000-0001-6417-4083 FU Agence Nationale de Recherche sur le SIDA et les Hepatites (ANRS, Paris, France); ANRS; Region Centre; Sidaction (France) FX Supported by the Agence Nationale de Recherche sur le SIDA et les Hepatites (ANRS, Paris, France). M. Morgand was supported by a doctoral fellowship from the ANRS. M. Bouvin-Pley was supported by doctoral fellowships from the Region Centre and Sidaction (France). NR 37 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2016 VL 71 IS 3 BP 237 EP 245 DI 10.1097/QAI.0000000000000854 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DF7FB UT WOS:000371522100001 PM 26413851 ER PT J AU Rutstein, SE Pettifor, AE Phiri, S Kamanga, G Hoffman, IF Hosseinipour, MC Rosenberg, NE Nsona, D Pasquale, D Tegha, G Powers, KA Phiri, M Tembo, B Chege, W Miller, WC AF Rutstein, Sarah E. Pettifor, Audrey E. Phiri, Sam Kamanga, Gift Hoffman, Irving F. Hosseinipour, Mina C. Rosenberg, Nora E. Nsona, Dominic Pasquale, Dana Tegha, Gerald Powers, Kimberly A. Phiri, Mcleod Tembo, Bisweck Chege, Wairimu Miller, William C. TI Incorporating Acute HIV Screening into Routine HIV Testing at Sexually Transmitted Infection Clinics, and HIV Testing and Counseling Centers in Lilongwe, Malawi SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV testing and counseling; AHI screening; Malawi; acute HIV infection ID IMMUNODEFICIENCY-VIRUS-INFECTION; UNITED-STATES; SOUTH-AFRICA; COST-EFFECTIVENESS; COASTAL KENYA; REAL-TIME; TRANSMISSION; POPULATION; PREVENTION; MEN AB Background and Objectives: Integrating acute HIV-infection (AHI) testing into clinical settings is critical to prevent transmission, and realize potential treatment-as-prevention benefits. We evaluated acceptability of AHI testing and compared AHI prevalence at sexually transmitted infection (STI) clinics and HIV testing and counseling (HTC) clinics in Lilongwe, Malawi. Methods: We conducted HIV RNA testing for HIV-seronegative patients visiting STI and HTC clinics. AHI was defined as positive RNA and negative/discordant rapid antibody tests. We evaluated demographic, behavioral, and transmission-risk differences between STI and HTC patients and assessed performance of a risk-score for targeted screening. Results: Nearly two-thirds (62.8%, 9280/14,755) of eligible patients consented to AHI testing. We identified 59 persons with AHI (prevalence = 0.64%)-a 0.9% case-identification increase. Prevalence was higher at STI [1.03% (44/4255)] than at HTC clinics [0.3% (15/5025), P < 0.01], accounting for 2.3% of new diagnoses vs 0.3% at HTC clinic. Median viral load (VL) was 758,050 copies per milliliter; 25% (15/59) had VL >= 10,000,000 copies per milliliter. Median VL was higher at STI (1,000,000 copies/mL) compared with HTC (153,125 copies/mL, P = 0.2). Among persons with AHI, those tested at STI clinics were more likely to report genital sores compared with those tested at HTC clinics (54.6% vs 6.7%, P < 0.01). The risk score algorithm performed well in identifying persons with AHI at HTC clinics (sensitivity = 73%, specificity = 89%). Conclusions: The majority of patients consented to AHI testing. AHI prevalence was substantially higher in STI clinics than HTC clinics. Remarkably high VLs and concomitant genital scores demonstrate the potential for transmission. Universal AHI screening at STI clinics, and targeted screening at HTC centers, should be considered. C1 [Rutstein, Sarah E.] Univ N Carolina, Dept Hlth Policy & Management, CB 7411, Chapel Hill, NC 27599 USA. [Rutstein, Sarah E.; Hoffman, Irving F.; Hosseinipour, Mina C.; Miller, William C.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC 27599 USA. [Pettifor, Audrey E.; Pasquale, Dana; Powers, Kimberly A.; Miller, William C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Phiri, Sam; Nsona, Dominic; Phiri, Mcleod; Tembo, Bisweck] Lighthouse Trust, Lilongwe, Malawi. [Kamanga, Gift; Hosseinipour, Mina C.; Rosenberg, Nora E.; Tegha, Gerald] UNC Project, Lilongwe, Malawi. [Chege, Wairimu] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Rutstein, SE (reprint author), Univ N Carolina, Dept Hlth Policy & Management, CB 7411, Chapel Hill, NC 27599 USA. EM sarah_rutstein@med.unc.edu FU NIH/NIAID [R01 AI083059]; NIH/NIMH [F30 MH098731]; NIH/NIGMS [T32-GM008719] FX Supported by NIH/NIAID R01 AI083059. S. E. R. was supported by NIH/NIMH (F30 MH098731) and NIH/NIGMS (T32-GM008719). NR 41 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2016 VL 71 IS 3 BP 272 EP 280 DI 10.1097/QAI.0000000000000853 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DF7FB UT WOS:000371522100005 PM 26428231 ER PT J AU Mirembe, BG Kelly, CW Mgodi, N Greenspan, S Dai, JY Mayo, A Piper, J Akello, CA Kiweewa, FM Magure, T Nakabiito, C Marrazzo, JM AF Mirembe, Brenda G. Kelly, Clifton W. Mgodi, Nyaradzo Greenspan, Susan Dai, James Y. Mayo, Ashley Piper, Jeanna Akello, Carolyne A. Kiweewa, Flavia M. Magure, Tsitsi Nakabiito, Clemensia Marrazzo, Jeanne M. TI Bone Mineral Density Changes Among Young, Healthy African Women Receiving Oral Tenofovir for HIV Preexposure Prophylaxis SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE tenofovir; bone density; preexposure prophylaxis; HIV prevention; African women ID ANTIRETROVIRAL PROPHYLAXIS; HIV-1-INFECTED PATIENTS; ABACAVIR-LAMIVUDINE; DISOPROXIL FUMARATE; FRACTURES; EMTRICITABINE; COMBINATION; EFAVIRENZ; INFECTION; EFFICACY AB Background: Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial. Methods: HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks. Results: Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%-100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH. Conclusions: TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women. C1 [Mirembe, Brenda G.; Akello, Carolyne A.; Kiweewa, Flavia M.; Nakabiito, Clemensia] Makerere Univ Johns Hopkins Univ Res Collaborat, Upper Mulago Hill Rd,POB 23491, Kampala, Uganda. [Kelly, Clifton W.; Dai, James Y.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Mgodi, Nyaradzo; Magure, Tsitsi] Univ Zimbabwe, Univ Calif San Francisco, Dept Obstet & Gynaecol, Harare, Zimbabwe. [Greenspan, Susan] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Mayo, Ashley] FHI 360, Durham, NC USA. [Piper, Jeanna] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Marrazzo, Jeanne M.] Univ Washington, Dept Med & Global Hlth, Seattle, WA 98195 USA. RP Mirembe, BG (reprint author), Makerere Univ Johns Hopkins Univ Res Collaborat, Upper Mulago Hill Rd,POB 23491, Kampala, Uganda. EM bgati@mujhu.org OI Kelly, Clifton/0000-0003-0794-3901; Marrazzo, Jeanne/0000-0002-9277-7364 FU National Institute of Allergy and Infectious Diseases [UM1AI068633, UM1AI068615, UM1AI1106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Maternal Health, of the US National Institutes of Health; NIH [UM1AI069436, UM1AI069530, P30AG024827] FX Supported by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI1106707) with cofunding from Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Maternal Health, all components of the US National Institutes of Health. Additional funding to the clinical sites was provided by NIH grants UM1AI069436 (UZ-UCSF CTU) and UM1AI069530 (MU-JHU CTU), and P30AG024827 (Osteoporosis Research Center at the University of Pittsburgh). Study medications were provided by Gilead Sciences. NR 29 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2016 VL 71 IS 3 BP 287 EP 294 DI 10.1097/QAI.0000000000000858 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DF7FB UT WOS:000371522100007 PM 26866954 ER PT J AU Volkow, ND Swanson, JM Evins, AE DeLisi, LE Meier, MH Gonzalez, R Bloomfield, MAP Curran, HV Baler, R AF Volkow, Nora D. Swanson, James M. Evins, A. Eden DeLisi, Lynn E. Meier, Madeline H. Gonzalez, Raul Bloomfield, Michael A. P. Curran, H. Valerie Baler, Ruben TI Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review SO JAMA PSYCHIATRY LA English DT Review ID HIGH-POTENCY CANNABIS; SWEDISH CONSCRIPTS; MEMORY IMPAIRMENT; GENETIC-VARIATION; ADULT PSYCHOSIS; SEX-DIFFERENCES; SCHIZOPHRENIA; RISK; ADOLESCENT; MARIJUANA AB With a political debate about the potential risks and benefits of cannabis use as a backdrop, the wave of legalization and liberalization initiatives continues to spread. Four states (Colorado, Washington, Oregon, and Alaska) and the District of Columbia have passed laws that legalized cannabis for recreational use by adults, and 23 others plus the District of Columbia now regulate cannabis use for medical purposes. These policy changes could trigger a broad range of unintended consequences, with profound and lasting implications for the health and social systems in our country. Cannabis use is emerging as one among many interacting factors that can affect brain development and mental function. To inform the political discourse with scientific evidence, the literature was reviewed to identify what is known and not known about the effects of cannabis use on human behavior, including cognition, motivation, and psychosis. C1 [Volkow, Nora D.; Baler, Ruben] NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [Swanson, James M.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA USA. [Evins, A. Eden] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Evins, A. Eden] Harvard Univ, Sch Med, Boston, MA USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Meier, Madeline H.] Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. [Gonzalez, Raul] Florida Int Univ, Dept Psychol, Ctr Children & Families, Miami, FL 33199 USA. [Bloomfield, Michael A. P.] UCL, Div Psychiat, London, England. [Bloomfield, Michael A. P.] Hammersmith Hosp, MRC, Ctr Clin Sci, Psychiat Imaging Grp, London, England. [Curran, H. Valerie] UCL, Clin Psychopharmacol Unit, Clin Hlth Psychol, London, England. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU Forum Pharmaceuticals from the National Institute of Drug Abuse [R01 DA030992]; Pfizer from the National Institute of Drug Abuse [R01 DA021245]; National Institutes of Health Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism) [DE-AC02-98CH10886]; National Institute of Drug Abuse [R01 DA021576]; United Kingdom Medical Research Council; National Institute of Health Research; British Medical Association; United Kingdom National Institute of Health Research Biomedical Research Council; United Kingdom Medical Research Council grant FX This work was financed in part by support from the following: Forum Pharmaceuticals to support grant R01 DA030992 from the National Institute of Drug Abuse and Pfizer to support grant R01 DA021245 from the National Institute of Drug Abuse (Dr Evins); National Institutes of Health Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism) using the infrastructure of the Brookhaven National Laboratory under contract DE-AC02-98CH10886 (Dr Volkow); grant R01 DA021576 from the National Institute of Drug Abuse (Dr DeLisi); United Kingdom Medical Research Council, National Institute of Health Research, and British Medical Association (Dr Bloomfield); and a grant from the United Kingdom National Institute of Health Research Biomedical Research Council to King's College London and a United Kingdom Medical Research Council grant (Dr Curran). NR 84 TC 32 Z9 32 U1 55 U2 120 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAR PY 2016 VL 73 IS 3 BP 292 EP 297 DI 10.1001/jamapsychiatry.2015.3278 PG 6 WC Psychiatry SC Psychiatry GA DF8NC UT WOS:000371613500017 PM 26842658 ER PT J AU Guardado, P Olivera, A Rusch, HL Roy, M Martin, C Lejbman, N Lee, H Gill, JM AF Guardado, Pedro Olivera, Anlys Rusch, Heather L. Roy, Michael Martin, Christiana Lejbman, Natasha Lee, Hwyunhwa Gill, Jessica M. TI Altered gene expression of the innate immune, neuroendocrine, and nuclear factor-kappa B (NF-kappa B) systems is associated with posttraumatic stress disorder in military personnel SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Gene expression; Innate immune; Neuroendocrine; NF-kappa B; PTSD; Trauma ID TRAUMATIC BRAIN-INJURY; QUALITY-OF-LIFE; COMBAT VETERANS; IMPROVED SLEEP; ANIMAL-MODEL; PTSD RISK; DEPRESSION; SYMPTOMS; MEMORY; INFLAMMATION AB Whole transcriptome analysis provides an unbiased examination of biological activity, and likely, unique insight into the mechanisms underlying posttraumatic stress disorder (PTSD) and comorbid depression and traumatic brain injury. This study compared gene-expression profiles in military personnel with PTSD (n =28) and matched controls without PTSD (n =27) using HG-U133 Plus 2.0 microarrays (Affymetrix), which contain 54,675 probe sets representing more than 38,500 genes. Analysis of expression profiles revealed 203 differentially expressed genes in PTSD, of which 72% were upregulated. Using Partek Genomics Suite 6.6, differentially expressed transcription clusters were filtered based on a selection criterion of <= 1.5 relative fold change at a false discovery rate of <= 5%. Ingenuity Pathway Analysis (Qiagen) of the differentially expressed genes indicated a dysregulation of genes associated with the innate immune, neuroendocrine, and NF-kappa B systems. These findings provide novel insights that may lead to new pharmaceutical agents for PTSD treatments and help mitigate mental and physical comorbidity risk. (c) 2016 Published by Elsevier Ltd. C1 [Guardado, Pedro; Olivera, Anlys; Rusch, Heather L.; Martin, Christiana; Lejbman, Natasha; Gill, Jessica M.] NINR, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rusch, Heather L.] Henry M Jackson Fdn Adv Mil Med, 6720A Rockledge Dr 100, Bethesda, MD 20817 USA. [Roy, Michael] Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Lee, Hwyunhwa] Univ Nevada, Sch Nursing, 4505 South Maryland Pkwy, Las Vegas, NV 89154 USA. RP Gill, JM (reprint author), 1 Cloister Court 256, Bethesda, MD 20892 USA. EM gillj@mail.nih.gov NR 65 TC 4 Z9 4 U1 5 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 EI 1873-7897 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD MAR PY 2016 VL 38 BP 9 EP 20 DI 10.1016/j.janxdis.2015.12.004 PG 12 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DF6EQ UT WOS:000371449100002 PM 26751122 ER PT J AU Wentzensen, N Schiffman, M Palmer, T Arbyn, M AF Wentzensen, Nicolas Schiffman, Mark Palmer, Timothy Arbyn, Marc TI Triage of HPV positive women in cervical cancer screening SO JOURNAL OF CLINICAL VIROLOGY LA English DT Review DE HPV; Triage; Cervical cancer screening; Cytology; p16/Ki-67; Methylation ID RANDOMIZED CONTROLLED-TRIAL; ASC-US CYTOLOGY; HUMAN-PAPILLOMAVIRUS; INTRAEPITHELIAL NEOPLASIA; METHYLATION ANALYSIS; CLINICAL VALIDATION; MILD DYSKARYOSIS; DNA METHYLATION; RISK; GUIDELINES AB Despite HPV vaccines, screening will remain central for decades to control cervical cancer. Recently, HPV testing alone or with cytology was introduced as an alternative to cytology screening. However, most HPV infections are harmless and additional tests are required to identify women with progressing infections or precancer. With three options for primary screening, and without clear strategies for triage of screen-positive women, there is great confusion about the best approach. Also, increasing HPV vaccination coverage will lead to lower disease prevalence, and force new screening approaches. Currently recommended triage strategies for primary HPV screening include HPV genotyping for HPV16 and HPV18 and cytology. Other alternatives that are currently evaluated include p16/Ki-67 dual stain cytology, host methylation, and viral methylation testing. Clinical management of women with cervical cancer screening results is moving to use risk thresholds rather than individual test results. Specific risk thresholds have been defined for return to primary screening, repeat testing, referral to colposcopy, and immediate treatment. Choice of test algorithms is based on comparison of absolute risk estimates from triage tests with established clinical thresholds. Importantly, triage tests need to be evaluated together with the primary screening test and the downstream clinical management. An optimal integrated screening and triage strategy should reassure the vast majority of women that they are at very low risk of cervical cancer, send the women at highest risk to colposcopy at the right time, when disease can be colposcopically detected, and minimize the intermediate risk group that requires continued surveillance. Published by Elsevier B.V. C1 [Wentzensen, Nicolas; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Palmer, Timothy] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Arbyn, Marc] Sci Inst Publ Hlth, Belgian Canc Ctr, Unit Canc Epidemiol, Brussels, Belgium. 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 seventh framework program of DG Research of the European Commission, through the COHEAHR Network [603019]; European Union; KCE-Centre d'Expertise (Brussels, Belgium); German Guideline Program in Oncology (German Cancer Aid project) [110163]; Intramural Research Program of the US National Cancer Institute FX M. Arbyn is supported by the seventh framework program of DG Research of the European Commission, through the COHEAHR Network (grant No 603019), the Joint Action CANCON which has received funding from the European Union in the framework of the Health Programme (2008-13), the KCE-Centre d'Expertise (Brussels, Belgium) and the German Guideline Program in Oncology (German Cancer Aid project # 110163). N. Wentzensen and M. Schiffman are supported by the Intramural Research Program of the US National Cancer Institute. NCI has received cervical cancer screening assays in-kind or at reduced cost from BD, Cepheid, Hologic, and Roche. NR 68 TC 14 Z9 14 U1 7 U2 9 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 MAR PY 2016 VL 76 SU 1 BP S49 EP S55 DI 10.1016/j.jcv.2015.11.015 PG 7 WC Virology SC Virology GA DG0VZ UT WOS:000371785200007 PM 26643050 ER PT J AU Thurber, K Tycko, R AF Thurber, Kent Tycko, Robert TI Low-temperature dynamic nuclear polarization with helium-cooled samples and nitrogen-driven magic-angle spinning SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Solid state NMR; Dynamic nuclear polarization; Low-temperature NMR; Magic-angle spinning; Protein structure ID SOLID-STATE NMR; MAGNETIC-RESONANCE; CONFORMATIONAL DISTRIBUTIONS; HIV-1 GP120; V3 LOOP; 25 K; SPECTROSCOPY; PROTEIN; TARGET; CALMODULIN AB We describe novel instrumentation for low-temperature solid state nuclear magnetic resonance (NMR) with dynamic nuclear polarization (DNP) and magic-angle spinning (MAS), focusing on aspects of this instrumentation that have not been described in detail in previous publications. We characterize the performance of an extended interaction oscillator (EIO) microwave source, operating near 264 GHz with 1.5 W output power, which we use in conjunction with a quasi-optical microwave polarizing system and a MAS NMR probe that employs liquid helium for sample cooling and nitrogen gas for sample spinning. Enhancement factors for cross-polarized 13C NMR signals in the 100-200 range are demonstrated with DNP at 25 K. The dependences of signal amplitudes on sample temperature, as well as microwave power, polarization, and frequency, are presented. We show that sample temperatures below 30 K can be achieved with helium consumption rates below 1.3 l/h. To illustrate potential applications of this instrumentation in structural studies of biochemical systems, we compare results from low-temperature DNP experiments on a calmodulin-binding peptide in its free and bound states. Published by Elsevier Inc. C1 [Thurber, Kent; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health; NIH Intramural AIDS Targeted Antiviral Program FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health, and by the NIH Intramural AIDS Targeted Antiviral Program. We thank Nicholas Anthis and Marius Clore for providing the unlabeled calmodulin for experiments in Fig, 6, and Wai-Ming Yau for synthesizing the labeled M13 peptide. NR 46 TC 2 Z9 2 U1 14 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD MAR PY 2016 VL 264 BP 99 EP 106 DI 10.1016/j.jmr.2016.01.011 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA DG0JJ UT WOS:000371750800012 PM 26920835 ER PT J AU Tabb, DL Wang, X Carr, SA Clauser, KR Mertins, P Chambers, MC Holman, JD Wang, J Zhang, B Zimmerman, LJ Chen, X Gunawardena, HP Davies, SR Ellis, MJC Li, SQ Townsend, RR Boja, ES Ketchum, KA Kinsinger, CR Mesri, M Rodriguez, H Liu, T Kim, S McDermott, JE Payne, SH Petyuk, VA Rodland, KD Smith, RD Yang, F Chan, DW Zhang, B Zhang, H Zhang, Z Zhou, JY Liebler, DC AF Tabb, David L. Wang, Xia Carr, Steven A. Clauser, Karl R. Mertins, Philipp Chambers, Matthew C. Holman, Jerry D. Wang, Jing Zhang, Bing Zimmerman, Lisa J. Chen, Xian Gunawardena, Harsha P. Davies, Sherri R. Ellis, Matthew J. C. Li, Shunqiang Townsend, R. Reid Boja, Emilsy S. Ketchum, Karen A. Kinsinger, Christopher R. Mesri, Mehdi Rodriguez, Henry Liu, Tao Kim, Sangtae McDermott, Jason E. Payne, Samuel H. Petyuk, Vladislav A. Rodland, Karin D. Smith, Richard D. Yang, Feng Chan, Daniel W. Zhang, Bai Zhang, Hui Zhang, Zhen Zhou, Jian-Ying Liebler, Daniel C. TI Reproducibility of Differential Proteomic Technologies in CPTAC Fractionated Xenografts SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Differential proteomics; label-free; iTRAQ quality control; xenografts; technology assessment; CPTAC ID SPECTROMETRY-BASED PROTEOMICS; ABSOLUTE QUANTITATION ITRAQ; RELATIVE PROTEIN ABUNDANCE; TANDEM MASS-SPECTROMETRY; DATABASE SEARCH TOOL; SHOTGUN PROTEOMICS; LABEL-FREE; PEPTIDE IDENTIFICATION; ISOBARIC TAGS; CANCER AB The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows. We evaluated iTRAQ reporter ions, label-free spectral counts, and label-free extracted ion chromatograms as strategies for data interpretation (source code is available from http://homepages.uc.edu/ similar to wang2x7/Research.htm). From these assessments, we found that differential genes from a single replicate were confirmed by other replicates on the same instrument from 61 to 93% of the time. When comparing across different instruments and quantitative technologies, using multiple replicates, differential genes were reproduced by other data sets from 67 to 99% of the time. Projecting gene differences to biological pathways and networks increased the degree of similarity. These overlaps send an encouraging message about the maturity of technologies for proteomic differentiation. C1 [Tabb, David L.; Chambers, Matthew C.; Holman, Jerry D.; Wang, Jing; Zhang, Bing] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. [Zimmerman, Lisa J.; Liebler, Daniel C.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Wang, Xia] Univ Cincinnati, Dept Math Sci, Cincinnati, OH 45221 USA. [Carr, Steven A.; Clauser, Karl R.; Mertins, Philipp] Broad Inst MIT & Harvard, Prote Platform, Cambridge, MA 02142 USA. [Chen, Xian; Gunawardena, Harsha P.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Davies, Sherri R.; Ellis, Matthew J. C.; Li, Shunqiang; Townsend, R. Reid] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Boja, Emilsy S.; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. [Ketchum, Karen A.] Enterprise Sci & Comp Inc, Rockville, MD 20850 USA. [Liu, Tao; Kim, Sangtae; McDermott, Jason E.; Payne, Samuel H.; Petyuk, Vladislav A.; Rodland, Karin D.; Smith, Richard D.; Yang, Feng] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Chan, Daniel W.; Zhang, Bai; Zhang, Hui; Zhang, Zhen; Zhou, Jian-Ying] Johns Hopkins Univ, JHMI, Baltimore, MD 21231 USA. [Chan, Daniel W.; Zhang, Bai; Zhang, Hui; Zhang, Zhen; Zhou, Jian-Ying] Johns Hopkins Univ, Div Clin Chem, Baltimore, MD 21231 USA. [Ellis, Matthew J. C.] Baylor Coll Med, Smith Breast Ctr, Houston, TX 77030 USA. RP Tabb, DL (reprint author), Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. EM dtabb@sun.ac.za RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Payne, Samuel/0000-0002-8351-1994 FU Washington University in St. Louis [U24-CA-160035]; Vanderbilt University [U24-CA-159988]; Broad Institute [U24-CA-160034]; Pacific Northwest National Lab [U24-CA-160019]; Johns Hopkins University [U24-CA-160036]; CTSA [UL1 RR024992]; Leidos Biomedical Research [13XS029]; [BCTR0707808]; [KG090422]; [HHSN261201100106C] FX CPTAC includes support from U24-CA-160035 (Washington University in St. Louis), U24-CA-159988 (Vanderbilt University), U24-CA-160034 (Broad Institute), U24-CA-160019 (Pacific Northwest National Lab), and U24-CA-160036 (Johns Hopkins University). The PDX models were developed through grants to Matthew J. Ellis by Susan G. Komen for the Cure (grant nos. BCTR0707808 and KG090422). The HAMLET Core that provided the xenograft tumors was supported by CTSA grant UL1 RR024992. Public dissemination of underlying raw data at the CPTAC Public Portal was made possible through contract HHSN261201100106C to ESAC, Inc. Biological network analysis was enabled through Leidos Biomedical Research contract 13XS029. NR 59 TC 6 Z9 6 U1 3 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2016 VL 15 IS 3 BP 691 EP 706 DI 10.1021/acs.jproteome.5b00859 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DG0KQ UT WOS:000371754100003 PM 26653538 ER PT J AU Rudnick, PA Markey, SP Roth, J Mirokhin, Y Yan, XJ Tchekhovskoi, DV Edwards, NJ Thangudu, RR Ketchum, KA Kinsinger, CR Mesri, M Rodriguez, H Stein, SE AF Rudnick, Paul A. Markey, Sanford P. Roth, Jeri Mirokhin, Yuri Yan, Xinjian Tchekhovskoi, Dmitrii V. Edwards, Nathan J. Thangudu, Ratna R. Ketchum, Karen A. Kinsinger, Christopher R. Mesri, Mehdi Rodriguez, Henry Stein, Stephen E. TI A Description of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) Common Data Analysis Pipeline SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE proteomics data resource; bioinformatics; cancer; CPTAC; data analysis pipeline ID PEPTIDE IDENTIFICATION; MASS-SPECTROMETRY; SEARCH; CANCER AB The Clinical Proteomic Tumor Analysis Consortium (CPTAC) has produced large proteomics data sets from the mass spectrometric interrogation of tumor samples previously analyzed by The Cancer Genome Atlas (TCGA) program. The availability of the genomic and proteomic data is enabling proteogenomic study for both reference (i.e., contained in major sequence databases) and nonreference markers of cancer. The CPTAC laboratories have focused on colon, breast, and ovarian tissues in the first round of analyses; spectra from these data sets were produced from 2D liquid chromatography tandem mass spectrometry analyses and represent deep coverage. To reduce the variability introduced by disparate data analysis platforms (e.g., software packages, versions, parameters, sequence databases, etc.), the CPTAC Common Data Analysis Platform (CDAP) was created. The CDAP produces both peptide-spectrum-match (PSM) reports and gene-level reports. The pipeline processes raw mass spectrometry data according to the following: (1) peak-picking and quantitative data extraction, (2) database searching, (3) gene based protein parsimony, and (4) false-discovery rate-based filtering. The pipeline also produces localization scores for the phosphopeptide enrichment studies using the PhosphoRS program. Quantitative information for each of the data sets is specific to the sample processing, with PSM and protein reports containing the spectrum-level or gene-level ("rolled-up") precursor peak areas and spectral counts for label-free or reporter ion log-ratios for 4plex iTRAQ The reports are available in simple tab delimited formats and, for the PSM-reports, in mzIdentML. The goal of the CDAP is to provide standard, uniform reports for all of the CPTAC data to enable comparisons between different samples and cancer types as well as across the major omics fields. C1 [Rudnick, Paul A.] Spectragen Informat, Bainbridge Isl, WA 98110 USA. [Rudnick, Paul A.; Markey, Sanford P.; Roth, Jeri; Mirokhin, Yuri; Yan, Xinjian; Tchekhovskoi, Dmitrii V.; Stein, Stephen E.] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Edwards, Nathan J.] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. [Thangudu, Ratna R.; Ketchum, Karen A.] ESAC Inc, Rockville, MD 20850 USA. [Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. RP Rudnick, PA (reprint author), Spectragen Informat, Bainbridge Isl, WA 98110 USA.; Rudnick, PA (reprint author), NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. EM paul.rudnick@spectragen-informatics.com FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors thank all of the contributing CPTAC laboratories for their work generating these large datasets and for valuable feedback during the design and testing phases of the pipeline. In particular, the authors would like to thank Karl Clauser and Philip Mertins (Broad Institute); Sam Payne, Matt Monroe, and Tao Liu (PNNL); David Fenyo (NYU); Rob Slebos, Bing Zhang, and David Tabb (Vanderbilt University Medical Center); Bai Zhang (JHU); and Alexey Nesvizhskii (UMich). We are also grateful to Nuno Bandeira and June Snedecor for their help with assessing phosphosite assignment algorithms. NCI CPTAC 2 NIST/NCI IAA ACO13004 ("Proteomics Measurement Quality Assurance Program"). This project has been funded in whole or in part with Federal funds from National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services; in addition, mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Certain commercial instruments are identified in this document. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology; in addition, it does not imply that the products identified are necessarily the best available for the purpose. NR 17 TC 1 Z9 1 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2016 VL 15 IS 3 BP 1023 EP 1032 DI 10.1021/acs.jproteome.5b01091 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DG0KQ UT WOS:000371754100035 PM 26860878 ER PT J AU Ruggles, KV Tang, ZJ Wang, XY Grover, H Askenazi, M Teubl, J Cao, S McLellan, MD Clauser, KR Tabb, DL Mertins, P Slebos, R Erdmann-Gilmore, P Li, SQ Gunawardena, HP Xie, L Liu, T Zhou, JY Sun, SS Hoadley, KA Perou, CM Chen, X Davies, SR Maher, CA Kinsinger, CR Rodland, KD Zhang, H Zhang, Z Ding, L Townsend, RR Rodriguez, H Chan, D Smith, RD Liebler, DC Carr, SA Payne, S Ellis, MJ Fenyo, D AF Ruggles, Kelly V. Tang, Zuojian Wang, Xuya Grover, Himanshu Askenazi, Manor Teubl, Jennifer Cao, Song McLellan, Michael D. Clauser, Karl R. Tabb, David L. Mertins, Philipp Slebos, Robbert Erdmann-Gilmore, Petra Li, Shunqiang Gunawardena, Harsha P. Xie, Ling Liu, Tao Zhou, Jian-Ying Sun, Shisheng Hoadley, Katherine A. Perou, Charles M. Chen, Xian Davies, Sherri R. Maher, Christopher A. Kinsinger, Christopher R. Rodland, Karen D. Zhang, Hui Zhang, Zhen Ding, Li Townsend, R. Reid Rodriguez, Henry Chan, Daniel Smith, Richard D. Liebler, Daniel C. Carr, Steven A. Payne, Samuel Ellis, Matthew J. Fenyo, David TI An Analysis of the Sensitivity of Proteogenomic Mapping of Somatic Mutations and Novel Splicing Events in Cancer SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID RNA-SEQ DATA; MASS-SPECTROMETRY DATA; PROTEIN IDENTIFICATION; BREAST-CANCER; GENOME; DISCOVERY; DATABASES; VARIANTS; TRANSCRIPTOME; VALIDATION AB Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations, and splice variants identified in cancer cells are translated. Herein, we apply a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast-cancer-patient-derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS sample process replicates defined here as an independent tandem MS experiment using identical sample material. Despite analysis of over 30 sample process replicates, only about 10% of SNVs (somatic and germline) detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNVs without a detectable mRNA transcript were also observed, suggesting that transcriptome coverage was incomplete (approximate to 80%). In contrast to germline variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than in the luminal tumor, raising the possibility of differential translation or protein degradation effects. In conclusion, this large-scale proteogenomic integration allowed us to determine the degree to which mutations are translated and identify gaps in sequence coverage, thereby benchmarking current technology and progress toward whole cancer proteome and transcriptome analysis. C1 [Ruggles, Kelly V.; Tang, Zuojian; Wang, Xuya; Grover, Himanshu; Teubl, Jennifer; Fenyo, David] NYU, Sch Med, 227 East 30th St, New York, NY 10016 USA. [Askenazi, Manor] Biomed Hosting LLC, Arlington, MA USA. [Cao, Song; McLellan, Michael D.; Erdmann-Gilmore, Petra; Li, Shunqiang; Davies, Sherri R.; Maher, Christopher A.; Ding, Li; Townsend, R. Reid; Ellis, Matthew J.] Washington Univ, 660 South Euclid Ave, St Louis, MO 63110 USA. [Clauser, Karl R.; Mertins, Philipp; Carr, Steven A.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Tabb, David L.; Slebos, Robbert; Liebler, Daniel C.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Gunawardena, Harsha P.; Xie, Ling; Hoadley, Katherine A.; Perou, Charles M.; Chen, Xian] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Liu, Tao; Rodland, Karen D.; Smith, Richard D.; Payne, Samuel] Pacific NW Natl Lab, 902 Battelle Blvd, Richland, WA 99354 USA. [Zhou, Jian-Ying; Sun, Shisheng; Zhang, Hui; Zhang, Zhen; Chan, Daniel] Johns Hopkins Univ, Baltimore, MD USA. [Kinsinger, Christopher R.; Rodriguez, Henry] NCI, Off Canc Clin Proteom Res, Bethesda, MD 20892 USA. RP Fenyo, D (reprint author), NYU, Sch Med, 227 East 30th St, New York, NY 10016 USA.; Ellis, MJ (reprint author), Washington Univ, 660 South Euclid Ave, St Louis, MO 63110 USA.; Payne, S (reprint author), Pacific NW Natl Lab, 902 Battelle Blvd, Richland, WA 99354 USA. EM Samuel.Payne@pnnl.gov; mellis@dom.wustl.edu; david@fenyolab.org RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Perou, Charles/0000-0001-9827-2247; Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU National Cancer Institute (NCI) CPTAC award [U24CA159988, U24CA160019, U24CA160034, U24CA160035, U24CA160036]; CPTAC contract from Leidos Biomedical Research, Inc. [13XS068] FX This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA159988, U24CA160019, U24CA160034, U24CA160035, U24CA160036 and by CPTAC contract 13XS068 from Leidos Biomedical Research, Inc. This work has utilized computing resources at the High Performance Computing Facility of the Center for Health Informatics and Bioinformatics at the NYU Langone Medical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 31 TC 11 Z9 12 U1 2 U2 10 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 MAR PY 2016 VL 15 IS 3 SI SI BP 1060 EP 1071 DI 10.1074/mcp.M115.056226 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DG2KB UT WOS:000371894700024 PM 26631509 ER PT J AU Berndt, SI Camp, NJ Skibola, CF Vijai, J Wang, ZM Gu, J Nieters, A Kelly, RS Smedby, KE Monnereau, A Cozen, W Cox, A Wang, SS Lan, Q Teras, LR Machado, M Yeager, M Brooks-Wilson, AR Hartge, P Purdue, MP Birmann, BM Vajdic, CM Cocco, P Zhang, YW Giles, GG Zeleniuch-Jacquotte, A Lawrence, C Montalvan, R Burdett, L Hutchinson, A Ye, YQ Call, TG Shanafelt, TD Novak, AJ Kay, NE Liebow, M Cunningham, JM Allmer, C Hjalgrim, H Adami, HO Melbye, M Glimelius, B Chang, ET Glenn, M Curtin, K Cannon-Albright, LA Diver, WR Link, BK Weiner, GJ Conde, L Bracci, PM Riby, J Arnett, DK Zhi, DG Leach, JM Holly, EA Jackson, RD Tinker, LF Benavente, Y Sala, N Casabonne, D Becker, N Boffetta, P Brennan, P Foretova, L Maynadie, M McKay, J Staines, A Chaffee, KG Achenbach, SJ Vachon, CM Goldin, LR Strom, SS Leis, JF Weinberg, JB Caporaso, NE Norman, AD De Roos, AJ Morton, LM Severson, RK Riboli, E Vineis, P Kaaks, R Masala, G Weiderpass, E Chirlaque, MD Vermeulen, RCH Travis, RC Southey, MC Milne, RL Albanese, D Virtamo, J Weinstein, S Clavel, J Zheng, TZ Holford, TR Villano, DJ Maria, A Spinelli, JJ Gascoyne, RD Connors, JM Bertrand, KA Giovannucci, E Kraft, P Kricker, A Turner, J Ennas, MG Ferri, GM Miligi, L Liang, LM Ma, BS Huang, JY Crouch, S Park, JH Chatterjee, N North, KE Snowden, JA Wright, J Fraumeni, JF Offit, K Wu, XF de Sanjose, S Cerhan, JR Chanock, SJ Rothman, N Slager, SL AF Berndt, Sonja I. Camp, Nicola J. Skibola, Christine F. Vijai, Joseph Wang, Zhaoming Gu, Jian Nieters, Alexandra Kelly, Rachel S. Smedby, Karin E. Monnereau, Alain Cozen, Wendy Cox, Angela Wang, Sophia S. Lan, Qing Teras, Lauren R. Machado, Moara Yeager, Meredith Brooks-Wilson, Angela R. Hartge, Patricia Purdue, Mark P. Birmann, Brenda M. Vajdic, Claire M. Cocco, Pierluigi Zhang, Yawei Giles, Graham G. Zeleniuch-Jacquotte, Anne Lawrence, Charles Montalvan, Rebecca Burdett, Laurie Hutchinson, Amy Ye, Yuanqing Call, Timothy G. Shanafelt, Tait D. Novak, Anne J. Kay, Neil E. Liebow, Mark Cunningham, Julie M. Allmer, Cristine Hjalgrim, Henrik Adami, Hans-Olov Melbye, Mads Glimelius, Bengt Chang, Ellen T. Glenn, Martha Curtin, Karen Cannon-Albright, Lisa A. Diver, W. Ryan Link, Brian K. Weiner, George J. Conde, Lucia Bracci, Paige M. Riby, Jacques Arnett, Donna K. Zhi, Degui Leach, Justin M. Holly, Elizabeth A. Jackson, Rebecca D. Tinker, Lesley F. Benavente, Yolanda Sala, Nuria Casabonne, Delphine Becker, Nikolaus Boffetta, Paolo Brennan, Paul Foretova, Lenka Maynadie, Marc McKay, James Staines, Anthony Chaffee, Kari G. Achenbach, Sara J. Vachon, Celine M. Goldin, Lynn R. Strom, Sara S. Leis, Jose F. Weinberg, J. Brice Caporaso, Neil E. Norman, Aaron D. De Roos, Anneclaire J. Morton, Lindsay M. Severson, Richard K. Riboli, Elio Vineis, Paolo Kaaks, Rudolph Masala, Giovanna Weiderpass, Elisabete Chirlaque, Maria-Dolores Vermeulen, Roel C. H. Travis, Ruth C. Southey, Melissa C. Milne, Roger L. Albanese, Demetrius Virtamo, Jarmo Weinstein, Stephanie Clavel, Jacqueline Zheng, Tongzhang Holford, Theodore R. Villano, Danylo J. Maria, Ann Spinelli, John J. Gascoyne, Randy D. Connors, Joseph M. Bertrand, Kimberly A. Giovannucci, Edward Kraft, Peter Kricker, Anne Turner, Jenny Ennas, Maria Grazia Ferri, Giovanni M. Miligi, Lucia Liang, Liming Ma, Baoshan Huang, Jinyan Crouch, Simon Park, Ju-Hyun Chatterjee, Nilanjan North, Kari E. Snowden, John A. Wright, Josh Fraumeni, Joseph F. Offit, Kenneth Wu, Xifeng de Sanjose, Silvia Cerhan, James R. Chanock, Stephen J. Rothman, Nathaniel Slager, Susan L. TI Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia SO NATURE COMMUNICATIONS LA English DT Article ID TRANSCRIPTION FACTOR EOMESODERMIN; FAS GENE-MUTATIONS; SUSCEPTIBILITY LOCI; FOLLICULAR LYMPHOMA; RISK; VARIANTS; EXPRESSION; BANK1; PRIORITIZATION; CLASSIFICATION AB Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P = 2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P = 1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P = 3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P = 1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P = 7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P = 2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. C1 [Berndt, Sonja I.; Lan, Qing; Machado, Moara; Hartge, Patricia; Goldin, Lynn R.; Caporaso, Neil E.; Morton, Lindsay M.; Albanese, Demetrius; Weinstein, Stephanie; Chatterjee, Nilanjan; Fraumeni, Joseph F.; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Camp, Nicola J.] Huntsman Canc Inst, Dept Internal Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. [Skibola, Christine F.; Conde, Lucia; Riby, Jacques; Arnett, Donna K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA. [Skibola, Christine F.; Conde, Lucia; Riby, Jacques; Arnett, Donna K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA. [Skibola, Christine F.; Conde, Lucia; Riby, Jacques] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Vijai, Joseph; Villano, Danylo J.; Maria, Ann; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Wang, Zhaoming; Yeager, Meredith; Burdett, Laurie; Hutchinson, Amy] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA. [Gu, Jian; Ye, Yuanqing; Strom, Sara S.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79108 Freiburg, Baden Wurttembe, Germany. [Kelly, Rachel S.; Adami, Hans-Olov; Bertrand, Kimberly A.; Giovannucci, Edward; Kraft, Peter; Liang, Liming; Ma, Baoshan; Huang, Jinyan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kelly, Rachel S.; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London W2 1PG, England. [Smedby, Karin E.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden. [Monnereau, Alain; Clavel, Jacqueline] Sorbonne Paris Cite CRESS, INSERM, Ctr Res Epidemiol & Stat, Epidemiol Childhood & Adolescent Canc Grp, F-94807 Paris, France. [Monnereau, Alain; Clavel, Jacqueline] Univ Paris 05, F-75270 Paris, France. [Monnereau, Alain] Inst Bergonie, Registre Hemopathies Malignes Gironde, F-33076 Bordeaux, France. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Cox, Angela; Snowden, John A.; Wright, Josh] Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Duarte, CA 91030 USA. [Teras, Lauren R.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Machado, Moara] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, BR-31270901 Belo Horizonte, MG, Brazil. [Brooks-Wilson, Angela R.] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Brooks-Wilson, Angela R.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Purdue, Mark P.] Ontario Hlth Study, Toronto, ON M5G 0A3, Canada. [Birmann, Brenda M.; Bertrand, Kimberly A.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Birmann, Brenda M.; Bertrand, Kimberly A.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Vajdic, Claire M.] Univ New S Wales, Ctr Big Data Res Hlth, Sydney, NSW 2052, Australia. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, I-09042 Cagliari, Italy. [Zhang, Yawei; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA. [Zeleniuch-Jacquotte, Anne] NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY 10016 USA. [Lawrence, Charles; Montalvan, Rebecca] WESTAT Corp, Rockville, MD 20850 USA. [Call, Timothy G.; Kay, Neil E.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Shanafelt, Tait D.; Novak, Anne J.; Liebow, Mark] Mayo Clin, Dept Med, Rochester, MN 55905 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Allmer, Cristine; Chaffee, Kari G.; Achenbach, Sara J.; Vachon, Celine M.; Norman, Aaron D.; Cerhan, James R.; Slager, Susan L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Hjalgrim, Henrik; Melbye, Mads] Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Adami, Hans-Olov; Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Melbye, Mads] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Glimelius, Bengt] Uppsala Univ, Dept Immunol Genet & Pathol, S-75105 Uppsala, Sweden. [Chang, Ellen T.] Exponent Inc, Ctr Epidemiol & Computat Biol, Hlth Sci, Menlo Pk, CA 94025 USA. [Chang, Ellen T.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. [Glenn, Martha] Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT 84112 USA. [Curtin, Karen; Cannon-Albright, Lisa A.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84108 USA. [Cannon-Albright, Lisa A.] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA. [Link, Brian K.; Weiner, George J.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA. [Zhi, Degui; Leach, Justin M.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35233 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Tinker, Lesley F.; De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98117 USA. [Benavente, Yolanda; de Sanjose, Silvia] Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Programme, Barcelona 08908, Spain. [Benavente, Yolanda; Chirlaque, Maria-Dolores; de Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain. [Sala, Nuria] Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona 08908, Spain. [Sala, Nuria] Catalan Inst Oncol IDIBELL, Translat Res Lab, Barcelona 08908, Spain. [Casabonne, Delphine] Inst Catala Oncol, IDIBELL, Canc Epidemiol Res Programme, Unit Infect & Canc UNIC, Barcelona 08908, Spain. [Casabonne, Delphine] CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain. [Becker, Nikolaus; Kaaks, Rudolph] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Baden Wurttembe, Germany. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Brennan, Paul; McKay, James] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno 65653, Czech Republic. [Foretova, Lenka] MF MU, Brno 65653, Czech Republic. [Maynadie, Marc] Univ Burgundy, Registre Hemopathies Malignes Cote dOr, EA 4184, F-21070 Dijon, France. [Maynadie, Marc] Dijon Univ Hosp, F-21070 Dijon, France. [Staines, Anthony] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Leis, Jose F.] Mayo Clin, Div Hematol Oncol, Phoenix, AZ 85054 USA. [Weinberg, J. Brice] Duke Univ, Dept Med, Durham, NC 27710 USA. [Weinberg, J. Brice] VA Med Ctr, Durham, NC 27710 USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England. [Vineis, Paolo] Human Genet Fdn, I-10126 Turin, Italy. [Masala, Giovanna] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, I-50139 Florence, Italy. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Dept Community Med, Fac Hlth Sci, N-9037 Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, N-0304 Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, FI-00250 Helsinki, Finland. [Chirlaque, Maria-Dolores] Murcia Reg Hlth Author, Dept Epidemiol, E-30008 Murcia, Spain. [Vermeulen, Roel C. H.] Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. [Vermeulen, Roel C. H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands. [Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, FI-00271 Helsinki, Finland. [Holford, Theodore R.] Yale Univ, Sch Publ Hlth, Dept Stat, New Haven, CT 06520 USA. [Spinelli, John J.] BC Canc Agcy, Canc Control Res, Vancouver, BC V5Z 1L3, Canada. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, Canada. [Gascoyne, Randy D.; Connors, Joseph M.] BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada. [Gascoyne, Randy D.] Univ British Columbia, Dept Pathol, Vancouver, BC V6T 1Z3, Canada. [Connors, Joseph M.] Univ British Columbia, Dept Med, Vancouver, BC V6T 1Z3, Canada. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter; Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Turner, Jenny] Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW 2109, Australia. [Turner, Jenny] Douglass Hanly Moir Pathol, Dept Histopathol, N Ryde, NSW 2113, Australia. [Ennas, Maria Grazia] Univ Cagliari, Dept Biomed Sci, I-09042 Cagliari, Italy. [Ferri, Giovanni M.] Univ Bari, Interdisciplinary Dept Med, I-70124 Bari, Italy. [Miligi, Lucia] Canc Prevent & Res Inst ISPO, Environm & Occupat Epidemiol Unit, I-50139 Florence, Italy. [Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning Provin, Peoples R China. [Crouch, Simon] Univ York, Dept Hlth Sci, York Y010 5DD, N Yorkshire, England. [Park, Ju-Hyun] Dongguk Univ, Dept Stat, Seoul 100715, South Korea. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Snowden, John A.; Wright, Josh] Sheffield Teaching Hosp NHS Fdn Trust, Royal Hallamshire Hosp, Dept Haematol, Sheffield S10 2TN, S Yorkshire, England. RP Berndt, SI (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM berndts@mail.nih.gov RI Brooks-Wilson, Angela/E-9399-2012; de Sanjose Llongueras, Silvia/H-6339-2014; Weiderpass, Elisabete/M-4029-2016; Clavel, Jacqueline/Q-2750-2016; Vermeulen, Roel/F-8037-2011; OI Giles, Graham/0000-0003-4946-9099; Brooks-Wilson, Angela/0000-0003-1009-6408; Weiderpass, Elisabete/0000-0003-2237-0128; Clavel, Jacqueline/0000-0002-3616-7676; Vermeulen, Roel/0000-0003-4082-8163; Sala, Nuria/0000-0003-3585-7613; albright, lisa/0000-0003-2602-3668; Joseph, Vijai/0000-0002-7933-151X; Masala, Giovanna/0000-0002-5758-9069; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU intramural programme of the Division of Cancer Epidemiology and Genetics; National Cancer Institute [30 CA086862, P30 CA15083, P30 CA015083]; US National Institutes of Health; Intramural Research Program of the NIH; Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; Canadian Institutes for Health Research (CIHR); Michael Smith Foundation for Health Research; American Cancer Society; NCI; Division of Cancer Epidemiology and Genetics; Centers for Disease Control and Prevention National Program of Cancer Registries; National Cancer Institute Surveillance Epidemiology and End Results program; Leukaemia AMP; Lymphoma Research; Association pour la Recherche contre le Cancer (ARC); Institut National du Cancer (INCa); Fondation de France; Fondation contre la Leucemie; Agence nationale de securite sanitaire de l'alimentation, de l'environnement et du travail (ANSES); Coordinated Action [006438, SP23-CT-2005-006438]; HuGeF (Human Genetics Foundation), Torino, Italy; European Commission [QLK4-CT-2000-00422, FOOD-CT-2006-023103]; Spanish Ministry of Health [CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095]; Marato de TV3 Foundation [051210]; Agencia de Gestiod' AjutsUniversitarisi de Recerca-Generalitat de Catalunya [2014SRG756]; NIH [NO1-CO-12400, CA118444, CA148690, CA92153, K08CA134919, CA167552, CA149445, CA098122, CA098566, K07 CA115687, R01 CA92153, CA186107, CA87969, CA49449, 5R01 CA69669-02, CA1046282, CA154643, HHSN261201000026C]; Compagnia di San Paolo-Programma Oncologia; Federal Office for Radiation Protection [StSch4261, StSch4420]; Jose Carreras Leukemia Foundation [DJCLS-R12/23]; German Federal Ministry for Education and Research [BMBF-01-EO-1303]; Health Research Board, Ireland; MH CZ-DRO (MMCI) [00209805]; RECAMO [CZ.1.05/2.1.00/03.0101]; Fondation de France and Association de Recherche Contre le Cancer; National Cancer Institute and Veterans Affairs Research Service; Leukemia AMP; Lymphoma Society Career Development Award; Bernstein Family Fund for Leukemia and Lymphoma Research; National Center for Advancing Translational Science [UL1 TR000135]; NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer [P50 CA97274]; Henry J. Predolin Foundation; Italian Association for Cancer Research (AIRC) [11855]; Fondazione Banco di Sardegna; Regione Autonoma della Sardegna (LR7) [CRP-59812/2012]; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; infrastructure provided by Cancer Council Victoria; Instituto de Salud Carlos III (ISCIII-Spanish Government) [CIBERESP, PI11/01810, PI14/01219, RCESP C03/09]; Agencia de Gestiod' AjutsUniversitarisi de Recerca (AGAUR)-Generalitat de Catalunya (Catalonian Government) [2014SGR756]; Center for Translational and Public Health Genomics; MSKCC-Geoffrey Beene Cancer Research Grant, Lymphoma Foundation [LF5541]; Barbara K. Lipman Lymphoma Research Fund [74419]; Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative [57470]; ENCODE; NCI-SEER-Intramural Research Program of the National Cancer Institute; Public Health Service [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105]; Australian National Health and Medical Research Council [ID990920]; Cancer Council NSW; University of Sydney Faculty of Medicine; NYU-WHS-National Cancer Institute [R01 CA098661, P30 CA016087]; National Institute of Environmental Health Sciences [ES000260]; Intramural Research Program of the National Cancer Institute; Division of Cancer Prevention; DHHS; SCALE-Swedish Cancer Society [2009/659]; Stockholm County Council [20110209]; Strategic Research Program in Epidemiology at Karolinska Institute; Swedish Cancer Society grant [02 6661]; California Department of Health Services, statewide cancer reporting program mandated by California Health and Safety Code Section [103885]; National Cancer Institute's Surveillance, Epidemiology, and End Results Program [HHSN261201000140C]; Cancer Prevention Institute of California [HHSN261201000035C]; University of Southern California [HHSN261201000034C]; Public Health Institute; Centers for Disease Control and Prevention's National Program of Cancer Registries [1U58 DP000807-01]; UTAH/Sheffield-NIH [CA134674]; Utah Population Database (UPDB); Utah Cancer Registry (UCR); Huntsman Cancer Institute (HCI); HCI Cancer Center Support grant [P30 CA42014]; National Cancer Institute SEER Program; Utah State Department of Health; University of Utah; Yorkshire Cancer Research; US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; YALE-National Cancer Institute [CA62006, CA165923]; NSFC-the National Natural Science Foundation of China [61471078]; National Heart, Lung, and Blood Institute; Canadian Cancer Society; Cancer Research UK; Cancer Research Ireland, Czech Republic; Sheffield Experimental Cancer Medicine Centre FX We thank I. Brock, K. Butterbach, A. Chabrier, D. Chan-Lam, D. Connley, H. Cramp, R. Cutting, C. Dalley, H. Dykes, A. Gabbas, P. Gaddam, P. Hui, L. Irish, L. Jacobus, S. Kaul, L. Klareskog, A. Lai, J. Lunde, M. McAdams, L. Padyukov, D. Parisi, V. Rajamanickam, T. Rattle, L. Rigacci, R. Sargent, G. Specchia, M. Stagner, P. Taylor, C. Tornow, J. WiIliams and G. Wood. The overall GWAS project was supported by the intramural programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health. ATBC-This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. In addition, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. BC-This reasearch was supported by Canadian Institutes for Health Research (CIHR), Canadian Cancer Society and Michael Smith Foundation for Health Research. CPS-II-The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples were supported by the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics. We acknowledge the contribution to this study from Central Cancer Registries supported by the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. ELCCS-This study was supported by Leukaemia & Lymphoma Research. ENGELA-This research was supported by Association pour la Recherche contre le Cancer (ARC), Institut National du Cancer (INCa), Fondation de France, Fondation contre la Leucemie, Agence nationale de securite sanitaire de l'alimentation, de l'environnement et du travail (ANSES). EPIC-This study was supported by Coordinated Action (contract no. 006438, SP23-CT-2005-006438); HuGeF (Human Genetics Foundation), Torino, Italy, and Cancer Research UK. EpiLymph-This study was supported by European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006-023103), the Spanish Ministry of Health (grant references CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10 and RTIC RD06/0020/0095), the Marato de TV3 Foundation (grant reference 051210), the Agencia de Gestiod' AjutsUniversitarisi de Recerca-Generalitat de Catalunya (grant reference 2014SRG756) who had no role in the data collection, analysis or interpretation of the results, the NIH (contract NO1-CO-12400), the Compagnia di San Paolo-Programma Oncologia, the Federal Office for Radiation Protection grants StSch4261 and StSch4420, the Jose Carreras Leukemia Foundation grant DJCLS-R12/23, the German Federal Ministry for Education and Research (BMBF-01-EO-1303), the Health Research Board, Ireland and Cancer Research Ireland, Czech Republic supported by MH CZ-DRO (MMCI, 00209805) and RECAMO, CZ.1.05/2.1.00/03.0101, and Fondation de France and Association de Recherche Contre le Cancer. GEC/Mayo GWAS-This reaearch was supported by NIH (grant numbers CA118444, CA148690 and CA92153), Intramural Research Program of the NIH, National Cancer Institute and Veterans Affairs Research Service. Data collection for Duke University was supported by a Leukemia & Lymphoma Society Career Development Award, the Bernstein Family Fund for Leukemia and Lymphoma Research, the NIH (K08CA134919) and National Center for Advancing Translational Science (UL1 TR000135).; r HPFS-HPFS was supported in part by NIH grants CA167552, CA149445, CA098122, CA098566 and K07 CA115687. We thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of these data. Iowa-Mayo SPORE-This was supported by NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer (P50 CA97274), National Cancer Institute (30 CA086862 and P30 CA15083) and Henry J. Predolin Foundation. Italian GxE-This was supported by Italian Association for Cancer Research (AIRC, Investigator Grant 11855, P. C.), Fondazione Banco di Sardegna 2010-2012 and Regione Autonoma della Sardegna (LR7 CRP-59812/2012, M.G.E.). Mayo Clinic Case-Control-It was supported by NIH (R01 CA92153) and National Cancer Institute (P30 CA015083). MCCS-The Melbourne Collaborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711, and also by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). MCC-Spain-This study is funded by The Instituto de Salud Carlos III (ISCIII-Spanish Government, PI11/01810, PI14/01219, RCESP C03/09 and CIBERESP) and the Agencia de Gestiod' AjutsUniversitarisi de Recerca (AGAUR)-Generalitat de Catalunya (Catalonian Government, 2014SGR756). Nadia Garcia and Marleny Vergara (ICO-IDIBELL) provided technical support for this study. MD Anderson provided Institutional support to the Center for Translational and Public Health Genomics. MSKCC-Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541); Barbara K. Lipman Lymphoma Research Fund (74419); Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470); U01 HG007033; ENCODE and U01 HG007033. NCI-SEER-Intramural Research Program of the National Cancer Institute, NIH, and Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010 and N02-PC-71105). NHS-The NHS was supported in part by NIH grants CA186107, CA87969, CA49449, CA149445, CA098122, CA098566 and K07 CA115687. We thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of these data. NSW-NSW was supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW and the University of Sydney Faculty of Medicine. NYU-WHS-National Cancer Institute (R01 CA098661, P30 CA016087) and National Institute of Environmental Health Sciences (ES000260). PLCO-This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. SCALE-Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institute. Swedish Cancer Society grant (02 6661). NIH (5R01 CA69669-02), Plan Denmark.; r UCSF2-The UCSF studies were supported by the NCI, NIH (CA1046282 and CA154643). The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement no. 1U58 DP000807-01 awarded to the Public Health Institute. UTAH/Sheffield-NIH CA134674. Partial support for data collection at the Utah site was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all data sets within the UPDB is provided by the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014. The UCR is supported in part by NIH contract HHSN261201000026C from the National Cancer Institute SEER Program with additional support from the Utah State Department of Health and the University of Utah. Partial support for data collection in Sheffield, UK was made possible by funds from Yorkshire Cancer Research and the Sheffield Experimental Cancer Medicine Centre. We thank the NCRI Haemato-oncology Clinical Studies Group, colleagues in the North Trent Cancer Network the North Trent Haemato-oncology Database. WHI-The investigators of WHI are as follows: Program Office (National Heart, Lung, and Blood Institute, Bethesda, MD, USA) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford and Nancy Geller; Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) Garnet Anderson, Ross Prentice, Andrea LaCroix and Charles Kooperberg; Investigators and Academic Centers (Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC, USA) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA, USA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH, USA) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ, USA) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY, USA) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL, USA) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA, USA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA, USA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker; and Women's Health Initiative Memory Study (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services by contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. YALE-National Cancer Institute (CA62006 and CA165923). Other support includes: NSFC-the National Natural Science Foundation of China (no. 61471078). NR 48 TC 7 Z9 7 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10933 DI 10.1038/ncomms10933 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0CH UT WOS:000371729200001 PM 26956414 ER PT J AU Ebrahim, S Avenarius, MR Grati, M Krey, JF Windsor, AM Sousa, AD Ballesteros, A Cui, RJ Millis, BA Salles, FT Baird, MA Davidson, MW Jones, SM Choi, D Dong, LJ Raval, MH Yengo, CM Barr-Gillespie, PG Kachar, B AF Ebrahim, Seham Avenarius, Matthew R. Grati, M'hamed Krey, Jocelyn F. Windsor, Alanna M. Sousa, Aurea D. Ballesteros, Angela Cui, Runjia Millis, Bryan A. Salles, Felipe T. Baird, Michelle A. Davidson, Michael W. Jones, Sherri M. Choi, Dongseok Dong, Lijin Raval, Manmeet H. Yengo, Christopher M. Barr-Gillespie, Peter G. Kachar, Bechara TI Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like SO NATURE COMMUNICATIONS LA English DT Article ID ACTIN-BUNDLING PROTEINS; HAIR-CELL STEREOCILIA; HEARING-LOSS; MOLECULAR ARCHITECTURE; LENGTH REGULATION; BIRD COCHLEA; INNER-EAR; IN-VIVO; FILAMENTS; MODEL AB Hair cells tightly control the dimensions of their stereocilia, which are actin-rich protrusions with graded heights that mediate mechanotransduction in the inner ear. Two members of the myosin-III family, MYO3A and MYO3B, are thought to regulate stereocilia length by transporting cargos that control actin polymerization at stereocilia tips. We show that eliminating espin-1 (ESPN-1), an isoform of ESPN and a myosin-III cargo, dramatically alters the slope of the stereocilia staircase in a subset of hair cells. Furthermore, we show that espin-like (ESPNL), primarily present in developing stereocilia, is also a myosin-III cargo and is essential for normal hearing. ESPN-1 and ESPNL each bind MYO3A and MYO3B, but differentially influence how the two motors function. Consequently, functional properties of different motor-cargo combinations differentially affect molecular transport and the length of actin protrusions. This mechanism is used by hair cells to establish the required range of stereocilia lengths within a single cell. C1 [Ebrahim, Seham; Grati, M'hamed; Windsor, Alanna M.; Sousa, Aurea D.; Ballesteros, Angela; Cui, Runjia; Millis, Bryan A.; Salles, Felipe T.; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Avenarius, Matthew R.; Krey, Jocelyn F.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Avenarius, Matthew R.; Krey, Jocelyn F.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 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. [Jones, Sherri M.] Univ Nebraska, Dept Special Educ & Commun Disorders, Lincoln, NE 68583 USA. [Choi, Dongseok] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Dong, Lijin] NEI, Genet Engn Core, NIH, Bethesda, MD 20892 USA. [Raval, Manmeet H.; Yengo, Christopher M.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. RP Kachar, B (reprint author), NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA.; Barr-Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA.; Barr-Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. EM gillespp@ohsu.edu; kacharb@nidcd.nih.gov FU University of Virginia W.M. Keck Biomedical Mass Spectrometry Lab; OHSU Proteomics Shared Resource; NIH [P30 EY010572, P30 CA069533, S10 OD012246, R01 DC002368, R01 DC011034, P30 DC005983]; NIH/NIDCD/IRP; [R01 EY018141] FX We thank David Kohrman for genetics advice and Rachel Dumont for assistance with SEM. We received support from the following core facilities: mass spectrometry from the University of Virginia W.M. Keck Biomedical Mass Spectrometry Lab and the OHSU Proteomics Shared Resource (partial support from NIH core grants P30 EY010572 and P30 CA069533; Orbitrap Fusion S10 OD012246); CRISPR-mediated mouse knockouts from OHSU Transgenic Mouse Model Shared Resource; and confocal microscopy from the OHSU Advanced Light Microscopy Core @ The Jungers Center. P.G.B.-G. was supported by NIH grants R01 DC002368, R01 DC011034 and P30 DC005983; C.M.Y. by R01 EY018141, and B.K. by NIH/NIDCD/IRP. NR 61 TC 4 Z9 4 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10833 DI 10.1038/ncomms10833 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF9SC UT WOS:000371700400001 PM 26926603 ER PT J AU Gomez-Rodriguez, J Meylan, F Handon, R Hayes, ET Anderson, SM Kirby, MR Siegel, RM Schwartzberg, PL AF Gomez-Rodriguez, Julio Meylan, Francoise Handon, Robin Hayes, Erika T. Anderson, Stacie M. Kirby, Martha R. Siegel, Richard M. Schwartzberg, Pamela L. TI Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4 SO NATURE COMMUNICATIONS LA English DT Article ID T-CELL-RECEPTOR; ALLERGIC AIRWAY INFLAMMATION; TEC FAMILY KINASES; LUNG INFLAMMATION; TGF-BETA; NFATC TRANSLOCATION; MICE LACKING; T(H)9 CELLS; IFN-GAMMA; EXPRESSION AB Th9 cells produce interleukin (IL)-9, a cytokine implicated in allergic asthma and autoimmunity. Here we show that Itk, a mediator of T cell receptor signalling required for Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation. In a model of allergic lung disease, Itk-deficient mice show reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, Itk(-/-) CD4(+) T cells do not produce IL-9 and have reduced levels of IRF4 (Interferon Regulator Factor 4), a critical transcription factor for effector T cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or constitutively active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, demonstrating one mechanism by which IL-2 rescues weakly activated T cells. Itk inhibition also reduces IL-9 expression by human T cells, implicating ITK as a key regulator of Th9 induction. C1 [Gomez-Rodriguez, Julio; Handon, Robin; Anderson, Stacie M.; Kirby, Martha R.; Schwartzberg, Pamela L.] NHGRI, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. [Meylan, Francoise; Hayes, Erika T.; Siegel, Richard M.] NIAMSD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Gomez-Rodriguez, J (reprint author), NHGRI, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM jrgomez@mail.nih.gov; pams@mail.nih.gov FU intramural program of NHGRI; intramural program of NIAMS FX We thank J. Reilley and N. Richoz for technical assistance, J. Fekecs for help with graphics and J. Zhu for reading the manuscript. This work was supported by the intramural programs of NHGRI and NIAMS. NR 70 TC 7 Z9 7 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10857 DI 10.1038/ncomms10857 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF9WF UT WOS:000371712200001 PM 26936133 ER PT J AU Grabundzija, I Messing, SA Thomas, J Cosby, RL Bilic, I Miskey, C Gogol-Doring, A Kapitonov, V Diem, T Dalda, A Jurka, J Pritham, EJ Dyda, F Izsvak, Z Ivics, Z AF Grabundzija, Ivana Messing, Simon A. Thomas, Jainy Cosby, Rachel L. Bilic, Ilija Miskey, Csaba Gogol-Doering, Andreas Kapitonov, Vladimir Diem, Tanja Dalda, Anna Jurka, Jerzy Pritham, Ellen J. Dyda, Fred Izsvak, Zsuzsanna Ivics, Zoltan TI A Helitron transposon reconstructed from bats reveals a novel mechanism of genome shuffling in eukaryotes SO NATURE COMMUNICATIONS LA English DT Article ID ROLLING-CIRCLE TRANSPOSONS; SUPERCOILING IN-VIVO; SINGLE-STRANDED-DNA; MAIZE GENOME; GENE; REPLICATION; EVOLUTION; ELEMENTS; TRANSCRIPTION; FAMILY AB Helitron transposons capture and mobilize gene fragments in eukaryotes, but experimental evidence for their transposition is lacking in the absence of an isolated active element. Here we reconstruct Helraiser, an ancient element from the bat genome, and use this transposon as an experimental tool to unravel the mechanism of Helitron transposition. A hairpin close to the 3'-end of the transposon functions as a transposition terminator. However, the 3'-end can be bypassed by the transposase, resulting in transduction of flanking sequences to new genomic locations. Helraiser transposition generates covalently closed circular intermediates, suggestive of a replicative transposition mechanism, which provides a powerful means to disseminate captured transcriptional regulatory signals across the genome. Indeed, we document the generation of novel transcripts by Helitron promoter capture both experimentally and by transcriptome analysis in bats. Our results provide mechanistic insight into Helitron transposition, and its impact on diversification of gene function by genome shuffling. C1 [Grabundzija, Ivana; Bilic, Ilija; Dalda, Anna; Izsvak, Zsuzsanna] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Grabundzija, Ivana; Messing, Simon A.; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Thomas, Jainy; Cosby, Rachel L.; Pritham, Ellen J.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Miskey, Csaba; Diem, Tanja; Ivics, Zoltan] Paul Ehrlich Inst, Div Med Biotechnol, D-63225 Langen, Germany. [Gogol-Doering, Andreas] German Ctr Integrat Biodivers Res iDiv, D-04103 Halle Jena Leipzig, Germany. [Gogol-Doering, Andreas] Univ Halle Wittenberg, Inst Comp Sci, D-06099 Halle, Germany. [Kapitonov, Vladimir; Jurka, Jerzy] Genet Informat Res Inst, Los Altos, CA 94022 USA. RP Ivics, Z (reprint author), Paul Ehrlich Inst, Div Med Biotechnol, D-63225 Langen, Germany. EM zoltan.ivics@pei.de OI Izsvak, Zsuzsanna/0000-0002-2053-2384 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Dieseases, NIH, Bethesda MD, USA FX We are grateful to T. Rasko and A. Szvetnik for their technical assistance in some of the experiments, A. Hickman for invaluable advice and help in writing the manuscript, and C. Feschotte and L. Hurst for critically reading the manuscript. This research was partially funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Dieseases, NIH, Bethesda MD, USA. NR 51 TC 5 Z9 5 U1 5 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10716 DI 10.1038/ncomms10716 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF9UY UT WOS:000371708600001 PM 26931494 ER PT J AU Gu, XL Mao, X Lussier, MP Hutchison, MA Zhou, L Hamra, FK Roche, KW Lu, W AF Gu, Xinglong Mao, Xia Lussier, Marc P. Hutchison, Mary Anne Zhou, Liang Hamra, F. Kent Roche, Katherine W. Lu, Wei TI GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons SO NATURE COMMUNICATIONS LA English DT Article ID TRANSMEMBRANE AUXILIARY SUBUNITS; CALCIUM-PERMEABLE AMPARS; LONG-TERM POTENTIATION; 2 DISTINCT MECHANISMS; GLUTAMATE RECEPTORS; CORNICHON PROTEINS; TOPOLOGY PREDICTION; STEM-CELLS; TRAFFICKING; PLASTICITY AB Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity. In the brain, AMPARs assemble with a number of auxiliary subunits, including TARPs, CNIHs and CKAMP44, which are important for AMPAR forward trafficking to synapses. Here we report that the membrane protein GSG1L negatively regulates AMPAR-mediated synaptic transmission. Overexpression of GSG1L strongly suppresses, and GSG1L knockout (KO) enhances, AMPAR-mediated synaptic transmission. GSG1L-dependent regulation of AMPAR synaptic transmission relies on the first extracellular loop domain and its carboxyl-terminus. GSG1L also speeds up AMPAR deactivation and desensitization in hippocampal CA1 neurons, in contrast to the effects of TARPs and CNIHs. Furthermore, GSG1L association with AMPARs inhibits CNIH2-induced slowing of the receptors in heterologous cells. Finally, GSG1L KO rats have deficits in LTP and show behavioural abnormalities in object recognition tests. These data demonstrate that GSG1L represents a new class of auxiliary subunit with distinct functional properties for AMPARs. C1 [Gu, Xinglong; Mao, Xia; Hutchison, Mary Anne; Zhou, Liang; Lu, Wei] NINDS, Synapse & Neural Circuit Res Unit, NIH, 35 Convent Dr,3C1000, Bethesda, MD 20892 USA. [Lussier, Marc P.; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, 35 Convent Dr,32C903, Bethesda, MD 20892 USA. [Hamra, F. Kent] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA. [Lussier, Marc P.] Univ Quebec, Dept Chim, Montreal, PQ H3C 3P8, Canada. RP Lu, W (reprint author), NINDS, Synapse & Neural Circuit Res Unit, NIH, 35 Convent Dr,3C1000, Bethesda, MD 20892 USA. EM luw4@mail.nih.gov RI gu, xinglong/A-3054-2011; OI gu, xinglong/0000-0002-0437-5606; Roche, Katherine/0000-0001-7282-6539 FU NINDS Intramural Research Program; National Center for Research Resources [R24RR03232601]; [R24OD011108] FX We thank Dr Tianyi Wang at the University of Pittsburgh for the Claudin1 plasmid. We also appreciate Dr Bernd Fakler at the University of Freiburg, Germany for sharing the GSG1L data from his lab with us. We are grateful to Drs Jeffrey Diamond and Mark Mayer for critical comments on the manuscript. This work was supported by the NINDS Intramural Research Program (W.L. and K.W.R.). Gsg1l mutant rats were produced by the NIH Mutant Rat Resource at UT Southwestern Medical Center in Dallas under grants from the National Center for Research Resources, R24RR03232601 and the Office of the Director, R24OD011108 to F.K.H. NR 70 TC 2 Z9 2 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10873 DI 10.1038/ncomms10873 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF9VL UT WOS:000371710000001 PM 26932439 ER PT J AU Lee, S Chang, J Blackstone, C AF Lee, Seongju Chang, Jaerak Blackstone, Craig TI FAM21 directs SNX27-retromer cargoes to the plasma membrane by preventing transport to the Golgi apparatus SO NATURE COMMUNICATIONS LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; WASH COMPLEX; RETROGRADE TRANSPORT; ARP2/3 ACTIVATOR; PARKINSON DISEASE; RETROMER COMPLEX; PROTEIN; ENDOSOME; GENE; TRAFFICKING AB The endosomal network maintains cellular homeostasis by sorting, recycling and degrading endocytosed cargoes. Retromer organizes the endosomal sorting pathway in conjunction with various sorting nexin (SNX) proteins. The SNX27-retromer complex has recently been identified as a major endosomal hub that regulates endosome-to-plasma membrane recycling by preventing lysosomal entry of cargoes. Here, we show that SNX27 directly interacts with FAM21, which also binds retromer, within the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex. This interaction is required for the precise localization of SNX27 at an endosomal subdomain as well as for recycling of SNX27-retromer cargoes. Furthermore, FAM21 prevents cargo transport to the Golgi apparatus by controlling levels of phosphatidylinositol 4-phosphate, which facilitates cargo dissociation at the Golgi. Together, our results demonstrate that the SNX27-retromer-WASH complex directs cargoes to the plasma membrane by blocking their transport to lysosomes and the Golgi. C1 [Lee, Seongju; Chang, Jaerak; Blackstone, Craig] NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Chang, Jaerak] Ajou Univ, Sch Med, Dept Biomed Sci, Suwon 443380, South Korea. [Chang, Jaerak] Ajou Univ, Sch Med, Dept Brain Sci, Suwon 443380, South Korea. [Chang, Jaerak] Ajou Univ, Sch Med, Grad Program Neurosci, Suwon 443380, South Korea. RP Blackstone, C (reprint author), NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. Ethan Tyler (NIH Medical Arts Branch) provided artistic assistance. NR 54 TC 6 Z9 6 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10939 DI 10.1038/ncomms10939 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0CK UT WOS:000371729500001 PM 26956659 ER PT J AU Meyer, PA Socias, S Key, J Ransey, E Tjon, EC Buschiazzo, A Lei, M Botka, C Withrow, J Neau, D Rajashankar, K Anderson, KS Baxter, RH Blacklow, SC Boggon, TJ Bonvin, AMJJ Borek, D Brett, TJ Caflisch, A Chang, CI Chazin, WJ Corbett, KD Cosgrove, MS Crosson, S Dhe-Paganon, S Di Cera, E Drennan, CL Eck, MJ Eichman, BF Fan, QR Ferre-D'Amare, AR Fromme, JC Garcia, KC Gaudet, R Gong, P Harrison, SC Heldwein, EE Jia, ZC Keenan, RJ Kruse, AC Kvansakul, M McLellan, JS Modis, Y Nam, Y Otwinowski, Z Pai, EF Pereira, PJB Petosa, C Raman, S Rapoport, TA Roll-Mecak, A Rosen, MK Rudenko, G Schlessinger, J Schwartz, TU Shamoo, Y Sondermann, H Tao, YZJ Tolia, NH Tsodikov, OV Westover, KD Wu, H Foster, I Fraser, JS Maia, FRNC Gonen, T Kirchhausen, T Diederichs, K Crosas, M Sliz, P AF Meyer, Peter A. Socias, Stephanie Key, Jason Ransey, Elizabeth Tjon, Emily C. Buschiazzo, Alejandro Lei, Ming Botka, Chris Withrow, James Neau, David Rajashankar, Kanagalaghatta Anderson, Karen S. Baxter, Richard H. Blacklow, Stephen C. Boggon, Titus J. Bonvin, Alexandre M. J. J. Borek, Dominika Brett, Tom J. Caflisch, Amedeo Chang, Chung-I Chazin, Walter J. Corbett, Kevin D. Cosgrove, Michael S. Crosson, Sean Dhe-Paganon, Sirano Di Cera, Enrico Drennan, Catherine L. Eck, Michael J. Eichman, Brandt F. Fan, Qing R. Ferre-D'Amare, Adrian R. Fromme, J. Christopher Garcia, K. Christopher Gaudet, Rachelle Gong, Peng Harrison, Stephen C. Heldwein, Ekaterina E. Jia, Zongchao Keenan, Robert J. Kruse, Andrew C. Kvansakul, Marc McLellan, Jason S. Modis, Yorgo Nam, Yunsun Otwinowski, Zbyszek Pai, Emil F. Barbosa Pereira, Pedro Jose Petosa, Carlo Raman, S. Rapoport, Tom A. Roll-Mecak, Antonina Rosen, Michael K. Rudenko, Gabby Schlessinger, Joseph Schwartz, Thomas U. Shamoo, Yousif Sondermann, Holger Tao, Yizhi J. Tolia, Niraj H. Tsodikov, Oleg V. Westover, Kenneth D. Wu, Hao Foster, Ian Fraser, James S. Maia, Filipe R. N. C. Gonen, Tamir Kirchhausen, Tom Diederichs, Kay Crosas, Merce Sliz, Piotr TI Data publication with the structural biology data grid supports live analysis SO NATURE COMMUNICATIONS LA English DT Article ID X-RAY SCATTERING; PROTEIN DATA-BANK; MACROMOLECULAR CRYSTALLOGRAPHY; STRUCTURE MODELS; DATA QUALITY; SYNCHROTRON; SOFTWARE; SCIENCE; EXPERIENCES; RESOLUTION AB Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data. sbgrid. org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis. C1 [Meyer, Peter A.; Socias, Stephanie; Key, Jason; Ransey, Elizabeth; Tjon, Emily C.; Blacklow, Stephen C.; Eck, Michael J.; Harrison, Stephen C.; Kruse, Andrew C.; Wu, Hao; Sliz, Piotr] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Buschiazzo, Alejandro] Inst Pasteur Montevideo, Lab Mol & Struct Microbiol, Montevideo 11400, Uruguay. [Buschiazzo, Alejandro] Inst Pasteur, Dept Biol Struct & Chem, F-75015 Paris, France. [Lei, Ming] Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. [Botka, Chris] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Withrow, James; Neau, David; Rajashankar, Kanagalaghatta] Cornell Univ, Argonne Natl Lab, NE CAT, Bldg 436E,9700S Cass Ave, Argonne, IL 60439 USA. [Withrow, James; Neau, David; Rajashankar, Kanagalaghatta] Cornell Univ, Argonne Natl Lab, Dept Chem & Chem Biol, Bldg 436E,9700S Cass Ave, Argonne, IL 60439 USA. [Anderson, Karen S.; Boggon, Titus J.] Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 USA. [Anderson, Karen S.; Baxter, Richard H.; Boggon, Titus J.] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, 333 Cedar St, New Haven, CT 06520 USA. [Baxter, Richard H.] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA. [Bonvin, Alexandre M. J. J.] Univ Utrecht, Bijvoet Ctr, Fac Sci, NL-3584 CH Utrecht, Netherlands. [Borek, Dominika; Otwinowski, Zbyszek] Univ Texas SW Med Ctr Dallas, Dept Biophys & Biochem, Dallas, TX 75390 USA. [Brett, Tom J.] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Caflisch, Amedeo] Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland. [Chang, Chung-I] Acad Sinica, Inst Biol Chem, Taipei 11529, Taiwan. [Chazin, Walter J.] Vanderbilt Univ, Dept Biochem, Struct Biol Ctr, Nashville, TN 37232 USA. [Chazin, Walter J.] Vanderbilt Univ, Dept Chem, Struct Biol Ctr, Nashville, TN 37232 USA. [Corbett, Kevin D.] Ludwig Inst Canc Res, San Diego Branch, La Jolla, CA 92093 USA. [Corbett, Kevin D.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Cosgrove, Michael S.] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA. [Crosson, Sean; Keenan, Robert J.] Univ Chicago, Dept Biochem & Mol Biol, 920 E 58Th St, Chicago, IL 60637 USA. [Dhe-Paganon, Sirano; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Di Cera, Enrico] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA. [Drennan, Catherine L.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Drennan, Catherine L.] MIT, Dept Biol, Cambridge, MA 02139 USA. MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Eichman, Brandt F.] Vanderbilt Univ, Dept Biol, Nashville, TN 37235 USA. [Eichman, Brandt F.] Vanderbilt Univ, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Fan, Qing R.] Columbia Univ, Dept Pharmacol, New York, NY 10032 USA. [Fan, Qing R.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Ferre-D'Amare, Adrian R.] NHLBI, Lab RNA Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fromme, J. Christopher] Cornell Univ, Dept Mol Biol & Genet, Weill Inst Cell & Mol Biol, Ithaca, NY 14853 USA. [Garcia, K. Christopher] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. [Garcia, K. Christopher] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA. [Garcia, K. Christopher] Stanford Univ, Dept Biol Struct, Sch Med, Stanford, CA 94305 USA. [Gaudet, Rachelle] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Gong, Peng] Chinese Acad Sci, Key Lab Special Pathogens & Biosafety, Wuhan Inst Virol, Wuhan 430071, Peoples R China. [Harrison, Stephen C.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Harrison, Stephen C.] Harvard Univ, Mol Med Lab, Boston Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Heldwein, Ekaterina E.] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Jia, Zongchao] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON K7M 3G5, Canada. [Kvansakul, Marc] La Trobe Univ, Dept Biochem & Genet, Melbourne, Vic, Australia. [McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH 03755 USA. [Modis, Yorgo] Univ Cambridge, Dept Med, MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England. [Nam, Yunsun] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Pai, Emil F.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Pai, Emil F.] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8, Canada. [Pai, Emil F.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Pai, Emil F.] Univ Hlth Network, Ontario Canc Inst, Campbell Family Inst Canc Res, Toronto, ON M5G 2M9, Canada. [Barbosa Pereira, Pedro Jose] Univ Porto, Inst Biol Mol & Celular, P-4150 Oporto, Portugal. [Barbosa Pereira, Pedro Jose] Univ Porto, Inst Invest & Inovacao Saude, P-4150 Oporto, Portugal. [Petosa, Carlo] Univ Grenoble Alpes, CNRS, CFA, Inst Biol Struct, F-38027 Grenoble, France. [Raman, S.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Rapoport, Tom A.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Rapoport, Tom A.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Roll-Mecak, Antonina] Natl Inst Neurol Disorders & Stroke, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Roll-Mecak, Antonina] NHLBI, Bethesda, MD 20892 USA. [Rosen, Michael K.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Rosen, Michael K.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Rudenko, Gabby] Univ Texas Med Branch, Dept Pharmacol & Toxicol, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA. [Schlessinger, Joseph] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Schwartz, Thomas U.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Shamoo, Yousif; Tao, Yizhi J.] Rice Univ, Dept Biosci, Houston, TX 77005 USA. [Sondermann, Holger] Cornell Univ, Dept Mol Med, Coll Vet Med, Ithaca, NY 14853 USA. [Tolia, Niraj H.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Tsodikov, Oleg V.] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA. [Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Westover, Kenneth D.] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Wu, Hao; Kirchhausen, Tom] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Foster, Ian] Argonne Natl Lab, Math & Comp Sci Div, 9700 S Cass Ave, Argonne, IL 60439 USA. [Foster, Ian] Univ Chicago, Dept Comp Sci, Chicago, IL 60637 USA. [Fraser, James S.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA. [Maia, Filipe R. N. C.] Uppsala Univ, Lab Mol Biophys, Dept Cell & Mol Biol, Husargatan 3,Box 596, SE-75124 Uppsala, Sweden. [Maia, Filipe R. N. C.] Lawrence Berkeley Natl Lab, NERSC, Berkeley, CA 94720 USA. [Gonen, Tamir] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Kirchhausen, Tom] Boston Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. [Kirchhausen, Tom] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kirchhausen, Tom] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Diederichs, Kay] Univ Konstanz, Dept Biol, D-78457 Constance, Germany. [Crosas, Merce] Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. RP Sliz, P (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM sliz@hkl.hms.harvard.edu RI Bonvin, Alexandre/A-5420-2009; Borek, Dominika/D-2943-2011; Pereira, Pedro/F-8972-2011; OI Bonvin, Alexandre/0000-0001-7369-1322; Gaudet, Rachelle/0000-0002-9177-054X; Borek, Dominika/0000-0002-4321-6253; Pereira, Pedro/0000-0003-0969-5438; Corbett, Kevin/0000-0001-5854-2388; Modis, Yorgo/0000-0002-6084-0429; Fraser, James/0000-0002-5080-2859; Pai, Emil/0000-0002-1162-7242; Kvansakul, Marc/0000-0003-2639-2498 FU Leona M. and Harry B. Helmsley Charitable Trust [2016PG-BRI002]; NSF [1448069]; NIH [P41 GM103403, 1S10RR028832, 1U54EB020406-01]; DOE [DE-AC02-06CH11357]; NIST [60NANB15D077] FX Development of the Structural Biology Data Grid is funded by The Leona M. and Harry B. Helmsley Charitable Trust 2016PG-BRI002 to PS and MC. Development of citation workflows is supported NSF 1448069 (to PS). DAA is being developed as a pilot project of the National Data Service, with additional funds to support storage and technology development, including NIH P41 GM103403 (NE-CAT) and 1S10RR028832 (HMS) and DOE DE-AC02-06CH11357; NIH 1U54EB020406-01, Big Data for Discovery Science Center; and NIST 60NANB15D077 (Globus Project). AB acknowledges Ariel Chaparro for assistance with the DAA setup (Inst Pasteur Montevideo). Collections of pilot data sets were supported by various grants (see Supplementary Table 1). NR 52 TC 12 Z9 12 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10882 DI 10.1038/ncomms10882 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF9YS UT WOS:000371719200001 PM 26947396 ER PT J AU Kaufman, AR Koblitz, AR Persoskie, A Ferrer, RA Klein, WMP Dwyer, LA Park, ER AF Kaufman, Annette R. Koblitz, Amber R. Persoskie, Alexander Ferrer, Rebecca A. Klein, William M. P. Dwyer, Laura A. Park, Elyse R. TI Factor Structure and Stability of Smoking-Related Health Beliefs in the National Lung Screening Trial SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID CANCER-RISK PERCEPTIONS; QUIT SMOKING; SMOKERS; SUSCEPTIBILITY; INTENTIONS; BEHAVIOR; WOMEN; WORRY; PARTICIPANTS; ASSOCIATION AB Absolute and comparative risk perceptions, worry, perceived severity, perceived benefits, and self-efficacy are important theoretical determinants of tobacco use, but no measures have been validated to ensure the discriminant validity as well as test-retest reliability of these measures in the tobacco context. The purpose of the current study is to examine the reliability and factor structure of a measure assessing smoking-related health cognitions and emotions in a national sample of current and former heavy smokers in the National Lung Screening Trial. A sub-study of the National Lung Screening Trial assessed current and former smokers' (age 55-74; N = 4379) self-reported health cognitions and emotions at trial enrollment and at 12-month follow-up. Items were derived from the Health Belief Model and Self-Regulation Model. An exploratory factor analysis of baseline responses revealed a five-factor structure for former smokers (risk perceptions, worry, perceived severity, perceived benefits, and self-efficacy) and a six-factor structure for current smokers, such that absolute risk and comparative risk perceptions emerged as separate factors. A confirmatory factor analysis of 12-month follow-up responses revealed a good fit for the five latent constructs for former smokers and six latent constructs for current smokers. Longitudinal stability of these constructs was also demonstrated. This is the first study to examine tobacco-related health cognition and emotional constructs over time in current and former heavy smokers undergoing lung screening. This study found that the theoretical constructs were stable across time and that the factor structure differed based on smoking status (current vs. former). C1 [Kaufman, Annette R.] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Koblitz, Amber R.; Persoskie, Alexander; Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Ferrer, Rebecca A.] NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Dwyer, Laura A.] NCI, Hlth Behav Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Park, Elyse R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Park, Elyse R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Kaufman, AR (reprint author), Natl Canc Inst, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,3-E-546, Rockville, MD 20850 USA. EM kaufmana@mail.nih.gov FU American Cancer Society Mentored Research Scholar Award [MRSG-005-05-CPPB]; National Cancer Institute [U01 CA079778, U01 CA080098] FX This work was funded by an American Cancer Society Mentored Research Scholar Award (MRSG-005-05-CPPB) to ERP, and the American College of Radiology Imaging Network (ACRIN) received funding from the National Cancer Institute through the grants U01 CA079778 and U01 CA080098. NR 50 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAR PY 2016 VL 18 IS 3 BP 321 EP 329 DI 10.1093/ntr/ntv091 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DF8HP UT WOS:000371598600013 PM 25964503 ER PT J AU Browning, B Page, KE Kuhn, RL DiLiberto, MA Deschenes, J Taillie, E Tomanio, E Holubkov, R Dean, JM Moler, FW Meert, K Pemberton, VL AF Browning, Brittan Page, Kent E. Kuhn, Renee L. DiLiberto, Mary Ann Deschenes, Jendar Taillie, Eileen Tomanio, Elyse Holubkov, Richard Dean, J. Michael Moler, Frank W. Meert, Kathleen Pemberton, Victoria L. TI Nurses' Attitudes Toward Clinical Research: Experience of the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE heart arrest; perceptions; research; pediatrics; nurses ID RANDOMIZED CONTROLLED-TRIALS; CARE; CHILDREN; INFANTS; PARENTS; ENCEPHALOPATHY; PHYSICIANS AB Objectives: To understand factors affecting nurses' attitudes toward the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials and association with approach/consent rates. Design: Cross-sectional survey of pediatric/cardiac intensive care nurses' perceptions of the trials. Setting: Study was conducted at 16 of 38 self-selected study sites. Subjects: Pediatric and cardiac intensive care nurses. Measurements and Main Results: The primary outcome was the proportion of nurses with positive perceptions, as defined by agree or strongly agree with the statement "I am happy to take care of a Therapeutic Hypothermia after Pediatric Cardiac Arrest patient". Associations between perceptions and study approach/consent rates were also explored. Of 2,241 nurses invited, 1,387 (62%) completed the survey and 77% reported positive perceptions of the trials. Nurses, who felt positively about the scientific question, the study team, and training received, were more likely to have positive perceptions of the trials (p < 0.001). Nurses who had previously cared for a research patient had significantly more positive perceptions of Therapeutic Hypothermia After Pediatric Cardiac Arrest compared with those who had not (79% vs 54%; p < 0.001). Of the 754 nurses who cared for a Therapeutic Hypothermia After Pediatric Cardiac Arrest patient, 82% had positive perceptions, despite 86% reporting it required more work. Sixty-nine percent believed that hypothermia reduces brain injury and mortality; sites had lower consent rates when their nurses believed that hypothermia was beneficial. Institution-specific approach rates were positively correlated with nurses' perceptions of institutional support for the trial (r = 0.54; p = 0.04), ICU support (r = 0.61; p = 0.02), and the importance of conducting the trial in children (r = 0.61; p = 0.01). Conclusions: The majority of nurses had positive perceptions of the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials. Institutional, colleague, and study team support and training were contributing factors. Despite increased work, nurses remained enthusiastic demonstrating that studies with intensive bedside nursing procedures are feasible. Institutions whose nurses believed hypothermia was beneficial had lower consent rates, suggesting that educating nurses on study rationale and equipoise may enhance study participation. C1 [Browning, Brittan] Univ Utah, Salt Lake City, UT USA. [Page, Kent E.; Kuhn, Renee L.; Holubkov, Richard; Dean, J. Michael] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [DiLiberto, Mary Ann] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. [Deschenes, Jendar] Univ Arizona, Dept Pediat, Tucson, AZ 85721 USA. [Taillie, Eileen] Univ Rochester, Med Ctr, Golisano Childrens Hosp, Dept Pediat, Rochester, NY 14642 USA. [Tomanio, Elyse] Childrens Natl Med Ctr, Dept Crit Care, Washington, DC 20010 USA. [Moler, Frank W.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Meert, Kathleen] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Pemberton, Victoria L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. RP Browning, B (reprint author), Univ Utah, Salt Lake City, UT USA. EM Brittan.browning@hsc.utah.edu FU National Institutes of Health (NIH); NIH; NHLBI; Pfizer; St. Jude Medical Inc.; Fibrocell Inc; NIH/NHLBI FX Dr. Browning received support for article research from the National Institutes of Health (NIH). Dr. Page received support for article research from the NIH. Dr. Kuhn received support for article research from the NIH. Her institution received financial support from the NHLBI. Dr. Tallie received support for article research from the NIH. Dr. Holubkov received financial support from Pfizer (consulting fees for DSMB membership), St. Jude Medical Inc. (biostatistical consulting), and Fibrocell Inc (DSMB member). He disclosed that he is also a biostatistical consultant for Physicians' Committee for Responsible Medicine, a nonprofit in Washington, D.C. He received support for article research from the NIH. His institution received financial support from the NIH/NHLBI (this grant gave salary support to Dr. Holubkov as well as general support to the Coordinating Center). Dr. Dean received support for article research from the NIH. His institution received financial support from the NHLBI. Dr. Moler received support for article research from the NIH. His institution received financial support from the NIH/NHLBI (U01 awards to University of Michigan and University of Utah). Dr. Meert received support for article research from the NIH. Her institution received financial support from the NIH. Dr. Pemberton received support for article research from the Government. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 24 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD MAR PY 2016 VL 17 IS 3 BP e121 EP e129 DI 10.1097/PCC.0000000000000609 PG 9 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA DG0ID UT WOS:000371747600004 PM 26669643 ER PT J AU Bishop, SL Thurm, A Farmer, C Lord, C AF Bishop, Somer L. Thurm, Audrey Farmer, Cristan Lord, Catherine TI Autism Spectrum Disorder, Intellectual Disability, and Delayed Walking SO PEDIATRICS LA English DT Article ID MOTOR DEVELOPMENT; DIAGNOSTIC INTERVIEW; MENTAL-RETARDATION; CHILDREN; INDIVIDUALS; INFANTS; AGE; POPULATION; PHENOTYPES; RISK AB OBJECTIVE: Delayed onset of independent walking is common in intellectual disability (ID). However, in children with autism spectrum disorders (ASD), delayed walking has not been reported as frequently, despite the high rate of concurrent ID in ASD. This study directly examined the relationship between delayed walking and severity of ID in children with ASD versus other non-ASD diagnoses. METHOD Participants were 1185 individuals (ASD, n = 903; non-ASD, n = 282) who received an assessment at age 4 to 12 years (6.89 +/- 2.25) that yielded an estimate of nonverbal IQ (NVIQ) and retrospectively reported age of walking from the Autism Diagnostic Interview-Revised. The relationship between diagnostic group and delayed walking (defined as occurring at >= 16 months) as a function of NVIQ was explored using the Cox proportional hazards model. RESULTS: Children with ASD were less likely to exhibit delayed walking than those with non-ASD diagnoses, and this difference was larger at lower levels of NVIQ (P =.002). For example, rates of delayed walking for ASD and non-ASD were 13% and 19%, respectively, in those with NVIQ > 85 but 31% and 60% in children with NVIQ < 70. CONCLUSIONS: Although lower IQ scores were associated with increased rates of late walking in both ASD and non-ASD groups, children with low IQ were more likely to show delayed walking in the absence of ASD. This raises the possibility of separate etiological pathways to ID in children with and without ASD. C1 [Bishop, Somer L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Thurm, Audrey; Farmer, Cristan] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Lord, Catherine] Weill Cornell Med Coll, New York, NY USA. RP Bishop, SL (reprint author), 401 Parnassus Ave, San Francisco, CA 94143 USA. EM somer.bishop@ucsf.edu FU Health Resources and Services Administration (HRSA) [R40MC28145]; National Institute of Child Health and Human Development (NICHD) [R01HD065277]; National Institute of Mental Health [R01MH081873-01A1, R01-MH066496]; NICHD [U19-HD 35482] FX This project was supported by grants from the Health Resources and Services Administration (HRSA; R40MC28145) and National Institute of Child Health and Human Development (NICHD; R01HD065277) to Dr Bishop and the National Institute of Mental Health (R01MH081873-01A1 and R01-MH066496) and NICHD (U19-HD 35482) to Dr Lord. NR 42 TC 1 Z9 1 U1 2 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2016 VL 137 IS 3 AR e20152959 DI 10.1542/peds.2015-2959 PG 8 WC Pediatrics SC Pediatrics GA DF5MK UT WOS:000371395800038 PM 26908679 ER PT J AU Reigstad, MM Larsen, IK Myklebust, TA Robsahm, TE Oldereid, NB Brinton, LA Storeng, R AF Reigstad, Marte Myhre Larsen, Inger Kristin Myklebust, Tor Age Robsahm, Trude Eid Oldereid, Nan Birgitte Brinton, Louise A. Storeng, Ritsa TI Risk of Cancer in Children Conceived by Assisted Reproductive Technology SO PEDIATRICS LA English DT Article ID IN-VITRO FERTILIZATION; POPULATION-BASED COHORT; CHILDHOOD-CANCER; INFERTILITY TREATMENT; ACUTE-LEUKEMIA; FERTILITY PROBLEMS; NATIONWIDE COHORT; ONCOLOGY GROUP; BIRTH-DEFECTS; PARENTAL AGE AB BACKGROUND AND OBJECTIVE: An increasing number of children are born after assisted reproductive technology (ART), and monitoring their long-term health effects is of interest. This study compares cancer risk in children conceived by ART to that in children conceived without. METHODS: The Medical Birth Registry of Norway contains individual information on all children born in Norway (including information of ART conceptions). All children born between 1984 and 2011 constituted the study cohort, and cancer data were obtained from the Cancer Registry of Norway. Follow-up started at date of birth and ended on the date of the first cancer diagnosis, death, emigration, or December 31, 2011. A Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of overall cancer risk between children conceived by ART and those not. Cancer risk was also assessed separately for all childhood cancer types. RESULTS: The study cohort comprised 1 628 658 children, of which 25 782 were conceived by ART. Of the total 4554 cancers, 51 occurred in ART-conceived children. Risk of overall cancer was not significantly elevated (HR 1.21; 95% CI 0.90-1.63). However, increased risk of leukemia was observed for children conceived by ART compared with those who were not (HR 1.67; 95% CI 1.02-2.73). Elevated risk of Hodgkin's lymphoma was also found for ART-conceived children (HR 3.63; 95% CI 1.12-11.72), although this was based on small numbers. CONCLUSIONS: This population-based cohort study found elevated risks of leukemia and Hodgkin's lymphoma in children conceived by ART. C1 [Reigstad, Marte Myhre; Storeng, Ritsa] Natl Hosp Norway, Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, POB 4950 Nydalen, N-0424 Oslo, Norway. [Oldereid, Nan Birgitte] Natl Hosp Norway, Oslo Univ Hosp, Dept Gynecol, Sect Reprod Med, N-0424 Oslo, Norway. [Reigstad, Marte Myhre; Larsen, Inger Kristin; Myklebust, Tor Age; Robsahm, Trude Eid] Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway. [Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. RP Reigstad, MM (reprint author), Natl Hosp Norway, Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, POB 4950 Nydalen, N-0424 Oslo, Norway. EM martereigstad@gmail.com FU Intramural NIH HHS [Z01 CP010128-12] NR 63 TC 3 Z9 3 U1 3 U2 8 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2016 VL 137 IS 3 AR e20152061 DI 10.1542/peds.2015-2061 PG 12 WC Pediatrics SC Pediatrics GA DF5MK UT WOS:000371395800020 PM 26908669 ER PT J AU Nakato, G Hase, K Sato, T Kimura, S Sakakibara, S Sugiyama, M Obata, Y Hanazato, M Iwanaga, T Ohno, H AF Nakato, Gaku Hase, Koji Sato, Takao Kimura, Shunsuke Sakakibara, Sayuri Sugiyama, Machiko Obata, Yuuki Hanazato, Misaho Iwanaga, Toshihiko Ohno, Hiroshi TI Epithelium-Intrinsic MicroRNAs Contribute to Mucosal Immune Homeostasis by Promoting M-Cell Maturation SO PLOS ONE LA English DT Article ID FOLLICLE-ASSOCIATED EPITHELIUM; INTESTINAL M-CELLS; PEYERS-PATCHES; SPI-B; DIFFERENTIATION; DICER; EXPRESSION; RECEPTOR; PROTEIN; ABSENCE AB cells in the follicle-associated epithelium (FAE) of Peyer's patches (PPs) serve as a main portal for external antigens and function as a sentinel in mucosal immune responses. The scarcity of these cells has hampered identification of M cell-specific molecules. Recent efforts have begun to provide insight into antigen transcytosis and differentiation of M cells; however, the molecular mechanisms underlying these processes are not fully elucidated. Small non-coding RNAs including microRNA (miRNA) have been reported to regulate gene expression and control various biological processes such as cellular differentiation and function. To evaluate the expression of miRNAs in FAE, including M cells, we previously performed microarray analysis comparing intestinal villous epithelium (VE) and PP FAE. Here we confirmed FAE specific miRNA expression levels by quantitative PCR. To gain insight into miRNA function, we generated mice with intestinal epithelial cell-specific deletion of Dicer1 (Dicer(Delta IEC)) and analyzed intestinal phenotypes, including M-cell differentiation, morphology and function. Dicer(Delta IEC) mice had a marked decrease in M cells compared to control floxed Dicer mice, suggesting an essential role of miRNAs in maturation of these cells. Furthermore, transmission electron microscopic analysis revealed that depletion of miRNA caused the loss of endosomal structures in M cells. In addition, antigen uptake by M cells was impaired in Dicer(Delta IEC) mice. These results suggest that miRNAs play a significant role in M cell differentiation and help secure mucosal immune homeostasis. C1 [Nakato, Gaku; Hase, Koji; Sato, Takao; Sakakibara, Sayuri; Obata, Yuuki; Hanazato, Misaho; Ohno, Hiroshi] RIKEN Ctr Integrat Med Sci IMS RCAI, RCAI, Lab Intestinal Ecosyst, Yokohama, Kanagawa, Japan. [Nakato, Gaku; Sato, Takao; Sugiyama, Machiko; Hanazato, Misaho; Ohno, Hiroshi] Yokohama City Univ, Grad Sch Med Life Sci, Immunobiol Lab, Yokohama, Kanagawa, Japan. [Hase, Koji] Univ Tokyo, Inst Med Sci, Int Res & Dev Ctr Mucosal Vaccines, Div Mucosal Barriol, Tokyo, Japan. [Hase, Koji] Japan Sci & Technol Agcy, PRESTO, Tokyo, Japan. [Iwanaga, Toshihiko] Hokkaido Univ, Grad Sch Med, Lab Histol & Cytol, Sapporo, Hokkaido 060, Japan. [Obata, Yuuki] Chiba Univ, Grad Sch Med & Pharmaceut Sci, Chiba, Japan. [Nakato, Gaku] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Hase, Koji] Keio Univ, Div Biochem, Fac Pharm, Tokyo, Japan. RP Ohno, H (reprint author), RIKEN Ctr Integrat Med Sci IMS RCAI, RCAI, Lab Intestinal Ecosyst, Yokohama, Kanagawa, Japan.; Ohno, H (reprint author), Yokohama City Univ, Grad Sch Med Life Sci, Immunobiol Lab, Yokohama, Kanagawa, Japan. EM hiroshi.ohno@riken.jp RI Kimura, Shunsuke/D-7093-2012; OI Kimura, Shunsuke/0000-0001-9408-2884; Obata, Yuuki/0000-0001-5461-3521 FU Japan Society for the Promotion of Science [22890238, 24790485, 22689017, 24249029]; Ministry of Education, Culture, Sports, Science and Technology of Japan, AMED-CREST, AMED [19041072]; Japan Agency for Medical Research and Development, Advanced Research and Development Programs for Medical Innovation [15gm0710009h0002]; Japan Science Society [22-453]; Sumitomo Foundation [100737]; Uehara Memorial Foundation [201120109]; Takeda Science Foundation FX The work was supported by the following: From The Japan Society for the Promotion of Science, Grant-in-Aid for Research Activity Start-up (G.N.) (Grant number: 22890238), Grants-in-Aid for Young Scientists (B) (G.N.) (Grant number: 24790485), Grants-in-Aid for Young Scientists (A) (K.H.) (Grant number: 22689017), Grants-in-Aid for Scientific Research (A) (H.O.) (Grant number: 24249029); From The Ministry of Education, Culture, Sports, Science and Technology of Japan, AMED-CREST, AMED, Grant-in-Aid For Scientific Research on Priority Areas (K.H. and H.O.) (Grant number: 19041072); From The Japan Agency for Medical Research and Development, Advanced Research and Development Programs for Medical Innovation (H.O.) (Grant number: 15gm0710009h0002); Sasakawa Scientific Research Grant from the Japan Science Society (G.N.) (Grant number:22-453); The Sumitomo Foundation (K.H.) (Grant number:100737); The Uehara Memorial Foundation (K.H.) (Grant number:201120109); and Takeda Science Foundation (H.O.) (http://www.takeda-sci.or.jp/). NR 32 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 1 PY 2016 VL 11 IS 3 AR e0150379 DI 10.1371/journal.pone.0150379 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF5ZW UT WOS:000371434500137 PM 26930511 ER PT J AU Ramena, G Yin, YF Yu, Y Walla, V Elble, RC AF Ramena, Grace Yin, Yufang Yu, Yang Walla, Vijay Elble, Randolph C. TI CLCA2 Interactor EVA1 Is Required for Mammary Epithelial Cell Differentiation SO PLOS ONE LA English DT Article ID ACTIVATED CHLORIDE CHANNEL; TO-MESENCHYMAL TRANSITION; BREAST-CANCER CELLS; BETA-CATENIN; E-CADHERIN; ADHESION MOLECULE; GENE-EXPRESSION; IMMUNOGLOBULIN SUPERFAMILY; SIGNALING CASCADES; TIGHT JUNCTION AB CLCA2 is a p53-, p63-inducible transmembrane protein that is frequently downregulated in breast cancer. It is induced during differentiation of human mammary epithelial cells, and its knockdown causes epithelial-to-mesenchymal transition (EMT). To determine how CLCA2 promotes epithelial differentiation, we searched for interactors using membrane dihybrid screening. We discovered a strong interaction with the cell junctional protein EVA1 (Epithelial V-like Antigen 1) and confirmed it by co-immunoprecipitation. Like CLCA2, EVA1 is a type I transmembrane protein that is regulated by p53 and p63. It is thought to mediate homophilic cell-cell adhesion in diverse epithelial tissues. We found that EVA1 is frequently downregulated in breast tumors and breast cancer cell lines, especially those of mesenchymal phenotype. Moreover, knockdown of EVA1 in immortalized human mammary epithelial cells (HMEC) caused EMT, implying that EVA1 is essential for epithelial differentiation. Both EVA1 and CLCA2 co-localized with E-cadherin at cell-cell junctions. The interacting domains were delimited by deletion analysis, revealing the site of interaction to be the transmembrane segment (TMS). The primary sequence of the CLCA2 TMS was found to be conserved in CLCA2 orthologs throughout mammals, suggesting that its interaction with EVA1 co-evolved with the mammary gland. A screen for other junctional interactors revealed that CLCA2 was involved in two different complexes, one with EVA1 and ZO-1, the other with beta catenin. Overexpression of CLCA2 caused downregulation of beta catenin and beta catenin-activated genes. Thus, CLCA2 links a junctional adhesion molecule to cytosolic signaling proteins that modulate proliferation and differentiation. These results may explain how attenuation of CLCA2 causes EMT and why CLCA2 and EVA1 are frequently downregulated in metastatic breast cancer cell lines. C1 [Ramena, Grace; Yu, Yang] So Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Springfield, IL 62794 USA. [Yin, Yufang; Elble, Randolph C.] So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA. [Elble, Randolph C.] So Illinois Univ, Sch Med, Simmons Canc Inst, Springfield, IL 62794 USA. [Walla, Vijay] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Elble, RC (reprint author), So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA.; Elble, RC (reprint author), So Illinois Univ, Sch Med, Simmons Canc Inst, Springfield, IL 62794 USA. EM relble2@siumed.edu FU National Cancer Institute [1R15CA151094-01] FX This work was supported by National Cancer Institute 1R15CA151094-01 to RCE. http://www.cancer.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 4 Z9 4 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 1 PY 2016 VL 11 IS 3 AR e0147489 DI 10.1371/journal.pone.0147489 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF5ZW UT WOS:000371434500004 PM 26930581 ER PT J AU Mullins, N Power, RA Fisher, HL Hanscombe, KB Euesden, J Iniesta, R Levinson, DF Weissman, MM Potash, JB Shi, J Uher, R Cohen-Woods, S Rivera, M Jones, L Jones, I Craddock, N Owen, MJ Korszun, A Craig, IW Farmer, AE McGuffin, P Breen, G Lewis, CM AF Mullins, N. Power, R. A. Fisher, H. L. Hanscombe, K. B. Euesden, J. Iniesta, R. Levinson, D. F. Weissman, M. M. Potash, J. B. Shi, J. Uher, R. Cohen-Woods, S. Rivera, M. Jones, L. Jones, I. Craddock, N. Owen, M. J. Korszun, A. Craig, I. W. Farmer, A. E. McGuffin, P. Breen, G. Lewis, C. M. TI Polygenic interactions with environmental adversity in the aetiology of major depressive disorder SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Depression; genetics; gene-environment interactions; polygenic risk scoring ID STRESSFUL LIFE EVENTS; GENOME-WIDE ASSOCIATION; TRANSPORTER GENE 5-HTT; CONTROL-STUDY BACCS; CHILDHOOD MALTREATMENT; THREATENING EXPERIENCES; MENTAL-DISORDERS; METAANALYSIS; RISK; HERITABILITY AB Background. Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. Method. The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. Results. PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 x 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 x 10(-4) and p = 5.12 x 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. Conclusions. CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits. C1 [Mullins, N.; Power, R. A.; Fisher, H. L.; Euesden, J.; Iniesta, R.; Uher, R.; Rivera, M.; Craig, I. W.; Farmer, A. E.; McGuffin, P.; Breen, G.; Lewis, C. M.] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC Social Genet & Dev Psychiat Ctr, 16 De Crespigny Pk, London SE5 8AF, England. [Hanscombe, K. B.; Lewis, C. M.] Kings Coll London, Sch Med, Guys Hosp, Div Genet & Mol Med, London SE5 8AF, England. [Levinson, D. F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Weissman, M. M.] Columbia Univ, Dept Psychiat, New York, NY USA. [Weissman, M. M.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Potash, J. B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Shi, J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Uher, R.] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. [Cohen-Woods, S.] Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia. [Rivera, M.] Univ Granada, CIBERSAM, Granada, Spain. [Rivera, M.] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Granada, Spain. [Jones, L.] Univ Birmingham, Dept Psychiat, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Jones, I.; Craddock, N.; Owen, M. J.] Cardiff Univ, Neurosci & Mental Hlth Res Inst, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Korszun, A.] Queen Mary Univ London, Barts & London Med Sch, London, England. [Breen, G.] South London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr Mental Hlth, London, England. [Breen, G.] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. RP Mullins, N (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC Social Genet & Dev Psychiat Ctr, 16 De Crespigny Pk, London SE5 8AF, England. EM Niamh.mullins@kcl.ac.uk RI Lewis, Cathryn/A-5225-2010; Iniesta, Raquel/E-6127-2017; OI Lewis, Cathryn/0000-0002-8249-8476; Fisher, Helen/0000-0003-4174-2126; Cohen-Woods, Sarah/0000-0003-2199-6129 FU UK Medical Research Council [G0701420]; GlaxoSmithKline [G0701420]; National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London; Maudsley NHS Foundation Trust; Institute of Psychiatry, Psychology and Neuroscience, King's College London; European Commission Framework 6 grant (EC) [LSHB-CT-2003-503428]; National Institute of Mental Health (NIMH) [MH061686, MH059542, MH075131, MH059552, MH059541, MH060912]; NIMH [5RC2MH089916]; European Community [286213]; MQ Fellows Award [MQ14F40]; Canada Research Chairs programme FX The RADIANT studies were funded by a joint grant from the UK Medical Research Council, GlaxoSmithKline (G0701420) and by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King's College London. The GENDEP study was funded by a European Commission Framework 6 grant (EC contract ref.: LSHB-CT-2003-503428). The GenRED project was supported by National Institute of Mental Health (NIMH) R01 grants MH061686 (D.F.L.), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (J.B.P.), MH059541 (WA Scheftner) and MH060912 (M.M.W.). We acknowledge the contributions of Dr George S. Zubenko and Dr Wendy N. Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine to the GenRED 1 project. The DGN study was supported by the NIMH (grant 5RC2MH089916). N.M. and C.M.L. have received funding from the European Community's Seventh Framework Programme under the Marie Curie Industry-Academia Partnership and Pathways (grant 286213). H.L.F. is supported by an MQ Fellows Award (MQ14F40). R.U. is supported by the Canada Research Chairs programme (http://www.chairs-chaires.gc.ca/). NR 53 TC 4 Z9 5 U1 5 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD MAR PY 2016 VL 46 IS 4 BP 759 EP 770 DI 10.1017/S0033291715002172 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DF8PX UT WOS:000371621500007 PM 26526099 ER PT J AU Yao, L Yip, AL Shrader, JA Mesdaghinia, S Volochayev, R Jansen, AV Miller, FW Rider, LG AF Yao, Lawrence Yip, Adrienne L. Shrader, Joseph A. Mesdaghinia, Sepehr Volochayev, Rita Jansen, Anna V. Miller, Frederick W. Rider, Lisa G. TI Magnetic resonance measurement of muscle T2, fat-corrected T2 and fat fraction in the assessment of idiopathic inflammatory myopathies SO RHEUMATOLOGY LA English DT Article DE MRI; T2; fat fraction; juvenile dermatomyositis; dermatomyositis; polymyositis; idiopathic inflammatory myopathies; muscle; myositis ID JUVENILE DERMATOMYOSITIS; DISEASE-ACTIVITY; INTERNATIONAL CONSENSUS; PEDIATRIC RHEUMATOLOGY; CLINICAL-ASSESSMENTS; RELAXATION-TIMES; ADULT; POLYMYOSITIS; MRI; RESPONSIVENESS AB Objective. This study examines the utility of MRI, including T2 maps and T2 maps corrected for muscle fat content, in evaluating patients with idiopathic inflammatory myopathy. Methods. A total of 44 patients with idiopathic inflammatory myopathy, 18 of whom were evaluated after treatment with rituximab, underwent MRI of the thighs and detailed clinical assessment. T2, fat fraction (FF) and fat corrected T2 (fc-T2) maps were generated from standardized MRI scans, and compared with semi-quantitative scoring of short tau inversion recovery (STIR) and T1-weighted sequences, as well as various myositis disease metrics, including the Physician Global Activity, the modified Childhood Myositis Assessment Scale and the muscle domain of the Myositis Disease Activity Assessment Tool-muscle (MDAAT-muscle). Results. Mean T2 and mean fc-T2 correlated similarly with STIR scores (Spearman r(s)=0.64 and 0.64, P < 0.01), while mean FF correlated with T1 damage scores (r(s)=0.69, P < 0.001). Baseline T2, fc-T2 and STIR scores correlated significantly with the Physician Global Activity, modified Childhood Myositis Assessment Scale and MDAAT-muscle (r(s) range = 0.41-0.74, P < 0.01). The response of MRI measures to rituximab was variable, and did not significantly agree with a standardized clinical definition of improvement. Standardized response means for the MRI measures were similar. Conclusion. Muscle T2, fc-T2 and FF measurements exhibit content validity with reference to semi-quantitative scoring of STIR and T1 MRI, and also exhibit construct validity with reference to several myositis activity and damage measures. T2 was as responsive as fc-T2 and STIR scoring, although progression of muscle damage was negligible during the study. C1 [Yao, Lawrence] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD USA. [Yip, Adrienne L.; Mesdaghinia, Sepehr; Volochayev, Rita; Jansen, Anna V.; Miller, Frederick W.; Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Shrader, Joseph A.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. RP Rider, LG (reprint author), NIEHS, NIH, MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural Research Program of National Institute of Environmental Health Sciences, National Institutes of Health FX This study was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 34 TC 6 Z9 6 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2016 VL 55 IS 3 BP 441 EP 449 DI 10.1093/rheumatology/kev344 PG 9 WC Rheumatology SC Rheumatology GA DF7SL UT WOS:000371557800009 PM 26412808 ER PT J AU Wu, UI Holland, SM AF Wu, Un-In Holland, Steven M. TI A genetic perspective on granulomatous diseases with an emphasis on mycobacterial infections SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Tuberculosis; Nontuberculous; Mycobacteria; IFN-gamma; IL-12 ID INTERFERON-GAMMA-RECEPTOR; B ESSENTIAL MODULATOR; BACILLE CALMETTE-GUERIN; INHERITED INTERLEUKIN-12 DEFICIENCY; CHRONIC MUCOCUTANEOUS CANDIDIASIS; HUMAN STAT1 DEFICIENCY; IFN-GAMMA; NONTUBERCULOUS MYCOBACTERIA; MENDELIAN SUSCEPTIBILITY; AUTOSOMAL-DOMINANT AB Identification of the genetic factors predisposing to mycobacterial infections has been a subject of intense research activities. Current knowledge of the genetic and immunological basis of susceptibility to mycobacteria largely comes from natural human and experimental models of Bacille Calmette Gu,rin (BCG) and nontuberculous mycobacterial infections. These observations support the central role of the IL-12/IFN-gamma pathway in controlling mycobacterial infection. In this review, we discuss the knowledge that associates both simple and complex inheritance with susceptibility to mycobacterial diseases. We place a special emphasis on monogenic disorders, since these clearly pinpoint pathways and can adduce mechanism. We also describe the clinical, immunological, and pathological features that may steer clinical investigation in the appropriate directions. C1 [Wu, Un-In] Natl Taiwan Univ Hosp, Div Infect Dis, Taipei, Taiwan. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM uninwu@gmail.com; smh@nih.gov OI WU, UN-IN/0000-0001-8182-6071 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 117 TC 1 Z9 1 U1 2 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 MAR PY 2016 VL 38 IS 2 BP 199 EP 212 DI 10.1007/s00281-015-0552-y PG 14 WC Immunology; Pathology SC Immunology; Pathology GA DF8UI UT WOS:000371634900006 PM 26733044 ER PT J AU Mott, M Janis, S Koroshetz, WJ AF Mott, Meghan Janis, Scott Koroshetz, Walter J. TI StrokeNet Takes Off National Institute of Neurological Disorders and Stroke Organizational Update SO STROKE LA English DT Editorial Material DE clinical trial; image-guided intervention; National Institute of Neurological Disorders and Stroke; thrombectomy; reperfusion injury C1 [Mott, Meghan; Janis, Scott; Koroshetz, Walter J.] NINDS, NIH, Bldg 31,Room 8A52,31 Ctr Dr,MSC 2540, Bethesda, MD 20892 USA. RP Koroshetz, WJ (reprint author), NINDS, NIH, Bldg 31,Room 8A52,31 Ctr Dr,MSC 2540, Bethesda, MD 20892 USA. EM koroshetzw@mail.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2016 VL 47 IS 3 BP E51 EP E52 DI 10.1161/STROKEAHA.115.012063 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DF6VU UT WOS:000371496400003 PM 26814236 ER PT J AU Lee, M Huang, RL Tong, WD AF Lee, Mikyung Huang, Ruili Tong, Weida TI Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model SO TOXICOLOGICAL SCIENCES LA English DT Article DE nuclear receptor; transcriptional regulation; Tox21; toxicogenomics project; author-topic model; integrative analysis ID BREAST-CANCER; RETINOIC ACID; PPAR-GAMMA; X RECEPTOR; EXPRESSION; APOPTOSIS; CELLS; PROMOTER; COMPLEX; BINDING AB Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships. C1 [Lee, Mikyung; Huang, Ruili] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Weida.tong@fda.hhs.gov FU U.S. Food and Drug Administration; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the U.S. Food and Drug Administration and the National Center for Advancing Translational Sciences, National Institutes of Health. We would also like to thank Dr. Rajarshi Guha for helpful discussion. The views expressed in this article are those of the authors and do not necessarily reflect the statements, opinions, views, conclusions, or policies of the National Center for Advancing Translational Sciences, National Institutes of Health, U.S. Food and Drug Administration, or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 26 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2016 VL 150 IS 1 BP 64 EP 73 DI 10.1093/toxsci/kfv261 PG 10 WC Toxicology SC Toxicology GA DF8NS UT WOS:000371615300007 PM 26643261 ER PT J AU Lau, WW Tsang, JS AF Lau, William W. Tsang, John S. TI Humoral Fingerprinting of Immune Responses: 'Super-Resolution', High-Dimensional Serology SO TRENDS IN IMMUNOLOGY LA English DT Editorial Material ID BIOLOGY C1 [Lau, William W.] NIH, Off Intramural Res, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Tsang, John S.] NIAID, Syst Genom & BioInformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & BioInformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.tsang@nlh.gov FU Intramural NIH HHS [Z99 AI999999, ZIA AI001152-05] NR 9 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD MAR PY 2016 VL 37 IS 3 BP 167 EP 169 DI 10.1016/j.it.2016.01.003 PG 3 WC Immunology SC Immunology GA DG1OW UT WOS:000371838400001 PM 26830541 ER PT J AU Wilson, MM Bernstein, HD AF Wilson, Marlena M. Bernstein, Harris D. TI Surface-Exposed Lipoproteins: An Emerging Secretion Phenomenon in Gram-Negative Bacteria SO TRENDS IN MICROBIOLOGY LA English DT Review ID OUTER-MEMBRANE PROTEINS; COLI CELL WALL; BORRELIA-BURGDORFERI; ESCHERICHIA-COLI; NEISSERIA-MENINGITIDIS; BINDING-PROTEIN; MUREIN-LIPOPROTEIN; HAEMOPHILUS-INFLUENZAE; KLEBSIELLA-PNEUMONIAE; FUNCTIONAL-CHARACTERIZATION AB Bacterial lipoproteins are hydrophilic proteins that are anchored to a cell membrane by N-terminally linked fatty acids. It is widely believed that nearly all lipoproteins produced by Gram-negative bacteria are either retained in the inner membrane (IM) or transferred to the inner leaflet of the outer membrane (OM). Lipoproteins that are exposed on the cell surface have also been reported but are generally considered to be rare. Results from a variety of recent studies, however, now suggest that the prevalence of surface-exposed lipoproteins has been underestimated. In this review we describe the evidence that the surface exposure of lipoproteins in Gram-negative bacteria is a widespread phenomenon and discuss possible mechanisms by which these proteins might be transported across the OM. C1 [Wilson, Marlena M.; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Jessica Pierce for helpful comments on the manuscript. Research conducted in the authors' laboratory is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 86 TC 2 Z9 2 U1 3 U2 10 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 MAR PY 2016 VL 24 IS 3 BP 198 EP 208 DI 10.1016/j.tim.2015.11.006 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA DF7PT UT WOS:000371550800009 PM 26711681 ER PT J AU Yu, SJ Wu, KJ Bae, EK Hsu, MJ Richie, CT Harvey, BK Wang, Y AF Yu, Seong-Jin Wu, Kou-Jen Bae, Eun K. Hsu, Man-Jung Richie, Christopher T. Harvey, Brandon K. Wang, Yun TI Methamphetamine induces a rapid increase of intracellular Ca++ levels in neurons overexpressing GCaMP5 SO ADDICTION BIOLOGY LA English DT Article DE Calcium; glutamate; magnesium; methamphetamine ID GATED CALCIUM-CHANNEL; DOPAMINE RELEASE; NUCLEUS-ACCUMBENS; GENE-EXPRESSION; IN-VIVO; NOREPINEPHRINE TRANSPORTER; STRIATAL NEURONS; NEURAL ACTIVITY; LIMBIC SYSTEM; PC12 CELLS AB In this study, methamphetamine (Meth)- and glutamate (Glu)-mediated intracellular Ca++ (Ca(++)i) signals were examined in real time in primary cortical neurons overexpressing an intracellular Ca++ probe, GCaMP5, by adeno-associated viral (AAV) serotype 1. Binding of Ca++ to GCaMP increased green fluorescence intensity in cells. Both Meth and Glu induced a rapid increase in Ca(++)i, which was blocked by MK801, suggesting that Meth enhanced Ca(++)i through Glu receptor in neurons. The Meth-mediated Ca++ signal was also blocked by Mg++, low Ca++ or the L-type Ca++ channel inhibitor nifedipine. The ryanodine receptor inhibitor dantrolene did not alter the initial Ca++ influx but partially reduced the peak of Ca(++)i. These data suggest that Meth enhanced Ca++ influx through membrane Ca++ channels, which then triggered the release of Ca++ from the endoplasmic reticulum in the cytosol. AAV-GCaMP5 was also injected to the parietal cortex of adult rats. Administration of Meth enhanced fluorescence in the ipsilateral cortex. Using immunohistochemistry, Meth-induced green fluorescence was found in the NeuN-containing cells in the cortex, suggesting that Meth increased Ca++ in neurons in vivo. In conclusion, we have used in vitro and in vivo techniques to demonstrate a rapid increase of Ca(++)i by Meth in cortical neurons through overexpression of GCaMP5. As Meth induces behavioral responses and neurotoxicity through Ca(++)i, modulation of Ca(++)i may be useful to reduce Meth-related reactions. C1 [Yu, Seong-Jin; Wu, Kou-Jen; Bae, Eun K.; Hsu, Man-Jung; Wang, Yun] Natl Hlth Res Inst, Ctr Neuropsychiat Res, 35 Keyan Rd, Zhunan, Taiwan. [Richie, Christopher T.; Harvey, Brandon K.] NIDA, NIH, Baltimore, MD USA. RP Yu, SJ; Wang, Y (reprint author), Natl Hlth Res Inst, Ctr Neuropsychiat Res, 35 Keyan Rd, Zhunan, Taiwan. EM b7508@nhri.org.tw; ywang@nhri.org.tw FU National Health Research Institutes, Taiwan FX The authors thank Doug Howard and Lowella Fortuno for their technical assistance (vector production and in vitro testing, respectively). This study was supported by the National Health Research Institutes, Taiwan. NR 50 TC 3 Z9 3 U1 4 U2 11 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 MAR PY 2016 VL 21 IS 2 BP 255 EP 266 DI 10.1111/adb.12193 PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA DF2CW UT WOS:000371148700004 PM 25377775 ER PT J AU Anizan, S Concheiro, M Lehner, KR Bukhari, MO Suzuki, M Rice, KC Baumann, MH Huestis, MA AF Anizan, Sebastien Concheiro, Marta Lehner, Kurt R. Bukhari, Mohammad O. Suzuki, Masaki Rice, Kenner C. Baumann, Michael H. Huestis, Marilyn A. TI Linear pharmacokinetics of 3,4-methylenedioxypyrovalerone (MDPV) and its metabolites in the rat: relationship to pharmacodynamic effects SO ADDICTION BIOLOGY LA English DT Article DE bath salts; designer drugs; MDPV; metabolites; PK/PD; synthetic cathinones ID BATH SALTS; LOCOMOTOR-ACTIVITY; DESIGNER CATHINONES; MASS-SPECTROMETRY; IN-VITRO; DRUG; STIMULANT; PHARMACOLOGY; CONSTITUENT; DOPAMINE AB 3,4-Methylenedioxypyrovalerone (MDPV) is a commonly abused synthetic cathinone in the United States and is associated with dangerous side effects. MDPV is a dopamine transporter blocker that is 10-fold more potent than cocaine as a locomotor stimulant in rats. Previous in vitro and in vivo metabolism studies identified 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) as the two primary MDPV metabolites. This study examined MDPV pharmacokinetics and metabolism, along with associated pharmacodynamic effects in rats receiving 0.5, 1.0 and 2.0mg/kg subcutaneous (s.c.) MDPV. Blood was collected by an indwelling jugular catheter before dosing and at 10, 20, 30, 60, 120, 240 and 480 minutes thereafter. Plasma specimens were analyzed by liquid chromatography coupled to high-resolution tandem mass spectrometry. Maximum concentrations (C-max) and area-under-the-curve (AUC) for MDPV and two metabolites increased proportionally with administered dose, showing linear pharmacokinetics. MDPV exhibited the highest C-max at all doses (74.2-271.3g/l) and 4-OH-3-MeOH-PV the highest AUC (11366-47724 minutes per g/l), being the predominant metabolite. MDPV time to C-max (T-max) was 12.9-18.6 minutes, while 3,4-catechol-PV and 4-OH-3-MeO-PV peaked later with T-max 188.6-240 minutes after s.c. dosing. Horizontal locomotor activity (HLA) and stereotypy correlated positively with plasma MDPV concentrations, while HLA correlated negatively with MDPV metabolites. These results suggest that the parent compound mediates motor stimulation after systemic MDPV administration, but additionally, metabolites may be inhibitory, may not be active or may not pass the blood brain barrier. C1 [Anizan, Sebastien; Concheiro, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. [Lehner, Kurt R.; Bukhari, Mohammad O.; Baumann, Michael H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Suzuki, Masaki; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Suzuki, Masaki; Rice, Kenner C.] NIAAA, NIH, Baltimore, MD USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, 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 (NIDA); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and by the National Institutes of Health (NIH). NR 36 TC 6 Z9 6 U1 4 U2 15 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 MAR PY 2016 VL 21 IS 2 BP 339 EP 347 DI 10.1111/adb.12201 PG 9 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA DF2CW UT WOS:000371148700011 PM 25475011 ER PT J AU Hutsell, BA Cheng, KJ Rice, KC Negus, SS Banks, ML AF Hutsell, Blake A. Cheng, Kejun Rice, Kenner C. Negus, Sidney Stevens Banks, Matthew L. TI Effects of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) on cocaine versus food choice and extended-access cocaine intake in rhesus monkeys SO ADDICTION BIOLOGY LA English DT Article DE Addiction; choice; cocaine; kappa opioid receptor; nor-binaltorphimine; rhesus monkey ID BASAL EXTRACELLULAR DOPAMINE; NUCLEUS-ACCUMBENS; ENVIRONMENTAL MANIPULATIONS; ALTERNATIVE REINFORCER; MESSENGER-RNA; AGONIST; RATS; NEUROCHEMISTRY; HUMANS; PHENDIMETRAZINE AB The dynorphin/kappa opioid receptor (KOR) system has been implicated as one potential neurobiological modulator of the abuse-related effects of cocaine and as a potential target for medications development. This study determined effects of the KOR antagonist nor-binaltorphimine (nor-BNI) on cocaine self-administration under a novel procedure that featured two daily components: (1) a 2-hour choice' component (9:00-11:00 am) when monkeys could choose between food pellets and cocaine injections (0-0.1mg/kg per injection, intravenous) and (2) a 20-hour extended-access' component (noon to 8:00 am) when cocaine (0.1mg/kg per injection) was available under a fixed-ratio schedule to promote high daily cocaine intakes. Rhesus monkeys (n=4) were given 14 days of exposure to the choice+extended-access procedure then treated with nor-BNI (3.2 or 10.0mg/kg, intramuscular), and cocaine choice and extended-access cocaine intake were evaluated for an additional 14 days. Consistent with previous studies, cocaine maintained both a dose-dependent increase in cocaine choice during choice components and a high level of cocaine intake during extended-access components. Neither 3.2 nor 10mg/kg nor-BNI significantly altered cocaine choice or extended-access cocaine intake. In two additional monkeys, nor-BNI also had no effect on cocaine choice or extended-access cocaine intake when it was administered at the beginning of exposure to the extended-access components. Overall, these results do not support a major role for the dynorphin/KOR system in modulating cocaine self-administration under these conditions in non-human primates nor do they support the clinical utility of KOR antagonists as a pharmacotherapeutic strategy for cocaine addiction. C1 [Hutsell, Blake A.; Negus, Sidney Stevens; Banks, Matthew L.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 North 12th St,POB 980613, Richmond, VA 23298 USA. [Negus, Sidney Stevens; Banks, Matthew L.] Virginia Commonwealth Univ, Inst Drug & Alcohol Abuse Studies, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, Chem Biol Branch, NIH, Bethesda, MD USA. [Cheng, Kejun] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Banks, ML (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 North 12th St,POB 980613, Richmond, VA 23298 USA. EM mbanks7@vcu.edu RI Banks, Matthew/K-4429-2014 OI Banks, Matthew/0000-0003-4949-5246 FU National Institute on Drug Abuse of the National Institutes of Health [R01 DA026946, T32 DA007027] FX Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under award numbers R01 DA026946 and T32 DA007027. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health and the Food and Drug Administration. We thank Jennifer Gough and Crystal Reyns for technical assistance and Kevin Costa for writing the original computer program version. NR 60 TC 2 Z9 2 U1 3 U2 4 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 MAR PY 2016 VL 21 IS 2 BP 360 EP 373 DI 10.1111/adb.12206 PG 14 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA DF2CW UT WOS:000371148700013 PM 25581305 ER PT J AU Colton, B McConeghy, KW Schreckenberger, PC Danziger, LH AF Colton, Benjamin McConeghy, Kevin W. Schreckenberger, Paul C. Danziger, Larry H. TI IV minocycline revisited for infections caused by multidrug-resistant organisms SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID GRAM-NEGATIVE BACILLI; IN-VITRO ACTIVITIES; ACINETOBACTER-BAUMANNII; INTRAVENOUS MINOCYCLINE; CARBAPENEM-RESISTANCE; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; RENAL-FAILURE; RIBOSOMAL-RNA; TIGECYCLINE AB Purpose. The evidence supporting the potential use of i.v. minocycline for serious infections caused by multidrug-resistant organisms (MDROs) is summarized. Summary. Minocycline achieves good tissue penetration and excellent oral absorption. Minocycline achieves serum concentrations comparable to other tetracyclines, with peak serum concentrations ranging from 3 to 8.75 mg/L following i.v. administration of 200 mg. Minocycline retains antimicrobial activity against methicillin-sensitive and methicillin-resistant Staphylococcus aureus as well as many gram-negative pathogens, such as Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Stenotrophomonas maltophilia. Minocycline has been used to treat respiratory infections caused by Acinetobacter baumannii and bloodstream infections. The majority of these gram-negative infections were treated with combination therapy, with results similar to those seen with first-line agents. The ability to switch from parenteral to oral therapy and its favorable tissue penetration make minocycline an attractive option for severe respiratory or skin and skin structure infections. For A. baumannii infections, minocycline is the second most active agent in vitro and may be the only therapeutic option in certain cases. The overall clinical experience with minocycline supports its use to treat A. baumannii infections alone or in combination with other agents. Minocycline could be used to treat other MDRO gram negative infections but only as an agent of last resort due to the limited data available. Conclusion. The available pharmacokinetic and clinical data support the use of i.v. minocycline for the treatment of MDRO infections, including infections due to S. aureus coagulase-negative and gram-negative pathogens. C1 [Colton, Benjamin] NIH, Ctr Clin, Bethesda, MD 20892 USA. [McConeghy, Kevin W.] Vet Affairs Med Ctr, Providence, RI USA. [Schreckenberger, Paul C.] Loyola Univ, Sch Med, Chicago, IL 60611 USA. [Danziger, Larry H.] Univ Illinois, Coll Pharm, Chicago, IL USA. RP Danziger, LH (reprint author), Univ Illinois, Coll Pharm, Chicago, IL USA. EM danziger@uic.edu NR 46 TC 3 Z9 3 U1 0 U2 5 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD MAR 1 PY 2016 VL 73 IS 5 BP 279 EP 285 DI 10.2146/ajhp150290 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DF5FB UT WOS:000371376100009 PM 26896499 ER PT J AU You, LH Zheng, BJ Wang, SM Ci, YZ Yu, P Shi, ZH Fan, YM Wang, LP Chang, SY Rouault, TA Anderson, GJ Wang, FD Duan, XL Chang, YZ AF You, Lin-Hao Zheng, Bing-Jie Wang, Shu-Min Ci, Yun-Zhe Yu, Peng Shi, Zhen-Hua Fan, Yu-Mei Wang, Li-Peng Chang, Shi-Yang Rouault, Tracey A. Anderson, Gregory J. Wang, Fudi Duan, Xiang-Lin Chang, Yan-Zhong TI ASTROCYTE HEPCIDIN REGULATE IRON TRAFFIC ACROSS THE BRAIN ENDOTHELIUM SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [You, Lin-Hao; Zheng, Bing-Jie; Wang, Shu-Min; Ci, Yun-Zhe; Yu, Peng; Shi, Zhen-Hua; Fan, Yu-Mei; Wang, Li-Peng; Chang, Shi-Yang; Duan, Xiang-Lin; Chang, Yan-Zhong] Hebei Normal Univ, Shijiazhuang, Hebei, Peoples R China. [Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Anderson, Gregory J.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Wang, Fudi] Zhejiang Univ, Hangzhou, Zhejiang, Peoples R China. 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 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2016 VL 91 IS 3 MA 65 BP E265 EP E265 PG 1 WC Hematology SC Hematology GA DF2HI UT WOS:000371162800246 ER PT J AU Safaeian, M Robbins, HA Berndt, SI Lynch, CF Fraumeni, JF Engels, EA AF Safaeian, M. Robbins, H. A. Berndt, S. I. Lynch, C. F. Fraumeni, J. F., Jr. Engels, E. A. TI Risk of Colorectal Cancer After Solid Organ Transplantation in the United States SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Scope: health services and outcomes research; translational research; science; Discipline: organ transplantation in general; Focus: cancer; malignancy; neoplasia: risk factors; epidemiology ID PRIMARY SCLEROSING CHOLANGITIS; INFLAMMATORY-BOWEL-DISEASE; LIVER-TRANSPLANTATION; KIDNEY-TRANSPLANTATION; RECIPIENTS; POPULATION; COHORT; METAANALYSIS; NATIONWIDE; NEOPLASIA AB Solid organ transplant recipients have increased colorectal cancer (CRC) risk. We assessed CRC risk among transplant recipients and identified factors contributing to this association. The US transplant registry was linked to 15 population-based cancer registries (1987-2010). We compared CRC risk in recipients to the general population by using standardized incidence ratios (SIRs) and identified CRC risk factors by using Poisson regression. Based on 790 cases of CRC among 224 098 transplant recipients, the recipients had elevated CRC risk (SIR 1.12, 95% confidence interval [CI] 1.04 to 1.20). The increase was driven by an excess of proximal colon cancer (SIR 1.69, 95% CI 1.53 to 1.87), while distal colon cancer was not increased (SIR 0.93, 95% CI 0.80 to 1.07), and rectal cancer was reduced (SIR 0.64, 95% CI 0.54 to 0.76). In multivariate analyses, CRC was increased markedly in lung recipients with cystic fibrosis (incidence rate ratio [IRR] 12.3, 95% CI 6.94 to 21.9, vs. kidney recipients). Liver recipients with primary sclerosing cholangitis and inflammatory bowel disease also had elevated CRC risk (IRR 5.32, 95% CI 3.73 to 7.58). Maintenance therapy with cyclosporine and azathioprine was associated with proximal colon cancer (IRR 1.53, 95% CI 1.05 to 2.23). Incidence was not elevated in a subgroup of kidney recipients treated with tacrolimus and mycophenolate mofetil, pointing to the relevance of the identified risk factors. Transplant recipients have increased proximal colon cancer risk, likely related to underlying medical conditions (cystic fibrosis and primary sclerosing cholangitis) and specific immunosuppressive regimens. C1 [Safaeian, M.; Robbins, H. A.; Berndt, S. I.; Fraumeni, J. F., Jr.; Engels, E. A.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lynch, C. F.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Robbins, H. A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM safaeianm@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [P30 CA086862, T32 CA009314] NR 35 TC 5 Z9 5 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2016 VL 16 IS 3 BP 960 EP 967 DI 10.1111/ajt.13549 PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA DF3JQ UT WOS:000371240500028 PM 26731613 ER PT J AU Medina, SH Miller, SE Keim, AI Gorka, AP Schnermann, MJ Schneider, JP AF Medina, Scott H. Miller, Stephen E. Keim, Allison I. Gorka, Alexander P. Schnermann, Martin J. Schneider, Joel P. TI An Intrinsically Disordered Peptide Facilitates Non-Endosomal Cell Entry SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE cell-penetrating peptides; drug delivery; gene expression; live-cell microscopy; translocation ID BETA-HAIRPIN PEPTIDES; PENETRATING PEPTIDES; SECONDARY STRUCTURE; LIPID-BILAYER; MEMBRANE; DEFENSINS; MECHANISM; DELIVERY; BINDING AB Many cell-penetrating peptides (CPPs) fold at cell surfaces, adopting - or -structure that enable their intracellular transport. However, the same structural folds that facilitate cellular entry can also elicit potent membrane-lytic activity, limiting their use in delivery applications. Further, a distinct CPP can enter cells through many mechanisms, often leading to endosomal entrapment. Herein, we describe an intrinsically disordered peptide (CLIP6) that exclusively employs non-endosomal mechanisms to cross cellular membranes, while being remarkably biocompatible and serum-stable. We show that a single anionic glutamate residue is responsible for maintaining the disordered bioactive state of the peptide, defines its mechanism of cellular entry, and is central to its biocompatibility. CLIP6 can deliver membrane-impermeable cargo directly to the cytoplasm of cells, suggesting its broad utility for delivery of drug candidates limited by poor cell permeability and endosomal degradation. C1 [Medina, Scott H.; Miller, Stephen E.; Keim, Allison I.; Gorka, Alexander P.; Schnermann, Martin J.; Schneider, Joel P.] NCI, Biol Chem Lab, Natl Inst Hlth Ft Detrick, 376 Boyle St, Frederick, MD 21702 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, Natl Inst Hlth Ft Detrick, 376 Boyle St, Frederick, MD 21702 USA. EM Joel.Schneider@nih.gov FU National Cancer Institute, National Institutes of Health FX We thank Drs. Susan Mackem and Jianjian Zhu, who established the MEF transgenic cell line. Research funding was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 25 TC 4 Z9 4 U1 10 U2 31 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD MAR 1 PY 2016 VL 55 IS 10 BP 3369 EP 3372 DI 10.1002/anie.201510518 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DF5UO UT WOS:000371418200025 PM 26835878 ER PT J AU Teterina, NL Maximova, OA Kenney, H Liu, GP Pletnev, AG AF Teterina, Natalya L. Maximova, Olga A. Kenney, Heather Liu, Guangping Pletnev, Alexander G. TI MicroRNA-based control of tick-borne flavivirus neuropathogenesis: Challenges and perspectives SO ANTIVIRAL RESEARCH LA English DT Article DE Flavivirus; microRNAs; Neuropathogenesis ID WEST NILE VIRUS; CENTRAL-NERVOUS-SYSTEM; 3' NONCODING REGION; STRAIN TP21 E5; ENCEPHALITIS-VIRUS; LANGAT VIRUS; IMMUNODEFICIENT MICE; VACCINE CANDIDATE; DENGUE TYPE-4; NEUROINVASIVENESS AB In recent years, microRNA-targeting has become an effective strategy for selective control of tissue tropism and pathogenicity of both DNA and RNA viruses. Previously, we reported the successful application of this strategy to control the neurovirulent phenotype of a model chimeric tick-borne encephalitis/dengue type 4 virus (TBEV/DEN4), containing the structural protein genes of a highly virulent TBEV in the genetic backbone of non-neuroinvasive DEN4 virus. In the present study, we investigated the suitability of this approach for the attenuation of the more neurovirulent chimeric virus (TBEV/LGTV), which is based on the genetic backbone of the naturally attenuated member of the TBEV serocomplex, a Langat virus (LGTV). Unlike the TBEV/DEN4, the TBEV/LGTV virus retained the ability of its parental viruses to spread from the peripheral site of inoculation to the CNS. We evaluated ten potential sites in the 3'NCR of the TBEV/LGTV genome for placement of microRNA (miRNA) targets and found that the TBEV/LGTV genome is more restrictive for such genetic manipulations compared to TBEV/DEN4. In addition, unlike TBEV/DEN4 virus, the introduction of multiple miRNA targets into either the 3'NCR or ORF of the TBEV/LGTV genome had only a modest effect on virus attenuation in the developing CNS of highly permissive newborn mice. However, simultaneous miRNA-targeting in the ORF and 3'NCR had synergistic effect on control and silencing of virus replication in the brain and completely abolished the virus neurotropism. Furthermore, neuroinvasiveness of miRNA-targeted TBEV/LGTV viruses in very sensitive immunodeficient SCID mice was significantly limited. Immunocompetent animals immunized with such viruses were completely protected against challenge with the neurovirulent LGTV parent. These findings support the rationale of the miRNA-targeting approach to develop live attenuated virus vaccines against various neurotropic viruses. Published by Elsevier B.V. C1 [Teterina, Natalya L.; Maximova, Olga A.; Kenney, Heather; Liu, Guangping; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Pletnev, AG (reprint author), NIAID, NIH, Bldg 33,Room 3W10A,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We would like to thank Dr. E. Ehrenfeld for critical reading of the manuscript, Dr. K. Shen (BCBB, NIAID, NIH) for help with statistical analysis, and Dr. A. Engle for help in constructing the TBEV/LGTV viruses. This work was supported by the Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 1 Z9 1 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2016 VL 127 BP 57 EP 67 DI 10.1016/j.antiviral.2016.01.003 PG 11 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DF5CC UT WOS:000371368400007 PM 26794396 ER PT J AU Canna, SW Nigrovic, PA AF Canna, Scott W. Nigrovic, Peter A. TI 21st Century Storm Chasers: Defining Macrophage Activation Syndrome SO ARTHRITIS & RHEUMATOLOGY LA English DT Editorial Material ID JUVENILE IDIOPATHIC ARTHRITIS; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; GUIDELINES; MUTATION; AUTOINFLAMMATION C1 [Canna, Scott W.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Nigrovic, Peter A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Nigrovic, Peter A.] Boston Childrens Hosp, Boston, MA USA. RP Canna, SW (reprint author), NIAMSD, Autoinflammatory Pathogenesis Unit, NIH, 10 Ctr Dr,Bldg 10,Room 13c103,MSC 1930, Bethesda, MD 20892 USA.; Nigrovic, PA (reprint author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Smith Bldg,Room 516b,One Jimmy Fund Way, Boston, MA 02115 USA. EM scott.canna@nih.gov; pnigrovic@partners.org FU Intramural NIH HHS; NIAMS NIH HHS [AR-065538, AR-061602] NR 15 TC 0 Z9 0 U1 1 U2 3 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 MAR PY 2016 VL 68 IS 3 BP 557 EP 560 DI 10.1002/art.39329 PG 4 WC Rheumatology SC Rheumatology GA DF3ON UT WOS:000371254300001 PM 26314501 ER PT J AU Habers, GEA Huber, AM Mamyrova, G Targoff, IN O'Hanlon, TP Adams, S Pandey, JP Boonacker, C van Brussel, M Miller, FW van Royen-Kerkhof, A Rider, LG AF Habers, G. Esther A. Huber, Adam M. Mamyrova, Gulnara Targoff, Ira N. O'Hanlon, Terrance P. Adams, Sharon Pandey, Janardan P. Boonacker, Chantal van Brussel, Marco Miller, Frederick W. van Royen-Kerkhof, Annet Rider, Lisa G. CA Childhood Myositis Heterogeneity S TI Association of Myositis Autoantibodies, Clinical Features, and Environmental Exposures at Illness Onset With Disease Course in Juvenile Myositis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; PROGNOSTIC-FACTORS; GENE POLYMORPHISMS; SYMPTOM ONSET; DERMATOMYOSITIS; PHENOTYPES; CHILDREN; DURATION; POLYMYOSITIS; MULTICENTER AB Objective. To identify early factors associated with disease course in patients with juvenile idiopathic inflammatory myopathies (IIMs). Methods. Univariable and multivariable multinomial logistic regression analyses were performed in a large juvenile IIM registry (n = 365) and included demographic characteristics, early clinical features, serum muscle enzyme levels, myositis autoantibodies, environmental exposures, and immunogenetic polymorphisms. Results. Multivariable associations with chronic or polycyclic courses compared to a monocyclic course included myositis-specific autoantibodies (multinomial odds ratio [OR] 4.2 and 2.8, respectively), myositis-associated autoantibodies (multinomial OR 4.8 and 3.5), and a documented infection within 6 months of illness onset (multinomial OR 2.5 and 4.7). A higher overall clinical symptom score at diagnosis was associated with chronic or monocyclic courses compared to a polycyclic course. Furthermore, severe illness onset was associated with a chronic course compared to monocyclic or polycyclic courses (multinomial OR 2.1 and 2.6, respectively), while anti-p155/140 autoantibodies were associated with chronic or polycyclic courses compared to a monocyclic course (multinomial OR 3.9 and 2.3, respectively). Additional univariable associations of a chronic course compared to a monocyclic course included photosensitivity, V-sign or shawl sign rashes, and cuticular overgrowth (OR 2.2-3.2). The mean ultraviolet index and highest ultraviolet index in the month before diagnosis were associated with a chronic course compared to a polycyclic course in boys (OR 1.5 and 1.3), while residing in the Northwest was less frequently associated with a chronic course (OR 0.2). Conclusion. Our findings indicate that myositis autoantibodies, in particular anti-p155/140, and a number of early clinical features and environmental exposures are associated with a chronic course in patients with juvenile IIM. These findings suggest that early factors, which are associated with poorer outcomes in juvenile IIM, can be identified. C1 [Habers, G. Esther A.; Boonacker, Chantal; van Brussel, Marco; van Royen-Kerkhof, Annet] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Huber, Adam M.] IWK Hlth Ctr, Halifax, NS, Canada. [Huber, Adam M.] Dalhousie Univ, Halifax, NS, Canada. [Mamyrova, Gulnara] George Washington Univ, Sch Med, Washington, DC USA. [Targoff, Ira N.] Univ Oklahoma, Hlth Sci Ctr, VAMC, Oklahoma City, OK USA. [Targoff, Ira N.] Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA. [O'Hanlon, Terrance P.; Miller, Frederick W.; Rider, Lisa G.] NIEHS, NIH, Bethesda, MD USA. [Adams, Sharon] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Pandey, Janardan P.] Med Univ S Carolina, Charleston, SC USA. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, Clin Res Branch, Clin Res Ctr, Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural Research Program of the National Institute of Environmental Health Sciences, NIH; Cure JM Foundation FX Supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. Dr. Mamyrova's work was supported by the Cure JM Foundation. NR 29 TC 3 Z9 3 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 MAR PY 2016 VL 68 IS 3 BP 761 EP 768 DI 10.1002/art.39466 PG 8 WC Rheumatology SC Rheumatology GA DF3ON UT WOS:000371254300026 PM 26474155 ER PT J AU Heitkemper, MM Han, CJ Jarrett, ME Gu, HW Djukovic, D Shulman, RJ Raftery, D Henderson, WA Cain, KC AF Heitkemper, Margaret M. Han, Claire Jungyoun Jarrett, Monica E. Gu, Haiwei Djukovic, Danijel Shulman, Robert J. Raftery, Daniel Henderson, Wendy A. Cain, Kevin C. TI Serum Tryptophan Metabolite Levels During Sleep in Patients With and Without Irritable Bowel Syndrome (IBS) SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE metabolomics; irritable bowel syndrome; sleep; tryptophan; melatonin ID KYNURENINE PATHWAY; MELATONIN; SEVERITY; SYMPTOMS; DISORDER; WOMEN AB Poor sleep and stress are more frequently reported by women with irritable bowel syndrome (IBS) than by healthy control (HC) women. The pathophysiology linking poor sleep and stress to gastrointestinal symptoms remains poorly understood. We used a metabolomic approach to determine whether tryptophan (TRP) metabolites differ between women with and without IBS and whether the levels are associated with sleep indices and serum cortisol levels. This study sample included 38 women with IBS and 21 HCs. The women were studied in a sleep laboratory for three consecutive nights. On the third night of the study, a social stressor was introduced, then blood samples were drawn every 20 min and sleep indices were measured. Metabolites were determined by targeted liquid chromatography tandem mass spectrometry in a sample collected 1 hr after the onset of sleep. The ratios of each metabolite to TRP were used for analyses. Correlations were controlled for age and oral contraceptive use. Melatonin/TRP levels were lower (p = .005) in the IBS-diarrhea group versus the IBS-constipation and HC groups, and kynurenine/TRP ratios tended to be lower (p = .067) in the total IBS and IBS-diarrhea groups compared to HCs. Associations within the HC group included melatonin/TRP with polysomnography-sleep efficiency (r = .61, p = .006) and weaker positive correlations with the other ratios for either sleep efficiency or percentage time in rapid eye movement sleep (r > .40, p = .025-.091). This study suggests that reductions in early nighttime melatonin/TRP levels may be related to altered sleep quality in IBS, particularly those with diarrhea. C1 [Heitkemper, Margaret M.; Han, Claire Jungyoun; Jarrett, Monica E.] Univ Washington, Dept Biobehav Nursing & Hlth Syst, Box 357266, Seattle, WA 98195 USA. [Gu, Haiwei; Djukovic, Danijel; Raftery, Daniel] Univ Washington, Northwest Metabol Res Ctr, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Shulman, Robert J.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Raftery, Daniel] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Henderson, Wendy A.] NINR, Digest Disorders Unit,Biobehav Branch, Div Intramural Res, NIH,DHHS, Bethesda, MD 20892 USA. [Cain, Kevin C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Cain, Kevin C.] Univ Washington, Off Nursing Res, Seattle, WA 98195 USA. RP Heitkemper, MM (reprint author), Univ Washington, Dept Biobehav Nursing & Hlth Syst, Box 357266, Seattle, WA 98195 USA. EM heit@u.washington.edu OI Henderson, Wendy/0000-0003-3924-7118 FU NINR, NIH [NR04101] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by the NINR, NIH (NR04101). NR 18 TC 2 Z9 2 U1 3 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 MAR PY 2016 VL 18 IS 2 BP 193 EP 198 DI 10.1177/1099800415594251 PG 6 WC Nursing SC Nursing GA DF4HM UT WOS:000371308600009 PM 26156003 ER PT J AU Giovinazzo, H Kumar, P Sheikh, A Brooks, KM Ivanovic, M Walsh, M Caron, WP Kowalsky, RJ Song, G Whitlow, A Clarke-Pearson, DL Brewster, WR Van Le, L Zamboni, BA Bae-Jump, V Gehrig, PA Zamboni, WC AF Giovinazzo, Hugh Kumar, Parag Sheikh, Arif Brooks, Kristina M. Ivanovic, Marija Walsh, Mark Caron, Whitney P. Kowalsky, Richard J. Song, Gina Whitlow, Ann Clarke-Pearson, Daniel L. Brewster, Wendy R. Van Le, Linda Zamboni, Beth A. Bae-Jump, Victoria Gehrig, Paola A. Zamboni, William C. TI Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pharmacokinetics; Pharmacodynamics; Liposomes; TSC; PEGylated liposomal doxorubicin; Phenotypic probe; Ovarian cancer ID STERICALLY STABILIZED LIPOSOMES; RETICULOENDOTHELIAL SYSTEM; ADVANCED MALIGNANCIES; TUMOR DISPOSITION; CKD-602 S-CKD602; SOLID TUMORS; STEALTH; ANTHRACYCLINES; CISPLATIN; PLATINUM AB Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer. TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30-40 mg/m(2) IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling. There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R (2) = 0.61, p = 0.02), particularly in patients receiving PLD alone (R (2) = 0.81, p = 0.04). There was a positive relationship (rho = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands. TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development. C1 [Giovinazzo, Hugh; Kumar, Parag; Walsh, Mark; Caron, Whitney P.; Song, Gina; Zamboni, William C.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, 120 Mason Farm Rd,Suite 1013,CB 7361, Chapel Hill, NC 27599 USA. [Giovinazzo, Hugh] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, 725 N Wolfe St, Baltimore, MD 21205 USA. [Kumar, Parag; Brooks, Kristina M.] NIH, Clin Pharmacokinet Res Lab, Clin Ctr Pharm Dept, 10 Ctr Dr Bldg 10,1C-240G, Bethesda, MD 20892 USA. [Sheikh, Arif; Ivanovic, Marija; Kowalsky, Richard J.; Whitlow, Ann; Clarke-Pearson, Daniel L.; Brewster, Wendy R.; Van Le, Linda; Bae-Jump, Victoria; Gehrig, Paola A.] Univ N Carolina, Sch Med, 321 S Columbia St, Chapel Hill, NC 27599 USA. [Clarke-Pearson, Daniel L.; Brewster, Wendy R.; Van Le, Linda; Bae-Jump, Victoria; Gehrig, Paola A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, 103B Phys Off Bldg CB 7572, Chapel Hill, NC 27599 USA. [Clarke-Pearson, Daniel L.; Brewster, Wendy R.; Van Le, Linda; Bae-Jump, Victoria; Gehrig, Paola A.; Zamboni, William C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, 101 Manning Dr, Chapel Hill, NC 27514 USA. [Zamboni, Beth A.] Carlow Univ, Dept Math, Pittsburgh, PA USA. [Zamboni, William C.] Univ N Carolina, Inst Pharmacogenom & Individualized Therapy, 120 Mason Farm Rd, Chapel Hill, NC 27599 USA. [Zamboni, William C.] Carolina Ctr Canc Nanotechnol Excellence, 1079 Genet Med Bldg, Chapel Hill, NC 27599 USA. [Zamboni, William C.] North Carolina Biomed Innovat Network, 013 Genet Med Bldg CB 7361, Chapel Hill, NC 27599 USA. RP Zamboni, WC (reprint author), Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, 120 Mason Farm Rd,Suite 1013,CB 7361, Chapel Hill, NC 27599 USA.; Zamboni, WC (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, 101 Manning Dr, Chapel Hill, NC 27514 USA.; Zamboni, WC (reprint author), Univ N Carolina, Inst Pharmacogenom & Individualized Therapy, 120 Mason Farm Rd, Chapel Hill, NC 27599 USA.; Zamboni, WC (reprint author), Carolina Ctr Canc Nanotechnol Excellence, 1079 Genet Med Bldg, Chapel Hill, NC 27599 USA.; Zamboni, WC (reprint author), North Carolina Biomed Innovat Network, 013 Genet Med Bldg CB 7361, Chapel Hill, NC 27599 USA. EM zamboni@email.unc.edu OI Brooks, Kristina/0000-0002-3832-8699 FU Lineberger Comprehensive Cancer Center; UNC University Cancer Research Fund (UCRF); Carolina Center of Cancer Nanotechnology Excellence (C-CCNE) Pilot grant (NIH/NCI) [CA119343] FX This study was funded by the Lineberger Comprehensive Cancer Center, UNC University Cancer Research Fund (UCRF) and the Carolina Center of Cancer Nanotechnology Excellence (C-CCNE) Pilot grant (NIH/NCI CA119343). The investigators would like to thank the faculty and staff of the UNC School of Medicine, Divisions of Gynecologic Oncology and Nuclear Medicine; UNC North Carolina Translational and Clinical Sciences Institute, Clinical and Translational Research Center; UNC Eshelman School of Pharmacy, Translational Oncology and Nanoparticle Drug Development Initiative Lab; the CCNE; and the patients, families, and friends who made this work possible. NR 38 TC 2 Z9 3 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAR PY 2016 VL 77 IS 3 BP 565 EP 573 DI 10.1007/s00280-015-2945-y PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DF3LQ UT WOS:000371246100012 PM 26822231 ER PT J AU Ruan, XB Li, P Cangelosi, A Yang, L Cao, HM AF Ruan, Xiangbo Li, Ping Cangelosi, Andrew Yang, Ling Cao, Haiming TI A Long Non-coding RNA, IncLGR, Regulates Hepatic Glucokinase Expression and Glycogen Storage during Fasting SO CELL REPORTS LA English DT Article ID GENE-EXPRESSION; TRANSCRIPTION; METABOLISM; ROLES AB Glucose levels in mammals are tightly controlled through multiple mechanisms to meet systemic energy demands. Downregulation of hepatic glucokinase (GCK) during fasting facilitates the transition of the liver from a glucose-consuming to a gluconeogenic organ. Here, we report the transcriptional regulation of hepatic GCK by a long non-coding RNA (lncRNA) named liver GCK repressor (lncLGR). lncLGR is induced by fasting, and physiological overexpression of lncLGR to mimic fasting levels effectively suppresses GCK expression and reduces hepatic glycogen content in mice. Consistently, lncLGR knockdown enhances GCK expression and glycogen storage in fasted mice. Mechanistically, lncLGR specifically binds to heterogenous nuclear ribonucleoprotein L (hnRNPL), which is further confirmed to be a transcriptional repressor of GCK in vivo. Finally, we demonstrate that lncLGR facilitates the recruitment of hnRNPL to the GCK promoter and suppresses GCK transcription. Our data establish a lncRNA-mediated mechanism that regulates hepatic GCK expression and glycogen deposition in a physiological context. C1 [Ruan, Xiangbo; Li, Ping; Cangelosi, Andrew; Yang, Ling; Cao, Haiming] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cao, HM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM haiming.cao@nih.gov RI Yang, Ling/F-4404-2016; Cao, Haiming/P-4634-2016; Ruan, Xiangbo/P-9265-2016 FU Division of Intramural Research of the National Heart, Lung, and Blood Institute, NIH [HL006103, HL006159] FX This work was supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute, NIH (HL006103 and HL006159). We thank Yong Chen and Marjan Gucek from NHLBI Proteomics Core for their help with mass spectrometry analysis. NR 16 TC 3 Z9 5 U1 2 U2 5 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 MAR 1 PY 2016 VL 14 IS 8 BP 1867 EP 1875 DI 10.1016/j.celrep.2016.01.062 PG 9 WC Cell Biology SC Cell Biology GA DF3BC UT WOS:000371217700007 PM 26904944 ER PT J AU Wu, JQ Keng, VW Patmore, DM Kendall, JJ Patel, AV Jousma, E Jessen, WJ Choi, K Tschida, BR Silverstein, KAT Fan, DH Schwartz, EB Fuchs, JR Zou, YS Kim, MO Dombi, E Levy, DE Huang, G Cancelas, JA Stemmer-Rachamimov, AO Spinner, RJ Largaespada, DA Ratner, N AF Wu, Jianqiang Keng, Vincent W. Patmore, Deanna M. Kendall, Jed J. Patel, Ami V. Jousma, Edwin Jessen, Walter J. Choi, Kwangmin Tschida, Barbara R. Silverstein, Kevin A. T. Fan, Danhua Schwartz, Eric B. Fuchs, James R. Zou, Yuanshu Kim, Mi-Ok Dombi, Eva Levy, David E. Huang, Gang Cancelas, Jose A. Stemmer-Rachamimov, Anat O. Spinner, Robert J. Largaespada, David A. Ratner, Nancy TI Insertional Mutagenesis Identifies a STAT3/Arid1b/beta-catenin Pathway Driving Neurofibroma Initiation SO CELL REPORTS LA English DT Article ID NERVE SHEATH TUMORS; NATURAL ANTISENSE TRANSCRIPTS; PANCREATIC-CANCER; BETA-CATENIN; CELLS; NF1; PROGRESSION; GENE; ACTIVATION; TYPE-1 AB To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/beta-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and beta-catenin activity. beta-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and beta-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3 beta and the SWI/SNF gene Arid1b to increase beta-catenin. Knockdown of Arid1b or Gsk3 beta in Stat3(fl/fl); Nf1(fl/fl); DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/beta-catenin pathway inhibitors in neurofibroma therapeutic trials. C1 [Wu, Jianqiang; Patmore, Deanna M.; Kendall, Jed J.; Patel, Ami V.; Jousma, Edwin; Jessen, Walter J.; Choi, Kwangmin; Huang, Gang; Cancelas, Jose A.; Ratner, Nancy] Univ Cincinnati, Cincinnati Childrens Hosp, Canc & Blood Dis Inst, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Zou, Yuanshu; Kim, Mi-Ok] Univ Cincinnati, Cincinnati Childrens Hosp, Cincinnati Childrens Hosp Res Fdn, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Keng, Vincent W.; Tschida, Barbara R.; Largaespada, David A.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Keng, Vincent W.; Largaespada, David A.] Univ Minnesota, Dept Pediat Cell Biol & Dev, Minneapolis, MN 55455 USA. [Keng, Vincent W.; Tschida, Barbara R.; Largaespada, David A.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA. [Silverstein, Kevin A. T.; Fan, Danhua] Univ Minnesota, Biostat & Informat, Minneapolis, MN 55455 USA. [Schwartz, Eric B.; Fuchs, James R.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Dombi, Eva] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Levy, David E.] NYU, Sch Med, Dept Pathol, 550 First Ave, New York, NY 10016 USA. [Levy, David E.] NYU, Sch Med, Inst Canc, 550 First Ave, New York, NY 10016 USA. [Cancelas, Jose A.] Univ Cincinnati, Coll Med, Hoxworth Blood Ctr, Cincinnati, OH 45267 USA. [Stemmer-Rachamimov, Anat O.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Spinner, Robert J.] Mayo Clin, Dept Neurol Surg, Rochester, MN 55905 USA. [Keng, Vincent W.] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Kowloon, Hong Kong, Peoples R China. RP Ratner, N (reprint author), Univ Cincinnati, Cincinnati Childrens Hosp, Canc & Blood Dis Inst, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. EM nancy.ratner@cchmc.org OI Keng, Vincent/0000-0003-3473-0653; Levy, David/0000-0002-7320-7788 FU NIH [R01 NS28840, P50 NS057531]; DAMD New Investigator Award [W81XWH-11-1-0259]; Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant; American Cancer Society [IRG-67-00344] FX We thank the Minnesota Supercomputing Institute for computational resources for sequence analysis, Dr. Ari Melnick (Weil Cornell Medical School) for assistance in design of histone modification analysis, and Ms. Huiqing Li for animal husbandry. This work was supported by NIH R01 NS28840 (N.R.), NIH P50 NS057531 (N.R. and D.A.L.), a DAMD New Investigator Award (W81XWH-11-1-0259), an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (J.W.), and the American Cancer Society (IRG-67-003-44) (J.R.F.). The CHTN provided some benign neurofibromas used in this study. NR 40 TC 4 Z9 4 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 MAR 1 PY 2016 VL 14 IS 8 BP 1979 EP 1990 DI 10.1016/j.celrep.2016.01.074 PG 12 WC Cell Biology SC Cell Biology GA DF3BC UT WOS:000371217700017 PM 26904939 ER PT J AU Papadakis, GZ Millo, C Bagci, U Sadowski, SM Stratakis, CA AF Papadakis, Georgios Z. Millo, Corina Bagci, Ulas Sadowski, Samira M. Stratakis, Constantine A. TI Schmorl Nodes Can Cause Increased 68Ga DOTATATE Activity on PET/CT, Mimicking Metastasis in Patients With Neuroendocrine Malignancy SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE neuroendocrine tumor; Ga-68 DOTATATE PET/CT; Schmorl node; inflammation ID GA-68-DOTATATE PET/CT; SOMATOSTATIN; MACROPHAGES; EXPRESSION AB Schmorl node (SN) is the herniation of the nucleus pulposus through the cartilaginous and bony endplate into the adjacent vertebral body. It is documented that SNs produce areas of moderately increased F-18-FDG uptake. We present a case of a patient with history of neuroendocrine tumor, who underwent Ga-68 DOTATATE PET/CT for follow-up, showing increased focal vertebral uptake suggestive of bone metastasis. CT revealed typical findings of an SN. The presented case indicates that SNs should be considered when encountering focally increased skeletal uptake in Ga-68 DOTATATE PET/CT studies, which can mimic metastasis in patients with history of neuroendocrine tumors. C1 [Papadakis, Georgios Z.] NIH, Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Millo, Corina] NIH, Div Nucl Med, RAD&IS Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Bagci, Ulas] Univ Cent Florida, Ctr Comp Vis Res, Dept Comp Sci & Elect, Orlando, FL 32816 USA. [Sadowski, Samira M.] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC,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 HD008920-01] NR 15 TC 5 Z9 5 U1 0 U2 1 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 MAR PY 2016 VL 41 IS 3 BP 249 EP 250 DI 10.1097/RLU.0000000000001065 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DE2UI UT WOS:000370482300024 PM 26562580 ER PT J AU Manjula, A Pushpanathan, M Sathyavathi, S Gunasekaran, P Rajendhran, J AF Manjula, Arumugam Pushpanathan, Muthuirulan Sathyavathi, Sundararaju Gunasekaran, Paramasamy Rajendhran, Jeyaprakash TI Comparative Analysis of Microbial Diversity in Termite Gut and Termite Nest Using Ion Sequencing SO CURRENT MICROBIOLOGY LA English DT Article ID SOIL-FEEDING TERMITE; BACTERIAL COMMUNITY STRUCTURE; PHYLOGENETIC DIVERSITY; MOUNDS; LIGNOCELLULOSE; METHANOGENS; STABILITY; SYMBIONTS; DIGESTION; GENOME AB Termite gut and termite nest possess complex microbial communities. However, only limited information is available on the comparative investigation of termite gut and nest-associated microbial communities. In the present study, we examined and compared the bacterial diversity of termite gut and their respective nest by high-throughput sequencing of V3 hypervariable region of 16S rDNA. A total of 14 barcoded libraries were generated from seven termite gut samples and their respective nest samples, and sequenced using Ion Torrent platform. The sequences of each group were pooled, which yielded 170,644 and 132,000 reads from termite gut and termite nest samples, respectively. Phylogenetic analysis revealed significant differences in the bacterial diversity and community structure between termite gut and termite nest samples. Phyla Verrucomicrobia and Acidobacteria were observed only in termite gut, whereas Synergistetes and Chlorobi were observed only in termite nest samples. These variations in microbial structure and composition could be attributed with the differences in physiological conditions prevailing in the termite gut (anoxic and alkaline) and termite nest (oxic, slightly acidic and rich in organic matter) environment. Overall, this study unmasked the complexity of bacterial population in the respective niche. Interestingly, majority of the sequence reads could be classified only up to the domain level indicating the presence of a huge number of uncultivable or unidentified novel bacterial species in both termite gut and nest samples. Whole metagenome sequencing and assessing the metabolic potential of these samples will be useful for biotechnological applications. C1 [Manjula, Arumugam; Sathyavathi, Sundararaju; Gunasekaran, Paramasamy; Rajendhran, Jeyaprakash] Madurai Kamaraj Univ, Ctr Excellence Genom Sci, Sch Biol Sci, Dept Genet, Madurai 625021, Tamil Nadu, India. [Pushpanathan, Muthuirulan] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Rajendhran, J (reprint author), Madurai Kamaraj Univ, Ctr Excellence Genom Sci, Sch Biol Sci, Dept Genet, Madurai 625021, Tamil Nadu, India. EM jrajendhran@gmail.com OI Pushpanathan, Muthuirulan/0000-0001-6240-3073 FU CSIR-SRF (Council of Scientific and Industrial Research-Senior Research Fellowship) New Delhi FX The authors would like to thank CSIR-SRF (Council of Scientific and Industrial Research-Senior Research Fellowship) New Delhi for providing financial support. We would also extend our thanks to central facilities UGC-CAS, UGC-NRCBS, DBT-IPLS and DST-PURSE programs at School of Biological Sciences, Madurai Kamaraj University. NR 37 TC 1 Z9 1 U1 7 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0343-8651 EI 1432-0991 J9 CURR MICROBIOL JI Curr. Microbiol. PD MAR PY 2016 VL 72 IS 3 BP 267 EP 275 DI 10.1007/s00284-015-0947-y PG 9 WC Microbiology SC Microbiology GA DF3NM UT WOS:000371251200005 PM 26613615 ER PT J AU Hung, IH Schoenwolf, GC Lewandoski, M Ornitz, DM AF Hung, Irene H. Schoenwolf, Gary C. Lewandoski, Mark Ornitz, David M. TI A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE FGF; Chondrogenesis; Growth plate; Mouse ID GROWTH-FACTOR RECEPTOR-3; HYPERTROPHIC CHONDROCYTE DIFFERENTIATION; INDIAN-HEDGEHOG; BONE-GROWTH; MESSENGER-RNA; OSTEOBLAST DIFFERENTIATION; ENDOCHONDRAL OSSIFICATION; CBFA1-DEFICIENT MICE; DEVELOPMENT SUGGESTS; TARGETED DISRUPTION AB Fibroblast growth factor (FGF) signaling is a critical regulator of skeletal development. Fgf9 and Fgf18 are the only FGF ligands with identified functions in embryonic bone growth. Mice lacking Fgf9 or Fgf18 have distinct skeletal phenotypes; however, the extent of overlapping or redundant functions for these ligands and the stage-specific contributions of FGF signaling to chondrogenesis and osteogenesis are not known. To identify separate versus shared roles for FGF9 and FGF18, we generated a combined series of Fgf9 and Fgf18 null alleles. Analysis of embryos lacking alleles of Fgf9 and Fgf18 shows that both encoded ligands function redundantly to control all stages of skeletogenesis; however, they have variable potencies along the proximodistal limb axis, suggesting gradients of activity during formation of the appendicular skeleton. Congenital absence of both Fe and Fgf18 results in a striking osteochondrodysplasia and revealed functions for FGF signaling in early proximal limb chondrogenesis. Additional defects were also noted in craniofacial bones, vertebrae, and ribs. Loss of alleles of Fgf9 and Fgf18 also affect the expression of genes encoding other key intrinsic skeletal regulators, including IHH, PTHLH (PTHrP), and RUNX2, revealing potential direct, indirect, and compensatory mechanisms to coordinate chondrogenesis and osteogenesis. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hung, Irene H.; Schoenwolf, Gary C.] Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. [Hung, Irene H.; Lewandoski, Mark] NCI, Canc & Dev Biol Lab, 1050 Boyles St,Bldg 539,Rm 135, Frederick, MD 21701 USA. [Hung, Irene H.; Ornitz, David M.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Ornitz, David M.] Washington Univ, Sch Med, Rm 3902 South Bldg,Campus Box 8103, St Louis, MO 63110 USA. RP Hung, IH (reprint author), NCI, Canc & Dev Biol Lab, 1050 Boyles St,Bldg 539,Rm 135, Frederick, MD 21701 USA. EM irene.hung@hsc.utah.edu; dornitz@wustl.edu FU NIH Grants [CHRCDA K12HD0410, K08HD058219, DC011819, HD049808]; University of Utah Department of Pediatrics Seed Funding; Primary Children's Foundation Grants; Children's Health Research Center Funding; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Washington University Musculoskeletal Research Center [NIH P30 AR057235] FX We thank L. Li, H.H. Shi, J. Hunter, E. Truffer, and A. Ferris for technical help. IHH was supported by NIH Grants CHRCDA K12HD0410 and K08HD058219, University of Utah Department of Pediatrics Seed Funding, Primary Children's Foundation Grants, Children's Health Research Center Funding. GCS was supported by NIH Grant DC011819. ML was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. DMO was supported by NIH Grant HD049808, Washington University Musculoskeletal Research Center NIH P30 AR057235. NR 82 TC 4 Z9 4 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAR 1 PY 2016 VL 411 IS 1 BP 72 EP 84 DI 10.1016/j.ydbio.2016.01.008 PG 13 WC Developmental Biology SC Developmental Biology GA DF6CY UT WOS:000371444600007 PM 26794256 ER PT J AU Martina, JA Diab, HI Brady, OA Puertollano, R AF Martina, Jose A. Diab, Heba I. Brady, Owen A. Puertollano, Rosa TI TFEB and TFE3 are novel components of the integrated stress response SO EMBO JOURNAL LA English DT Article DE ATF4; ER stress; PERK; TFE3; TFEB ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; TRANSCRIPTION FACTOR TFE3; RENAL-CELL CARCINOMA; LYSOSOMAL BIOGENESIS; RAG GTPASES; ER STRESS; TRANSLATIONAL CONTROL; AUTOPHAGY; METABOLISM AB To reestablish homeostasis and mitigate stress, cells must activate a series of adaptive intracellular signaling pathways. The participation of the transcription factors TFEB and TFE3 in cellular adaptation to starvation is well established. Here, we show that TFEB and TFE3 also play an important role in the cellular response to ER stress. Treatment with ER stressors causes translocation of TFEB and TFE3 to the nucleus in a process that is dependent on PERK and calcineurin but not on mTORC1. Activated TFEB and TFE3 enhance cellular response to stress by inducing direct transcriptional upregulation of ATF4 and other UPR genes. Under conditions of prolonged ER stress, TFEB and TFE3 contribute to cell death, thus revealing an unexpected role for these proteins in controlling cell fate. This work evidences a broader role of TFEB and TFE3 in the cellular response to stress than previously anticipated and reveals an integrated cooperation between different cellular stress pathways. C1 [Martina, Jose A.; Diab, Heba I.; Brady, Owen A.; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov RI di Ronza, Alberto/H-7674-2016 OI di Ronza, Alberto/0000-0002-9813-5143 FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). We thank Dr. Philip McCoy and Dr. Pradeep Dagur (Flow Cytometry Core, NHLBI) for their assistance in the Annexin V apoptosis analysis. We also thank Dr. Gustavo Gutierrez and Dr. Hossein Zare (NIAMS) for their assistance in the analysis of the ChIP-seq data and Dr. Douglas Forrest (NIDDK) for assistance with the GloMax 96 Microplate Luminometer. NR 45 TC 10 Z9 10 U1 4 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD MAR 1 PY 2016 VL 35 IS 5 BP 479 EP 495 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DF6CH UT WOS:000371442300003 PM 26813791 ER PT J AU Falcone, EL Petts, JR Fasano, MB Ford, B Nauseef, WM Neves, JF Simoes, MJ Tierce, ML de la Morena, MT Greenberg, DE Zerbe, CS Zelazny, AM Holland, SM AF Falcone, E. Liana Petts, Jennifer R. Fasano, Mary Beth Ford, Bradley Nauseef, William M. Neves, Joao Farela Simoes, Maria Joao Tierce, Millard L. de la Morena, M. Teresa Greenberg, David E. Zerbe, Christa S. Zelazny, Adrian M. Holland, Steven M. TI Methylotroph Infections and Chronic Granulomatous Disease SO EMERGING INFECTIOUS DISEASES LA English DT Article ID PATHOGEN GRANULIBACTER-BETHESDENSIS; BACTERIAL PATHOGEN; PATIENT AB Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in production of phagocyte derived reactive oxygen species, which leads to recurrent infections with a characteristic group of pathogens not previously known to include methylotrophs. Methylotrophs are versatile environmental bacteria that can use single-carbon organic compounds as their sole source of energy; they rarely cause disease in immunocompetent persons. We have identified 12 infections with methylotrophs (5 reported here, 7 previously reported) in patients with CGD. Methylotrophs identified were Granulibacter bethesdensis (9 cases), Acidomonas methanolica (2 cases), and Methylobacterium lusitanum (1 case). Two patients in Europe died; the other 10, from North and Central America, recovered after prolonged courses of antimicrobial drug therapy and, for some, surgery. Methylotrophs are emerging as disease causing organisms in patients with CGD. For all patients, sequencing of the 16S rRNA gene was required for correct diagnosis. Geographic origin of the methylotroph strain may affect clinical management and prognosis. C1 [Falcone, E. Liana; Zerbe, Christa S.; Zelazny, Adrian M.; Holland, Steven M.] NIH, Rm B3-4141,9000 Rockville Pike Blvd 10-CRC, Bethesda, MD 20892 USA. [Petts, Jennifer R.; Fasano, Mary Beth; Ford, Bradley; Nauseef, William M.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Nauseef, William M.] Vet Adm Med Ctr, Iowa City, IA USA. [Neves, Joao Farela] Ctr Hosp Lisboa Cent, Lisbon, Portugal. [Simoes, Maria Joao] Inst Nacl Saude Dr Ricardo Jorge, Lisbon, Portugal. [Tierce, Millard L.] Detroit Med Ctr, Detroit, MI USA. [de la Morena, M. Teresa; Greenberg, David E.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Falcone, EL (reprint author), NIH, LCID NIAID, Rm B3-4141,9000 Rockville Pike Blvd 10-CRC, Bethesda, MD 20892 USA. EM emilia.falcone@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [ZO1-AI-00646-06] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA (grant no. ZO1-AI-00646-06). NR 14 TC 0 Z9 0 U1 1 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2016 VL 22 IS 3 BP 404 EP 409 DI 10.3201/eid2203.151265 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DF2RS UT WOS:000371192100006 PM 26886412 ER PT J AU Wei, BN Aiwis, KU Li, Z Wang, LQ Valentin-Blasini, L Sosnoff, CS Xia, Y Conway, KP Blount, BC AF Wei, Binnian Aiwis, K. Udeni Li, Zheng Wang, Lanqing Valentin-Blasini, Liza Sosnoff, Connie S. Xia, Yang Conway, Kevin P. Blount, Benjamin C. TI Urinary concentrations of PAH and VOC metabolites in marijuana users SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Cannabis smoke; Biomonitoring; PAHs; VOCs; Secondhand smoke; Environmental tobacco smoke (ETS) ID TANDEM MASS-SPECTROMETRY; POLYCYCLIC AROMATIC-HYDROCARBONS; PRENATAL CANNABIS EXPOSURE; TOBACCO-SMOKE; US POPULATION; SIDESTREAM MARIJUANA; ION CHROMATOGRAPHY; SECONDHAND SMOKE; CIGARETTE-SMOKE; LUNG-CANCER AB Background: Marijuana is seeing increased therapeutic use, and is the world's third most-popular recreational drug following alcohol and tobacco. This widening use poses increased exposure to potentially toxic combustion by-products from marijuana smoke and the potential for public health concerns. Objectives: To compare urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) among self-reported recent marijuana users and nonusers, while accounting for tobacco smoke exposure. Methods: Measurements of PAH and VOC metabolites in urine samples were combined with questionnaire data collected from participants in the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2012 in order to categorize participants (>= 18 years) into exclusive recent marijuana users and nonusers. Adjusted geometric means (GMs) of urinary concentrations were computed for these groups using multiple regression analyses to adjust for potential confounders. Results: Adjusted GMs of many individual monohydroxy PAHs (OH-PAHs) were significantly higher in recent marijuana users than in nonusers (p < 0.05). Urinary thiocyanate (p < 0.001) and urinary concentrations of many VOC metabolites, including metabolites of acrylonitrile (p < 0.001) and acrylamide (p < 0.001), were significantly higher in recent marijuana users than in nonusers. Conclusions: We found elevated levels of biomarkers for potentially harmful chemicals among self-identified, recent marijuana users compared with nonusers. These findings suggest that further studies are needed to evaluate the potential health risks to humans from the exposure to these agents when smoking marijuana. Published by Elsevier Ltd. C1 [Wei, Binnian; Aiwis, K. Udeni; Li, Zheng; Wang, Lanqing; Valentin-Blasini, Liza; Sosnoff, Connie S.; Xia, Yang; Blount, Benjamin C.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Conway, Kevin P.] NIH, Div Epidemiol Serv & Prevent Res, Bethesda, MD USA. RP Wei, BN (reprint author), Ctr Dis Control & Prevent, Div Sci Lab, 4770 Buford Hwy,NE Rd,Mail Stop F44, Atlanta, GA 30341 USA. EM bwei@cdc.gov OI Conway, Kevin/0000-0002-7638-339X; Wei, Binnian/0000-0003-0465-9964 FU Intramural CDC HHS [CC999999] NR 53 TC 2 Z9 2 U1 9 U2 43 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD MAR PY 2016 VL 88 BP 1 EP 8 DI 10.1016/j.envint.2015.12.003 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA DF4YU UT WOS:000371359300001 PM 26690539 ER PT J AU Jukic, AM Calafat, AM McConnaughey, DR Longnecker, MP Hoppin, JA Weinberg, CR Wilcox, AJ Baird, DD AF Jukic, Anne Marie Calafat, Antonia M. McConnaughey, D. Robert Longnecker, Matthew P. Hoppin, Jane A. Weinberg, Clarice R. Wilcox, Allen J. Baird, Donna D. TI Urinary Concentrations of Phthalate Metabolites and Bisphenol A and Associations with Follicular-Phase Length, Luteal-Phase Length, Fecundability, and Early Pregnancy Loss SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID OXIDATIVE STRESS; INTRAUTERINE IMPLANTATION; PRENATAL EXPOSURE; FERTILIZED OVA; IN-VITRO; WOMEN; CONCEPTION; PROGESTERONE; PROBABILITY; VARIABILITY AB BACKGROUND: Certain phthalates and bisphenol A (BPA) show reproductive effects in animal studies and potentially affect human ovulation, conception, and pregnancy loss. OBJECTIVES: We investigated these chemicals in relation to follicular-and luteal-phase lengths, time to pregnancy, and early pregnancy loss (within 6 weeks of the last menstrual period) among women attempting pregnancy. METHODS: Women discontinuing contraception provided daily first-morning urine specimens and recorded days with vaginal bleeding for up to 6 months. Specimens had previously been analyzed for estrogen and progesterone metabolites and human chorionic gonadotropin. A total of 221 participants contributed 706 menstrual cycles. We measured 11 phthalate metabolites and BPA in pooled urine from three specimens spaced throughout each menstrual cycle. We analyzed associations between chemical concentrations and outcomes using linear mixed models for follicular-and luteal-phase lengths, discrete-time fecundability models for time to pregnancy, and logistic regression for early pregnancy loss. RESULTS: Higher concentrations of monocarboxyoctyl phthalate (MCOP) were associated with shorter luteal phase [2nd tertile vs. 1st tertile: -0.5 days (95% CI: -0.9, -0.1), 3rd vs. 1st: -0.4 days (95% CI: -0.8, 0.01), p = 0.04]. BPA was also associated with shorter luteal phase [2nd vs. 1st: -0.8 days (95% CI: -1.2, -0.4), 3rd vs. 1st: -0.4 days (95% CI: -0.8, 0.02), p = 0.001]. CONCLUSIONS: BPA and MCOP (or its precursors) were associated with shorter luteal phase. Menstrual cycle-specific estimates of urinary BPA and phthalate metabolites were not associated with detrimental alterations in follicular-phase length, time to pregnancy, or early pregnancy loss, and in fact, DEHP [di(2-ethylhexyl) phthalate] metabolites {MEOHP [mono(2-ethyl-5oxohexyl) phthalate] and SDEHP} were associated with reduced early loss. These findings should be confirmed in future human studies. C1 [Jukic, Anne Marie; Longnecker, Matthew P.; Hoppin, Jane A.; Wilcox, Allen J.; Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, DHHS, POB 12233, Durham, NC 27709 USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA USA. [McConnaughey, D. Robert] Westat Corp, Durham, NC USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Weinberg, Clarice R.] NIEHS, Biostat Branch, NIH, DHHS, POB 12233, Durham, NC 27709 USA. [Jukic, Anne Marie] Yale Ctr Perinatal Pediat & Environm Epidemiol, One Church St,6th Floor, New Haven, CT 06510 USA. RP Jukic, AM (reprint author), NIEHS, Epidemiol Branch, POB 12233, Durham, NC 27709 USA. EM jukica@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Longnecker, Matthew/0000-0001-6073-5322; Wilcox, Allen/0000-0002-3376-1311 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES049003-23] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (grant Z01ES049003-23). NR 53 TC 8 Z9 8 U1 6 U2 25 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 MAR PY 2016 VL 124 IS 3 BP 321 EP 328 DI 10.1289/ehp.1408164 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF6CJ UT WOS:000371442500018 PM 26161573 ER PT J AU Rodriguez, KF Ungewitter, EK Crespo-Mejias, Y Liu, C Nicol, B Kissling, GE Yao, HHC AF Rodriguez, Karina F. Ungewitter, Erica K. Crespo-Mejias, Yasmin Liu, Chang Nicol, Barbara Kissling, Grace E. Yao, Humphrey Hung-Chang TI Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID GENE-EXPRESSION CHANGES; HIGH-FAT DIET; DRINKING-WATER; CARDIOVASCULAR-DISEASE; LUTEINIZING-HORMONE; OXIDATIVE STRESS; DNA METHYLATION; MOUSE STRAINS; LUNG; CARCINOGENESIS AB BACKGROUND: Mice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear. OBJECTIVES: We evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood. METHODS: Pregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood. RESULTS: Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance. CONCLUSION: Our findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice. C1 [Rodriguez, Karina F.; Ungewitter, Erica K.; Crespo-Mejias, Yasmin; Liu, Chang; Nicol, Barbara; Yao, Humphrey Hung-Chang] NIEHS, Reprod Dev Biol Grp, Reprod & Dev Biol Lab, NIH,Dept Hlth & Human Serv, 111 TW Alexander Dr,C4-10, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Natl Toxicol Program, NIH,Dept Hlth & Human Serv, 111 TW Alexander Dr,C4-10, Res Triangle Pk, NC 27709 USA. RP Yao, HHC (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr,C4-10, Res Triangle Pk, NC 27709 USA. EM humphrey.yao@nih.gov RI Yao, Humphrey Hung-Chang/B-4795-2010; OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469; Liu, Chang/0000-0002-8723-7363; Nicol, Barbara/0000-0002-3434-0658 FU NIH/NIEHS [ES102965] FX This research was supported by the Intramural Research Program (ES102965) of the NIH/NIEHS. NR 58 TC 1 Z9 1 U1 3 U2 14 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 MAR PY 2016 VL 124 IS 3 BP 336 EP 343 DI 10.1289/ehp.1509703 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF6CJ UT WOS:000371442500020 PM 26295903 ER PT J AU Wells, EM Herbstman, JB Lin, YH Jarrett, J Verdon, CP Ward, C Caldwell, KL Hibbeln, JR Witter, FR Halden, RU Goldman, LR AF Wells, Ellen M. Herbstman, Julie B. Lin, Yu Hong Jarrett, Jeffery Verdon, Carl P. Ward, Cynthia Caldwell, Kathleen L. Hibbeln, Joseph R. Witter, Frank R. Halden, Rolf U. Goldman, Lynn R. TI Cord Blood Methylmercury and Fetal Growth Outcomes in Baltimore Newborns: Potential Confounding and Effect Modification by Omega-3 Fatty Acids, Selenium, and Sex SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID MERCURY EXPOSURE; BIRTH-WEIGHT; POLYCHLORINATED-BIPHENYLS; PROSPECTIVE COHORT; FISHING COMMUNITY; INORGANIC MERCURY; GESTATIONAL-AGE; MATERNAL BLOOD; FATTY-ACIDS; RISK-FACTOR AB BACKGROUND: Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. OBJECTIVE: Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. METHODS: This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004-2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). RESULTS: Geometric mean cord blood MeHg was 0.94 mu g/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, beta ln(MeHg) = -0.045 (g/cm(3)) x 100 (95% CI: -0.084, -0.005). There was no evidence of a MeHg x sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg x n-3 HUFAs interaction with birth length [among low n-3 HUFAs, beta ln(MeHg) = 0.40 cm, 95% CI: -0.02, 0.81; among high n-3 HUFAs, beta ln(MeHg) = -0.15, 95% CI: -0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, beta ln(MeHg) = 0.01 cm, 95% CI: -0.27, 0.29; among high n-3 HUFAs, beta ln(MeHg) = -0.37, 95% CI: -0.63, -0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, beta ln(MeHg) without these variables was -16.8 g (95% CI: -75.0, 41.3) versus -29.7 (95% CI: -93.9, 34.6) with all covariates. Corresponding values for ponderal index were -0.030 (g/cm(3)) x 100 (95% CI: -0.065, 0.005) and -0.045 (95% CI: -0.084, -0005). CONCLUSION: We observed an association of increased MeHg with decreased ponderal index. There is evidence for interaction between MeHg and n-3 HUFAs; infants with higher MeHg and n-3 HUFAs had lower birth length and head circumference. These results should be verified with additional studies. C1 [Wells, Ellen M.] Purdue Univ, Sch Hlth Sci, Hampton Hall Civil Engn 1269,550 Stadium Mall Dr, W Lafayette, IN 47907 USA. [Herbstman, Julie B.] Columbia Univ, Columbia Ctr Childrens Environm Hlth, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. [Lin, Yu Hong; Hibbeln, Joseph R.] NIAAA, Lab Membrane Biochem & Biophys, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Jarrett, Jeffery; Verdon, Carl P.; Ward, Cynthia; Caldwell, Kathleen L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA USA. [Witter, Frank R.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Halden, Rolf U.] Arizona State Univ, Ctr Environm Secur, Biodesign Inst, Global Secur Initiat, Tempe, AZ USA. [Goldman, Lynn R.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Environm & Occupat Hlth, Washington, DC USA. RP Wells, EM (reprint author), Purdue Univ, Sch Hlth Sci, Hampton Hall Civil Engn 1269,550 Stadium Mall Dr, W Lafayette, IN 47907 USA. EM wells54@purdue.edu OI Jarrett, Jeffery/0000-0001-5755-3552; Wells, Ellen/0000-0002-7293-1395 FU Maryland Department of Health and Mental Hygiene Cigarette Restitution Program (Baltimore, MD); National Institute of Environmental Health Sciences/National Institutes of Health (NIH) (Bethesda, MD) [1R01ES015445]; U.S. Environmental Protection Agency (EPA) STAR Fellowship Program (Washington, DC) FX This study was funded by the Maryland Department of Health and Mental Hygiene Cigarette Restitution Program (Baltimore, MD), the National Institute of Environmental Health Sciences/National Institutes of Health (NIH) grant 1R01ES015445 (Bethesda, MD) (R.U.H.), and the U.S. Environmental Protection Agency (EPA) STAR Fellowship Program (Washington, DC) (E.M.W.). NR 55 TC 2 Z9 2 U1 6 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 MAR PY 2016 VL 124 IS 3 BP 373 EP 379 DI 10.1289/ehp.1408596 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF6CJ UT WOS:000371442500025 PM 26115160 ER PT J AU Rodriguez, KF Ungewitter, EK Crespo-Mejias, Y Liu, C Nicol, B Kissling, GE Yao, HHC AF Rodriguez, Karina F. Ungewitter, Erica K. Crespo-Mejias, Yasmin Liu, Chang Nicol, Barbara Kissling, Grace E. Yao, Humphrey Hung-Chang TI Response to "Comment on 'Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice'" SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID ADULTHOOD; PULMONARY; INDUCTION; TUMORS; WATER C1 [Rodriguez, Karina F.; Ungewitter, Erica K.; Crespo-Mejias, Yasmin; Liu, Chang; Nicol, Barbara; Kissling, Grace E.; Yao, Humphrey Hung-Chang] US Dept HHS, NIEHS, NIH, Res Triangle Pk, NC USA. RP Yao, HHC (reprint author), NIEHS, 111 TW Alexander Dr,Mail Drop C4-10, Res Triangle Pk, NC 27709 USA. EM humphrey.yao@nih.gov OI Liu, Chang/0000-0002-8723-7363; Yao, Humphrey Hung-Chang/0000-0003-2944-8469 NR 9 TC 0 Z9 0 U1 1 U2 4 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 MAR PY 2016 VL 124 IS 3 BP A46 EP A47 DI 10.1289/ehp.1511181 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF6CJ UT WOS:000371442500004 PM 26930461 ER PT J AU Suk, WA Ahanchian, H Asante, KA Carpenter, DO Diaz-Barriga, F Ha, EH Huo, X King, M Ruchirawat, M da Silva, ER Sly, L Sly, PD Stein, RT van den Berg, M Zar, H Landrigan, PJ AF Suk, William A. Ahanchian, Hamid Asante, Kwadwo Ansong Carpenter, David O. Diaz-Barriga, Fernando Ha, Eun-Hee Huo, Xia King, Malcolm Ruchirawat, Mathuros da Silva, Emerson R. Sly, Leith Sly, Peter D. Stein, Renato T. van den Berg, Martin Zar, Heather Landrigan, Philip J. TI Environmental Pollution: An Under-recognized Threat to Children's Health, Especially in Low- and Middle-Income Countries SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PERSISTENT ORGANIC POLLUTANTS; BISPHENOL-A CONCENTRATION; GLOBAL BURDEN; CHILDHOOD BEHAVIOR; LATIN-AMERICA; POLYCHLORINATED-BIPHENYLS; SYSTEMATIC ANALYSIS; HAVEN HYPOTHESIS; AIR-POLLUTION; KUZNETS CURVE AB Exposures to environmental pollutants during windows of developmental vulnerability in early life can cause disease and death in infancy and childhood as well as chronic, non-communicable diseases that may manifest at any point across the life span. Patterns of pollution and pollution-related disease change as countries move through economic development. Environmental pollution is now recognized as a major cause of morbidity and mortality in low-and middle-income countries (LMICs). According to the World Health Organization, pollution is responsible for 8.9 million deaths around the world each year; of these, 94% (8.4 million) are in LMICs. Toxic chemical pollution is growing into a major threat to children's health in LMICs. The disease and disability caused by environmental pollution have great economic costs, and these costs can undercut trajectories of national development. To combat pollution, improved programs of public health and environmental protection are needed in countries at every level of development. Pollution control strategies and technologies that have been developed in high-income countries must now be transferred to LMICs to assist these emerging economies to avoid the mistakes of the past. A new international clearinghouse is needed to define and track the health effects of pollution, quantify the economic costs of these effects, and direct much needed attention to environmental pollution as a risk factor for disease. C1 [Suk, William A.] NIEHS, Hazardous Subst Res Branch, Superfund Res Program, NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Ahanchian, Hamid] Mashhad Univ Med Sci, Ghaem Hosp, Dept Allergy & Clin Immunol, Mashhad, Iran. [Asante, Kwadwo Ansong] CSIR, Water Res Inst, Accra, Ghana. [Carpenter, David O.] SUNY Albany, Inst Hlth & Environm, Rensselaer, NY USA. [Diaz-Barriga, Fernando] Univ Autonoma San Luis Potosi, San Luis Potosi, Mexico. [Ha, Eun-Hee] Ewha Womans Univ, Sch Med, Dept Prevent Med, Seoul, South Korea. [Huo, Xia] Shantou Univ, Coll Med, Shantou, Peoples R China. [King, Malcolm] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC, Canada. [Ruchirawat, Mathuros] Chulabhorn Res Inst, Bangkok, Thailand. [da Silva, Emerson R.] Univ Caxias Do Sul, Sch Med, Dept Pediat, Caxias Do Sul, Brazil. [Sly, Leith; Sly, Peter D.] Univ Queensland, Queensland Childrens Med Res Inst, Childrens Hlth & Environm Program, Brisbane, Qld, Australia. [Sly, Peter D.] Pontificia Univ Catolica Rio Grande Do Sul, Biomed Res Inst, Ctr Infant, Porto Alegre, RS, Brazil. [van den Berg, Martin] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Zar, Heather] Univ Cape Town, MRC Unit Child & Adolescent Hlth, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, ZA-7925 Cape Town, South Africa. [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Arnhold Global Hlth Inst, New York, NY 10029 USA. RP Suk, WA (reprint author), NIEHS, Superfund Res Program, Div Extramural Res & Training, NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM suk@niehs.nih.gov NR 77 TC 3 Z9 3 U1 14 U2 46 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 MAR PY 2016 VL 124 IS 3 BP A41 EP A45 DI 10.1289/ehp.1510517 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF6CJ UT WOS:000371442500002 PM 26930243 ER PT J AU Weis, CP AF Weis, Christopher P. TI The Value of Alternatives Assessment SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Weis, Christopher P.] NIEHS, NIH, US Dept HHS, Bethesda, MD USA. RP Weis, CP (reprint author), NIEHS, NIH, US Dept HHS, Bethesda, MD USA. EM christopher.weis@nih.gov NR 4 TC 0 Z9 0 U1 6 U2 6 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 MAR PY 2016 VL 124 IS 3 BP A40 EP A40 DI 10.1289/ehp.1611248 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF6CJ UT WOS:000371442500001 PM 26930551 ER PT J AU Shimony, MK Schliep, KC Schisterman, EF Ahrens, KA Sjaarda, LA Rotman, Y Perkins, NJ Pollack, AZ Wactawski-Wende, J Mumford, SL AF Shimony, Maya K. Schliep, Karen C. Schisterman, Enrique F. Ahrens, Katherine A. Sjaarda, Lindsey A. Rotman, Yaron Perkins, Neil J. Pollack, Anna Z. Wactawski-Wende, Jean Mumford, Sunni L. TI The relationship between sugar-sweetened beverages and liver enzymes among healthy premenopausal women: a prospective cohort study SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Liver enzymes; Menstrual cycle; Fructose; Dietary sucrose; Sugar-sweetened beverages ID FRUCTOSE CONSUMPTION; METABOLIC SYNDROME; NUTRIENT DATABASE; DIETARY FRUCTOSE; MENSTRUAL-CYCLE; DISEASE; BIOCYCLE; PLASMA; ADULTS; FAT AB To prospectively assess the association between sugar-sweetened beverages (SSB), added sugar, and total fructose and serum concentrations of liver enzymes among healthy, reproductive-age women. A prospective cohort of 259 premenopausal women (average age 27.3 +/- A 8.2 years; BMI 24.1 +/- A kg/m(2)) were followed up for up to two menstrual cycles, providing up to eight fasting blood specimens/cycle and four 24-h dietary recalls/cycle. Women with a history of chronic disease were excluded. Alanine and aspartate aminotransferases (ALT and AST, respectively) were measured in serum samples. Linear mixed models estimated associations between average SSB, added sugar, and total fructose intake and log-transformed liver enzymes adjusting for age, race, body mass index, total energy and alcohol intake, and Mediterranean diet score. For every 1 cup/day increase in SSB consumption and 10 g/day increase in added sugar and total fructose, log ALT increased by 0.079 U/L (95 % CI 0.022, 0.137), 0.012 U/L (95 % CI 0.002, 0.022), and 0.031 (0.012, 0.050), respectively, and log AST increased by 0.029 U/L (-0.011, 0.069), 0.007 U/L (0.000, 0.014), and 0.017 U/L (0.004, 0.030), respectively. Women who consumed a parts per thousand yen1.50 cups/day (12 oz can) SSB versus less had 0.127 U/L (95 % CI 0.001, 0.254) higher ALT [percent change 13.5 % (95 % CI 0.1, 28.9)] and 0.102 (95 % CI 0.015, 0.190) higher AST [percent change 10.8 % (95 % CI 1.5, 20.9)]. Sugar-sweetened beverages were associated with higher serum ALT and AST concentrations among healthy premenopausal women, indicating that habitual consumption of even moderate SSB may elicit hepatic lipogenesis. C1 [Shimony, Maya K.; Schliep, Karen C.; Schisterman, Enrique F.; Ahrens, Katherine A.; Sjaarda, Lindsey A.; Perkins, Neil J.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. [Shimony, Maya K.] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Epidemiol & Biostat, Washington, DC USA. [Rotman, Yaron] NIDDK, Liver Dis Branch, NIH, Rockville, MD USA. [Pollack, Anna Z.] George Mason Univ, Coll Hlth & Human Serv, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14260 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X NR 31 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 EI 1436-6215 J9 EUR J NUTR JI Eur. J. Nutr. PD MAR PY 2016 VL 55 IS 2 BP 569 EP 576 DI 10.1007/s00394-015-0876-3 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DF3RD UT WOS:000371262400013 PM 25801628 ER PT J AU Park, KS Pfeifer, K AF Park, Ki-Sun Pfeifer, Karl TI Making choices-how stochastic decisions determine disease progression SO GENES & DEVELOPMENT LA English DT Editorial Material DE gene expression; imprinting; single cell AB In this issue of Genes & Development, Ginart and colleagues (pp. 567-578) study a mouse model for Russell-Silver syndrome (RSS) and show that similar cells within one individual can display distinct gene expression patterns because of epigenetic marks that are established stochastically during early development. Their results provide an excellent explanation for phenotypes seen in RSS and other imprinting disorders and especially help us understand how patients with similar or even identical genetic mutations can display distinct disease profiles. C1 [Park, Ki-Sun; Pfeifer, Karl] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20814 USA. RP Pfeifer, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20814 USA. EM pfeiferk@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X FU Intramural NIH HHS NR 4 TC 0 Z9 0 U1 0 U2 0 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 MAR 1 PY 2016 VL 30 IS 5 BP 485 EP 486 DI 10.1101/gad.278952.116 PG 2 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DF4BU UT WOS:000371293100001 PM 26944674 ER PT J AU Benyoucef, A Palii, CG Wang, CC Porter, CJ Chu, A Dai, FT Tremblay, V Rakopoulos, P Singh, K Huang, SM Pflumio, F Hebert, J Couture, JF Perkins, TJ Ge, K Dilworth, FJ Brand, M AF Benyoucef, Aissa Palii, Carmen G. Wang, Chaochen Porter, Christopher J. Chu, Alphonse Dai, Fengtao Tremblay, Veronique Rakopoulos, Patricia Singh, Kulwant Huang, Suming Pflumio, Francoise Hebert, Josee Couture, Jean-Francois Perkins, Theodore J. Ge, Kai Dilworth, F. Jeffrey Brand, Marjorie TI UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia SO GENES & DEVELOPMENT LA English DT Article DE UTX; TAL1; histone demethylation; leukemia; histone demethylase inhibitor; epigenetics ID H3K27ME3 DEMETHYLASE UTX; METHYLTRANSFERASE COMPLEX; GENE-EXPRESSION; STEM-CELLS; CANCER; TARGET; JMJD3; PROLIFERATION; HEMATOPOIESIS; CHROMATIN AB T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients. C1 [Benyoucef, Aissa; Palii, Carmen G.; Chu, Alphonse; Dai, Fengtao; Rakopoulos, Patricia; Singh, Kulwant; Perkins, Theodore J.; Dilworth, F. Jeffrey; Brand, Marjorie] Ottawa Gen Hosp, Res Inst, Regenerat Med Program, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8L6, Canada. [Benyoucef, Aissa; Dilworth, F. Jeffrey; Brand, Marjorie] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8L6, Canada. [Benyoucef, Aissa; Palii, Carmen G.; Tremblay, Veronique; Singh, Kulwant; Couture, Jean-Francois; Dilworth, F. Jeffrey; Brand, Marjorie] Ottawa Inst Syst Biol, Ottawa, ON K1H 8L6, Canada. [Wang, Chaochen; Ge, Kai] NIDDK, NIH, Bethesda, MD 20892 USA. [Porter, Christopher J.; Perkins, Theodore J.] Ottawa Hosp, Res Inst, Sprott Ctr Stem Cell Res, Ottawa Bioinformat Core Facil, Ottawa, ON K1H 8L6, Canada. [Tremblay, Veronique; Couture, Jean-Francois; Perkins, Theodore J.] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada. [Huang, Suming] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Pflumio, Francoise] Commissariat Energie Atom & Energies Alternat Dir, Inst Rech Radiobiol Cellulaire & Mol IRCM, Stem Cells & Radiat Dept SCSR, Lab Hematopoiet Stem Cells & Leukemia LSHL,U967, F-92265 Paris, France. [Pflumio, Francoise] INSERM, U967, F-92265 Paris, France. [Pflumio, Francoise] Univ Paris 11, Univ Paris Diderot, Sorbonne Paris Cite, UMR 967, F-92265 Paris, France. [Hebert, Josee] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Hebert, Josee] Maisonneuve Rosemont Hosp, Montreal, PQ H1T 2M4, Canada. RP Brand, M (reprint author), Ottawa Gen Hosp, Res Inst, Regenerat Med Program, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8L6, Canada.; Brand, M (reprint author), Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8L6, Canada.; Brand, M (reprint author), Ottawa Inst Syst Biol, Ottawa, ON K1H 8L6, Canada. EM mbrand@ohri.ca RI Pflumio, Francoise/E-2074-2017; OI Porter, Christopher/0000-0001-8636-4515; Ge, Kai/0000-0002-7442-5138; Perkins, Theodore J./0000-0002-6622-8003 FU Canadian Institutes of Health Research [MOP-82813, MOP-77778]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (USA); Cancer Research Network of Fonds de la Recherche du Quebec en Sante (FRSQ); Government of Ontario Ministry of Research and Innovation (MRI) grant FX We thank Achim Leutz (Max-Delbruck-Center for Molecular Medicine, Germany) for the pcDNA3 plasmid expressing human TAL1, Paul A. Khavari (Stanford University, USA) for JMJD3 plasmids, and Cheryl Arrowsmith (Structural Genomics Consortium; http://www.thesgc.org) for initially providing GSK-J4. We also thank Lawrence Puente (Ottawa Hospital Research Institute Proteomics Facility; http://www.ohri.ca/proteomics) and Gareth Palidwor (Ottawa Bioinformatics Core Facility; http://www.ohri.ca/bioinformatics) for MS and bioinformatic analyses. High-throughput DNA sequencing was performed at the Molecular Biology and Functional Genomics Core Facility of the Institut de Recherche Clinique de Montreal (IRCM, Canada). This project was funded with grants from the Canadian Institutes of Health Research (MOP-82813 to M.B., and MOP-77778 to F.J.D.). C.W. and K.G. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (USA). The Quebec Leukemia Cell Bank (http://www.bclq.org) is supported by a grant from the Cancer Research Network of Fonds de la Recherche du Quebec en Sante (FRSQ). The Ottawa Bioinformatics Core Facility is supported in part by a Government of Ontario Ministry of Research and Innovation (MRI) grant. NR 54 TC 12 Z9 12 U1 2 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD MAR 1 PY 2016 VL 30 IS 5 BP 508 EP 521 DI 10.1101/gad.276790.115 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DF4BU UT WOS:000371293100005 PM 26944678 ER PT J AU Hosseini-Vasoukolaei, N Mahmoudi, AR Khamesipour, A Yaghoobi-Ershadi, MR Kamhawi, S Valenzuela, JG Arandian, MH Mirhendi, H Emami, S Saeidi, Z Idali, F Jafari, R Jeddi-Tehrani, M Akhavan, AA AF Hosseini-Vasoukolaei, Nasibeh Mahmoudi, Ahmad-Reza Khamesipour, Ali Yaghoobi-Ershadi, Mohammad Reza Kamhawi, Shaden Valenzuela, Jesus G. Arandian, Mohammad Hossein Mirhendi, Hossein Emami, Shaghayegh Saeidi, Zahra Idali, Farah Jafari, Reza Jeddi-Tehrani, Mahmood Akhavan, Amir Ahmad TI Seasonal and Physiological Variations of Phlebotomus papatasi Salivary Gland Antigens in Central Iran SO JOURNAL OF ARTHROPOD-BORNE DISEASES LA English DT Article DE Antibody response; Phlebotomus papatasi; Rhombomys opimus; Salivary gland antigens; Iran ID ZOONOTIC CUTANEOUS LEISHMANIASIS; SAND FLIES DIPTERA; ANTIBODY-RESPONSE; PSYCHODIDAE; FLY; FOCUS; PROTECTION; SANDFLIES; PROTEINS; POPULATION AB Background: Sand fly saliva helps parasite establishment and induce immune responses in vertebrate hosts. In the current study, we investigated the modulation of Phlebotomus papatasi salivary gland antigen expression by seasonal and biological factors. Methods: Sand flies were grouped according to physiological stages such as unfed, fed, semi-gravid, gravid, parous, nulliparous, infected or non-infected with Leishmania major and based on the season in which they were collected. Salivary gland antigens (SGAs) were analyzed using SDS-PAGE and the antibody response against SGAs in Rhombomys opimus was determined by ELISA and Western blot. Results: The highest protein content was found in the salivary glands of unfed sand flies. The saliva content was higher in parous compared to nulliparous, in summer compared to spring, and in Leishmania-infected compared to non-infected flies. The salivary gland lysate (SGL) electrophoretic pattern variations were observed among sand flies with various physiological stages particularly from 4-9 protein bands of 14-70 kDa. The SGL of unfed and gravid flies had extra protein bands compared to fed and semi-gravid sand flies. There was missing protein bands in SGL of parous compared to nulliparous; and in summer compared to spring collected flies. Rhombomys opimus serum reacted strongly with an antigenic band of around 28 kDa in the SGL of all sand fly groups. Conclusion: Certain biological and environmental characteristics of wild populations of vector sand flies affect the protein content and antigenicity of saliva. This might have an important implication in the design of vector-based vaccines. C1 [Hosseini-Vasoukolaei, Nasibeh; Yaghoobi-Ershadi, Mohammad Reza; Saeidi, Zahra; Akhavan, Amir Ahmad] Univ Tehran Med Sci, Sch Publ Hlth, Dept Med Entomol & Vector Control, Tehran, Iran. [Mahmoudi, Ahmad-Reza; Emami, Shaghayegh; Jeddi-Tehrani, Mahmood] ACECR, Avicenna Res Inst, Monoclonal Antibody Res Ctr, Tehran, Iran. [Khamesipour, Ali] Univ Tehran Med Sci, Ctr Res & Training Skin Dis & Leprosy, Tehran, Iran. [Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Arandian, Mohammad Hossein; Jafari, Reza] Tehran Univ Med SciencesEsfahan, Natl Inst Hlth Res, Esfahan Hlth Res Stn, Tehran, Iran. [Mirhendi, Hossein] Univ Tehran Med Sci, Sch Publ Hlth, Dept Med Parasitol & Mycol, Tehran, Iran. [Idali, Farah] ACECR, Avicenna Res Inst, Reprod Immunol Res Ctr, Tehran, Iran. RP Akhavan, AA (reprint author), Univ Tehran Med Sci, Sch Publ Hlth, Dept Med Entomol & Vector Control, Tehran, Iran.; Jeddi-Tehrani, M (reprint author), ACECR, Avicenna Res Inst, Monoclonal Antibody Res Ctr, Tehran, Iran. EM mahjed@avicenna.ac.ir; aaakhavan@tums.ac.ir FU Research deputy of Tehran University of Medical Sciences [18511/16.5.2012]; Avicenna Research Institute [910206018] FX This research was supported by Research deputy of Tehran University of Medical Sciences, Project No. 18511/16.5.2012 and Avicenna Research Institute Project No. 910206018. We are very grateful to Dr Shabani for his valuable comment and Ms Babaei, Ms Balaei, Mr Hadavi for their technical assistance, from Avicenna Research Institute, ACECR. We also thank Ms. Shareghi, Esfahan Health Research Station, National Institute of Health Research, TUMS, for her assistance in the project. We are grateful to Ms. Ahmadi and Ms. Bolandian, School of Public Health, TUMS, for their assistance in sand fly rearing. The authors declare that there is no conflict of interests. NR 33 TC 1 Z9 1 U1 0 U2 1 PU IRANIAN SCIENTIFIC SOCIETY MEDICAL ENTOMOLOGY PI TEHRAN PA SCHOOL PUBLIC HEALTH & INST HEALTH RESEARCH, TEHRAN UNIV MEDICAL SCIENCES, P O BOX 6446-14155, TEHRAN, 00000, IRAN SN 2322-1984 EI 2322-2271 J9 J ARTHROPOD-BORNE DI JI J. Arthropod.-Borne Dis. PD MAR PY 2016 VL 10 IS 1 BP 39 EP 49 PG 11 WC Public, Environmental & Occupational Health; Parasitology SC Public, Environmental & Occupational Health; Parasitology GA DF2AZ UT WOS:000371142900004 PM 27047970 ER PT J AU Wilson, BAP Alam, MS Guszczynski, T Jakob, M Shenoy, SR Mitchell, CA Goncharova, EI Evans, JR Wipf, P Liu, G Ashwell, JD O'Keefe, BR AF Wilson, Brice A. P. Alam, Muhammad S. Guszczynski, Tad Jakob, Michal Shenoy, Shilpa R. Mitchell, Carter A. Goncharova, Ekaterina I. Evans, Jason R. Wipf, Peter Liu, Gang Ashwell, Jonathan D. O'Keefe, Barry R. TI Discovery and Characterization of a Biologically Active Non-ATP-Competitive p38 MAP Kinase Inhibitor SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE high throughput; p38; non-ATP competitive; enzyme kinetics ID SELECTIVE INHIBITOR; IN-VIVO; SUBSTRATE; P38-ALPHA; INFLAMMATION; ACTIVATION; MECHANISMS; POTENT; ASSAYS AB Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPKs whose activity is responsible for mediating an intracellular response to extracellular stimuli through a phosphorylation cascade. p38 is central to this signaling node and is activated by upstream kinases while being responsible for activating downstream kinases and transcription factors via phosphorylation. Dysregulated p38 activity is associated with numerous autoimmune disorders and has been implicated in the progression of several types of cancer. A number of p38 inhibitors have been tested in clinical trials, with none receiving regulatory approval. One characteristic shared by all of the compounds that failed clinical trials is that they are all adenosine triphosphate (ATP)-competitive p38 inhibitors. Seeing this lack of mechanistic diversity as an opportunity, we screened 32,000 substances in search of novel p38 inhibitors. Among the inhibitors discovered is a compound that is both non-ATP competitive and biologically active in cell-based models for p38 activity. This is the first reported discovery of a non-ATP-competitive p38 inhibitor that is active in cells and, as such, may enable new pharmacophore designs for both therapeutic and basic research to better understand and exploit non-ATP-competitive inhibitors of p38 activity. C1 [Wilson, Brice A. P.; Guszczynski, Tad; Shenoy, Shilpa R.; Mitchell, Carter A.; Goncharova, Ekaterina I.; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick Natl Lab Canc Res,NIH, Bldg 562,Rm 201, Frederick, MD 21702 USA. [Alam, Muhammad S.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jakob, Michal] Wroclaw Univ Technol, Fac Chem, Dept Biochem, PL-50370 Wroclaw, Poland. [Shenoy, Shilpa R.] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Goncharova, Ekaterina I.; Evans, Jason R.] Data Management Serv Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Wipf, Peter] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. [Liu, Gang] Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China. [Liu, Gang] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Peking Union Med Coll, Beijing 100084, Peoples R China. [Liu, Gang] Tsinghua Univ, Sch Med, Dept Pharmacol & Pharmaceut Sci, Beijing 100084, Peoples R China. [O'Keefe, Barry R.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bldg 562,Rm 201, Frederick, MD 21702 USA. RP O'Keefe, BR (reprint author), NCI, Bldg 562,Rm 201, Frederick, MD 21702 USA. EM okeefeba@mail.nih.gov FU National Institutes of Health (NIH) Intramural AIDS Targeted Antiviral Program; National Cancer Institute, NIH [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by funds from the National Institutes of Health (NIH) Intramural AIDS Targeted Antiviral Program (B.R.O. and M.J.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E (S.R.S.). This project has also been supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 35 TC 0 Z9 0 U1 1 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD MAR PY 2016 VL 21 IS 3 BP 277 EP 289 DI 10.1177/1087057115615518 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA DF4PH UT WOS:000371331100006 PM 26538432 ER PT J AU Ishikawa, M Williams, GL Ikeuchi, T Sakai, K Fukumoto, S Yamada, Y AF Ishikawa, Masaki Williams, Geneva L. Ikeuchi, Tomoko Sakai, Kiyoshi Fukumoto, Satoshi Yamada, Yoshihiko TI Pannexin 3 and connexin 43 modulate skeletal development through their distinct functions and expression patterns SO JOURNAL OF CELL SCIENCE LA English DT Article DE Pannexin 3; Connexin 43; Skeletal formation; Ossification; Chondrocyte; Osteoblast ID CELL-CELL COMMUNICATION; OSTEOBLAST DIFFERENTIATION; GAP-JUNCTION; BONE-FORMATION; GROWTH-PLATE; WNT; MICE; CARTILAGE; PROTEINS; PERLECAN AB Pannexin 3 (Panx3) and connexin 43 (Cx43; also known as GJA1) are two major gap junction proteins expressed in osteoblasts. Here, we studied their functional relationships in skeletal formation by generating Panx3(-/-) and Panx3(-/-); Cx43(-/-) mice and comparing their skeletal phenotypes with Cx43(-/-) mice. Panx3(-/-) mice displayed defects in endochondral and intramembranous ossification, resulting in severe dwarfism and reduced bone density. The skeletal abnormalities of Panx3(-/-); Cx43(-/-) mice were similar to those in Panx3(-/-) mice. The gross appearance of newborn Cx43(-/-) skeletons showed no obvious abnormalities, except for less mineralization of the skull. In Panx3(-/-) mice, proliferation of chondrocytes and osteoblasts increased and differentiation of these cells was inhibited. Panx3 promoted expression of osteogenic proteins such as ALP and Ocn (also known as ALPL and BGLAP, respectively), as well as Cx43, by regulating Osx (also known as SP7) expression. Panx3 was induced in the early differentiation stage and reduced during the maturation stage of osteoblasts, when Cx43 expression increased in order to promote mineralization. Furthermore, only Panx3 functioned as an endoplasmic reticulum (ER) Ca2+ channel to promote differentiation, and it could rescue mineralization defects in Cx43(-/-) calvarial cells. Our findings reveal that Panx3 and Cx43 have distinct functions in skeletal formation. C1 [Ishikawa, Masaki; Williams, Geneva L.; Ikeuchi, Tomoko; Sakai, Kiyoshi; Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20814 USA. [Ishikawa, Masaki] Tohoku Univ, Grad Sch Dent, Operat Dent, Sendai, Miyagi 9808575, Japan. [Williams, Geneva L.] Washington Univ, Div Biol & Biomed Sci, St Louis, MO 63110 USA. [Sakai, Kiyoshi] Nagoya Univ, Grad Sch Med, Dept Oral & Maxillofacial Surg, Nagoya, Aichi 4668550, Japan. [Fukumoto, Satoshi] Tohoku Univ, Grad Sch Dent, Dept Pediat Dent, Sendai, Miyagi 9808576, Japan. RP Yamada, Y (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20814 USA. EM yoshi.yamada@nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, USA [DE000483-24, DE000483-25, DE000483-26]; Ministry of Education, Science, and Culture of Japan [26670880]; NEXT program [LS010]; Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists FX This work was supported in part by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, USA [grant number DE000483-24, -25, and-26 to Y.Y.]; Grants-in-Aid from the Ministry of Education, Science, and Culture of Japan [grant number 26670880 to S.F.]; and the NEXT program [grant number LS010 to S.F.]. M.I. and T.I. were supported in part by the Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists. Deposited in PMC for release after 12 months. NR 39 TC 2 Z9 2 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD MAR 1 PY 2016 VL 129 IS 5 BP 1018 EP 1030 DI 10.1242/jcs.176883 PG 13 WC Cell Biology SC Cell Biology GA DF6AE UT WOS:000371435700014 PM 26759176 ER PT J AU Schoenmakers, E Carlson, B Agostini, M Moran, C Rajanayagam, O Bochukova, E Tobe, R Peat, R Gevers, E Muntoni, F Guicheney, P Schoenmakers, N Farooqi, S Lyons, G Hatfield, D Chatterjee, K AF Schoenmakers, Erik Carlson, Bradley Agostini, Maura Moran, Carla Rajanayagam, Odelia Bochukova, Elena Tobe, Ryuta Peat, Rachel Gevers, Evelien Muntoni, Francesco Guicheney, Pascale Schoenmakers, Nadia Farooqi, Sadaf Lyons, Greta Hatfield, Dolph Chatterjee, Krishna TI Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID METHYLATION AB Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNAE([ser]sec)). Here, we have identified a human tRNAE([Ser]Sec) mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2'-0-methylribosylation at uridine 34 in mutant tRNA([ser]sec). Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA([ser]sec). This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis. C1 [Schoenmakers, Erik; Agostini, Maura; Moran, Carla; Rajanayagam, Odelia; Bochukova, Elena; Schoenmakers, Nadia; Farooqi, Sadaf; Lyons, Greta; Chatterjee, Krishna] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Cambridge CB2 0QQ, England. [Carlson, Bradley; Tobe, Ryuta; Hatfield, Dolph] NIH, Mol Biol Selenium Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Peat, Rachel; Guicheney, Pascale] Univ Paris 06, Sorbonne Univ, Inst Cardiometab & Nutr ICAN, INSERM,UMR S1166, Paris, France. [Gevers, Evelien] Royal London Hosp, Dept Paediat Endocrinol, London E1 1BB, England. [Muntoni, Francesco] UCL, Inst Child Hlth, Dubowitz Neuromuscular Ctr, London, England. RP Chatterjee, K (reprint author), Univ Cambridge, Inst Metab Sci, Metab Res Labs, Addenbrookes Hosp, Level 4,Box 289, Cambridge CB2 0QQ, England. EM kkc1@medschl.cam.ac.uk OI Farooqi, Sadaf/0000-0001-7609-3504; Bochukova, Elena/0000-0003-0275-1548 FU Wellcome Trust [100585/Z/12/Z, 095564/Z/11/Z]; NIH Research Biomedical Research Centre Cambridge; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX Our research is supported by funding from the Wellcome Trust (100585/Z/12/Z to N. Schoenmakers, 095564/Z/11/Z to K. Chatterjee), the NIH Research Biomedical Research Centre Cambridge (to C. Moran, N. Schoenmakers, and K. Chatterjee) or Great Ormond Street (to F. Muntoni) and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH (to D.L. Hatfield). NR 11 TC 2 Z9 2 U1 1 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2016 VL 126 IS 3 BP 992 EP 996 DI 10.1172/JCI84747 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DF2SI UT WOS:000371193700019 PM 26854926 ER PT J AU Yu, HY Artomov, M Brahler, S Stander, MC Shamsan, G Sampson, MG White, JM Kretzler, M Miner, JH Jain, S Winkler, CA Mitra, RD Kopp, JB Daly, MJ Shaw, AS AF Yu, Haiyang Artomov, Mykyta Braehler, Sebastian Stander, M. Christine Shamsan, Ghaidan Sampson, Matthew G. White, J. Michael Kretzler, Matthias Miner, Jeffrey H. Jain, Sanjay Winkler, Cheryl A. Mitra, Robi D. Kopp, Jeffrey B. Daly, Mark J. Shaw, Andrey S. TI A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis (Retracted Article. See vol 126, pg 1603, 2016) SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article; Retracted Publication ID RESISTANT NEPHROTIC SYNDROME; HIV-ASSOCIATED NEPHROPATHY; EMBRYONIC STEM-CELLS; PODOCYTE INJURY; CD2-ASSOCIATED PROTEIN; GLOMERULAR-DISEASES; AFRICAN-AMERICANS; RNA INTERFERENCE; RENAL-DISEASE; MUTATIONS AB Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein 1:1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes. C1 [Yu, Haiyang; Braehler, Sebastian; Stander, M. Christine; Shamsan, Ghaidan; White, J. Michael; Shaw, Andrey S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Artomov, Mykyta; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Artomov, Mykyta; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA USA. [Artomov, Mykyta; Daly, Mark J.] Broad Inst, Cambridge, MA USA. [Artomov, Mykyta] Harvard Univ, Dept Chem, 12 Oxford St, Cambridge, MA 02138 USA. [Sampson, Matthew G.] Univ Michigan, Pediat Nephrol, Ann Arbor, MI 48109 USA. [Kretzler, Matthias] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Miner, Jeffrey H.; Jain, Sanjay] Washington Univ, Sch Med, Dept Med, Div Renal, St Louis, MO 63110 USA. [Winkler, Cheryl A.] NCI, Mol Genet Epidemiol Studies Sect, Frederick, MD 21701 USA. [Mitra, Robi D.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD USA. [Shaw, Andrey S.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Shaw, AS (reprint author), Genentech Inc, One DNA Way,Mail Stop 93B, San Francisco, CA 94080 USA.; Daly, MJ (reprint author), Massachusetts Gen Hosp, Richard B Simches Res Ctr, Analyt & Translat Genet Unit, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. EM mjdaly@atgu.mgh.harvard.edu; shawa6@gene.com FU NIDDK; HHMI; Intramural Research Programs of the NIDDK; NCI; Deutsche Forschungsgemeinschaft (DFG) FX This project was supported by grants from the NIDDK (to A.S. Shaw, J.H. Miner, M. Kretzler, and M.G. Sampson); the HHMI (to A.S. Shaw); and the Intramural Research Programs of the NIDDK (to J.B. Kopp), NCI (to C.A. Winkler), and the Deutsche Forschungsgemeinschaft (DFG) (to S. Brahler). We thank V. Vasioukhin for sharing Dlg5+/- mice, overexpression and RNAi lentiviral plasmids, and histology stainings of Dlg5-/- kidney. We also thank C. Der for sharing the Arhgefl7 cDNA construct. We also thank R. Kopan and members of the Shaw laboratory for critical discussions. NR 60 TC 4 Z9 4 U1 1 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2016 VL 126 IS 3 BP 1067 EP 1078 DI 10.1172/JCI82592 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DF2SI UT WOS:000371193700025 PM 26901816 ER PT J AU Masujin, K Orru, CD Miyazawa, K Groveman, BR Raymond, LD Hughson, AG Caughey, B AF Masujin, Kentaro Orru, Christina D. Miyazawa, Kohtaro Groveman, Bradley R. Raymond, Lynne D. Hughson, Andrew G. Caughey, Byron TI Detection of Atypical H-Type Bovine Spongiform Encephalopathy and Discrimination of Bovine Prion Strains by Real-Time Quaking-Induced Conversion SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; CEREBROSPINAL-FLUID; TRANSGENIC MICE; BIOCHEMICAL-CHARACTERIZATION; MAMMALIAN PRIONS; IN-VITRO; PROTEIN; TRANSMISSION; CATTLE; PRPSC AB Prion diseases of cattle include the classical bovine spongiform encephalopathy (C-BSE) and the atypical H-type BSE (H-BSE) and L-type BSE (L-BSE) strains. Although the C-and L-BSE strains can be detected and discriminated by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays, no such test has yet been described for the detection of H-BSE or the discrimination of each of the major bovine prion strains. Here, we demonstrate an RT-QuIC assay for H-BSE that can detect as little as 10(-9) dilutions of brain tissue and neat cerebrospinal fluid samples from clinically affected cattle. Moreover, comparisons of the reactivities with different recombinant prion protein substrates and/or immunoblot band profiles of proteinase K-treated RT-QuIC reaction products indicated that H-, L-, and C-BSE have distinctive prion seeding activities and can be discriminated by RT-QuIC on this basis. C1 [Masujin, Kentaro; Orru, Christina D.; Groveman, Bradley R.; Raymond, Lynne D.; Hughson, Andrew G.; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Masujin, Kentaro; Miyazawa, Kohtaro] Natl Agr & Food Res Org, Natl Inst Anim Hlth, Influenza & Prion Dis Res Ctr, Tsukuba, Ibaraki, Japan. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM bcaughey@nih.gov FU NARO; Alliance Biosecure Foundation under the aegis of the Fondation pour la Recherche Medicale [FABS 201401]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (DIR, NIAID); Intramural Research Program of the NIAID FX A research fellowship from NARO provided funding to Kentaro Masujin. Alliance Biosecure Foundation under the aegis of the Fondation pour la Recherche Medicale provided funding to Byron Caughey. The Intramural Research Program of the National Institute of Allergy and Infectious Diseases (DIR, NIAID) provided funding to Byron Caughey.; This work was supported in part by the Intramural Research Program of the NIAID, by the Alliance Biosecure Foundation under the aegis of the Fondation pour la Recherche Medicale (FABS 201401), and by a research fellowship from NARO to K. Masujin. NR 63 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2016 VL 54 IS 3 BP 676 EP 686 DI 10.1128/JCM.02731-15 PG 11 WC Microbiology SC Microbiology GA DF2EC UT WOS:000371152200026 PM 26739160 ER PT J AU Davids, M Kane, MS He, M Wolfe, LA Li, XL Raihan, MA Chao, KR Bone, WP Boerkoel, CF Gahl, WA Toro, C AF Davids, Mariska Kane, Megan S. He, Miao Wolfe, Lynne A. Li, Xueli Raihan, Mohd A. Chao, Katherine R. Bone, William P. Boerkoel, Cornelius F. Gahl, William A. Toro, Camilo TI Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration SO JOURNAL OF MEDICAL GENETICS LA English DT Article DE Molecular genetics; Cell biology; Neuromuscular disease ID INDEPENDENT PHOSPHOLIPASE A(2); P388D(1) MACROPHAGES; PHENOTYPIC SPECTRUM; MASS-SPECTROMETRY; ALZHEIMER-DISEASE; ACID RELEASE; BRAIN IRON; CELL-DEATH; O-GLCNAC; PLA2G6 AB Background Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2 group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to abnormal Golgi morphology might be a factor in the pathology of this disease. Methods Three patients presented with PLA2G6-associated neurodegeneration (PLAN); two had infantile neuroaxonal dystrophy (INAD) and one had adult-onset dystonia-parkinsonism. We analysed protein N-linked and O-linked glycosylation in cerebrospinal fluid, plasma, urine, and cultured skin fibroblasts using high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionisation - time of flight/mass spectrometry (MALDI-TOF/MS). We also assessed sialylation and Golgi morphology in cultured fibroblasts by immunofluorescence and performed rescue experiments using a lentiviral vector. Results The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A]. All three patients had altered Golgi morphology and abnormalities of protein O-linked glycosylation and sialylation in cultured fibroblasts that were rescued by lentiviral overexpression of wild type PLA2G6. Conclusions Our findings add altered Golgi morphology, O-linked glycosylation and sialylation defects to the phenotypical spectrum of PLAN; these pathways are essential for correct processing and distribution of proteins. Lewy body and Tau pathology, two neuropathological features of PLAN, could emerge from these defects. Therefore, Golgi morphology, O-linked glycosylation and sialylation may play a role in the pathogenesis of PLAN and perhaps other neurodegenerative disorders. C1 [Davids, Mariska; Kane, Megan S.; Wolfe, Lynne A.; Chao, Katherine R.; Bone, William P.; Boerkoel, Cornelius F.; Gahl, William A.; Toro, Camilo] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Davids, Mariska; Kane, Megan S.; Wolfe, Lynne A.; Chao, Katherine R.; Bone, William P.; Boerkoel, Cornelius F.; Gahl, William A.; Toro, Camilo] NIH, Off Clin Director, NHGRI, Bldg 10, Bethesda, MD 20892 USA. [He, Miao; Li, Xueli; Raihan, Mohd A.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [He, Miao; Li, Xueli; Raihan, Mohd A.] Childrens Hosp Philadelphia, Michael J Palmieri Metab Lab, Philadelphia, PA 19104 USA. RP Davids, M (reprint author), NIH, UDP Translat Lab, 5625 Fishers Lane Room 4N-15, Rockville, MD 20852 USA. EM mariska.davids@nih.gov FU National Human Genome Research Institute; NIH Office of the Director of the National Institutes of Health, Bethesda, Maryland, USA FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund of the NIH Office of the Director of the National Institutes of Health, Bethesda, Maryland, USA. NR 55 TC 1 Z9 2 U1 3 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD MAR PY 2016 VL 53 IS 3 BP 180 EP 189 DI 10.1136/jmedgenet-2015-103338 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DF4OT UT WOS:000371329600005 PM 26668131 ER PT J AU Odia, Y Iwamoto, FM Moustakas, A Fraum, TJ Salgado, CA Li, AG Kreisl, TN Sul, J Butman, JA Fine, HA AF Odia, Yazmin Iwamoto, Fabio M. Moustakas, Argirios Fraum, Tyler J. Salgado, Carlos A. Li, Aiguo Kreisl, Teri N. Sul, Joohee Butman, John A. Fine, Howard A. TI A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Enzastaurin; Bevacizumab; Trial; Glioma; Glioblastoma ID PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; RECURSIVE PARTITIONING ANALYSIS; SINGLE-AGENT BEVACIZUMAB; CENTRAL-NERVOUS-SYSTEM; GLIOBLASTOMA-MULTIFORME; CELL-GROWTH; IN-VIVO; SELECTIVE INHIBITOR; ANAPLASTIC GLIOMA AB We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7-9/24 (29.2-37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy. C1 [Odia, Yazmin; Iwamoto, Fabio M.; Kreisl, Teri N.] Columbia Univ Coll Phys & Surg, Neurooncol Div, Neurol Inst New York, 710 West 168th St,9th Floor,NI 9-017, New York, NY 10032 USA. [Moustakas, Argirios] Univ Vermont, Med Ctr, 89 South Williams St, Burlington, VT 05401 USA. [Fraum, Tyler J.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Campus Box 8131,510 S Kingshighway Blvd, St Louis, MO 63110 USA. [Salgado, Carlos A.] Univ Maryland, Sch Med, 655 West Baltimore St, Baltimore, MD 21201 USA. [Li, Aiguo] NCI, Ctr Canc Res, Bldg 37,Room 1142, Bethesda, MD USA. [Sul, Joohee] Fed Drug Adm, 10903 New Hampshire Ave,Bldg WO22 Rm 2331, Silver Spring, MD 20993 USA. [Butman, John A.] NIH, Ctr Clin, Dept Radiol, Bldg 10,Clinical Ctr 10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. [Fine, Howard A.] New York Presbyterian Hospital, Weill Cornell Med Ctr, Brain Tumor Ctr, Div Neurooncol, 1305 York Ave,9th Floor, New York, NY 10021 USA. RP Odia, Y (reprint author), Columbia Univ Coll Phys & Surg, Neurooncol Div, Neurol Inst New York, 710 West 168th St,9th Floor,NI 9-017, New York, NY 10032 USA. EM yo2240@cumc.columbia.edu FU National Cancer Institute Intramural Research Program FX National Cancer Institute Intramural Research Program. NR 43 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAR PY 2016 VL 127 IS 1 BP 127 EP 135 DI 10.1007/s11060-015-2020-x PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DF6HF UT WOS:000371455800014 PM 26643807 ER PT J AU Szatmari, P Chawarska, K Dawson, G Georgiades, S Landa, R Lord, C Messinger, DS Thurm, A Halladay, A AF Szatmari, Peter Chawarska, Katarzyna Dawson, Geraldine Georgiades, Stelios Landa, Rebecca Lord, Catherine Messinger, Daniel S. Thurm, Audrey Halladay, Alycia TI Prospective Longitudinal Studies of Infant Siblings of Children With Autism: Lessons Learned and Future Directions SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE autism; longitudinal; sibling; development; opportunities ID SPECTRUM DISORDER; RESEARCH CONSORTIUM; HIGH-RISK; MODIFIED CHECKLIST; DIAGNOSTIC STABILITY; 6-MONTH-OLD INFANTS; CLINICAL-DIAGNOSIS; TODDLERS; IDENTIFICATION; INTERVENTION AB Objective: The objectives of this review are to highlight the impact of the first decade of high-risk (HR) infant sibling work in autism spectrum disorder (ASD) and to identify potential areas of translational focus for the next decade of research. Method: A group of clinicians and researchers in ASD working both inside and outside of the HR design met on a regular basis to review the infant sibling research, and came to an agreement on areas that had changed clinical practice and areas that had the potential to change practice with further research. The group then outlined several methodological and translational challenges that must be addressed in the next decade of research if the field is to reach its potential. Results: The review concluded that the HR design has yielded an understanding that ASD often, but not alway, begins to emerge between 6 and 18 months, with early signs affecting social communication. Research using the HR design has also allowed a better understanding of the sibling recurrence risk (between 10% and 20%). Emerging areas of interest include the developmental trajectories of social communications skills in the early years, the expression of a milder phenotype in siblings not affected with ASD, and the possibility that early intervention with infant siblings may improve outcomes for those with ASD. Important challenges for the future include linking screening to intervention, collecting large sample sizes while ensuring cross-site reliability, and building in capacity for replication. Conclusion: Although there are significant methodological and translational challenges for high-risk infant sibling research, the potential of this design to improve long-term outcomes of all children with ASD is substantial. C1 [Szatmari, Peter] Univ Toronto, Hosp Sick Children, Child & Youth Mental Hlth Collaborat, Toronto, ON M6J 1H4, Canada. [Szatmari, Peter] Univ Toronto, Ctr Addict & Mental Hlth, 1001 Queen St West, Toronto, ON M6J 1H4, Canada. [Szatmari, Peter] Univ Toronto, Div Child & Youth Mental Hlth, Toronto, ON M6J 1H4, Canada. [Chawarska, Katarzyna] Yale Univ, Sch Med, Yale Child Study Ctr, Toddler Dev Disabil Clin, New Haven, CT USA. [Dawson, Geraldine] Duke Univ, Sch Med, Duke Inst Brain Sci, Durham, NC USA. [Georgiades, Stelios] McMaster Univ, Offord Ctr Child Studies, Hamilton, ON, Canada. [Landa, Rebecca] Kennedy Krieger Inst, Ctr Autism & Related Disorders, Baltimore, MD USA. [Lord, Catherine] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. [Lord, Catherine] Columbia Univ, Teachers Coll, New York, NY 10027 USA. [Messinger, Daniel S.] Univ Miami, Coral Gables, FL 33124 USA. [Thurm, Audrey] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Halladay, Alycia] Autism Sci Fdn, New York, NY USA. [Halladay, Alycia] Rutgers State Univ, New Brunswick, NJ 08903 USA. RP Szatmari, P (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, 1001 Queen St West, Toronto, ON M6J 1H4, Canada. EM peter.szatmari@utoronto.ca FU Autism Science Foundation FX The authors would like to thank the Baby Sibs Research Consortium for their thoughtful feedback on this paper, Autism Speaks for their longstanding support of the High Risk Baby Siblings Research Consortium (BSRC) activities, and the Autism Science Foundation for their support of multiple high-risk infant projects. NR 78 TC 4 Z9 4 U1 11 U2 37 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 MAR PY 2016 VL 55 IS 3 BP 179 EP 187 DI 10.1016/j.jaac.2015.12.014 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DF2RT UT WOS:000371192200007 PM 26903251 ER PT J AU Dunleavy, K AF Dunleavy, Kieron TI Immunomodulatory agents in mantle cell lymphoma SO LANCET ONCOLOGY LA English DT Editorial Material ID SURVIVAL; THERAPY; MCL C1 [Dunleavy, Kieron] Natl Canc Inst, Lymphoid Malignancies Branch, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), Natl Canc Inst, Lymphoid Malignancies Branch, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov NR 10 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2016 VL 17 IS 3 BP 262 EP 263 DI 10.1016/S1470-2045(16)00027-9 PG 3 WC Oncology SC Oncology GA DF3HN UT WOS:000371234900025 PM 26899779 ER PT J AU Li, SZ An, L Yu, S Araneta, MF Johnson, CS Wang, SM Shen, J AF Li, Shizhe An, Li Yu, Shao Araneta, Maria Ferraris Johnson, Christopher S. Wang, Shumin Shen, Jun TI C-13 MRS of human brain at 7 Tesla using [2-C-13]glucose infusion and low power broadband stochastic proton decoupling SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE C-13 MRS; human brain; stochastic decoupling; 7 T ID MAGNETIC-RESONANCE-SPECTROSCOPY; ENERGY-METABOLISM; NMR-SPECTROSCOPY; COIL; SENSITIVITY AB PurposeCarbon-13 (C-13) MR spectroscopy (MRS) of the human brain at 7 Tesla (T) may pose patient safety issues due to high radiofrequency (RF) power deposition for proton decoupling. The purpose of present work is to study the feasibility of in vivo C-13 MRS of human brain at 7 T using broadband low RF power proton decoupling. MethodsCarboxylic/amide C-13 MRS of human brain by broadband stochastic proton decoupling was demonstrated on a 7 T scanner. RF safety was evaluated using the finite-difference time-domain method. C-13 signal enhancement by nuclear Overhauser effect (NOE) and proton decoupling was evaluated in both phantoms and in vivo. ResultsAt 7 T, the peak amplitude of carboxylic/amide C-13 signals was increased by a factor of greater than 4 due to the combined effects of NOE and proton decoupling. The 7 T C-13 MRS technique used decoupling power and average transmit power of less than 35 watts (W) and 3.6 W, respectively. ConclusionIn vivo C-13 MRS studies of human brain can be performed at 7 T, well below the RF safety threshold, by detecting carboxylic/amide carbons with broadband stochastic proton decoupling. Magn Reson Med 75:954-961, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Li, Shizhe; Shen, Jun] NIMH, Magnet Resonance Spect Core Facil, NIH, Bethesda, MD 20892 USA. [An, Li; Araneta, Maria Ferraris; Johnson, Christopher S.; Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Yu, Shao; Wang, Shumin] Auburn Univ, Dept Elect & Comp Engn, Auburn, AL 36849 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health [IRP-NIMH-NIH] FX Grant sponsor: Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; Grant number: IRP-NIMH-NIH. NR 27 TC 2 Z9 2 U1 4 U2 8 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 MAR PY 2016 VL 75 IS 3 BP 954 EP 961 DI 10.1002/mrm.25721 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DE4IZ UT WOS:000370593700004 PM 25917936 ER PT J AU Pegoraro, G Misteli, T AF Pegoraro, Gianluca Misteli, Tom TI High-throughput Imaging as a versatile and unbiased discovery tool SO METHODS LA English DT Editorial Material C1 [Pegoraro, Gianluca; Misteli, Tom] NCI, 41 Lib Dr,Bldg 41, Bethesda, MD 20892 USA. RP Pegoraro, G; Misteli, T (reprint author), NCI, 41 Lib Dr,Bldg 41, Bethesda, MD 20892 USA. EM gianluca.pegoraro@nih.gov; mistelit@mail.nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 NR 14 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 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD MAR 1 PY 2016 VL 96 BP 1 EP 2 DI 10.1016/j.ymeth.2016.01.003 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF6CX UT WOS:000371444500001 PM 26774352 ER PT J AU Kubben, N Brimacombe, KR Donegan, M Li, ZY Misteli, T AF Kubben, Nard Brimacombe, Kyle R. Donegan, Megan Li, Zhuyin Misteli, Tom TI A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds SO METHODS LA English DT Article DE HGPS; Progerin; Retinoids; FDA-approved compounds; High-throughput screening; High-content imaging ID DNA-DAMAGE RESPONSES; DEFECTIVE MATURATION; DISEASE PHENOTYPES; PRELAMIN-A; LAMIN B1; FARNESYLTRANSFERASE INHIBITOR; AMPK ACTIVATION; NUCLEAR LAMINA; MOUSE MODEL; LIFE-SPAN AB Hutchinson-Gilford Progeria Syndrome (HGPS) is an early onset lethal premature aging disorder caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A. The presence of progerin causes extensive morphological, epigenetic and DNA damage related nuclear defects that ultimately disrupt tissue and organismal functions. Hypothesis-driven approaches focused on HGPS affected pathways have been used in attempts to identify druggable targets with anti-progeroid effects. Here, we report an unbiased discovery approach to HGPS by implementation of a high-throughput, high-content imaging based screening method that enables systematic identification of small molecules that prevent the formation of multiple progerin-induced aging defects. Screening a library of 2816 FDA approved drugs, we identified retinoids as a novel class of compounds that reverses aging defects in HGPS patient skin fibroblasts. These findings establish a novel approach to anti-progeroid drug discovery. (C) 2016 Published by Elsevier Inc. C1 [Kubben, Nard; Donegan, Megan; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Brimacombe, Kyle R.; Li, Zhuyin] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Li, Zhuyin] Bristol Meyers Squibb, Lead Discovery & Optimizat, 5 Res Pkwy, Wallingford, CT 06492 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research; grant for the Progeria Research Foundation FX We thank members of the Misteli lab for providing helpful feedback and experimental suggestions. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research and by a grant for the Progeria Research Foundation. NR 54 TC 7 Z9 7 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD MAR 1 PY 2016 VL 96 BP 46 EP 58 DI 10.1016/j.ymeth.2015.08.024 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF6CX UT WOS:000371444500008 PM 26341717 ER PT J AU Day, CR Chen, HM Coulon, A Meier, JL Larson, DR AF Day, Christopher R. Chen, Huimin Coulon, Antoine Meier, Jordan L. Larson, Daniel R. TI High-throughput single-molecule screen for small-molecule perturbation of splicing and transcription kinetics SO METHODS LA English DT Article DE Transcription; Splicing; Small-molecule; RNA; Fluorescence; Fluctuation; Single-molecule ID BET BROMODOMAIN INHIBITION; PRE-MESSENGER-RNA; GENE-EXPRESSION; TOPOISOMERASE-I; ELONGATION; IDENTIFICATION; REVEALS; CELLS; YEAST; TIME AB In eukaryotes, mRNA synthesis is catalyzed by RNA polymerase II and involves several distinct steps, including transcript initiation, elongation, cleavage, and transcript release. Splicing of RNA can occur during (co-transcriptional) or after (post-transcriptional) RNA synthesis. Thus, RNA synthesis and processing occurs through the concerted activity of dozens of enzymes, each of which is potentially susceptible to perturbation by small molecules. However, there are few, if any, high-throughput screening strategies for identifying drugs which perturb a specific step in RNA synthesis and processing. Here we have developed a high-throughput fluorescence microscopy approach in single cells to screen for inhibitors of specific enzymatic steps in RNA synthesis and processing. By utilizing the high affinity interaction between bacteriophage capsid proteins (MS2, PP7) and RNA stem loops, we are able to fluorescently label the intron and exon of a beta-globin reporter gene in human cells. This approach allows one to measure the kinetics of transcription, splicing and release in both fixed and living cells using a tractable, genetically encoded assay in a stable cell line. We tested this reagent in a targeted screen of molecules that target chromatin readers and writers and identified three compounds that slow transcription elongation without changing transcription initiation. Published by Elsevier Inc. C1 [Day, Christopher R.; Chen, Huimin; Larson, Daniel R.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Coulon, Antoine] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Meier, Jordan L.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Larson, DR (reprint author), NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dan.larson@nih.gov RI Meier, Jordan/N-2608-2014; Coulon, Antoine/A-9006-2012; Larson, Daniel/B-9829-2008 OI Larson, Daniel/0000-0001-9253-3055 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Institute of Diabetes and Digestive and Kidney Diseases FX High-throughput imaging was conducted in collaboration with the HiTIF core at NCI, with critical support from Gianluca Pegoraro and Laurent Ozbun. Murali Palangat and Ty Voss provided critical technical support, and Richard Day provided valuable feedback on the manuscript. Herboxidiene was a kind gift from Melissa Jurica, University of California at Santa Cruz. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 2 Z9 2 U1 4 U2 8 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 MAR 1 PY 2016 VL 96 BP 59 EP 68 DI 10.1016/j.ymeth.2015.11.025 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF6CX UT WOS:000371444500009 PM 26655523 ER PT J AU Lasota, J Felisiak-Golabek, A Wasag, B Kowalik, A Zieba, S ChIopek, M Wang, ZF Coates, T Kopczynski, J Gozdz, S Sarlomo-Rikala, M Miettinen, M AF Lasota, Jerzy Felisiak-Golabek, Anna Wasag, Bartosz Kowalik, Artur Zieba, Sebastian ChIopek, Malgorzata Wang, Zeng-Feng Coates, Tiffany Kopczynski, Janusz Gozdz, Stanislaw Sarlomo-Rikala, Maarit Miettinen, Markku TI Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases SO MODERN PATHOLOGY LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; SIGNALING PATHWAY; BREAST-CANCER; MUTATIONS; KIT; IMATINIB; RESISTANCE; INHIBITOR; PDGFRA; HETEROGENEITY AB Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors usually driven by the mutational activation of receptor tyrosine kinases, KIT, or PDGFRA. Oncogenic activation of phosphatidylinositide-3-kinase (P13K), a downstream effector in the KIT signaling pathway, has been identified in different types of cancer, with the P13K 110 alpha subunit encoded by PIK3CA being a common mutational target. In this study, the mutational hotspot in the PIK3CA kinase domain encoded by exon 20 was evaluated in 529 imatinib-naive GISTs using PCR amplification and Sanger sequencing. Eight mutations (two co-existing in one tumor) were identified. Subsequently, The cobas PIK3CA Mutation Test was employed to evaluate mutational hotspots in exons 1, 4, 7, and 9 in 119 PIK3CA exon 20-wild type tumors. In two cases, mutations in exons 1 and 9 were identified. In one GIST, previously undetected by Sanger sequencing, the exon 20 mutation was discovered. Altogether, eight primary and two metastatic GISTs carried PIK3CA mutations. The size of primary PIK3CA-mutant GISTs was >= 14 cm (mean size 17 cm), and mitotic activity varied from 0 to 72 per 50HPF (mean 5/50HPF). Follow-up data showed short survival in 6 of 7 studied cases. Detection of PIK3CA mutations in large or metastatic KIT-mutant GISTs may suggest that PIK3CA-mutant clones have a proliferative advantage during disease progression. Tyrosine kinase inhibitors have been successfully used in GIST treatment. However, resistance frequently develops due to secondary KIT mutations or activation of downstream to KIT signaling pathways, such as the PI3K/AKT/mTOR pathway. PIK3CA mutations similar to the ones detected in GISTs have been shown to cause such activation. Therefore, genotyping of PIK3CA in GISTs might help to pinpoint primary and metastatic tumors with the potential to develop resistance to tyrosine kinase inhibitors and guide therapy with PI3K inhibitors. C1 [Lasota, Jerzy; Felisiak-Golabek, Anna; Wang, Zeng-Feng; Coates, Tiffany; Miettinen, Markku] NCI, Pathol Lab, 10 Ctr Dr,Room B1B47, Bethesda, MD 20892 USA. [Wasag, Bartosz] Med Univ Gdansk, Dept Biol & Genet, Gdansk, Poland. [Kowalik, Artur; Zieba, Sebastian; ChIopek, Malgorzata] Holycross Canc Ctr, Dept Mol Diagnost, Kielce, Poland. [Kopczynski, Janusz] Holycross Canc Ctr, Dept Surg Pathol, Kielce, Poland. [Gozdz, Stanislaw] Holycross Canc Ctr, Dept Clin Oncol, Kielce, Poland. [Gozdz, Stanislaw] Jan Kochanowski Univ Humanities & Sci, Fac Hlth Sci, Kielce, Poland. [Sarlomo-Rikala, Maarit] Univ Helsinki, HUSLab, Helsinki, Finland. RP Lasota, J (reprint author), NCI, Pathol Lab, 10 Ctr Dr,Room B1B47, Bethesda, MD 20892 USA. EM jerzy.lasota@nih.gov RI Kielce, SCO/O-6702-2016; Gozdz, Stanislaw/D-3300-2013; OI Miettinen, Markku/0000-0002-3282-8107 NR 26 TC 3 Z9 3 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD MAR PY 2016 VL 29 IS 3 BP 275 EP 282 DI 10.1038/modpathol.2015.160 PG 8 WC Pathology SC Pathology GA DF2TM UT WOS:000371196800007 PM 26796526 ER PT J AU Wang, YX AF Wang, Yun-Xing TI RNA CONFORMATION Lightening up invisible states SO NATURE CHEMICAL BIOLOGY LA English DT News Item ID X-RAY-SCATTERING; ENSEMBLE; DYNAMICS; PROTEIN C1 [Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21701 USA. RP Wang, YX (reprint author), NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21701 USA. EM wangyunx@mail.nih.gov NR 10 TC 0 Z9 0 U1 4 U2 7 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 MAR PY 2016 VL 12 IS 3 BP 126 EP 127 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF5FK UT WOS:000371377000001 PM 26881762 ER PT J AU Stuckey, JI Dickson, BM Cheng, N Liu, YL Norris, JL Cholensky, SH Tempel, W Qin, S Huber, KG Sagum, C Black, K Li, FL Huang, XP Roth, BL Baughman, BM Senisterra, G Pattenden, SG Vedadi, M Browne, PJ Bedford, MT Min, JR Arrowsmith, CH James, LI Frye, SV AF Stuckey, Jacob I. Dickson, Bradley M. Cheng, Nancy Liu, Yanli Norris, Jacqueline L. Cholensky, Stephanie H. Tempel, Wolfram Qin, Su Huber, Katherine G. Sagum, Cari Black, Karynne Li, Fengling Huang, Xi-Ping Roth, Bryan L. Baughman, Brandi M. Senisterra, Guillermo Pattenden, Samantha G. Vedadi, Masoud Browne, Peter J. Bedford, Mark T. Min, Jinrong Arrowsmith, Cheryl H. James, Lindsey I. Frye, Stephen V. TI A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1 SO NATURE CHEMICAL BIOLOGY LA English DT Article ID CHROMOBOX PROTEIN CBX7; ONCOGENIC ROLE; CELLS; METHYLATION; CANCER; METHYLTRANSFERASES; DIFFERENTIATION; DEMETHYLATION; SPECIFICITY; INHIBITION AB We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a K-d of similar to 100 nM for each, and is 6- to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects. C1 [Stuckey, Jacob I.; Dickson, Bradley M.; Cheng, Nancy; Norris, Jacqueline L.; Cholensky, Stephanie H.; Huber, Katherine G.; Baughman, Brandi M.; Pattenden, Samantha G.; James, Lindsey I.; Frye, Stephen V.] Univ N Carolina, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC USA. [Liu, Yanli; Tempel, Wolfram; Qin, Su; Li, Fengling; Senisterra, Guillermo; Vedadi, Masoud; Browne, Peter J.; Min, Jinrong; Arrowsmith, Cheryl H.] Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada. [Sagum, Cari; Black, Karynne; Bedford, Mark T.] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Smithville, TX USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. RP James, LI; Frye, SV (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC USA. EM ingerman@email.unc.edu; svfrye@email.unc.edu FU National Institute of General Medical Sciences, US National Institutes of Health (NIH) [R01GM100919]; US Department of Energy (DOE) Office of Science User Facility; Carolina Partnership; University Cancer Research Fund; University of North Carolina at Chapel Hill; Welch Foundation [G-1847]; AbbVie [1097737]; Boehringer Ingelheim; Canada Foundation for Innovation (CFI); Canadian Institutes of Health Research (CIHR); Genome Canada; Ontario Genomics Institute Grant [OGI-055]; GlaxoSmithKline; Janssen; Lilly Canada; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust [092809/Z/10/Z]; Cancer Prevention Research Institute of Texas [RP130432]; Centre for Environmental and Molecular Carcinogenesis at the MD Anderson Cancer Center FX We thank K. Pearce (UNC Chapel Hill) for useful discussions and careful reading of the manuscript, O. Fedorov (SGC Oxford) for support with the bromodomain selectivity screening, A. Tumber (SGC Oxford) for support with the lysine demethylase selectivity screening and J.R. Walker for the review of the crystal structures. We thank G. Wang (UNC) for providing PHF1, PHF19, PHF23 and JARID1A protein constructs. We thank the labs of T. Magnuson (UNC) and D. Margolis (UNC) for providing EED and BMI-1 antibodies, respectively. We also thank N. Sciaky (UNC) for help with cell counting using the high content imaging microscope. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The research described here was supported by the National Institute of General Medical Sciences, US National Institutes of Health (NIH, grant R01GM100919), the Carolina Partnership and the University Cancer Research Fund, University of North Carolina at Chapel Hill, and the Welch Foundation (G-1847). The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation (CFI), the Canadian Institutes of Health Research (CIHR), Genome Canada, Ontario Genomics Institute Grant OGI-055, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and Wellcome Trust Grant 092809/Z/10/Z. M.T.B. directs the Protein Array Core, which is supported by the Cancer Prevention Research Institute of Texas (RP130432) and by the Centre for Environmental and Molecular Carcinogenesis at the MD Anderson Cancer Center. NR 50 TC 17 Z9 17 U1 2 U2 11 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 MAR PY 2016 VL 12 IS 3 BP 180 EP 187 DI 10.1038/NGHEMBIO.2007 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF5FK UT WOS:000371377000011 PM 26807715 ER PT J AU Klepac, K Kilic, A Gnad, T Brown, LM Herrmann, B Wilderman, A Balkow, A Glode, A Simon, K Lidell, ME Betz, MJ Enerback, S Wess, J Freichel, M Bluher, M Konig, G Kostenis, E Insel, PA Pfeifer, A AF Klepac, Katarina Kilic, Ana Gnad, Thorsten Brown, Loren M. Herrmann, Beate Wilderman, Andrea Balkow, Aileen Gloede, Anja Simon, Katharina Lidell, Martin E. Betz, Matthias J. Enerback, Sven Wess, Juergen Freichel, Marc Blueher, Matthias Koenig, Gabi Kostenis, Evi Insel, Paul A. Pfeifer, Alexander TI The G(q) signalling pathway inhibits brown and beige adipose tissue SO NATURE COMMUNICATIONS LA English DT Article ID COUPLED RECEPTOR EXPRESSION; LIPOPROTEIN-LIPASE GENE; ADIPOCYTES; FAT; ENDOTHELIN-1; OBESITY; DIFFERENTIATION; PROGENITORS; ACTIVATION; CELLS AB Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the G(q) family, and inhibition of G(q) signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of G(q) signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of G(q) signalling in brown adipocytes. Expression of a constitutively active G(q) protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of G(q) in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that G(q) signalling regulates brown/beige adipocytes and inhibition of G(q) signalling may be a novel therapeutic approach to combat obesity. C1 [Klepac, Katarina; Kilic, Ana; Gnad, Thorsten; Brown, Loren M.; Herrmann, Beate; Balkow, Aileen; Gloede, Anja; Pfeifer, Alexander] Univ Bonn, Univ Hosp Bonn, Inst Pharmacol & Toxicol, D-53127 Bonn, Germany. [Klepac, Katarina; Kilic, Ana; Herrmann, Beate; Simon, Katharina; Kostenis, Evi; Pfeifer, Alexander] Univ Bonn, Res Training Grp 1873, D-53127 Bonn, Germany. [Brown, Loren M.; Wilderman, Andrea; Insel, Paul A.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Simon, Katharina; Koenig, Gabi; Kostenis, Evi] Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany. [Lidell, Martin E.; Betz, Matthias J.; Enerback, Sven] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med & Clin Genet, SE-40530 Gothenburg, Sweden. [Wess, Juergen] NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Freichel, Marc] Heidelberg Univ, Inst Pharmacol, D-69120 Heidelberg, Germany. [Blueher, Matthias] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Insel, Paul A.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Pfeifer, Alexander] Univ Bonn, PharmaCtr, D-53127 Bonn, Germany. RP Pfeifer, A (reprint author), Univ Bonn, Univ Hosp Bonn, Inst Pharmacol & Toxicol, D-53127 Bonn, Germany.; Pfeifer, A (reprint author), Univ Bonn, Res Training Grp 1873, D-53127 Bonn, Germany.; Pfeifer, A (reprint author), Univ Bonn, PharmaCtr, D-53127 Bonn, Germany. EM alexander.pfeifer@uni-bonn.de FU DFG [FOR2372, GRK1873] FX We thank S. Kipschull and P. Zehner for expert technical assistance and Jennifer Naumann for assistance with culturing and differentiation of human cells. We thank C. Dani (University of Nice Sophia Antipolis) for providing hMADS, S. Gutkind and B. Roth for providing GqQL and Dq constructs, respectively. We thank the DFG for financial support (especially the FOR2372 and GRK1873). NR 45 TC 3 Z9 4 U1 8 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2016 VL 7 AR 10895 DI 10.1038/ncomms10895 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0CB UT WOS:000371728500001 PM 26955961 ER PT J AU Casellas, R Basu, U Yewdell, WT Chaudhuri, J Robbiani, D Di Noia, JM AF Casellas, Rafael Basu, Uttiya Yewdell, William T. Chaudhuri, Jayanta Robbiani, DavideF. Di Noia, Javier M. TI Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID INDUCED CYTIDINE DEAMINASE; CLASS-SWITCH RECOMBINATION; ACTIVATION-INDUCED DEAMINASE; RNA-POLYMERASE-II; DOUBLE-STRAND BREAKS; ANTIBODY DIVERSIFICATION ENZYME; 5 NONCODING REGION; PROTEIN-KINASE-A; NF-KAPPA-B; SOMATIC HYPERMUTATION AB As B cells engage in the immune response, they express activation-induced cytidine deaminase (AID) to initiate the hypermutation and recombination of immunoglobulin genes, which are crucial processes for the efficient recognition and disposal of pathogens. However, AID must be tightly controlled in B cells to minimize off-target mutations, which can drive chromosomal translocations and the development of B cell malignancies, such as lymphomas. Recent genomic and biochemical analyses have begun to unravel the mechanisms of how AID-mediated deamination is targeted outside immunoglobulin genes. Here, we discuss the transcriptional and topological features that are emerging as key drivers of AID promiscuous activity. C1 [Casellas, Rafael] NIAMSD, Genom & Immun, NCI, NIH, Bethesda, MD 20892 USA. [Basu, Uttiya] Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA. [Yewdell, William T.; Chaudhuri, Jayanta] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. [Yewdell, William T.] Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA. [Robbiani, DavideF.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Di Noia, Javier M.] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Di Noia, Javier M.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. RP Casellas, R (reprint author), NIAMSD, Genom & Immun, NCI, NIH, Bethesda, MD 20892 USA.; Di Noia, JM (reprint author), Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada.; Di Noia, JM (reprint author), Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. EM rafael.casellas@nih.gov; Javier.Di.Noia@ircm.qc.ca RI Di Noia, Javier/D-2285-2012 OI Di Noia, Javier/0000-0003-2896-0321 FU NCI NIH HHS [P30 CA008748, T32 CA009149]; NIAID NIH HHS [R21 AI112602] NR 135 TC 5 Z9 5 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD MAR PY 2016 VL 16 IS 3 BP 164 EP 176 DI 10.1038/nri.2016.2 PG 13 WC Immunology SC Immunology GA DF5LU UT WOS:000371394100009 PM 26898111 ER PT J AU Mulligan, C Fenollar-Ferrer, C Fitzgerald, GA Vergara-Jaque, A Kaufmann, D Li, Y Forrest, LR Mindell, JA AF Mulligan, Christopher Fenollar-Ferrer, Cristina Fitzgerald, Gabriel A. Vergara-Jaque, Ariela Kaufmann, Desiree Li, Yan Forrest, Lucy R. Mindell, Joseph A. TI The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MEMBRANE-TRANSPORT; ALTERNATING ACCESS; CRYSTAL-STRUCTURE; NEUROTRANSMITTER TRANSPORTERS; CONFORMATIONAL-CHANGES; VIBRIO-CHOLERAE; SLC13 FAMILY; SUPERFAMILY; TOPOLOGY AB Secondary transporters use alternating-access mechanisms to couple uphill substrate movement to downhill ion flux. Most known transporters use a 'rocking bundle' motion, wherein the protein moves around an immobile substrate-binding site. However, the glutamate-transporter homolog Glt(ph) translocates its substrate-binding site vertically across the membrane, through an 'elevator' mechanism. Here, we used the 'repeat swap' approach to computationally predict the outward-facing state of the Na+/succinate transporter VcINDY, from Vibrio cholerae. Our model predicts a substantial elevator-like movement of VcINDY's substrate-binding site, with a vertical translation of similar to 15 angstrom and a rotation of similar to 43 degrees. Our observation that multiple disulfide cross-links completely inhibit transport provides experimental confirmation of the model and demonstrates that such movement is essential. In contrast, cross-links across the VcINDY dimer interface preserve transport, thus revealing an absence of large-scale coupling between protomers. C1 [Mulligan, Christopher; Fitzgerald, Gabriel A.; Mindell, Joseph A.] NINDS, Membrane Transport Biophys Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Fenollar-Ferrer, Cristina; Vergara-Jaque, Ariela; Forrest, Lucy R.] NINDS, Computat Struct Biol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Fenollar-Ferrer, Cristina; Kaufmann, Desiree] Max Planck Inst Biophys, Frankfurt, Germany. [Li, Yan] NINDS, Prot Peptide Sequencing Facil, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Fitzgerald, Gabriel A.; Kaufmann, Desiree] Weill Cornell Med Coll, Dept Physiol, New York, NY USA. RP Mindell, JA (reprint author), NINDS, Membrane Transport Biophys Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.; Forrest, LR (reprint author), NINDS, Computat Struct Biol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM lucy.forrest@nih.gov; mindellj@ninds.nih.gov FU L'Oreal Chile-United Nations Educational, Scientific and Cultural Organization (UNESCO) Women in Science Fellowship; L'Oreal-UNESCO Rising Talent Award; Division of Intramural Research of the US National Institutes of Health, National Institute of Neurological Disorders and Stroke FX We thank A. Banerjee for helpful discussions and M. Maduke, J. Faraldo-Gomez, G. Rudnick and M. Mayer for critical review of the manuscript. A.V.-J. is supported as a recipient of the L'Oreal Chile-United Nations Educational, Scientific and Cultural Organization (UNESCO) Women in Science Fellowship and the L'Oreal-UNESCO Rising Talent Award. This work was supported by the Division of Intramural Research of the US National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 42 TC 8 Z9 8 U1 1 U2 9 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 MAR PY 2016 VL 23 IS 3 BP 256 EP 263 DI 10.1038/nsmb.3166 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DF6FY UT WOS:000371452500013 PM 26828963 ER PT J AU Cortese, I Ohayon, J Fenton, K Lee, CC Raffeld, M Cowen, EW DiGiovanna, JJ Bielekova, B AF Cortese, Irene Ohayon, Joan Fenton, Kaylan Lee, Chyi-Chia Raffeld, Mark Cowen, Edward W. DiGiovanna, John J. Bielekova, Bibiana TI Cutaneous adverse events in multiple sclerosis patients treated with daclizumab SO NEUROLOGY LA English DT Article ID NATURAL-KILLER-CELLS; INNATE LYMPHOID-CELLS; REGULATORY T-CELLS; PITYRIASIS-ROSEA; ANTIBODY DACLIZUMAB; NONINFECTIOUS UVEITIS; IMATINIB MESYLATE; DOUBLE-BLIND; SKIN; DISEASE AB Objective:To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP).Methods:A total of 31 participants in an institutional review board-approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4-9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts).Results:Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontinuation of DAC-HYP in 4 (13%). More severe rashes presented psoriasiform phenotype, but lesional biopsies lacked features of either psoriasis or drug hypersensitivity eruptions. Instead, irrespective of clinical severity, lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates. Pretreatment and posttreatment biopsies of normal-appearing skin demonstrated no histopathologic changes.Conclusions:Observed cutaneous AEs are likely related to the immunomodulatory effects DAC-HYP exerts on innate lymphoid cells, including natural killer cells. Vigilance and timely management of skin reactions may prevent treatment discontinuation in participants with severe rash. C1 [Cortese, Irene; Ohayon, Joan] NINDS, Neuroimmunol Clin, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lee, Chyi-Chia; Raffeld, Mark] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Cowen, Edward W.; DiGiovanna, John J.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fenton, Kaylan] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM bibi.bielekova@nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS), NIH; NINDS; Abbvie/Biogen-Idec FX This study was funded by the intramural research program of the National Institute of Neurological Disorders and Stroke (NINDS), NIH, and by a Collaborative Research Agreement (CRADA) between NINDS and Abbvie/Biogen-Idec. NR 33 TC 8 Z9 8 U1 2 U2 3 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 MAR 1 PY 2016 VL 86 IS 9 BP 847 EP 855 DI 10.1212/WNL.0000000000002417 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DF4TG UT WOS:000371343100007 PM 26843560 ER PT J AU Lagemaat, MW van de Bank, BL Sati, P Li, SZ Maas, MC Scheenen, TWJ AF Lagemaat, Miriam W. van de Bank, Bart L. Sati, Pascal Li, Shizhe Maas, Marnix C. Scheenen, Tom W. J. TI Repeatability of P-31 MRSI in the human brain at 7T with and without the nuclear Overhauser effect SO NMR IN BIOMEDICINE LA English DT Article DE repeatability; reproducibility; 7T; ultrahigh field; MRS ID MAGNETIC-RESONANCE-SPECTROSCOPY; IN-VIVO; RELAXATION-TIMES; HUMAN PROSTATE; MUSCLE; REPRODUCIBILITY; ENHANCEMENTS; METABOLITES; DISEASE; TUMORS AB An often-employed strategy to enhance signals in P-31 MRS is the generation of the nuclear Overhauser effect (NOE) by saturation of the water resonance. However, NOE allegedly increases the variability of the P-31 data, because variation is reported in NOE enhancements. This would negate the signal-to-noise (SNR) gain it generates. We hypothesized that the variation in NOE enhancement values is not caused by the variability in NOE itself, but is attributable to measurement uncertainties in the values used to calculate the enhancement. If true, the expected increase in SNR with NOE would improve the repeatability of P-31 MRS measurements. To verify this hypothesis, a repeatability study of native and NOE-enhanced P-31 MRSI was performed in the brains of seven healthy volunteers at 7T. The repeatability coefficient (RC) and the coefficient of variation in repeated measurements (CoVrepeat) were determined for each method, and the 95% limits of agreement (LoAs) between native and NOE-enhanced signals were calculated. The variation between the methods, defined by the LoA, is at least as great as that predicted by the RC of each method. The sources of variation in NOE enhancements were determined using variance component analysis. In the seven metabolites with a positive NOE enhancement (nine metabolite resonances assessed), CoVrepeat improved, on average, by 15%. The LoAs could be explained by the RCs of the individual methods for the majority of the metabolites, generally confirming our hypothesis. Variation in NOE enhancement was mainly attributable to the factor repeat, but between-voxel effects were also present for phosphoethanolamine and (glycero)phosphocholine. CoVrepeat and fitting error were strongly correlated and improved with positive NOE. Our findings generally indicate that NOE enhances the signal of metabolites, improving the repeatability of metabolite measurements. Additional variability as a result of NOE was minimal. These findings encourage the use of NOE-enhanced P-31 MRSI. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Lagemaat, Miriam W.; van de Bank, Bart L.; Maas, Marnix C.; Scheenen, Tom W. J.] Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, Nijmegen, Netherlands. [Sati, Pascal; Scheenen, Tom W. J.] NINDS, Lab Funct & Mol Imaging, NIH, Bldg 10, Bethesda, MD 20892 USA. [Li, Shizhe] NIMH, MRS Core Facil, NIH, Bethesda, MD 20892 USA. [Scheenen, Tom W. J.] Univ Duisburg Essen, Erwin L Hahn Inst Magnet Resonance Imaging, Essen, Germany. RP Lagemaat, MW (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, Post 766,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM miriamlagemaat@gmail.com RI Scheenen, Tom/I-5921-2013 FU European Research Council under the European Community [243115]; National Institute of Mental Health (NIMH); National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) FX This work was supported by grant number 243115 from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013). This work was partially supported by the intramural research programs of the National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH). NR 35 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD MAR PY 2016 VL 29 IS 3 BP 256 EP 263 DI 10.1002/nbm.3455 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DF5XK UT WOS:000371426000006 PM 26647020 ER PT J AU Liu, HS Shen, H Luo, Y Hoffer, BJ Wang, Y Yang, Y AF Liu, H. -S. Shen, H. Luo, Y. Hoffer, B. J. Wang, Y. Yang, Y. TI Post-treatment with cocaine- and amphetamine-regulated transcript enhances infarct resolution, reinnervation, and angiogenesis in stroke rats - an MRI study SO NMR IN BIOMEDICINE LA English DT Article DE MRI; susceptibility-weighted imaging; fractional anisotropy; cocaine- and amphetamine-regulated transcript ID TRANSIENT FOCAL ISCHEMIA; EMBOLIC STROKE; CART PEPTIDE; BRAIN; RECOVERY; NEUROGENESIS; ACTIVATION; EXPRESSION; THERAPY; CELLS AB Recent studies have shown that post-treatment with cocaine- and amphetamine-regulated transcript (CART) has neuroregenerative effects in animal models of stroke. The purpose of this study was to characterize CART-mediated neuronal and vascular repairments using non-invasive MRI techniques. Adult male rats were subjected to a 90 min middle cerebral artery occlusion (MCAo). Animals were separated into two groups with similar infarction sizes, measured by T-2-weighted MRI on Day 2 after MCAo, and were treated with CART or vehicle intranasally from Day 3 to Day 12. Diffusion tensor imaging was used to examine changes in plasticity of white matter elements. Susceptibility-weighted imaging (SWI) was used to measure angiogenesis. Post-treatment with CART significantly increased fractional anisotropy (FA) in lesioned cortex on Days 10 and 25 post stroke. A significant correlation between the behavioral recovery in body asymmetry and the change in FA was shown, suggesting that behavioral recovery was associated with reinnervation to the lesioned hemisphere. CART also increased the intensity of SWI and the immunoreactivity of the vascular marker alpha-smooth muscle actin in lesioned cortex. Together, our data support a non-invasive treatment strategy for stroke through angiogenesis and reinnervation by CART. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Liu, H. -S.; Yang, Y.] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA. [Wang, Y.] Natl Hlth Res Inst, Ctr Neuropsychiat Res, 35 Keyan Rd, Zhunan 35053, Miaoli County, Taiwan. [Liu, H. -S.] Taipei Med Univ, Coll Med, Grad Inst Clin Med, Taipei, Taiwan. [Liu, H. -S.] Taipei Med Univ Hosp, Dept Med Imaging, Taipei, Taiwan. [Shen, H.] NIDA, Synapt Plast Sect, Cellular Neurobiol Res Branch, NIH, Baltimore, MD USA. [Luo, Y.; Hoffer, B. J.] Case Western Reserve Univ, Dept Neurol Surg, Cleveland, OH 44106 USA. [Hoffer, B. J.] NIDA, Biomed Res Ctr, NIH, Baltimore, MD USA. [Liu, H. -S.] Taipei Med Univ Hosp, Radiogenom Res Ctr, Taipei, Taiwan. [Liu, H. -S.] Translat Imaging Res Ctr, Taipei, Taiwan. RP Yang, Y (reprint author), NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA.; Wang, Y (reprint author), Natl Hlth Res Inst, Ctr Neuropsychiat Res, 35 Keyan Rd, Zhunan 35053, Miaoli County, Taiwan. EM ywang@nhri.org.tw; yihongyang@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 41 TC 0 Z9 0 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD MAR PY 2016 VL 29 IS 3 BP 361 EP 370 DI 10.1002/nbm.3461 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DF5XK UT WOS:000371426000016 PM 26915794 ER PT J AU Yang, BY Yang, HP Ward, KK Sahasrabuddhe, VV McGlynn, KA AF Yang, Baiyu Yang, Hannah P. Ward, Kristy K. Sahasrabuddhe, Vikrant V. McGlynn, Katherine A. TI Bariatric Surgery and Liver Cancer in a Consortium of Academic Medical Centers SO OBESITY SURGERY LA English DT Article DE Bariatric surgery; Liver cancer; Administrative records; Obesity; Diabetes ID OBESE-PATIENTS; METAANALYSIS; MORTALITY; OUTCOMES AB Obesity is implicated as an important factor in the rising incidence of liver cancer in the USA. Bariatric surgery is increasingly used for treating morbid obesity and comorbidities. Using administrative data from UHC, a consortium of academic medical centers in the USA, we compared the prevalence of liver cancer among admissions with and without a history of bariatric surgery within a 3-year period. Admissions with a history of bariatric surgery had a 61 % lower prevalence of liver cancer compared to those without a history of bariatric surgery (prevalence ratio 0.39, 95 % confidence interval 0.35-0.44), and these inverse associations persisted within strata of sex, race, and ethnicity. This hospital administrative record-based analysis suggests that bariatric surgery could play a role in liver cancer prevention. C1 [Yang, Baiyu; Yang, Hannah P.; Sahasrabuddhe, Vikrant V.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sahasrabuddhe, Vikrant V.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Ward, Kristy K.] Univ Florida, Coll Med, Div Gynecol Oncol, Jacksonville, FL 32209 USA. RP Yang, BY (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM baiyu.yang@nih.gov; yanghan@mail.nih.gov; kristy.kay.ward@gmail.com; vikrant.sahasrabuddhe@nih.gov; mcglynnk@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 15 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 EI 1708-0428 J9 OBES SURG JI Obes. Surg. PD MAR PY 2016 VL 26 IS 3 BP 696 EP 700 DI 10.1007/s11695-016-2051-1 PG 5 WC Surgery SC Surgery GA DF3PV UT WOS:000371258100037 PM 26757918 ER PT J AU Higgins, RD Saade, G Polin, RA Grobman, WA Buhimschi, IA Watterberg, K Silver, RM Raju, TNK AF Higgins, Rosemary D. Saade, George Polin, Richard A. Grobman, William A. Buhimschi, Irina A. Watterberg, Kristi Silver, Robert M. Raju, Tonse N. K. CA Chorioamnionitis Workshop Particip TI Evaluation and Management of Women and Newborns With a Maternal Diagnosis of Chorioamnionitis Summary of a Workshop SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID C-REACTIVE PROTEIN; IMMEDIATE POSTNATAL-PERIOD; EPIDURAL-RELATED FEVER; ONSET NEONATAL SEPSIS; CLINICAL CHORIOAMNIONITIS; INTRAAMNIOTIC INFECTION; INTERLEUKIN-6; LABOR; RISK; PROCALCITONIN AB In January 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited an expert panel to a workshop to address numerous knowledge gaps and to provide evidence-based guidelines for the diagnosis and management of pregnant women with what had been commonly called chorioamnionitis and the neonates born to these women. The panel noted that the term chorioamnionitis has been used to label a heterogeneous array of conditions characterized by infection and inflammation or both with a consequent great variation in clinical practice for mothers and their newborns. Therefore, the panel proposed to replace the term chorioamnionitis with a more general, descriptive term: "intrauterine inflammation or infection or both," abbreviated as "Triple I." The panel proposed a classification for Triple I and recommended approaches to evaluation and management of pregnant women and their newborns with a diagnosis of Triple I. It is particularly important to recognize that an isolated maternal fever is not synonymous with chorioamnionitis. A research agenda was proposed to further refine the definition and management of this complex group of conditions. This article provides a summary of the workshop presentations and discussions. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. Columbia Univ, Dept Pediat, New York, NY 10027 USA. Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Ctr Perinatal Res,Res Inst, Columbus, OH 43210 USA. Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. Univ New Mexico, Hlth Sci Ctr, Dept Pediat, Albuquerque, NM 87131 USA. Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT USA. RP Higgins, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 47 TC 10 Z9 10 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2016 VL 127 IS 3 BP 426 EP 436 DI 10.1097/AOG.0000000000001246 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DE6DE UT WOS:000370723000002 PM 26855098 ER PT J AU Hobday, T Yin, J Pettinger, A Strosberg, J Reidy-Lagunes, D Chen, H Erlichman, C AF Hobday, Timothy Yin, Jun Pettinger, Adam Strosberg, Jonathan Reidy-Lagunes, Diane Chen, Helen Erlichman, Charles TI Multicenter Prospective Phase II Trial of Bevacizumab (bev) for Progressive Pancreatic Neuroendocrine Tumor (PNET) SO PANCREAS LA English DT Meeting Abstract C1 [Hobday, Timothy; Yin, Jun; Pettinger, Adam; Erlichman, Charles] Mayo Clin, Coll Med, Mayo Phase Consortium P2C 2, Rochester, MN USA. [Strosberg, Jonathan] Univ S Florida, H Lee Moffitt Canc Ctr, Southeast P2C, Tampa, FL 33682 USA. [Reidy-Lagunes, Diane] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Chen, Helen] Natl Canc Inst, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD MAR PY 2016 VL 45 IS 3 BP 477 EP 477 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE9KQ UT WOS:000370956600055 ER PT J AU Danziger-Isakov, L Frazier, TW Worley, S Williams, N Shellmer, D Dharnidharka, VR Gupta, NA Ikle, D Sweet, SC AF Danziger-Isakov, Lara Frazier, Thomas W. Worley, Sarah Williams, Nikki Shellmer, Diana Dharnidharka, Vikas R. Gupta, Nitika A. Ikle, David Sweet, Stuart C. CA CTOTC-05 Consortium TI Perceived barriers to medication adherence in pediatric and adolescent solid organ transplantation SO PEDIATRIC TRANSPLANTATION LA English DT Article DE adherence; pediatric; solid-organ transplant ID RECIPIENTS; NONADHERENCE; OUTCOMES; METAANALYSIS; REGIMEN; RISK AB Comparisons of perceived barriers to adherence in pediatric and adolescent SOT have not been systematically conducted despite association between medication non-adherence and poor outcome. Fifteen centers in CTOT-C enrolled patients in a cross-sectional study. Subjects' guardians completed the PMBS and subjects over eight completed the Adolescent Scale (AMBS). Association of three identified PMBS factors and subject age was assessed. Secondary analyses assessed associations between PMBS, AMBS, and patient demographics. Three hundred sixty-eight subjects or their guardians completed PMBS or AMBS. A total of 107 subjects were 6-11 yr; 261 were 12. Unadjusted and propensity-adjusted analyses indicated higher perceived barriers in guardians of adolescents as compared to guardians of pre-adolescents medication scheduling and frustration domains regardless of organ (p < 0.05). PMBS and AMBS comparisons revealed that guardians reported fewer ingestion issues than patients (p = 0.018), and differences appeared more pronounced within younger responders for scheduling (p = 0.025) and frustration (p = 0.019). Screening revealed guardians of older patients report increased perceived barriers to adherence independent of socioeconomic status. Guardians of adolescents reported fewer perceived barriers to ingestion/side effects than patients themselves, particularly in pre-adolescents (8-11 yr). Brief screening measures to assess perceived barriers should be further studied in adherence improvement programs. C1 [Danziger-Isakov, Lara] Cincinnati Childrens Hosp Med Ctr, MLC 7017,3333 Burnet Ave, Cincinnati, OH 45229 USA. [Frazier, Thomas W.; Worley, Sarah] Cleveland Clin Childrens, Cleveland, OH USA. [Williams, Nikki] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shellmer, Diana] Univ Pittsburgh, Childrens Hosp Pittsburgh, UPMC, Pittsburgh, PA 15213 USA. [Dharnidharka, Vikas R.; Sweet, Stuart C.] Washington Univ, Sch Med, St Louis Childrens Hosp, St Louis, MO USA. [Gupta, Nitika A.] Emory Univ, Sch Med, Atlanta, GA USA. [Ikle, David] Rho, Chapel Hill, NC USA. RP Danziger-Isakov, L (reprint author), Cincinnati Childrens Hosp Med Ctr, MLC 7017,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM Lara.Danziger-Isakov@cchmc.org FU National Institutes of Health U01 grant [U01 AI077810] FX This research was performed as a project of the CTOT-C, a collaborative clinical research project headquartered at the National Institute of Allergy and Infectious Diseases. The study was supported by a supplement to National Institutes of Health U01 grant (U01 AI077810) awarded to S. Sweet. We acknowledge feedback from Nancy Bridges at NIAID on the study design and interpretation of results. NR 22 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 EI 1399-3046 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD MAR PY 2016 VL 20 IS 2 BP 307 EP 315 DI 10.1111/petr.12648 PG 9 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA DF5ZM UT WOS:000371433100018 PM 26670870 ER PT J AU Kendall, GM Wakeford, R Athanson, M Vincent, TJ Carter, EJ McColl, NP Little, MP AF Kendall, G. M. Wakeford, R. Athanson, M. Vincent, T. J. Carter, E. J. McColl, N. P. Little, M. P. TI Levels of naturally occurring gamma radiation measured in British homes and their prediction in particular residences SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Article DE Gamma radiation; Natural background radiation; Childhood cancer; Leukaemia ID KINGDOM CHILDHOOD-CANCER; IONIZING-RADIATION; BACKGROUND-RADIATION; DOMESTIC SOURCES; GREAT-BRITAIN; LEUKEMIA; EXPOSURE; RISK; UNCERTAINTY; LIKELIHOOD AB Gamma radiation from natural sources (including directly ionising cosmic rays) is an important component of background radiation. In the present paper, indoor measurements of naturally occurring gamma rays that were undertaken as part of the UK Childhood Cancer Study are summarised, and it is shown that these are broadly compatible with an earlier UK National Survey. The distribution of indoor gamma-ray dose rates in Great Britain is approximately normal with mean 96 nGy/h and standard deviation 23 nGy/h. Directly ionising cosmic rays contribute about one-third of the total. The expanded dataset allows a more detailed description than previously of indoor gamma-ray exposures and in particular their geographical variation. Various strategies for predicting indoor natural background gamma-ray dose rates were explored. In the first of these, a geostatistical model was fitted, which assumes an underlying geologically determined spatial variation, superimposed on which is a Gaussian stochastic process with Mat,rn correlation structure that models the observed tendency of dose rates in neighbouring houses to correlate. In the second approach, a number of dose-rate interpolation measures were first derived, based on averages over geologically or administratively defined areas or using distance-weighted averages of measurements at nearest-neighbour points. Linear regression was then used to derive an optimal linear combination of these interpolation measures. The predictive performances of the two models were compared via cross-validation, using a randomly selected 70 % of the data to fit the models and the remaining 30 % to test them. The mean square error (MSE) of the linear-regression model was lower than that of the Gaussian-Mat,rn model (MSE 378 and 411, respectively). The predictive performance of the two candidate models was also evaluated via simulation; the OLS model performs significantly better than the Gaussian-Mat,rn model. C1 [Kendall, G. M.] Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. [Wakeford, R.] Univ Manchester, Inst Populat Hlth, Ctr Environm & Occupat Hlth, Ellen Wilkinson Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. [Athanson, M.] Univ Oxford, Bodleian Lib, Broad St, Oxford OX1 3BG, England. [Vincent, T. J.] Univ Oxford, Childhood Canc Res Grp, New Richards Bldg,Old Rd, Oxford, England. [Carter, E. J.] Univ Worcester, Earth Heritage Trust, Geol Records Ctr, Worcester WR2 6AJ, England. [McColl, N. P.] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Didcot OX11 0RQ, Oxon, England. [Little, M. P.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. RP Kendall, GM (reprint author), Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. EM Gerald.Kendall@ceu.ox.ac.uk OI Kendall, Gerry/0000-0002-9195-754X; Wakeford, Richard/0000-0002-2934-0987 FU Children with Cancer (UK); National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics; Department of Health; Scottish Government FX We are very grateful to Jill Simpson of the University of York and to the other UKCCS investigators for making available the indoor gamma-ray measurements made for the United Kingdom Childhood Cancer Study and for advice on the interpretation of the data. We are also very grateful to J D Appleton for advice on geological matters generally and in particular for suggesting geological classification schemes. We are grateful to Phil Gilvin, Luke Hager and Rick Tanner at Public Health England (PHE) for advice on the dosimetry of the National Survey and the UKCCS and to Simon Bouffler and other colleagues at PHE for allowing the use of the National Survey data and for advice on its interpretation. They also made helpful comments on the draft. Helpful comments were also made by the two referees and by Bernd Grosche, Michael Murphy and Graham Smith. This work was supported by Children with Cancer (UK) and by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. Much of the work by two of the authors (GMK and TJV) was undertaken at the Childhood Cancer Research Group, whose loss is much regretted. The research work of CCRG was supported by the Department of Health for England and Wales, Scottish Government and Children with Cancer (UK). NR 49 TC 2 Z9 2 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X EI 1432-2099 J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2016 VL 55 IS 1 BP 103 EP 124 DI 10.1007/s00411-016-0635-8 PG 22 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA DF4IY UT WOS:000371312400014 PM 26880257 ER PT J AU Javaheri, S Sharma, RK Wang, R Weng, J Rosen, BD Bluemke, DA Lima, JAC Redline, S AF Javaheri, Sogol Sharma, Ravi K. Wang, Rui Weng, Jia Rosen, Boaz D. Bluemke, David A. Lima, Joao A. C. Redline, Susan TI Association between Obstructive Sleep Apnea and Left Ventricular Structure by Age and Gender: the Multi-Ethnic Study of Atherosclerosis SO SLEEP LA English DT Article DE obstructive sleep apnea; left ventricular mass; cardiac magnetic resonance imaging; left ventricular mass/volume ratio ID POSITIVE AIRWAY PRESSURE; HEART-FAILURE; DIASTOLIC FUNCTION; CARDIOVASCULAR EVENTS; SYSTOLIC FUNCTION; BLOOD-PRESSURE; MASS; PREVALENCE; HYPERTENSION; HYPERTROPHY AB Study Objectives: The presence and severity of obstructive sleep apnea (OSA) are associated with impaired left ventricular (LV) structure and function. Our goal was to quantify the associations between LV systolic function and mass with severity of OSA in an ethnically diverse cohort, assessing variations by age and sex. Methods: We conducted a cross-sectional analysis of data from 1,412 racially/ethnically diverse participants across 6 US communities from the Multi-Ethnic Study of Atherosclerosis who underwent both overnight polysomnography and cardiac magnetic resonance imaging from 2010-2012. We evaluated the association between the obstructive apnea-hypopnea index (AHI) by clinical category (< 5, 5-15, 15-30, 30-50, > 50) and secondary measures of sleep apnea with the outcomes left ventricular (LV) mass adjusted for height, LV mass/volume ratio, and LV ejection fraction. Results: After adjusting for potential confounders and mediators, LV mass was significantly increased with increasing AHI category for subjects age 65 y or younger (beta = 1.84 +/- 0.47 g/m, P = 0.0001). The association between the AHI and LV mass appeared stronger in whites and Chinese compared to blacks and Hispanics, although interaction terms were not statistically significant. Additionally, while both LV mass and LV mass/volume ratio were significantly associated with hypoxia, ejection fraction was not associated with any OSA severity index. Comparable associations were observed in men and women. Conclusions: Independent of confounders, higher levels of AHI are significantly associated with increased LV mass in both men and women younger than 65 y from a community-based cohort. C1 [Javaheri, Sogol; Wang, Rui; Weng, Jia; Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Sleep & Circadian Disorders,Med Sch, Boston, MA 02115 USA. [Javaheri, Sogol; Wang, Rui; Weng, Jia; Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Div Sleep & Circadian Disorders,Med Sch, Boston, MA 02115 USA. [Javaheri, Sogol; Wang, Rui; Weng, Jia; Redline, Susan] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Sharma, Ravi K.; Rosen, Boaz D.; Lima, Joao A. C.] Johns Hopkins Univ Hosp, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. [Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. RP Javaheri, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, 221 Longwood Ave,BLI-225, Boston, MA 02115 USA. EM sjavaheri@partners.org OI Bluemke, David/0000-0002-8323-8086 FU NIH [5T32HL007901, 1R01HL083075, R01HL098433, R01 HL098433-02S1, 1U34HL105277-01, 1R01HL110068-01A1, 1R01HL113338-01]; Jazz Pharmaceuticals FX This was not an industry supported study. Funding was provided by NIH 5T32HL007901, 1R01HL083075, R01HL098433, R01 HL098433-02S1, 1U34HL105277-01, 1R01HL110068-01A1, and 1R01HL113338-01. Dr. Redline has received research support from Jazz Pharmaceuticals. The other authors have indicated no financial conflicts of interest. NR 39 TC 0 Z9 0 U1 0 U2 1 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD MAR 1 PY 2016 VL 39 IS 3 BP 523 EP 529 AR PII sp-00337-15 DI 10.5665/sleep.5518 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DF1RB UT WOS:000371115800006 PM 26888453 ER PT J AU Johnson, RF Bagci, U Keith, L Tang, XC Mollura, DJ Zeitlin, L Qin, J Huzella, L Bartos, CJ Bohorova, N Bohorov, O Goodman, C Kim, DH Paulty, MH Velasco, J Whaley, KJ Johnson, JC Pettitt, J Ork, BL Solomon, J Oberlander, N Zhu, Q Sun, JS Holbrook, MR Olinger, GG Baric, RS Hensley, LE Jahrling, PB Marasco, WA AF Johnson, Reed F. Bagci, Ulas Keith, Lauren Tang, Xianchun Mollura, Daniel J. Zeitlin, Larry Qin, Jing Huzella, Louis Bartos, Christopher J. Bohorova, Natasha Bohorov, Ognian Goodman, Charles Kim, Do H. Paulty, Michael H. Velasco, Jesus Whaley, Kevin J. Johnson, Joshua C. Pettitt, James Ork, Britini L. Solomon, Jeffrey Oberlander, Nicholas Zhu, Quan Sun, Jiusong Holbrook, Michael R. Olinger, Gene G. Baric, Ralph S. Hensley, Lisa E. Jahrling, Peter B. Marasco, Wayne A. TI 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012 SO VIROLOGY LA English DT Article DE MERS-CoV; Antibody therapy; Animal model, MERS; Respiratory syndrome; Human monoclonal antibody therapy ID EAST RESPIRATORY SYNDROME; SYNDROME CORONAVIRUS INFECTION; MOUSE MODEL; NEUTRALIZING ANTIBODIES; DROMEDARY CAMELS; SAUDI-ARABIA; VIRUS; TRACT; GENERATION; IDENTIFICATION AB Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5 x 10(6) PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment. Published by Elsevier Inc. C1 [Johnson, Reed F.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. [Bagci, Ulas; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Ctr Clin, Bethesda, MD 20892 USA. [Keith, Lauren; Huzella, Louis; Bartos, Christopher J.; Johnson, Joshua C.; Pettitt, James; Ork, Britini L.; Oberlander, Nicholas; Holbrook, Michael R.; Olinger, Gene G.; Hensley, Lisa E.; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Tang, Xianchun; Zhu, Quan; Sun, Jiusong; Marasco, Wayne A.] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02215 USA. [Zeitlin, Larry; Bohorova, Natasha; Bohorov, Ognian; Goodman, Charles; Kim, Do H.; Paulty, Michael H.; Velasco, Jesus; Whaley, Kevin J.] Mapp Biopharmaceut Inc, San Diego, CA 92121 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Baric, Ralph S.] Univ N Carolina, Dept Microbiol & Immunol, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Bagci, Ulas] Univ Cent Florida, CRCV, Dept Elect Elect & Comp Sci, Orlando, FL 32816 USA. [Solomon, Jeffrey] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Johnson, RF (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. EM johnsonreed@mail.nih.gov OI Bagci, Ulas/0000-0001-7379-6829 FU NIAID Division of Intramural Research; Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIAID [R01AI085524]; Defense Advanced Research Projects Agency [W911NF-10-0226] 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 figures. 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. B.L.O., M.R.H., J.C.J. performed this work as employees of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are: E.P. an employee of Tunnell Government Services, Inc; N.O., S.Y. and L.H. are employees of Charles River Laboratories, S.M. an employee of MRI Global, CB an employee of MedRelief. J.S. is an employee with Lei-dos. His part in the 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. W.A.M. and R.S.B. were supported by Grant R01AI085524 from NIAID. W.A.M also received support from Defense Advanced Research Projects Agency Grant W911NF-10-0226. The authors thank Drs. Yuri Gleba and Victor Klimyuk (Icon Genetics) for access to the magnICON expression technology and Dr. Herta Steinkellner (BOKU) for access to the N. benthamiana seed. NR 36 TC 8 Z9 8 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR PY 2016 VL 490 BP 49 EP 58 DI 10.1016/j.virol.2016.01.004 PG 10 WC Virology SC Virology GA DF6DF UT WOS:000371445400006 PM 26828465 ER PT J AU Patel, D Gara, SK Ellis, RJ Boufraqech, M Nilubol, N Millo, C Stratakis, CA Kebebew, E AF Patel, Dhaval Gara, Sudheer Kumar Ellis, Ryan J. Boufraqech, Myriem Nilubol, Naris Millo, Corina Stratakis, Constantine A. Kebebew, Electron TI FDG PET/CT Scan and Functional Adrenal Tumors: A Pilot Study for Lateralization SO WORLD JOURNAL OF SURGERY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; PRIMARY ALDOSTERONISM; CUSHINGS-SYNDROME; HEXOKINASE-II; MANAGEMENT; DIAGNOSIS; INCIDENTALOMAS; EXPRESSION; CHALLENGE AB Background Patients with Cushing's Syndrome (CS) and Conn's Syndrome with bilateral adrenal masses pose a dilemma. Uptake of 18F-FDG by hyperfunctioning adrenal glands has not been previously reported and may help lateralize. The aim was to determine if 18F-FDG PET/CT scan could identify hyperfunctioning adrenal masses and determine a biological basis for uptake. Methods Patients with nonfunctional adenomas (n = 9), CS (n = 11), and Conn's syndrome (n = 4) underwent an 18F-FDG PET/CT scan with a volume of interest circumscribing each mass to obtain a maximal standardized uptake value (SUVmax). Thirty-two adrenal masses were analyzed. Genome-wide expression data from an independent cohort were analyzed in nonfunctioning adenomas (n = 20), Conn's syndrome (n = 29), and CS (n = 24) focusing on GLUT genes. For genes differentially expressed, immunohistochemistry was performed on tissue samples. Results Cortisol-secreting masses (n = 16) had a higher average SUVmax of 5.9 compared to nonfunctioning masses (n = 11, average SUVmax 4.2) and aldosterone-hypersecreting masses (n = 5, average SUVmax 3.2) (p = 0.007). SUVmax cut-off of 5.33 had 50.0 % sensitivity and 81.8 % specificity in localizing a cortisol-secreting mass. GLUT3 expression was 2.19-fold higher in patients with CS compared to patients with nonfunctioning adenomas (p = 0.003) and 2.16-fold higher in patients with CS compared to Conn's syndrome (p = 0.006). GLUT3 immunohistochemistry showed 2.2-fold higher staining in CS tumor samples compared to nonfunctioning adenomas. Conclusions Differential 18F-FDG PET/CT uptake was observed in patients with nonfunctioning, aldosterone-hypersecreting, and cortisol-secreting masses. GLUT3 overexpression in cortisol-secreting tumor likely accounts for the differential uptake. Future larger cohort studies will need to be conducted to determine if 18F-FDG PET/CT uptake can lateralize cortisol-secreting adrenal masses in patients with bilateral adrenal masses. C1 [Patel, Dhaval; Gara, Sudheer Kumar; Boufraqech, Myriem; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Clin Res Ctr, NIH, Bldg 10-CRC,Room 3-5840, Bethesda, MD 20892 USA. [Ellis, Ryan J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Millo, Corina] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Clin Res Ctr, NIH, Bldg 10-CRC,Room 3-5840, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Gara, Sudheer Kumar/E-8084-2016; Boufraqech, Myriem/E-4823-2016; OI Patel, Dhaval/0000-0002-5744-568X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 22 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD MAR PY 2016 VL 40 IS 3 BP 683 EP 689 DI 10.1007/s00268-015-3242-y PG 7 WC Surgery SC Surgery GA DF4GH UT WOS:000371305500030 PM 26324161 ER PT J AU Nilubol, N Patel, D Kebebew, E AF Nilubol, Naris Patel, Dhaval Kebebew, Electron TI Does Lymphadenectomy Improve Survival in Patients with Adrenocortical Carcinoma? A Population-Based Study SO WORLD JOURNAL OF SURGERY LA English DT Article ID ADRENAL-CORTICAL CARCINOMA; LYMPH-NODE DISSECTION; SURGICAL-MANAGEMENT; DISEASE; IMPACT; CANCER; UPDATE; TABLES AB Background A recent study suggested a survival benefit in patients with adrenocortical carcinoma (ACC) who had undergone lymphadenectomy. The objective of this study was to study the effect of lymphadenectomy on the survival rates of patients with ACC. Methods Data from adult patients with histology-proven ACC from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 Registries (1973-2011) were analyzed to assess the impact of lymphadenectomy (>= 4 lymph nodes removed) on disease-specific survival (DSS). Results Of 1525 patients with ACC, 45 % were male. 36, 20, and 44 % of patients presented with localized, regional, and distant metastatic diseases, respectively. 8 % of patients (n = 67/802) underwent lymphadenectomy. We observed a higher rate of lymphadenectomy performed in patients with regional disease [locally advanced tumors (stage T3 and T4) and/or lymph node metastasis] and distant metastasis than in those with localized tumors (12.4 % and 12.0 vs. 5.1, respectively, p < 0.01) and in patients with primary tumor sizes >10 cm (12.4 vs. 4.2 %, p < 0.01). Lymph node metastasis was present in 12.8 % (19.2 % in locally advanced ACC). A lymphadenectomy was not associated with improved DSS on univariate analysis (p = 0.30), regardless of tumor size or staging. Independent prognostic factors included: ages >= 60 years (p < 0.01, HR 1.70), lymph node metastasis (p < 0.01, HR 1.7), distant metastasis (p < 0.01, HR 5.6), complete resection of tumor (p < 0.01, HR 0.47), and debulking surgery (p < 0.01, HR 0.49). Conclusion A lymphadenectomy is not commonly performed in patients with ACC in the U.S. Although we found no survival benefit in this cohort with a low rate of lymphadenectomy, a lymphadenectomy may be considered in patients with locally advanced tumors (T3 and T4) due to a higher rate of lymph node metastasis. C1 [Nilubol, Naris; Patel, Dhaval; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, 10 Ctr Dr,Rm 3-5840, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, 10 Ctr Dr,Rm 3-5840, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X NR 28 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD MAR PY 2016 VL 40 IS 3 BP 697 EP 705 DI 10.1007/s00268-015-3283-2 PG 9 WC Surgery SC Surgery GA DF4GH UT WOS:000371305500032 PM 26510563 ER PT J AU Tryggvason, G Jonasson, F Cotch, MF Li, CM Hoffman, HJ Themann, CL Eiriksdottir, G Sverrisdottir, JE Harris, TB Launer, LJ Gudnason, V Petersen, H AF Tryggvason, Geir Jonasson, Fridbert Cotch, Mary Frances Li, Chuan-Ming Hoffman, Howard J. Themann, Christa L. Eiriksdottir, Gudny Sverrisdottir, Johanna Eyrun Harris, Tamara B. Launer, Lenore J. Gudnason, Vilmundur Petersen, Hannes TI Hearing in older adults with exfoliation syndrome/exfoliation glaucoma or primary open-angle glaucoma SO ACTA OPHTHALMOLOGICA LA English DT Article DE adjustment for age and sex; exfoliation glaucoma; hearing; primary open-angle glaucoma ID PSEUDOEXFOLIATION SYNDROME; REYKJAVIK EYE; POPULATION; PREVALENCE; SUSCEPTIBILITY; ASSOCIATION; VARIANTS; RISK AB Purpose: To determine whether adults, aged 66-96 years, with exfoliation syndrome (XFS)/exfoliation glaucoma (XFG), or primary open-angle glaucoma (POAG) have poorer hearing than controls of similar age. Methods: Case (XFS/XFG and POAG) and control status was diagnosed in the Reykjavik Glaucoma Studies (RGS) using slit-lamp examination, visual field testing and optic disc photographs; the RGS data were merged with the Age, Gene/Environment Susceptibility-Reykjavik Study that collected hearing data using air-conduction, pure-tone thresholds obtained at 0.5, 1, 2, 3, 4, 6 and 8 kHz categorized by better ear and worse ear, based on pure-tone averages (PTAs) calculated separately for low and middle frequencies (PTA(512) - mean of thresholds at 0.5, 1 and 2 kHz) and high frequencies (PTA(3468) - mean of thresholds at 3, 4, 6 and 8 kHz). Multivariable linear regression was used to test for differences in PTAs between cases and controls. Results: Themeanage for 158XFS/XFGcases (30.4% male) was 77.4 years, 95POAG cases (35.8% male) was 77.9 years, and 123 controls (46.3% male) was 76.8 years. Using multivariable linear regression analysis, there were no consistent, statistically significant differences in PTAs between the two case groups and controls in either the low-or high-frequency range, evenwhenstratifiedbyagegroup. Conclusion: Among the older individuals examined in this study hearing loss is highly prevalent and strongly associated with male gender and increasing age. As we did not find consistent statistically significant difference in hearing between cases and controls the diagnosis of XFS/XFGorPOAG does not as such routinely call for audiological evaluation. C1 [Tryggvason, Geir] Oslo Univ Hosp, Dept Otolaryngol Head & Neck Surg, Oslo, Norway. [Jonasson, Fridbert] Landspitali Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Jonasson, Fridbert; Gudnason, Vilmundur; Petersen, Hannes] Univ Iceland, Fac Med, Reykjavik, Iceland. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Li, Chuan-Ming; Hoffman, Howard J.] NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Themann, Christa L.] NIOSH, Hearing Loss Prevent Team, Ctr Dis Control & Prevent CDC, Cincinnati, OH 45226 USA. [Eiriksdottir, Gudny; Sverrisdottir, Johanna Eyrun; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Populat Sci, NIH, Bethesda, MD 20892 USA. [Petersen, Hannes] Landspitali Univ Hosp, Dept Otolaryngol Head & Neck Surg, Reykjavik, Iceland. RP Jonasson, F (reprint author), Landspitali Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland.; Petersen, H (reprint author), Landspitali Univ Hosp, Dept Otolaryngol, Reykjavik, Iceland. EM fridbert@landspitali.is; hpet@hi.is FU National Institutes of Health NIA Intramural Research Program [N01-AG-1-2100]; National Eye Institute [ZIAEY000401]; National Institute on Deafness and Other Communication Disorders (NIDCD), Division of Scientific Programs [IAA Y2-DC1004-02]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); University of Iceland Research Fund; Helga Jonsdottir and Sigurlidi Kristjansson Research Fund FX This study has been funded by contract N01-AG-1-2100 from the National Institutes of Health NIA Intramural Research Program, an Intramural Research Program Award (ZIAEY000401) from the National Eye Institute, an award from the National Institute on Deafness and Other Communication Disorders (NIDCD), Division of Scientific Programs (IAA Y2-DC1004-02), Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), the University of Iceland Research Fund, and the Helga Jonsdottir and Sigurlidi Kristjansson Research Fund. We thank Ms. May Chiu, NIDCD, NIH, for classifying the AGES-R tympanograms based on the Liden-Jerger method. The researchers are indebted to the participants for their willingness to participate in the studies. NR 34 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD MAR PY 2016 VL 94 IS 2 BP 140 EP 146 DI 10.1111/aos.12914 PG 7 WC Ophthalmology SC Ophthalmology GA DE9KR UT WOS:000370956800024 PM 26547142 ER PT J AU Lee, J Romero, R Lee, KA Kim, EN Korzeniewski, SJ Chaemsaithong, P Yoon, BH AF Lee, JoonHo Romero, Roberto Lee, Kyung A. Kim, Eun Na Korzeniewski, Steven J. Chaemsaithong, Piya Yoon, Bo Hyun TI Meconium aspiration syndrome: a role for fetal systemic inflammation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE amniocentesis; fetal inflammatory response syndrome; funisitis; intraamniotic inflammation; matrix metalloproteinase-8; meconium-stained amniotic fluid; pregnancy ID STAINED AMNIOTIC-FLUID; ACID-BASE STATUS; DELIVERY ROOM MANAGEMENT; INDUCED LUNG INJURY; PASSAGE IN-UTERO; INTRAAMNIOTIC INFLAMMATION; PRETERM LABOR; MICROBIAL INVASION; UMBILICAL-CORD; RISK-FACTORS AB BACKGROUND: Meconium aspiration syndrome (MAS) is a leading cause of morbidity and mortality in term infants. Meconium-stained amniotic fluid (MSAF) occurs in approximately 1 of every 7 pregnancies, but only 5% of neonates exposed to MSAF develop MAS. Why some infants exposed to meconium develop MAS while others do not is a fundamental question. Patients with MSAF have a higher frequency of intraamniotic inflammation/infection than those with clear fluid. We propose that fetal systemic inflammation is a risk factor for the development of MAS in patients with MSAF. OBJECTIVE: We sought to investigate whether intraamniotic inflammation and funisitis, the histopathologic landmark of a fetal inflammatory response, predispose to MAS. STUDY DESIGN: A prospective cohort study was conducted from 1995 through 2009. Amniotic fluid (AF) samples (n = 1281) were collected at the time of cesarean delivery from women who delivered singleton newborns at term (gestational age >= 38 weeks). Intraamniotic inflammation was diagnosed if the AF concentration of matrix metalloproteinase-8 was > 23 ng/mL. Funisitis was diagnosed by histologic examination if inflammation was present in the umbilical cord. RESULTS: The prevalence of MSAF was 9.2% (118/1281), and 10.2% (12/118) of neonates exposed to MSAF developed MAS. There were no significant differences in the median gestational age or umbilical cord arterial pH at birth between neonates who developed MAS and those who did not (each P >.1). Mothers whose newborns developed MAS had a higher median of AF matrix metalloproteinase-8 (456.8 vs 157.2 ng/mL, P <.05). Newborns exposed to intraamniotic inflammation had a higher rate of MAS than those who were not exposed to intraamniotic inflammation [13.0% (10/77) vs 0% (0/32), P = .03], as did those exposed to funisitis [31.3% (5/16) vs 7.3% (6/82); relative risk, 4.3; 95% confidence interval, 1.5-12.3]. Among the 89 newborns for whom both AF and placental histology were available, MAS was more common in patients with both intraamniotic inflammation and funisitis than in those without intraamniotic inflammation and funisitis [28.6% (4/14) vs 0% (0/28), P = .009], while the rate of MAS did not show a significant difference between patients with intraamniotic inflammation alone (without funisitis) and those without intraamniotic inflammation and funisitis [10.9% (5/46) vs 0% (0/28)]. CONCLUSION: The combination of intraamniotic inflammation with fetal systemic inflammation is an important antecedent of MAS. This concept has implications for the understanding of the mechanisms of disease responsible for MAS and for the development of prognostic models and therapeutic interventions for this disorder. C1 [Lee, JoonHo; Lee, Kyung A.; Kim, Eun Na; Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept Hlth & Human Serv, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Korzeniewski, Steven J.; Chaemsaithong, Piya] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI USA. RP Yoon, BH (reprint author), Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea.; Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept Hlth & Human Serv, Bethesda, MD USA.; Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept Hlth & Human Serv, Detroit, MI USA.; Romero, R (reprint author), Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA.; Romero, R (reprint author), Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA.; Romero, R (reprint author), Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. EM romeror@mail.nih.gov; yoonbh@snu.ac.kr FU Seoul National University Hospital, Republic of Korea [03-2011-0200]; Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI12C0768]; Perinatology Research Branch, Division of Intramural Research, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/US Department of Health and Human Services FX Supported by Grant No. 03-2011-0200 from Seoul National University Hospital, Republic of Korea, and a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HI12C0768). This work was also supported, in part, by the Perinatology Research Branch, Division of Intramural Research, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/US Department of Health and Human Services. NR 134 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2016 VL 214 IS 3 AR 366. e1-e9 DI 10.1016/j.ajog.2015.10.009 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DF0JC UT WOS:000371024100022 PM 26484777 ER PT J AU Manuck, TA Esplin, MS Biggio, J Bukowski, R Parry, S Zhang, HP Huang, H Varner, MW Andrews, W Saade, G Sadovsky, Y Reddy, UM Ilekis, J AF Manuck, Tracy A. Esplin, M. Sean Biggio, Joseph Bukowski, Radek Parry, Samuel Zhang, Heping Huang, Hao Varner, Michael W. Andrews, William Saade, George Sadovsky, Yoel Reddy, Uma M. Ilekis, John CA Eunice Kennedy Shriver Natl Inst TI Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE decidual hemorrhage; progesterone; recurrent preterm birth; spontaneous preterm labor ID GESTATIONAL-AGE; RISK-FACTORS; DELIVERY; PREMATURITY; PREGNANCY; INFANTS; COHORT; RATES; WOMEN AB BACKGROUND: Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that used a fixed outcome of term delivery to define progesterone response. OBJECTIVE: We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder." STUDY DESIGN: This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with >= 1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproateetreated pregnancy and her earliest spontaneous preterm birth. Responders were defined as those with pregnancy that extended >= 3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression. RESULTS: One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort. CONCLUSION: Several historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention. C1 [Manuck, Tracy A.; Esplin, M. Sean; Varner, Michael W.] Univ Utah, Sch Med, Div Maternal Fetal Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Manuck, Tracy A.; Esplin, M. Sean; Varner, Michael W.] Intermt Healthcare Dept Maternal Fetal Med, Salt Lake City, UT USA. [Biggio, Joseph; Andrews, William] Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Maternal Fetal Med, Birmingham, AL 35294 USA. [Biggio, Joseph; Andrews, William] Univ Alabama Birmingham, Ctr Womens Reprod, Birmingham, AL USA. [Bukowski, Radek; Saade, George] Univ Texas Med Branch, Div Maternal Fetal Med, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Parry, Samuel] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Zhang, Heping; Huang, Hao] Yale Univ, Sch Publ Hlth, Collaborat Ctr Stat Sci, New Haven, CT USA. [Sadovsky, Yoel] Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Pittsburgh, PA USA. [Reddy, Uma M.; Ilekis, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Dev Biol & Perinatal Med, Pregnancy & Perinatol Branch, Bethesda, MD USA. RP Manuck, TA (reprint author), Univ Utah, Sch Med, Div Maternal Fetal Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA.; Manuck, TA (reprint author), Intermt Healthcare Dept Maternal Fetal Med, Salt Lake City, UT USA. EM tmanuck@med.unc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research [U01-HD-050062, U01-HD-050078, U01-HD-050080, U01-HD-050088, U01-HD-050094]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [5K23HD067224] FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research (U01-HD-050062; U01-HD-050078; U01-HD-050080; U01-HD-050088; U01-HD-050094; all authors) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5K23HD067224 (T.A.M.). NR 21 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2016 VL 214 IS 3 AR 376.e1-e8 DI 10.1016/j.ajog.2015.12.010 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DF0JC UT WOS:000371024100028 PM 26692181 ER PT J AU Baseler, LJ Falzarano, D Scott, DP Rosenke, R Thomas, T Munster, VJ Feldmann, H de Wit, E AF Baseler, Laura J. Falzarano, Darryl Scott, Dana P. Rosenke, Rebecca Thomas, Tina Munster, Vincent J. Feldmann, Heinz de Wit, Emmie TI An Acute Immune Response to Middle East Respiratory Syndrome Coronavirus Replication Contributes to Viral Pathogenicity SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HEALTH-CARE FACILITIES; MERS-COV; RHESUS MACAQUES; SAUDI-ARABIA; VIRUS-REPLICATION; INFECTION; TRACT; PNEUMONIA; INDUCTION; OUTCOMES AB Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in a human with severe pneumonia in 2012. Since then, infections have been detected in >1500 individuals, with disease severity ranging from asymptomatic to severe, fatal pneumonia. To elucidate the pathogenesis of this virus and investigate mechanisms underlying disease severity variation in the absence of autopsy data, a rhesus macaque and common marmoset model of MERS-CoV disease were analyzed. Rhesus macaques developed mild disease, and common marmosets exhibited moderate to severe, potentially Lethal, disease. Both nonhuman primate species exhibited respiratory clinical signs after inoculation, which were more severe and of longer duration in the marmosets, and developed bronchointerstitial pneumonia. In marmosets, the pneumonia was more extensive, with development of severe airway lesions. Quantitative analysis showed significantly higher Levels of pulmonary neutrophil infiltration and higher amounts of pulmonary viral antigen in marmosets. Pulmonary expression of the MERS-CoV receptor, dipeptidyl peptidase 4, was similar in marmosets and macaques. These results suggest that increased virus replication and the local immune response to MERS-CoV infection likely play a role in pulmonary pathology severity. Together, the rhesus macaque and common marmoset models of MERS-CoV span the wide range of disease severity reported in MERS-CoV infected humans, which will aid in investigating MERS-CoV disease pathogenesis. C1 [Baseler, Laura J.; Falzarano, Darryl; Thomas, Tina; Munster, Vincent J.; Feldmann, Heinz; de Wit, Emmie] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Scott, Dana P.; Rosenke, Rebecca] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Baseler, Laura J.] Purdue Univ, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. RP de Wit, E (reprint author), NIAID, Rocky Mt Labs, 903 S Fourth St, Hamilton, MT 59840 USA. EM emmie.dewit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU National Institute of Allergy and Infectious Diseases, NIH Intramural Research Program FX Supported by the National Institute of Allergy and Infectious Diseases, NIH Intramural Research Program. NR 28 TC 1 Z9 1 U1 0 U2 1 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 MAR PY 2016 VL 186 IS 3 BP 630 EP 638 DI 10.1016/j.ajpath.2015.10.025 PG 9 WC Pathology SC Pathology GA DE9WY UT WOS:000370991800017 PM 26724387 ER PT J AU Zhou, WX Chung, YJ Castellar, ERP Zheng, Y Chung, HJ Bandle, R Liu, JH Tessarollo, L Batchelor, E Aplan, PD Levens, D AF Zhou, Weixin Chung, Yang Jo Castellar, Edgardo R. Parrilla Zheng, Ying Chung, Hye-Jung Bandle, Russell Liu, Juhong Tessarollo, Lino Batchelor, Eric Aplan, Peter D. Levens, David TI Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID SINGLE-STRANDED-DNA; CELL SELF-RENEWAL; C-MYC; STEM-CELLS; HEPATOCELLULAR-CARCINOMA; BONE-MARROW; NONCANCEROUS TISSUE; GENE-EXPRESSION; FETAL LIVER; IN-VIVO AB The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1(-/-)) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pate livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1(-/-) hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1(-/-) hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc Levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1(-/-) embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression. C1 [Zhou, Weixin; Castellar, Edgardo R. Parrilla; Zheng, Ying; Chung, Hye-Jung; Bandle, Russell; Liu, Juhong; Batchelor, Eric; Levens, David] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Chung, Yang Jo; Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Tessarollo, Lino] NCI, Mouse Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Levens, D (reprint author), Pathol Lab, Gene Regulat Sect, 10 Ctr Dr,Bldg 10,Room 2N106, Bethesda, MD 20892 USA. EM levens@helix.nih.gov RI Aplan, Peter/K-9064-2016 FU NTH Intramural Research Program, Center for Cancer Research of the National Cancer Institute FX Supported by the NTH Intramural Research Program, Center for Cancer Research of the National Cancer Institute. NR 59 TC 0 Z9 0 U1 1 U2 5 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 MAR PY 2016 VL 186 IS 3 BP 701 EP 715 DI 10.1016/j.ajpath.2015.10.028 PG 15 WC Pathology SC Pathology GA DE9WY UT WOS:000370991800024 PM 26774856 ER PT J AU Hancock, CN Liu, W Alvord, WG Phang, JM AF Hancock, Chad N. Liu, Wei Alvord, W. Gregory Phang, James M. TI Co-regulation of mitochondrial respiration by proline dehydrogenase/oxidase and succinate SO AMINO ACIDS LA English DT Article DE Respiration; Reactive oxygen species; Redox; Energetics; Signaling ID RENAL-CELL CARCINOMA; COMPLEX-II; UBIQUINONE OXIDOREDUCTASE; QUINONE OXIDOREDUCTASES; OXIDASE; PARAGANGLIOMA; MUTATIONS; APOPTOSIS; GENE; SDHB AB Proline dehydrogenase/oxidase (PRODH/POX) is a mitochondrial protein critical to multiple stress pathways. Because of the roles of PRODH/POX in signaling, and its shared localization to the mitochondrial inner membrane with the electron transport chain (ETC), we investigated whether there was a direct relationship between PRODH/POX and regulation of the ETC. We found that PRODH/POX binds directly to CoQ1 and that CoQ1-dependent PRODH/POX activity required functional Complex III and Complex IV. PRODH/POX supported respiration in living cells during nutrient stress; however, expression of PRODH/POX resulted in an overall decrease in respiratory fitness. Effects on respiratory fitness were inhibited by DHP and NAC, indicating that these effects were mediated by PRODH/POX-dependent reactive oxygen species (ROS) generation. PRODH/POX expression resulted in a dose-dependent down-regulation of Complexes I-IV of the ETC, and this effect was also mitigated by the addition of DHP and NAC. We found that succinate was an uncompetitive inhibitor of PRODH/POX activity, inhibited ROS generation by PRODH/POX, and alleviated PRODH/POX effects on respiratory fitness. The findings demonstrate novel cross-talk between proline and succinate respiration in vivo and provide mechanistic insights into observations from previous animal studies. Our results suggest a potential regulatory loop between PRODH/POX and succinate in regulation of mitochondrial respiration. C1 [Hancock, Chad N.; Liu, Wei; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res, 1050 Boyles St,Bldg 538,Rm 144, Frederick, MD 21702 USA. [Alvord, W. Gregory] NCI, Data Management Serv, Frederick, MD 21702 USA. RP Hancock, CN; Phang, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res, 1050 Boyles St,Bldg 538,Rm 144, Frederick, MD 21702 USA. EM chad.hancock@nih.gov; phangj@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Allen R. Kane of Scientific Publications, Graphics & Media at NCI-Frederick for his assistance with figure compilation and design. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 56 TC 3 Z9 3 U1 2 U2 9 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD MAR PY 2016 VL 48 IS 3 BP 859 EP 872 DI 10.1007/s00726-015-2134-7 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DE7LJ UT WOS:000370817900019 PM 26660760 ER PT J AU Baden, LR Karita, E Mutua, G Bekker, LG Gray, G Page-Shipp, L Walsh, SR Nyombayire, J Anzala, O Roux, S Laher, F Innes, C Seaman, MS Cohen, YZ Peter, L Frahm, N McElrath, MJ Hayes, P Swann, E Grunenberg, N Grazia-Pau, M Weijtens, M Sadoff, J Dally, L Lombardo, A Gilmour, J Cox, J Dolin, R Fast, P Barouch, DH Laufer, DS AF Baden, Lindsey R. Karita, Etienne Mutua, Gaudensia Bekker, Linda-Gail Gray, Glenda Page-Shipp, Liesl Walsh, Stephen R. Nyombayire, Julien Anzala, Omu Roux, Surita Laher, Fatima Innes, Craig Seaman, Michael S. Cohen, Yehuda Z. Peter, Lauren Frahm, Nicole McElrath, M. Juliana Hayes, Peter Swann, Edith Grunenberg, Nicole Grazia-Pau, Maria Weijtens, Mo Sadoff, Jerry Dally, Len Lombardo, Angela Gilmour, Jill Cox, Josephine Dolin, Raphael Fast, Patricia Barouch, Dan H. Laufer, Dagna S. CA B003-IPCAVD004-HVTN091 Study Grp TI Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PHASE-I TRIAL; HEALTHY-ADULTS; IMMUNE-RESPONSES; ENV VACCINE; IPCAVD 001; NYVAC-C; ADENOVIRUS; INFECTION; TYPE-5; STEP AB Background: A prophylactic HIV-1 vaccine is a global health priority. Objective: To assess a novel vaccine platform as a prophylactic HIV-1 regimen. Design: Randomized, double-blind, placebo-controlled trial. Both participants and study personnel were blinded to treatment allocation. (ClinicalTrials.gov: NCT01215149) Setting: United States, East Africa, and South Africa. Patients: Healthy adults without HIV infection. Intervention: 2 HIV-1 vaccines (adenovirus serotype 26 with an HIV-1 envelope A insert [Ad26.EnvA] and adenovirus serotype 35 with an HIV-1 envelope A insert [Ad35.Env], both administered at a dose of 5 x 10(10) viral particles) in homologous and heterologous combinations. Measurements: Safety and immunogenicity and the effect of baseline vector immunity. Results: 217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30-300 to 3000). The heterologous regimen of Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States. Limitations: Because the 2 envelope inserts were not identical, the boosting responses were complex to interpret. Durability of the immune responses elicited beyond 1 year is unknown. Conclusion: Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not significantly affect responses. Second vaccinations in all regimens significantly boosted EnvA antibody titers, although vaccine order in the heterologous regimen had a modest effect on the immune response. Primary Funding Source: International AIDS Vaccine Initiative, National Institutes of Health, Ragon Institute, Crucell Holland. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Karita, Etienne; Nyombayire, Julien] Projet San Francisco, KK19Av 57,POB 780, Kigali, Rwanda. Kenya AIDS Vaccine Initiat, Nairobi, Kenya. Univ Nairobi, Nairobi, Kenya. Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Page-Shipp, Liesl; Innes, Craig] Aurum Inst Hlth Res, 2nd Floor,Room 201 Jade Sq, Klerksdorp, South Africa. Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Frahm, Nicole; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,POBox 19024, Seattle, WA 98104 USA. HIV Vaccine Trials Network, Seattle, WA USA. Int AIDS Vaccine Initiat Human Immunol Lab, London, England. [Swann, Edith] NIAID, 5601 Fishers Lane,Room 9C46, Bethesda, MD 20852 USA. [Grazia-Pau, Maria; Sadoff, Jerry] Janssen Pharmaceut Infect Dis & Vaccines, Crucell NV,POB 2048, NL-2301 CA Leiden, Netherlands. [Dally, Len] EMMES Corp, 401 North Washington St,Suite 700, Rockville, MD USA. [Lombardo, Angela; Cox, Josephine; Fast, Patricia; Laufer, Dagna S.] Int AIDS Vaccine Initiat, 125 Broad St,9th Floor, New York, NY 10004 USA. Global BioSolut, Craigieburn, Vic, Australia. [Baden, Lindsey R.; Walsh, Stephen R.] Brigham & Womens Hosp, Div Infect Dis, PBB A4,15 Francis St, Boston, MA 02115 USA. [Mutua, Gaudensia; Anzala, Omu] Univ Nairobi, Inst Clin Res, Kenya AIDS Vaccine Initiat, POB 19676-00202 KNH, Nairobi, Kenya. [Bekker, Linda-Gail; Roux, Surita] Desmond Tutu HIV Ctr, POB 13801, ZA-7705 Cape Town, South Africa. [Seaman, Michael S.; Peter, Lauren; Dolin, Raphael; Barouch, Dan H.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Cohen, Yehuda Z.] Rockefeller Univ, 1230 York Ave,Box 95, New York, NY 10065 USA. [Hayes, Peter; Gilmour, Jill] Chelsea & Westminster Hosp, Int AIDS Vaccine Initiat Human Immunol Lab, 2nd Floor,369 Fulham Rd, London SW10 9NH, England. RP Baden, LR (reprint author), Brigham & Womens Hosp, Div Infect Dis, PBB A4,15 Francis St, Boston, MA 02115 USA. EM lbaden@partners.org; ldally@emmes.com; dlaufer@iavi.org FU International AIDS Vaccine Initiative; National Institutes of Health; Ragon Institute; Crucell Holland FX International AIDS Vaccine Initiative, National Institutes of Health, Ragon Institute, Crucell Holland. NR 23 TC 2 Z9 2 U1 0 U2 0 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 MAR 1 PY 2016 VL 164 IS 5 BP 313 EP + DI 10.7326/M15-0880 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA DF3CC UT WOS:000371220300002 PM 26833336 ER PT J AU Kuhn, JH Lauck, M Bailey, AL Shchetinin, AM Vishnevskaya, TV Bao, YM Ng, TFF LeBreton, M Schneider, BS Gillis, A Tamoufe, U Diffo, JL Takuo, JM Kondov, NO Coffey, LL Wolfe, ND Delwart, E Clawson, AN Postnikova, E Bollinger, L Lackemeyer, MG Radoshitzky, SR Palacios, G Wada, J Shevtsova, ZV Jahrling, PB Lapin, BA Deriabin, PG Dunowska, M Alkhovsky, SV Rogers, J Friedrich, TC O'Connor, DH Goldberg, TL AF Kuhn, Jens H. Lauck, Michael Bailey, Adam L. Shchetinin, Alexey M. Vishnevskaya, Tatyana V. Bao, Yiming Ng, Terry Fei Fan LeBreton, Matthew Schneider, Bradley S. Gillis, Amethyst Tamoufe, Ubald Diffo, Joseph Le Doux Takuo, Jean Michel Kondov, Nikola O. Coffey, Lark L. Wolfe, Nathan D. Delwart, Eric Clawson, Anna N. Postnikova, Elena Bollinger, Laura Lackemeyer, Matthew G. Radoshitzky, Sheli R. Palacios, Gustavo Wada, Jiro Shevtsova, Zinaida V. Jahrling, Peter B. Lapin, Boris A. Deriabin, Petr G. Dunowska, Magdalena Alkhovsky, Sergey V. Rogers, Jeffrey Friedrich, Thomas C. O'Connor, David H. Goldberg, Tony L. TI Reorganization and expansion of the nidoviral family Arteriviridae SO ARCHIVES OF VIROLOGY LA English DT Article ID SIMIAN HEMORRHAGIC-FEVER; EQUINE ARTERITIS VIRUS; RESPIRATORY SYNDROME VIRUS; SUBGENOMIC MESSENGER-RNAS; ISOLATE ATCC VR-2332; INTERNATIONAL COMMITTEE; STANDARDIZED NOMENCLATURE; TAXONOMIC PROPOSALS; RATIFICATION VOTE; SPECIES LEVEL AB The family Arteriviridae presently includes a single genus Arterivirus. This genus includes four species as the taxonomic homes for equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV), porcine respiratory and reproductive syndrome virus (PRRSV), and simian hemorrhagic fever virus (SHFV), respectively. A revision of this classification is urgently needed to accommodate the recent description of eleven highly divergent simian arteriviruses in diverse African nonhuman primates, one novel arterivirus in an African forest giant pouched rat, and a novel arterivirus in common brushtails in New Zealand. In addition, the current arterivirus nomenclature is not in accordance with the most recent version of the International Code of Virus Classification and Nomenclature. Here we outline an updated, amended, and improved arterivirus taxonomy based on current data. Taxon-specific sequence cut-offs are established relying on a newly established open reading frame 1b phylogeny and pairwise sequence comparison (PASC) of coding-complete arterivirus genomes. As a result, the current genus Arterivirus is replaced by five genera: Equartevirus (for EAV), Rodartevirus (LDV + PRRSV), Simartevirus (SHFV + simian arteriviruses), Nesartevirus (for the arterivirus from forest giant pouched rats), and Dipartevirus (common brushtail arterivirus). The current species Porcine reproductive and respiratory syndrome virus is divided into two species to accommodate the clear divergence of the European and American "types" of PRRSV, both of which now receive virus status. The current species Simian hemorrhagic fever virus is divided into nine species to accommodate the twelve known simian arteriviruses. Non-Latinized binomial species names are introduced to replace all current species names to clearly differentiate them from virus names, which remain largely unchanged. C1 [Kuhn, Jens H.; Clawson, Anna N.; Postnikova, Elena; Bollinger, Laura; Lackemeyer, Matthew G.; Wada, Jiro; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. [Friedrich, Thomas C.; Goldberg, Tony L.] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Shchetinin, Alexey M.; Vishnevskaya, Tatyana V.; Deriabin, Petr G.; Alkhovsky, Sergey V.] Minist Hlth Russian Federat, DI Ivanovskii Virol Inst, Fed Res Ctr Epidemiol & Microbiol, Moscow, Russia. [Bao, Yiming] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Ng, Terry Fei Fan; Kondov, Nikola O.; Delwart, Eric] Blood Syst Res Inst, San Francisco, CA USA. [LeBreton, Matthew] Mosaic, Yaounde, Cameroon. [LeBreton, Matthew; Schneider, Bradley S.; Gillis, Amethyst; Wolfe, Nathan D.] Metabiota, San Francisco, CA USA. [Tamoufe, Ubald; Diffo, Joseph Le Doux; Takuo, Jean Michel] Global Viral Cameroon, Yaounde, Cameroon. [Radoshitzky, Sheli R.; Palacios, Gustavo] US Army, Med Res Inst Infect Dis, Frederick, MD USA. [Shevtsova, Zinaida V.] Sci Res Inst Expt Pathol & Therapy, Sukhumi, Autonomous Repu, Rep of Georgia. [Lapin, Boris A.] Russian Acad Med Sci, Sci Res Inst Med Primatol, Soci, Russia. [Dunowska, Magdalena] Massey Univ, Inst Vet Anim & Biomed Sci, Palmerston North, New Zealand. [Rogers, Jeffrey] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Lauck, Michael; Bailey, Adam L.; Friedrich, Thomas C.; O'Connor, David H.; Goldberg, Tony L.] Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Coffey, Lark L.] Univ Calif Davis, Ctr Vectorborne Dis, Dept Pathol Microbiol & Immunol, Sch Vet Med, Davis, CA 95616 USA. [O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA.; Goldberg, TL (reprint author), Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA.; Goldberg, TL (reprint author), Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. EM kuhnjens@mail.nih.gov; tgoldberg@vetmed.wisc.edu RI Palacios, Gustavo/I-7773-2015; OI Palacios, Gustavo/0000-0001-5062-1938; Shchetinin, Alexey/0000-0003-1842-3899; Schneider, Bradley S/0000-0001-7642-0018; Vishnevskaya, Tatyana/0000-0002-6963-8681; Kuhn, Jens H./0000-0002-7800-6045; Lauck, Michael/0000-0003-2813-3705 FU Battelle Memorial Institute's prime [HHSN272200700016I]; National Institutes of Health (NIH) as part of the joint NIH-NSF Ecology of Infectious Disease program [TW009237, R01 AI077376]; Office of Research Infrastructure Programs (ORIP) [P51OD011106]; Intramural Research Program of the National Institutes of Health; National Library of Medicine FX 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. Battelle employees involved in this work are: L.B. and J.W. Subcontractors to Battelle Memorial Institute who performed this work are: J.H.K and E.P., employees of Tunnell Government Services, Inc.; A.N.C. the owner of Logos Consulting, Inc.; and M.G.L., an employee of Lovelace Respiratory Research Institute. This work was also funded in part through National Institutes of Health (NIH) grant TW009237 as part of the joint NIH-NSF Ecology of Infectious Disease program, grant R01 AI077376, and by the Office of Research Infrastructure Programs (ORIP) grant P51OD011106. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine (Y.B.), and benefited from contributions from the PREDICT project of the United States Agency for International Development (USAID) Emerging Pandemic Threats Program. We thank the Cameroon government for their support during the implementation of this project. NR 59 TC 6 Z9 6 U1 3 U2 6 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 MAR PY 2016 VL 161 IS 3 BP 755 EP 768 DI 10.1007/s00705-015-2672-z PG 14 WC Virology SC Virology GA DF0SR UT WOS:000371049800034 PM 26608064 ER PT J AU Stowkowy, J Liu, L Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Bearden, CE Mathalon, DH Heinssen, R Addington, J AF Stowkowy, Jacqueline Liu, Lu Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Bearden, Carrie E. Mathalon, Daniel H. Heinssen, Robert Addington, Jean TI Core Schemas in Youth at Clinical High Risk for Psychosis SO BEHAVIOURAL AND COGNITIVE PSYCHOTHERAPY LA English DT Article DE Clinical high risk; psychosis; schemas; beliefs; NAPLS ID CALGARY DEPRESSION SCALE; SCHIZOPHRENIA AB Background: Schema Theory proposes that the development of maladaptive schemas are based on a combination of memories, emotions and cognitions regarding oneself and one's relationship to others. A cognitive model of psychosis suggests that schemas are crucial to the development and persistence of psychosis. Little is known about the impact that schemas may have on those considered to be at clinical high risk (CHR) of developing psychosis. Aims: To investigate schemas over time in a large sample of CHR individuals and healthy controls. Method: Sample included 765 CHR participants and 280 healthy controls. Schemas were assessed at baseline, 6 and 12 months using the Brief Core Schema Scale (BCSS). Baseline schemas were compared to 2-year clinical outcome. Results: CHR participants evidenced stable and more maladaptive schemas over time compared to controls. Schemas at initial contact did not vary amongst the different clinical outcome groups at 2 years although all CHR outcome groups evidenced significantly worse schemas than healthy controls. Although there were no differences on baseline schemas between those who later transitioned to psychosis compared to those who did not, those who transitioned to psychosis had more maladaptive negative self-schemas at the time of transition. Associations between negative schemas were positively correlated with earlier abuse and bullying. Conclusions: These findings demonstrate a need for interventions that aim to improve maladaptive schemas among the CHR population. Therapies targeting self-esteem, as well as schema therapy may be important work for future studies. C1 [Stowkowy, Jacqueline; Liu, Lu; Addington, Jean] Univ Calgary, Calgary, AB T2N 4Z6, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] UCSD, La Jolla, CA USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, New Haven, CT USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Long Isl City, NY USA. [Perkins, Diana O.] Univ N Carolina, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Elaine F.] Emory Univ, Atlanta, GA 30322 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Mathalon, Daniel H.] UCSF, San Francisco, CA USA. [Heinssen, Robert] NIMH, Bethesda, MD 20892 USA. RP Stowkowy, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM stowkowy@ucalgary.ca FU National Institute of Mental Health [U01MH081984, U01 MH081928, P50 MH080272, SCDMH82101008006, R01 MH60720, U01MH082022, K24 MH76191, U01MH081902, P50 MH066286, U01MH082004, U01MH081988, UO1 MH081857-05] FX This study was supported by the National Institute of Mental Health (grant U01MH081984 to Dr Addington; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to Dr Seidman; grants R01 MH60720, U01MH082022 and K24 MH76191 to Dr Cadenhead; grant U01MH081902 to Dr Cannon; P50 MH066286 (Prodromal Core) to Dr Bearden; grant U01MH082004to Dr Perkins; grant U01MH081988 to Dr Walker; grant U01MH082022 to Dr Woods; and UO1 MH081857-05 grant to Dr Cornblatt. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 15 TC 0 Z9 0 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1352-4658 EI 1469-1833 J9 BEHAV COGN PSYCHOTH JI Behav. Cognit. Psychther. PD MAR PY 2016 VL 44 IS 2 BP 203 EP 213 DI 10.1017/S1352465815000144 PG 11 WC Psychology, Clinical SC Psychology GA DE8AA UT WOS:000370857000007 PM 25896713 ER PT J AU Hsieh, MM AF Hsieh, Matthew M. TI A Standard Nonmyeloablative Transplantation Regimen for Adults with Sickle Cell Disease: Are We There Yet? SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material C1 [Hsieh, Matthew M.] NHLBI, Mol & Clin Hematol Branch, NIH, 9000 Rockville Pike,Bldg 10-9N112, Bethesda, MD 20892 USA. RP Hsieh, MM (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, 9000 Rockville Pike,Bldg 10-9N112, Bethesda, MD 20892 USA. EM matthewhs@nhlbi.nih.gov OI Hsieh, Matthew/0000-0002-3706-6615 FU Intramural NIH HHS NR 7 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 BP 397 EP 398 DI 10.1016/j.bbmt.2015.12.002 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TS UT WOS:000370910200001 PM 26685772 ER PT J AU Anthias, C Shaw, BE Kiefer, DM Liesveld, JL Yared, J Kamble, RT D'Souza, A Hematti, P Seftel, MD Norkin, M DeFilipp, Z Kasow, KA Abidi, MH Savani, BN Shah, NN Anderlini, P Diaz, MA Malone, AK Halter, JP Lazarus, HM Logan, BR Switzer, GE Pulsipher, MA Confer, DL O'Donnell, PV AF Anthias, Chloe Shaw, Bronwen E. Kiefer, Deidre M. Liesveld, Jane L. Yared, Jean Kamble, Rammurti T. D'Souza, Anita Hematti, Peiman Seftel, Matthew D. Norkin, Maxim DeFilipp, Zachariah Kasow, Kimberly A. Abidi, Muneer H. Savani, Bipin N. Shah, Nirali N. Anderlini, Paolo Diaz, Miguel A. Malone, Adriana K. Halter, Joerg P. Lazarus, Hillard M. Logan, Brent R. Switzer, Galen E. Pulsipher, Michael A. Confer, Dennis L. O'Donnell, Paul V. TI Significant Improvements in the Practice Patterns of Adult Related Donor Care in US Transplantation Centers SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Related donor; Accreditation; Hematopoietic cell donation ID STEM-CELL DONATION; CONSENSUS STATEMENT; WORLDWIDE NETWORK; PBSC DONORS; BLOOD; COLLECTION; EVENTS; ISSUES; LIVER; BM AB Recent investigations have found a higher incidence of adverse events associated with hematopoietic cell donation in related donors (RDs) who have morbidities that if present in an unrelated donor (UD) would preclude donation. In the UD setting, regulatory standards ensure independent assessment of donors, one of several crucial measures to safeguard donor health and safety. A survey conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) Donor Health and Safety Working Committee in 2007 reported a potential conflict of interest in >70% of US centers, where physicians had simultaneous responsibility for RDs and their recipients. Consequently, several international organizations have endeavored to improve practice through regulations and consensus recommendations. We hypothesized that the changes in the 2012 Foundation for the Accreditation of Cellular Therapy and the Joint Accreditation Committee International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation standards resulting from the CIBMTR study would have significantly impacted practice. Accordingly, we conducted a follow-up survey of US transplantation centers to assess practice changes since 2007, and to investigate additional areas where RD care was predicted to differ from UD care. A total of 73 centers (53%), performing 79% of RD transplantations in the United States, responded. Significant improvements were observed since the earlier survey; 62% centers now ensure separation of RD and recipient care (P < .0001). This study identifies several areas where RD management does not meet international donor care standards, however. Particular concerns include counseling and assessment of donors before HLA typing, with 61% centers first disclosing donor HLA results to an individual other than the donor, the use of unlicensed mobilization agents, and the absence of long-term donor follow-up. Recommendations for improvement are made. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Anthias, Chloe] Anthony Nolan Res Inst, 2 Heathgate Pl,75-87 Agincourt Rd, London NW3 2NU, England. [Shaw, Bronwen E.; D'Souza, Anita; Logan, Brent R.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Kiefer, Deidre M.] Be The Match, Natl Marrow Donor Program, Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Liesveld, Jane L.] Univ Rochester, Med Ctr, Strong Mem Hosp, Dept Med, Rochester, NY 14642 USA. [Yared, Jean] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Dept Med, Baltimore, MD 21201 USA. [Kamble, Rammurti T.] Baylor Coll Med, Div Hematol & Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Hematti, Peiman] Univ Wisconsin Hosp & Clin, Div Hematol Oncol Bone Marrow Transplantat, Madison, WI 53792 USA. [Seftel, Matthew D.] Univ Manitoba, CancerCare Manitoba, Dept Med Oncol & Haematol, Winnipeg, MB, Canada. [Norkin, Maxim] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [DeFilipp, Zachariah] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Kasow, Kimberly A.] Univ N Carolina, Dept Pediat, Div Hematol Oncol, Chapel Hill, NC USA. [Abidi, Muneer H.] Michigan State Univ, Dept Oncol, Spectrum Hlth, Grand Rapids, MI USA. [Savani, Bipin N.] Vanderbilt Univ Sch Med, Div Hematol Oncol, Nashville, TN USA. [Shah, Nirali N.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Diaz, Miguel A.] Hosp Infantil Univ Nino Jesus, Dept Hematol Oncol, Madrid, Spain. [Malone, Adriana K.] Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. [Halter, Joerg P.] Univ Basel Hosp, Dept Hematol, Basel, Switzerland. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Logan, Brent R.] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Switzer, Galen E.] Univ Pittsburgh, VA Med Healthcare Syst, Pittsburgh, PA USA. [Pulsipher, Michael A.] USC Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA USA. [Confer, Dennis L.] Be The Match, Natl Marrow Donor Program, Minneapolis, MN USA. [O'Donnell, Paul V.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP Anthias, C (reprint author), Anthony Nolan Res Inst, 2 Heathgate Pl,75-87 Agincourt Rd, London NW3 2NU, England. EM chloe.anthias@anthonynolan.org OI Abidi, Muneer/0000-0002-9936-6031; Yared, Jean/0000-0002-5346-6299 FU Public Health Service from the National Cancer Institute (NCI) [U24-CA076518]; Public Health Service from National Heart, Lung and Blood Institute (NHLBI) [U24-CA076518]; Public Health Service from National Institute of Allergy and Infectious Diseases (NIAID) [U24-CA076518]; NHLBI [5U10HL069294]; NCI [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; 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, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; 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; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; University of Minnesota; University of Utah; Wellpoint, Inc. 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); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; 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, Inc.; 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, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; 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; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. 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 (HRSA) or any other agency of the U.S. Government. NR 26 TC 1 Z9 1 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 MAR PY 2016 VL 22 IS 3 BP 520 EP 527 DI 10.1016/j.bbmt.2015.11.008 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TS UT WOS:000370910200020 PM 26597080 ER PT J AU Anandi, P Chinian, F Cantilena, CR Dunavin, N Hensel, N Draper, D Koklanaris, E Maxwell, S Superata, J Muranski, P Battiwalla, M Paczesny, S Barrett, AJ Ito, S AF Anandi, Prathima Chinian, Fariba Cantilena, Caroline R. Dunavin, Neil Hensel, Nancy Draper, Debbie Koklanaris, Eleftheria Maxwell, Sandra Superata, Jeanine Muranski, Pawel Battiwalla, Minoo Paczesny, Sophie Barrett, A. John Ito, Sawa TI Improved Reproducibility of Gvhd Biomarker Assay Application of Multiplex Microfluidic Channel System SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Anandi, Prathima; Chinian, Fariba; Cantilena, Caroline R.; Dunavin, Neil; Hensel, Nancy; Draper, Debbie; Koklanaris, Eleftheria; Maxwell, Sandra; Superata, Jeanine; Muranski, Pawel; Battiwalla, Minoo; Barrett, A. John; Ito, Sawa] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Paczesny, Sophie] Indiana Univ, Sch Med, Indianapolis, IN USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 582 BP S388 EP S388 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300583 ER PT J AU Aydin, S Freeman, AF Su, H Hickstein, D Pai, SY Geha, R Chatila, T Arnaout, RK Al-Mousa, H Al-Dhekri, H Renner, ED Belohradsky, BH Notheis, G Aydin, R Gaspar, BH Al-Herz, W Gennery, A Slatter, M Metin, A Isik, P Azik, F Ikinciogullari, A Haskologlu, S Dogu, F Kumar, A Ifversen, M Schuster, F Woessmann, W Bredius, R Barlogis, V Kainulainen, L Picard, C Neven, B Shereck, E Schulz, A Dueckers, G Van Montfrans, J Matthes-Martin, S Keles, S Ochs, H Albert, MH AF Aydin, Susanne Freeman, Alexandra F. Su, Helen Hickstein, Dennis Pai, Sung-Yun Geha, Raif Chatila, Talal Arnaout, Rand K. Al-Mousa, Hamoud Al-Dhekri, Hasan Renner, Ellen D. Belohradsky, Bernd H. Notheis, Gundula Aydin, Roland Gaspar, Bobby H. Al-Herz, Waleed Gennery, Andrew Slatter, Mary Metin, Ayse Isik, Pamir Azik, Fatih Ikinciogullari, Aydan Haskologlu, Sule Dogu, Figen Kumar, Ashish Ifversen, Marianne Schuster, Friedhelm Woessmann, Wilhelm Bredius, Robbert Barlogis, Vincent Kainulainen, Leena Picard, Capucine Neven, Benedicte Shereck, Evan Schulz, Ansgar Dueckers, Gregor Van Montfrans, Joris Matthes-Martin, Susanne Keles, Sevgi Ochs, Hans Albert, Michael H. TI HSCT for DOCK8 Deficiency - an International Study on 74 Patients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Aydin, Susanne; Renner, Ellen D.; Belohradsky, Bernd H.; Notheis, Gundula] Dr von Hauner Univ Childrens Hosp, Munich, Germany. [Freeman, Alexandra F.; Su, Helen] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hickstein, Dennis] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Pai, Sung-Yun] Boston Childrens Hosp, Hematol Oncol, Boston, MA USA. [Geha, Raif; Chatila, Talal] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Arnaout, Rand K.] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Pediat Allergy & Immunol, Riyadh 11211, Saudi Arabia. [Al-Mousa, Hamoud] King Faisal Specialist Hosp & Res Ctr, Pediat, Riyadh 11211, Saudi Arabia. [Al-Dhekri, Hasan] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Pediat Allergy & Immunol, Riyadh 11211, Saudi Arabia. [Aydin, Roland] Tech Univ Munich, D-80290 Munich, Germany. [Gaspar, Bobby H.] UCL, Inst Child Hlth, London, England. [Al-Herz, Waleed] Kuwait Univ, Dept Pediat, Fac Med, Kuwait, Kuwait. [Gennery, Andrew] Newcastle Univ, Paediat Immunol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Slatter, Mary] Great North Childrens Hosp, Newcastle Upon Tyne, Tyne & Wear, England. [Metin, Ayse] SB Ankara Diskapi Childrens Hosp, Pediat Immunol Unit, Ankara, Turkey. [Isik, Pamir; Azik, Fatih] Ankara Childrens Hematol & Oncol Educ & Res Hosp, Clin Pediat Hematol, Ankara, Turkey. [Ikinciogullari, Aydan] Ankara Univ, Sch Med, Dept Pediat Immunol & Allergy, TR-06100 Ankara, Turkey. [Ikinciogullari, Aydan] Ankara Univ, Sch Med, BMT Unit, TR-06100 Ankara, Turkey. [Kumar, Ashish] Cincinnati Childrens Hosp Med Ctr, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Ifversen, Marianne] Copenhagen Univ Hosp, Rigshosp, Paediat Clin 2, Copenhagen, Denmark. [Schuster, Friedhelm] Univ Munich, Kinderklin, Abt Hamatol Onkol, D-80539 Munich, Germany. [Woessmann, Wilhelm] Univ Giessen, Dept Pediat Hematol & Oncol, D-35390 Giessen, Germany. [Bredius, Robbert] Leiden Univ, Med Ctr, Leiden, Netherlands. [Barlogis, Vincent] Aix Marseille Univ, La Timone Hosp, APHM, Dept Paediat Haematol Oncol, Marseille, France. [Kainulainen, Leena] Turku Univ Hosp, Dept Pediat, FIN-20520 Turku, Finland. [Picard, Capucine] Necker Enfant Malad Hosp, AP HP, Pediat Hematol Immunol Unit, Paris, France. [Picard, Capucine] Paris Descartes Univ, Sorbonne Paris Cite, Lab Human Genet Infect Dis, Necker Branch,INSERM,UMR1163,Imagine Inst, Paris, France. [Neven, Benedicte] Hop Univ Necker Enfants Malad, Paris, France. [Shereck, Evan] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Schulz, Ansgar] Univ Ulm Klinikum, Klin Kinder, Ulm, Germany. [Dueckers, Gregor] HELIOS Childrens Hosp Krefeld, Krefeld, Germany. [Van Montfrans, Joris] UMCU, Pediat Immunol, Utrecht, Netherlands. [Matthes-Martin, Susanne] St Anna Childrens Hosp, BMT Unit, A-1090 Vienna, Austria. [Keles, Sevgi] Konya Necmettin Erbakan Univ, Konya, Turkey. [Ochs, Hans] Univ Washington, Pediat, Seattle, WA 98195 USA. [Ochs, Hans] Seattle Childrens, Seattle, WA USA. [Albert, Michael H.] Dr von Hauner Univ Childrens Hosp, Pediat Hematol Oncol, Munich, Germany. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 108 BP S103 EP S104 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300113 ER PT J AU Buxbaum, NP Carpenter, A Castro, E Eckhaus, M Bosselut, R Gress, R AF Buxbaum, Nataliya Prokopenko Carpenter, Andrea Castro, Ehydel Eckhaus, Michael Bosselut, Remy Gress, Ronald TI Pathogenic T Cells Target the Intraepithelial Lymphocyte Layer of Small Intestine in Cgvhd SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Buxbaum, Nataliya Prokopenko; Castro, Ehydel; Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Carpenter, Andrea; Bosselut, Remy] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael] NCI, Diagnost & Res Serv Branch, NIH, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 587 BP S390 EP S391 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300588 ER PT J AU Cantilena, CR Dunavin, N Chinian, F Anandi, P Hensel, N Draper, D Koklanaris, E Maxwell, S Superata, J Muranski, P Ito, S Paczesny, S Barrett, AJ Battiwalla, M AF Cantilena, Caroline R. Dunavin, Neil Chinian, Fariba Anandi, Prathima Hensel, Nancy Draper, Debbie Koklanaris, Eleftheria Maxwell, Sandra Superata, Jeanine Muranski, Pawel Ito, Sawa Paczesny, Sophie Barrett, A. John Battiwalla, Minoo TI ST2 is Associated with GVHD in Ex Vivo Graft Manipulation Strategies for Allogeneic Peripheral Blood Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Cantilena, Caroline R.; Dunavin, Neil; Chinian, Fariba; Anandi, Prathima; Hensel, Nancy; Draper, Debbie; Koklanaris, Eleftheria; Maxwell, Sandra; Superata, Jeanine; Muranski, Pawel; Ito, Sawa; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Paczesny, Sophie] Indiana Univ, Sch Med, Indianapolis, IN USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 572 BP S380 EP S381 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300573 ER PT J AU Carpenter, PA Logan, BR Lee, SJ Weisdorf, DJ Johnston, L Costa, LJ Kitko, CL Bolanos-Meade, J Alousi, AM Horowitz, MM Abhyankar, S Waller, EK Mendizabal, A Wang, YL Lazaryan, A Carter, SL Nemecek, ER Pavletic, SZ Cutler, CS Arora, M AF Carpenter, Paul A. Logan, Brent R. Lee, Stephanie J. Weisdorf, Daniel J. Johnston, Laura Costa, Luciano J. Kitko, Carrie L. Bolanos-Meade, Javier Alousi, Amin M. Horowitz, Mary M. Abhyankar, Sunil Waller, Edmund K. Mendizabal, Adam Wang, Yanli Lazaryan, Aleksandr Carter, Shelly L. Nemecek, Eneida R. Pavletic, Steven Z. Cutler, Corey S. Arora, Mukta CA BMT CTN TI Prednisone (PDN)/Sirolimus (SRL) Compared to PDN/SRL/Calcineurin Inhibitor (CNI) as Treatment for Chronic Graft-Versus-Host-Disease (cGVHD): A Randomized Phase II Study from the Blood and Marrow Transplant Clinical Trials Network SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Carpenter, Paul A.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Weisdorf, Daniel J.] Univ Minnesota, Div Hematol Oncol & Transplantat, Med, Minneapolis, MN USA. [Johnston, Laura] Stanford Univ, Med Ctr, Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Costa, Luciano J.] Univ Alabama Birmingham, Birmingham, AL USA. [Kitko, Carrie L.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Bolanos-Meade, Javier] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Alousi, Amin M.] UT MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX USA. [Horowitz, Mary M.] CIBMTR, Dept Med, Milwaukee, WI USA. [Horowitz, Mary M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Abhyankar, Sunil] Univ Kansas, Med Ctr, Blood & Marrow Transplant, Westwood, KS USA. [Waller, Edmund K.] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Div BMT, Atlanta, GA 30322 USA. [Mendizabal, Adam; Wang, Yanli; Carter, Shelly L.] EMMES Corp, Rockville, MD USA. [Lazaryan, Aleksandr; Arora, Mukta] Univ Minnesota, Hematol Oncol & Transplantat, Minneapolis, MN USA. [Nemecek, Eneida R.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Cutler, Corey S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Hematol Malignancies, 44 Binney St, Boston, MA 02115 USA. [BMT CTN] BMT CTN, Milwaukee, WI USA. NR 0 TC 0 Z9 0 U1 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 42 BP S50 EP S52 PG 3 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300047 ER PT J AU Curtis, LM Pirsl, F Hsu, J Steinberg, SM Mitchell, SA Masuch, L Im, A Baruffaldi, JL Mays, J Halverson, D Fowler, D Gress, R Pavletic, SZ AF Curtis, Lauren M. Pirsl, Filip Hsu, Jennifer Steinberg, Seth M. Mitchell, Sandra A. Masuch, Licia Im, Annie Baruffaldi, Judy L. Mays, Jacqueline Halverson, David Fowler, Daniel Gress, Ronald Pavletic, Steven Z. TI Predictors for Permanent Discontinuation of Systemic Immunosuppression in Patients with Moderate to Severe Chronic Graft-Versus-Host-Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Curtis, Lauren M.; Pirsl, Filip; Hsu, Jennifer; Masuch, Licia; Baruffaldi, Judy L.; Halverson, David; Fowler, Daniel; Gress, Ronald; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. [Im, Annie] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Mays, Jacqueline] NIDCR, NIH, Bethesda, MD USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 41 BP S49 EP S50 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300046 ER PT J AU Duncan, C Brazauskas, R Huang, JX Shaw, BE Majhail, NS Savani, BN Flowers, MED Battiwalla, M Beebe, K Dietz, AC Dvorak, CC Giller, R Jacobsohn, DA Kletzel, M Martin, PJ Nemecek, ER Talano, JAM Pulsipher, MA Baker, KS AF Duncan, Christine Brazauskas, Ruta Huang, Jiaxing Shaw, Bronwen E. Majhail, Navneet S. Savani, Bipin N. Flowers, Mary E. D. Battiwalla, Minoo Beebe, Kristen Dietz, Andrew C. Dvorak, Christopher C. Giller, Roger Jacobsohn, David A. Kletzel, Morris Martin, Paul J. Nemecek, Eneida R. Talano, Julie-An M. Pulsipher, Michael A. Baker, K. Scott TI Late Cardiovascular Morbidity Following Pediatric Allogeneic Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Duncan, Christine] Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. [Duncan, Christine] Dana Farber Canc Inst, Boston, MA 02115 USA. [Brazauskas, Ruta] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Huang, Jiaxing] Med Coll Wisconsin, CIBMTR, Dept Med, Milwaukee, WI 53226 USA. [Shaw, Bronwen E.] CIBMTR, Dept Med, Milwaukee, WI USA. [Shaw, Bronwen E.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Majhail, Navneet S.] Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Flowers, Mary E. D.; Martin, Paul J.; Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Beebe, Kristen] Mayo Clin Arizonia, Phoenix, AZ USA. [Beebe, Kristen] Phoenix Childrens Hosp, Phoenix, AZ USA. [Dietz, Andrew C.] Childrens Hosp Los Angeles, Pediat Heme Onc BMT, Los Angeles, CA 90027 USA. [Dvorak, Christopher C.] Univ Calif San Francisco, Dept Pediat, Med Ctr, San Francisco, CA USA. [Giller, Roger] Childrens Hosp Colorado, Dept Pediat, Sect Hematol Oncol & BMT, Aurora, CO USA. [Jacobsohn, David A.] Childrens Natl Hlth Syst, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders, Washington, DC USA. [Kletzel, Morris] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Div Hematol Oncol & Stem Cell Transplantat, Chicago, IL 60611 USA. [Nemecek, Eneida R.] Doernbecher Childrens Hosp, Dept Pediat, Pediat Blood & Marrow Transplant Program, Portland, OR USA. [Nemecek, Eneida R.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Talano, Julie-An M.] Med Coll Wisconsin, Pediat Hematol Oncol & BMT, Milwaukee, WI 53226 USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RI Huang, Jiaxing/B-7521-2009 NR 0 TC 0 Z9 0 U1 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 55 BP S60 EP S60 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300060 ER PT J AU Fitzhugh, C Hsieh, M Taylor, T Coles, W Luznik, L Powell, J Tisdale, JF AF Fitzhugh, Courtney Hsieh, Matthew Taylor, Tiffani Coles, Wynona Luznik, Leo Powell, Jonathan Tisdale, John F. TI Post-Transplant Cyclophosphamide Improves Engraftment in Patients with Sickle Cell Disease (SCD) and Severe Organ Damage who Undergo Haploidentical Peripheral Blood Stem Cell Transplantation (PBSCT) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Fitzhugh, Courtney] NHLBI, Sickle Cell Branch, Mol & Clin Hematol Branch, NIDDK,NIH, Bethesda, MD 20892 USA. [Hsieh, Matthew; Taylor, Tiffani; Coles, Wynona; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bethesda, MD 20892 USA. [Luznik, Leo] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Powell, Jonathan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 472 BP S319 EP S319 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300473 ER PT J AU Fowler, D Hakim, FT Fellowes, V Khuu, H Stroncek, DE Schuver, BB Carpenter, A Cotton, S Carroll, E Ghosh, M Ali, SA Halverson, D Hardy, N Pavletic, SZ Bishop, MR Gress, R Korngold, R Pecora, A Donato, ML Rowley, S Vesole, DH Siegel, D Sportes, C AF Fowler, Daniel Hakim, Fran T. Fellowes, Vicki Khuu, Hanh Stroncek, David E. Schuver, Bazetta Blacklock Carpenter, Ashley Cotton, Stephanie Carroll, Ellen Ghosh, Monalisa Ali, Syed Abbas Halverson, David Hardy, Nancy Pavletic, Steven Z. Bishop, Michael R. Gress, Ronald Korngold, Robert Pecora, Andrew Donato, Michele L. Rowley, Scott Vesole, David H. Siegel, David Sportes, Claude TI Autologous Rapamycin-Resistant T Cell Therapy of Multiple Myeloma SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Fowler, Daniel; Hakim, Fran T.; Schuver, Bazetta Blacklock; Carroll, Ellen; Ghosh, Monalisa; Ali, Syed Abbas; Halverson, David; Pavletic, Steven Z.; Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Fellowes, Vicki] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Khuu, Hanh; Stroncek, David E.] NIH, Dept Transfus Med, Bldg 10, Bethesda, MD 20892 USA. [Carpenter, Ashley] NCI, Bethesda, MD 20892 USA. [Cotton, Stephanie] NCI, ETIB, Bethesda, MD 20892 USA. [Hardy, Nancy] NCI, Expt Transplantat & Immunol, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Korngold, Robert] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Pecora, Andrew; Donato, Michele L.; Rowley, Scott] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Vesole, David H.] Hackensack UMC, Myeloma Div, John Theurer Canc Ctr, Hackenscak, NJ USA. [Siegel, David] Hackensack Univ, John Theurer Canc Ctr, Hackensack, NJ USA. [Sportes, Claude] NCI, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 63 BP S65 EP S66 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300068 ER PT J AU Ghosh, M Schuver, BB Carroll, E Khuu, H Stroncek, DF Pavletic, SZ Gress, R Halverson, D Fowler, D AF Ghosh, Monalisa Schuver, Bazetta Blacklock Carroll, Ellen Khuu, Hanh Stroncek, David F. Pavletic, Steven Z. Gress, Ronald Halverson, David Fowler, Daniel TI DLI Therapy Using T-Rapa Cells: Graft-Versus-Lymphoma and GvHD Effects SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Ghosh, Monalisa; Schuver, Bazetta Blacklock; Carroll, Ellen; Pavletic, Steven Z.; Gress, Ronald; Halverson, David; Fowler, Daniel] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Khuu, Hanh; Stroncek, David F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 594 BP S395 EP S396 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300595 ER PT J AU Graupner, S Spellman, A Jacobson, S Bryan, L Sportes, C Pantin, J Mian, MAH AF Graupner, Scott Spellman, Alison Jacobson, Stephanie Bryan, Locke Sportes, Claude Pantin, Jeremy Mian, M. Anwarul Huq TI Impact of Socio-Economic Disparities and Distance to Bone Marrow Transplant Center on Transplantation Outcomes SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Graupner, Scott] Georgia Regents Univ, Internal Med, Augusta, GA USA. [Spellman, Alison] Georgia Regents Univ, Heme Onc, Augusta, GA USA. [Jacobson, Stephanie; Bryan, Locke] Georgia Regents Univ, BMT, Augusta, GA USA. [Sportes, Claude] NCI, Bethesda, MD 20892 USA. [Pantin, Jeremy; Mian, M. Anwarul Huq] Georgia Regents Med Ctr, Augusta, GA USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 252 BP S187 EP S187 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300257 ER PT J AU Halverson, D Rowley, S Bishop, MR Hansen, B Cotton, S Schuver, BB Steinberg, SM Hakim, FT Gea-Banacloche, J Hardy, N Sportes, C Pavletic, SZ Khuu, H Stroncek, DE Levine, BL June, CH Donato, ML Goy, A Pecora, A Gress, R Fowler, D AF Halverson, David Rowley, Scott Bishop, Michael R. Hansen, Brenna Cotton, Stephanie Schuver, Bazetta Blacklock Steinberg, Seth M. Hakim, Fran T. Gea-Banacloche, Juan Hardy, Nancy Sportes, Claude Pavletic, Steven Z. Khuu, Hanh Stroncek, David E. Levine, Bruce L. June, Carl H. Donato, Michele L. Goy, Andre Pecora, Andrew Gress, Ronald Fowler, Daniel TI Preemptive T-Rapa Cell DLI after Low Intensity Allogeneic HCT May Allow for Improved Overall Survival in High Risk Lymphoid Malignancies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Halverson, David; Schuver, Bazetta Blacklock; Hakim, Fran T.; Pavletic, Steven Z.; Gress, Ronald; Fowler, Daniel] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Rowley, Scott; Donato, Michele L.; Goy, Andre; Pecora, Andrew] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Bishop, Michael R.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Hansen, Brenna; Cotton, Stephanie; Gea-Banacloche, Juan] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hardy, Nancy] Greenebaum Canc Ctr, Med Oncol, Baltimore, MD USA. [Sportes, Claude] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Khuu, Hanh; Stroncek, David E.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Levine, Bruce L.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [June, Carl H.] Univ Penn, Abramson Canc Ctr, Ctr Cellular Immunotherapies, Translat Res Programs, Philadelphia, PA 19104 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 167 BP S139 EP S140 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300172 ER PT J AU Heimall, J Logan, BR Cowan, MJ Notarangelo, LD Puck, J Fleisher, T Griffith, LM Kohn, DB Pulsipher, MA Shearer, W Hanson, IC Kapoor, N O'Reilly, RJ Boyer, M Pai, SY Parikh, S Goldman, F Burroughs, L Marsh, RA Kletzel, M Thakar, M Connelly, JA Cuvellier, G Loechelt, B Shereck, E Knudsen, A Sullivan, K DeSantes, K Gillio, AP Haddad, E Petrovic, A Quigg, TC Smith, AR Stenger, E Dvorak, CC Buckley, RH AF Heimall, Jennifer Logan, Brent R. Cowan, Morton J. Notarangelo, Luigi D. Puck, Jennifer Fleisher, Thomas Griffith, Linda M. Kohn, Donald B. Pulsipher, Michael A. Shearer, William Hanson, Imelda C. Kapoor, Neena O'Reilly, Richard J. Boyer, Michael Pai, Sung-Yun Parikh, Suhag Goldman, Frederick Burroughs, Lauri Marsh, Rebecca A. Kletzel, Morris Thakar, Monica Connelly, James A. Cuvellier, Geoff Loechelt, Brett Shereck, Evan Knudsen, Alan Sullivan, Kathleen DeSantes, Kenneth Gillio, Alfred P. Haddad, Elie Petrovic, Aleksandra Quigg, Troy C. Smith, Angela R. Stenger, Elizabeth Dvorak, Christopher C. Buckley, Rebecca H. TI Poor T Cell Reconstitution at 100 Days after T Cell-Replete Hematopoietic Cell Transplantation (HCT) for SCID Is Associated with Later Risk of Death or Need for 2nd Transplant in the 6901 Prospective Study of the Pidtc SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Heimall, Jennifer] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Cowan, Morton J.; Puck, Jennifer; Dvorak, Christopher C.] UCSF Benioff Childrens Hosp, Pediat Allergy Immunol & Blood & Marrow Transplan, San Francisco, CA USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Primary Immunodeficiencies, Boston, MA USA. [Fleisher, Thomas] NIH, Host Def Lab, Bldg 10, Bethesda, MD 20892 USA. [Griffith, Linda M.] NIAID, DAIT, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kohn, Donald B.] Univ Calif Los Angeles, Mattel Childrens Hosp, Div Hematol Oncol, Los Angeles, CA USA. [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Shearer, William; Hanson, Imelda C.] Texas Childrens Hosp, Baylor Coll Med, Immunol Allergy & Rheumatol, Houston, TX 77030 USA. [Kapoor, Neena] Childrens Hosp Los Angeles, Blood & Marrow Transplant Program, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90027 USA. [O'Reilly, Richard J.] Mem Sloan Kettering Canc Ctr, Dept Pediat, Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Boyer, Michael] Univ Utah, Hematol BMT, Park City, UT USA. [Pai, Sung-Yun] Boston Childrens Hosp, Hematol Oncol, Boston, MA USA. [Parikh, Suhag] Duke Univ, Med Ctr, Pediat Blood & Marrow Transplantat, Durham, NC USA. [Goldman, Frederick] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Burroughs, Lauri] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Marsh, Rebecca A.] Cincinnati Childrens Hosp Med Ctr, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Kletzel, Morris] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Thakar, Monica] Med Coll Wisconsin, Pediat Hematol Oncol BMT, Milwaukee, WI 53226 USA. [Connelly, James A.] Univ Michigan, Blood & Marrow Transplantat Program, Ann Arbor, MI 48109 USA. [Cuvellier, Geoff] CC Manitoba, Winnipeg, MB, Canada. [Loechelt, Brett] Childrens Natl Med Ctr, Blood & Marrow Transplantat, Washington, DC 20010 USA. [Shereck, Evan] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Knudsen, Alan] St Louis Univ, St Louis, MO 63103 USA. [Sullivan, Kathleen] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [DeSantes, Kenneth] Univ Wisconsin, Dept Pediat, Div Hematol Oncol & Bone Marrow, Amer Family Childrens Hosp, Madison, WI USA. [Gillio, Alfred P.] Hackensack Univ, Med Ctr, Inst Pediat Canc & Blood Disorders, Hackensack, NJ USA. [Haddad, Elie] Ste Justine Hosp, Paediat Immunol, Montreal, PQ, Canada. [Petrovic, Aleksandra] All Childrens Hosp Johns Hopkins Med, Blood & Marrow Transplant, St Petersburg, FL USA. [Quigg, Troy C.] Riley Hosp Children, Pediat Hematol Oncol HSCT, Indianapolis, IN USA. [Smith, Angela R.] Univ Minnesota, Dept Pediat, Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Stenger, Elizabeth] Emory Univ, Sch Med, Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Atlanta, GA USA. [Buckley, Rebecca H.] Duke Univ, Med Ctr, Durham, NC USA. RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 106 BP S101 EP S102 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300111 ER PT J AU Jacobson, S Clemmons, AB Shah, A Albrecht, B Sportes, C Biyan, L Pantin, J AF Jacobson, Stephanie Clemmons, Amber Bradley Shah, Arpita Albrecht, Benjamin Sportes, Claude Biyan, Locke Pantin, Jeremy TI Impact of Fluoroquinolone Prophylaxis on Survival Outcomes after Hematopoietic Stem Cell Transplantation: A Single-Center Experience SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Jacobson, Stephanie; Shah, Arpita; Biyan, Locke] Georgia Regents Univ, BMT, Augusta, GA USA. [Clemmons, Amber Bradley; Pantin, Jeremy] Georgia Regents Med Ctr, Augusta, GA USA. [Clemmons, Amber Bradley; Albrecht, Benjamin] Univ Georgia, Coll Pharm, Augusta, GA USA. [Sportes, Claude] NCI, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 216 BP S167 EP S168 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300221 ER PT J AU Jaglowski, S Waller, EK Kindwall-Keller, TL McCarty, JM Dugan, M Yellin, M Davis, T Devine, SM AF Jaglowski, Samantha Waller, Edmund K. Kindwall-Keller, Tamila L. McCarty, John Michael Dugan, Michael Yellin, Michael Davis, Thomas Devine, Steven M. TI Preliminary Safety and Efficacy Data Using CDX-301 (Flt3 ligand) As a Sole Agent to Mobilize Hematopoietic Cells Prior to HLA-Matched Sibling Donor Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Jaglowski, Samantha] Ohio State Univ, James Canc Ctr, Columbus, OH 43210 USA. [Waller, Edmund K.] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Div BMT, Atlanta, GA 30322 USA. [Kindwall-Keller, Tamila L.] Univ Virginia, Sch Med, Hematol Oncol, Charlottesville, VA 22908 USA. [McCarty, John Michael] VCU Massey Canc Ctr, Richmond, VA USA. [Dugan, Michael] Indinana Blood & Marrow Transplantat, Beech Grove, IN USA. [Yellin, Michael] Celldex Therapeut Inc, Needham, MA USA. [Davis, Thomas] NIH, Rockville, MD USA. [Devine, Steven M.] Ohio State Med Ctr, James Canc Ctr, Div Hematol, Columbus, OH USA. RI Jaglowski, Samantha/E-3304-2011 NR 0 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 479 BP S324 EP S325 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300480 ER PT J AU Kang, EM Parta, M Hilligoss, D Marquesen, M Kelly, C Kwatemaa, A Malech, HL AF Kang, Elizabeth M. Parta, Mark Hilligoss, Dianne Marquesen, Martha Kelly, Corin Kwatemaa, Akua Malech, Harry L. TI Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High Risk Chronic Granulomatous Disease (CGD) Patients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Kang, Elizabeth M.; Hilligoss, Dianne; Marquesen, Martha; Kelly, Corin; Kwatemaa, Akua; Malech, Harry L.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Parta, Mark] Leidos Biomedical Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Bethesda, MD USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 482 BP S327 EP S328 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300483 ER PT J AU Lad, DP Zypchen, L Ryan, F Elwood, K Holland, S Hickstein, D Nantel, SH AF Lad, Deepesh P. Zypchen, Leslie Ryan, Frank Elwood, Kevin Holland, Steven Hickstein, Dennis Nantel, Stephen H. TI Successful Allogeneic Hematopoietic Cell Transplantation Using Flu-Bu-ATG Conditioning for "Mono-MAC Syndrome" [GATA2 Deficiency] SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Lad, Deepesh P.; Nantel, Stephen H.] BC Canc Agcy, Leukemia Bone Marrow Transplant Program British C, Vancouver, BC, Canada. [Zypchen, Leslie] BC Canc Agcy, Div Hematol, Vancouver, BC, Canada. [Ryan, Frank] Vancouver Gen Hosp, Div Resp Med, Vancouver, BC, Canada. [Elwood, Kevin] BC Ctr Dis Control Soc, TB Control, Vancouver, BC, Canada. [Holland, Steven] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hickstein, Dennis] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 493 BP S333 EP S333 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300494 ER PT J AU Martin, S Abel, CB Wolters, PL Toledo-Tamula, MA Fitzhugh, C Hsieh, M Tisdale, JF AF Martin, Staci Abel, Cristina B. Wolters, Pamela L. Toledo-Tamula, Mary Anne Fitzhugh, Courtney Hsieh, Matthew Tisdale, John F. TI Neurocognitive Functioning in Adults Who Underwent Nonmyeloablative HLA-Matched Sibling Hematopoietic Stem Cell Transplant (SCT) for Sickle Cell Disease (SCD) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Martin, Staci; Abel, Cristina B.; Wolters, Pamela L.] NCI, Hlth Psychol & Neurobehav Res Grp, Bethesda, MD 20892 USA. [Toledo-Tamula, Mary Anne] Leidos Biomed Res Inc, Clin Monitoring Res Program, Clin Res Directorate, Frederick, MD USA. [Fitzhugh, Courtney] NHLBI, Sickle Cell Branch, Mol & Clin Hematol Branch, NIDDK,NIH, Bldg 10, Bethesda, MD 20892 USA. [Hsieh, Matthew; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 258 BP S190 EP S190 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300263 ER PT J AU Maxwell, S Millan, N Nottidge, J Draper, D Koklanaris, E Superata, J Battiwalla, M Barrett, AJ Wolff, EF Ito, S AF Maxwell, Sandra Millan, Nicole Nottidge, Jacqueline Draper, Debbie Koklanaris, Eleftheria Superata, Jeanine Battiwalla, Minoo Barrett, A. John Wolff, Erin F. Ito, Sawa TI Fertility Preservation Prior to Myeloablative Allogeneic Peripheral Blood Stem Cell Transplant in Clinical Trials for Hematological Malignancies - Practical Challenges in Transplant Coordination SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Maxwell, Sandra; Draper, Debbie; Koklanaris, Eleftheria; Superata, Jeanine; Battiwalla, Minoo; Barrett, A. John; Ito, Sawa] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Millan, Nicole; Nottidge, Jacqueline; Wolff, Erin F.] NICHHD, Reprod Endocrinol & Gynecol, NIH, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 124 BP S113 EP S114 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300129 ER PT J AU Mays, JW Weller, ML Bassim, CW Dhamala, S Curtis, LM Rose, JJ Pavletic, SZ Hakim, FT AF Mays, Jacqueline W. Weller, Melodie L. Bassim, Carol W. Dhamala, Susan Curtis, Lauren M. Rose, Jeremy J. Pavletic, Steven Z. Hakim, Fran T. TI Th17 Recruitment and Interferon Pathway Activation in Oral Chronic Graft-Versus-Host Disease Tissues SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Mays, Jacqueline W.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Weller, Melodie L.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Bassim, Carol W.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Dhamala, Susan; Curtis, Lauren M.; Rose, Jeremy J.; Pavletic, Steven Z.; Hakim, Fran T.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 94 BP S90 EP S91 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300099 ER PT J AU Moffet, JR Mahadeo, KM Fitzgerald, J Gertz, S Hall, M Loomis, AL McArthur, J Nitu, M Tamburro, R Duncan, C Rowan, C AF Moffet, Jerelyn R. Mahadeo, Kris Michael Fitzgerald, Julie Gertz, Shira Hall, Mark Loomis, Ashley Loomis McArthur, Jennifer Nitu, Mara Tamburro, Robert Duncan, Christine Rowan, Courtney TI The Impact of Neutrophil Engraftment on the Survival of Intubated Pediatric HCT Patients: A Pediatric Acute Lung Injury and Sepsis Network Study SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Moffet, Jerelyn R.] Duke Univ, Med Ctr, Pediat BMT Program, Durham, NC USA. [Mahadeo, Kris Michael] Childrens Hosp Montefiore, Pediat Hematol Oncol & Blood & Marrow Cell Transp, Bronx, NY USA. [Fitzgerald, Julie] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Gertz, Shira] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Hall, Mark] Nationwide Childrens Hosp, Intens Care Unit, Columbus, OH USA. [Loomis, Ashley Loomis] Univ Minnesota, Pediat Crit Care, Minneapolis, MN USA. [McArthur, Jennifer] Med Coll Wisconsin, Pediat Crit Care, Milwaukee, WI 53226 USA. [Nitu, Mara; Rowan, Courtney] Indiana Univ, Indianapolis, IN 46204 USA. [Tamburro, Robert] NIH, Rockville, MD USA. [Duncan, Christine] Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. [Rowan, Courtney] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 56 BP S60 EP S61 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300061 ER PT J AU Muffly, L Pasquini, MC Martens, M Brazauskas, R Zhu, XC Adekola, K Aljurf, MD Artz, AS Bajel, A Ballen, KK Battiwalla, M Beitinjaneh, A Cahn, JY Carabasi, M Chen, YB Chhabra, S Ciurea, SO Copelan, EA D'Souza, A Edwards, J Freytes, CO Fung, HC Gale, RP Giralt, SA Hashmi, SK Hematti, P Hildebrandt, GC Ho, VT Jakubowski, AA Lazarus, HM McCarthy, PL Olin, RL Olsson, R Rezvani, A Rizzieri, DA Seftel, M Seo, S Sorror, ML Szer, J Wood, WA AF Muffly, Lori Pasquini, Marcelo C. Martens, Michael Brazauskas, Ruta Zhu, Xiaochun Adekola, Kehinde Aljurf, Mahmoud D. Artz, Andrew S. Bajel, Ashish Ballen, Karen K. Battiwalla, Minoo Beitinjaneh, Amer Cahn, Jean-Yves Carabasi, Matthew Chen, Yi-Bin Chhabra, Saurabh Ciurea, Stefan O. Copelan, Edward A. D'Souza, Anita Edwards, John Freytes, Cesar O. Fung, Henry C. Gale, Robert Peter Giralt, Sergio A. Hashmi, Shahrukh K. Hematti, Peiman Hildebrandt, Gerhard C. Ho, Vincent T. Jakubowski, Ann A. Lazarus, Hillard M. McCarthy, Philip L. Olin, Rebecca L. Olsson, Richard Rezvani, Andrew Rizzieri, David A. Seftel, Matthew Seo, Sachiko Sorror, Mohamed L. Szer, Jeffrey Wood, William A. TI Increasing Use of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients Age 70 Years and Older: A CIBMTR Study of Trends and Outcomes SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Muffly, Lori] Stanford Univ, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Pasquini, Marcelo C.; Zhu, Xiaochun; D'Souza, Anita] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Martens, Michael] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Brazauskas, Ruta] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Adekola, Kehinde] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Artz, Andrew S.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Bajel, Ashish; Szer, Jeffrey] Royal Melbourne Hosp, Clin Haematol & Bone Marrow Transplant Serv, Parkville, Vic 3050, Australia. [Ballen, Karen K.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Beitinjaneh, Amer] Univ Virginia, Sch Med, Hematol Oncol, Charlottesville, VA 22908 USA. [Cahn, Jean-Yves] Univ Hosp, Dept Hematol, Grenoble, France. [Carabasi, Matthew] Thomas Jefferson Univ, Med Oncol, Philadelphia, PA 19107 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Bone Marrow Transplant Unit, Boston, MA 02114 USA. [Chhabra, Saurabh] Med Univ S Carolina, Blood & Marrow Transplant Program, Charleston, SC 29425 USA. [Ciurea, Stefan O.] Univ Texas MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Copelan, Edward A.] Carolinas HealthCare Syst, Levine Canc Inst, Dept Hematol Oncol & Blood Disorders, Charlotte, NC USA. [Edwards, John] Indiana Blood & Marrow Transplantat, Indianapolis, IN USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fung, Henry C.] Temple Univ Hosp & Med Sch, Fox Chase Canc Ctr, Dept Hematol & Oncol, Philadelphia, PA 19140 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Giralt, Sergio A.; Jakubowski, Ann A.] Mem Sloan Kettering Canc Ctr, Dept Med, Adult Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Hashmi, Shahrukh K.] Mayo Clin, Div Hematol, Rochester, MN USA. [Hematti, Peiman] Univ Wisconsin Hosp & Clin, Dept Med, Div Hematol Oncol Bone Marrow Transplantat, Madison, WI 53792 USA. [Hildebrandt, Gerhard C.] Univ Kentucky, Chandler Med Ctr, Hematol & Blood & Marrow Transplant, Lexington, KY USA. [Ho, Vincent T.] Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Adult Hematol Malignancies & Stem Cell Transplant, Cleveland, OH USA. [McCarthy, Philip L.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Olin, Rebecca L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Olsson, Richard] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Rezvani, Andrew] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Rizzieri, David A.] Duke Univ, Med Ctr, Div Hematol Malignancies & Cellular Therapy, Durham, NC USA. [Seftel, Matthew] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Seo, Sachiko; Sorror, Mohamed L.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Wood, William A.] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 67 BP S68 EP S69 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300072 ER PT J AU Pulsipher, MA Logan, BR Kiefer, DM Chitphakdithai, P Switzer, GE Riches, ML Rizzo, JD Anderlini, P Leitman, SF Varni, JW Kobusingye, H Besser, RM Shaw, BE O'Donnell, PV Miller, JP Drexler, RJ King, RJ Horowitz, MM Confer, DL AF Pulsipher, Michael A. Logan, Brent R. Kiefer, Deidre M. Chitphakdithai, Pintip Switzer, Galen E. Riches, Marcie L. Rizzo, J. Douglas Anderlini, Paolo Leitman, Susan F. Varni, James W. Kobusingye, Hati Besser, RaeAnne M. Shaw, Bronwen E. O'Donnell, Paul V. Miller, John P. Drexler, Rebecca J. King, Roberta J. Horowitz, Mary M. Confer, Dennis L. TI Pain, Donation-Related Symptoms and the Trajectory of Recovery in Children after Bone Marrow (BM) Donation Are Influenced By Age (Pre vs. Post-Puberty) and Sex: Primary Analysis of the Pediatric Toxicity Cohort of the Related Donor Safety Study (RDSafe) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Pulsipher, Michael A.] Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90027 USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Logan, Brent R.] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Kiefer, Deidre M.; Chitphakdithai, Pintip; Kobusingye, Hati; Besser, RaeAnne M.; Drexler, Rebecca J.; King, Roberta J.] Be The Match, CIBMTR, Natl Marrow Donor Program, Minneapolis, MN USA. [Switzer, Galen E.] Univ Pittsburgh, Med Psychiat & Clin & Translat Sci, Pittsburgh, PA USA. [Riches, Marcie L.] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. [Rizzo, J. Douglas; Shaw, Bronwen E.; Horowitz, Mary M.] CIBMTR, Dept Med, Milwaukee, WI USA. [Rizzo, J. Douglas; Shaw, Bronwen E.; Horowitz, Mary M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Leitman, Susan F.] NHLBI, Dept Transfus Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Varni, James W.] Texas A&M Univ, College Stn, TX USA. [O'Donnell, Paul V.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Miller, John P.] Dept Donor Med Serv, Natl Marrow Donor Program, Minneapolis, MN USA. [Confer, Dennis L.] CIBMTR, Minneapolis, MN USA. [Confer, Dennis L.] Be The Match, Natl Marrow Donor Program, Minneapolis, MN USA. NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 97 BP S93 EP S94 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300102 ER PT J AU Schoemans, HM Goris, K Van Durm, R Vanhoof, J Greinix, DWPH Pavletic, SZ Lee, SJ Maertens, JA De Geest, S Dobbels, F Duarte, RF AF Schoemans, Helene M. Goris, Kathy Van Durm, Raf Vanhoof, Jasper Greinix, Daniel Wolff Prof Hildegard Pavletic, Steven Z. Lee, Stephanie J. Maertens, Johan A. De Geest, Sabina Dobbels, Fabienne Duarte, Rafael F. TI The 'EBMT GVHD App' Improves the Accuracy of Graft-Versus-Host-Disease Assessment According to NIH Criteria Compared to Standard Practice SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Schoemans, Helene M.; Goris, Kathy; Maertens, Johan A.] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Hematol, Leuven, Belgium. [Van Durm, Raf] Katholieke Univ Leuven, Univ Hosp Leuven, IT Dept, Leuven, Belgium. [Vanhoof, Jasper; De Geest, Sabina; Dobbels, Fabienne] Katholieke Univ Leuven, Acad Ctr Nursing & Midwifery, Leuven, Belgium. [Greinix, Daniel Wolff Prof Hildegard] Univ Regensburg, Dept Hematol & Clin Oncol, D-93053 Regensburg, Germany. [Greinix, Daniel Wolff Prof Hildegard] Med Univ Graz, Div Hematol, Vienna, Austria. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [De Geest, Sabina; Dobbels, Fabienne] Univ Basel, Inst Nursing Sci, Basel, Switzerland. [Duarte, Rafael F.] Hosp Llobregat, ICO Hosp Duran I Reynals, Barcelona, Spain. NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 412 BP S284 EP S284 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300414 ER PT J AU Shanis, D Scrivani, C Bevans, M Yang, L Grants, C Welshans, K Stratton, P AF Shanis, Dana Scrivani, Claire Bevans, Margaret Yang, Li Grants, Caitlin Welshans, Katelyn Stratton, Pamela TI Impairment in Sexual Function Persists in Clinically-Stable Female Survivors of Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Shanis, Dana] NICHD, NIH, Bethesda, MD USA. [Scrivani, Claire] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Scrivani, Claire] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bevans, Margaret; Yang, Li] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Grants, Caitlin] Howard Community Coll, Columbia, MD USA. [Welshans, Katelyn] Commonwealth Med Coll, Scranton, PA USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 86 BP S85 EP S85 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300091 ER PT J AU Shanis, D Anandi, P Grant, C Bachi, A Vyas, N Pophali, PA Koklanaris, E Ito, S Savani, BN Barrett, AJ Battiwalla, M Stratton, P AF Shanis, Dana Anandi, Prathima Grant, Caitlin Bachi, Averyl Vyas, Nina Pophali, Priyanka A. Koklanaris, Eleftheria Ito, Sawa Savani, Bipin N. Barrett, A. John Battiwalla, Minoo Stratton, Pamela TI Risk Factors for Human Papilloma Virus Reactivation in the Genital Tract of Female Stem Cell Transplant Survivors SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Shanis, Dana] NICHD, NIH, Bethesda, MD USA. [Anandi, Prathima; Pophali, Priyanka A.; Koklanaris, Eleftheria; Ito, Sawa; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Grant, Caitlin] Howard Community Coll, Columbia, MD USA. [Bachi, Averyl] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Vyas, Nina] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. RI Pophali, Priyanka/P-8646-2016 NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 9 BP S26 EP S26 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300014 ER PT J AU Sharma, KR Choi, U Thompson, RD Rodman, LE Malech, HL Kang, EM AF Sharma, Karlie Roxanne Choi, Uimook Thompson, Robert D. Rodman, Larry E. Malech, Harry L. Kang, Elizabeth M. TI A Novel Method for Screening Adenosine Receptor Specific Agonists for Use in Autoimmune Diseases SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Sharma, Karlie Roxanne; Choi, Uimook; Malech, Harry L.; Kang, Elizabeth M.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Thompson, Robert D.; Rodman, Larry E.] Lewis & Clark Pharmaceut INC, Charlottesville, VA USA. NR 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 623 BP S413 EP S414 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300623 ER PT J AU Sharma, KR Bryant, S Koontz, SM Malech, HL Kang, EM AF Sharma, Karlie Roxanne Bryant, Sarah Koontz, Sherry M. Malech, Harry L. Kang, Elizabeth M. TI Loss of Expression of the Autoimmune Regulator Protein Contributes to Autoimmune Phenotypes in GvHD and Colitis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Sharma, Karlie Roxanne; Koontz, Sherry M.; Malech, Harry L.; Kang, Elizabeth M.] NIAID, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bryant, Sarah] Providence Coll, Providence, RI 02918 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 136 BP S120 EP S120 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300141 ER PT J AU Soni, S Tisdale, JF Hsieh, M Kanter, J Leboulch, P Cavazzana, M AF Soni, Sandeep Tisdale, John F. Hsieh, Matthew Kanter, Julie Leboulch, Philippe Cavazzana, Marina TI Outcomes of Gene Therapy for Severe Sickle Cell Disease (SCD) via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral beta(AT87Q_Globin) Vector SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Soni, Sandeep] Bluebird Biotech Inc, Hematol BMT, Cambridge, MA USA. [Tisdale, John F.; Hsieh, Matthew] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD 20892 USA. [Kanter, Julie] Med Univ S Carolina, Pediat Hematol Oncol, Charleston, SC 29425 USA. [Leboulch, Philippe] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Leboulch, Philippe] Harvard Univ, Sch Med, Boston, MA USA. [Leboulch, Philippe] Univ Paris Sud, IMETi, CEA, Fontenay Aux Roses, France. [Leboulch, Philippe] Univ Paris Sud, CEA, INSERM, UMR 962, Fontenay Aux Roses, France. [Cavazzana, Marina] Hosp Necker Enfants Malad, Paris, France. NR 0 TC 0 Z9 0 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 60 BP S63 EP S63 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300065 ER PT J AU Vrooman, L Millard, H Brazauskas, R Majhail, NS Battiwallas, M Flowers, MED Savani, BN Akpek, G Aljurf, MD Bajwa, R Baker, KS Beitinjaneh, A Bitan, M Buchbinder, D Dandoy, CE Gale, RP Hayashi, RJ Hematti, P Kamble, RT Kasow, KA Kletzel, M Lazarus, HM Malone, AK O'Brien, T Olsson, R Reddy, V Willert, JR Ringden, O Schears, RM Seo, S Steinberg, A Yu, LC Shaw, BE Duncan, C AF Vrooman, Lynda Millard, Heather Brazauskas, Ruta Majhail, Navneet S. Battiwallas, Minoo Flowers, Mary E. D. Savani, Bipin N. Akpek, Goerguen Aljurf, Mahmoud D. Bajwa, Rajinder Baker, K. Scott Beitinjaneh, Amer Bitan, Menachem Buchbinder, David Dandoy, Christopher E. Gale, Robert Peter Hayashi, Robert J. Hematti, Peiman Kamble, Rammurti T. Kasow, Kimberly A. Kletzel, Morris Lazarus, Hillard M. Malone, Adriana K. O'Brien, Tracey Olsson, Richard Reddy, Vijay Willert, Jennifer Reikes Ringden, Olle Schears, Raquel M. Seo, Sachiko Steinberg, Amir Yu, Lolie C. Shaw, Bronwen E. Duncan, Christine TI Survival and Late Effects of Children Undergoing Myeloablative Allogeneic HCT at Less Than Three Years of Age: A Report from the Center for International Blood and Marrow Transplant Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Vrooman, Lynda] Dana Farber Canc Inst, Boston, MA 02115 USA. [Millard, Heather] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Brazauskas, Ruta] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Majhail, Navneet S.] Cleveland Clin, Blood & Marrow Transplant Program, Taussig Canc Inst, Cleveland, OH 44106 USA. [Battiwallas, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Flowers, Mary E. D.; Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Gilbert, AZ USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Bajwa, Rajinder] Nationwide Childrens, Bone Marrow Transplantat, Columbus, OH USA. [Beitinjaneh, Amer] Univ Virginia, Sch Med, Hematol Oncol, Charlottesville, VA 22908 USA. [Bitan, Menachem] Tel Aviv Sourasky Med Ctr, Pediat Hematol Oncol & BMT, Tel Aviv, Israel. [Buchbinder, David] Childrens Hosp Orange Cty, Div Pediat Hematol, Orange, CA 92668 USA. [Dandoy, Christopher E.] Cincinnati Childrens Hosp Med Ctr, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Hayashi, Robert J.] Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. [Hematti, Peiman] Univ Wisconsin Hosp & Clin, Dept Med, Div Hematol Oncol Bone Marrow Transplantat, Madison, WI 53792 USA. [Kamble, Rammurti T.] Baylor Coll Med, Div Hematol & Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Kasow, Kimberly A.] Univ N Carolina, Div Hematol Oncol, Dept Pediat, Chapel Hill, NC USA. [Kletzel, Morris] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Div Hematol Oncol & Stem Cell Transplantat, Chicago, IL 60611 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Adult Hematol Malignancies & Stem Cell Transplant, Cleveland, OH USA. [Malone, Adriana K.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [O'Brien, Tracey] Sydney Childrens Hosp, Kids Canc Ctr, Blood & Marrow Transplant Program, Sydney, NSW, Australia. [Olsson, Richard] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Olsson, Richard; Ringden, Olle] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Reddy, Vijay] Univ Cent Florida, Dept Internal Med, Gainesville, FL USA. [Willert, Jennifer Reikes] Univ Calif San Diego, Rady Childrens Hosp, Pediat Hematol Oncol BMT, San Diego, CA USA. [Ringden, Olle] Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Schears, Raquel M.] Mayo Clin, Rochester, MN USA. [Seo, Sachiko] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Steinberg, Amir] Mt Sinai Hosp, Dept Hematol Oncol, New York, NY 10029 USA. [Yu, Lolie C.] Louisiana State Univ, Med Ctr, Childrens Hosp, Div Hematol Oncol, New Orleans, LA USA. [Yu, Lolie C.] Louisiana State Univ, Med Ctr, Childrens Hosp, Ctr Canc & Blood Disorders,HSCT, New Orleans, LA USA. [Shaw, Bronwen E.] CIBMTR, Dept Med, Milwaukee, WI USA. [Shaw, Bronwen E.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Duncan, Christine] Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. [Duncan, Christine] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 12 BP S28 EP S29 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300017 ER PT J AU Williams, KM Hakim, FT Rosenberg, A Kleiner, D Mitchell, SA Tamm, M Avila, D Lee, SJ Halter, J Prince, SS Bubendorf, L Bollard, CM Pavletic, SZ Gress, R AF Williams, Kirsten M. Hakim, Fran T. Rosenberg, Avi Kleiner, David Mitchell, Sandra A. Tamm, Michael Avila, Daniele Lee, Stephanie J. Halter, Joerg Prince, Spasenija Savic Bubendorf, Lukas Bollard, Catherine M. Pavletic, Steven Z. Gress, Ronald TI Plasma Osteopontin Is a Biomarlcer Specifically Associated with Bronchiolitis Obliterans Syndrome after HCT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Williams, Kirsten M.] Childrens Natl Med Ctr, BMT, Washington, DC 20010 USA. [Hakim, Fran T.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Rosenberg, Avi] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Kleiner, David] NIH, Bldg 10, Bethesda, MD 20892 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. [Tamm, Michael; Bubendorf, Lukas] Univ Spital Basel, Basel, Switzerland. [Avila, Daniele] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Clin Res Div, 1124 Columbia St, Seattle, WA 98104 USA. [Halter, Joerg] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Prince, Spasenija Savic] Univ Spital Basel, Pathol, Basel, Switzerland. [Bollard, Catherine M.] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2016 VL 22 IS 3 SU 1 MA 630 BP S417 EP S418 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300630 ER PT J AU Williams, KM Holter-Chakrabarty, JL Lindenberg, L Adler, S Chai, A Kurdziel, K Lin, F Blacklock-Schuver, BAJ Avila, D Kanakry, CG Vesely, SK Havlicek, JP Duong, NQT Nguyen, CT Selby, G Bollard, CM Choyke, P Gress, R AF Williams, Kirsten M. Holter-Chakrabarty, Jennifer L. Lindenberg, Liza Adler, Steve Chai, Amy Kurdziel, Karen Lin, Frank Blacklock-Schuver, Bazetta A. J. Avila, Daniele Kanakry, Christopher G. Vesely, Sara K. Havlicek, Joseph P. Duong, Ngoc Quyen T. Nguyen, Chuong T. Selby, George Bollard, Catherine M. Choyke, Peter Gress, Ronald TI Novel PET Imaging with Fluorothymidine (FLT) Predicts Relapse Quantitatively at Day 28 Post Transplantation in Patients with Acute Leukemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 18-22, 2016 CL Honolulu, HI SP Ctr Int Blood & Marrow Transplant Res, Amer Soc Blood & Marrow Transplantat C1 [Williams, Kirsten M.] Childrens Natl Med Ctr, BMT, Washington, DC 20010 USA. [Holter-Chakrabarty, Jennifer L.] Univ Oklahoma, Oklahoma City, OK USA. [Lindenberg, Liza; Adler, Steve; Kurdziel, Karen; Choyke, Peter] NIH, Mol Imaging Branch, Bldg 10, Bethesda, MD 20892 USA. [Chai, Amy; Blacklock-Schuver, Bazetta A. J.; Avila, Daniele] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Lin, Frank] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. [Kanakry, Christopher G.] NCI, ETIB, Bethesda, MD 20892 USA. [Vesely, Sara K.; Duong, Ngoc Quyen T.] Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK USA. [Havlicek, Joseph P.; Nguyen, Chuong T.] Univ Oklahoma, Sch Elect & Comp Engn, Norman, OK 73019 USA. [Selby, George] Univ Oklahoma, Med Ctr, Norman, OK 73019 USA. [Bollard, Catherine M.] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2016 VL 22 IS 3 SU 1 MA 295 BP S213 EP S214 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DE8TT UT WOS:000370910300300 ER PT J AU Tyc, KM Herwald, SE Hogan, JA Pierce, JV Klipp, E Kumamoto, CA AF Tyc, Katarzyna M. Herwald, Sanna E. Hogan, Jennifer A. Pierce, Jessica V. Klipp, Edda Kumamoto, Carol A. TI The game theory of Candida albicans colonization dynamics reveals host status-responsive gene expression SO BMC SYSTEMS BIOLOGY LA English DT Article DE Candida albicans; Colonization; Fungal pathogen; Microbiota; Efg1p; Evolutionary game theory; Mathematical modeling ID PROTECTIVE TH1 RESPONSES; BALB-C MICE; SYSTEMIC CANDIDIASIS; GASTROINTESTINAL COLONIZATION; INTRAGASTRIC COLONIZATION; TRANSCRIPTIONAL RESPONSE; INTESTINAL COLONIZATION; HYPHAL DEVELOPMENT; ENDOGENOUS ORIGIN; BIOFILM FORMATION AB Background: The fungal pathogen Candida albicans colonizes the gastrointestinal (GI) tract of mammalian hosts as a benign commensal. However, in an immunocompromised host, the fungus is capable of causing life-threatening infection. We previously showed that the major transcription factor Efg1p is differentially expressed in GI-colonizing C. albicans cells dependent on the host immune status. To understand the mechanisms that underlie this host-dependent differential gene expression, we utilized mathematical modeling to dissect host-pathogen interactions. Specifically, we used principles of evolutionary game theory to study the mechanism that governs dynamics of EFG1 expression during C. albicans colonization. Results: Mathematical modeling predicted that down-regulation of EFG1 expression within individual fungal cells occurred at different average rates in different hosts. Rather than using relatively transient signaling pathways to adapt to a new environment, we demonstrate that C. albicans overcomes the host defense strategy by modulating the activity of diverse fungal histone modifying enzymes that control EFG1 expression. Conclusion: Based on our modeling and experimental results we conclude that C. albicans cells sense the local environment of the GI tract and respond to differences by altering EFG1 expression to establish optimal survival strategies. We show that the overall process is governed via modulation of epigenetic regulators of chromatin structure. C1 [Tyc, Katarzyna M.; Klipp, Edda] Humboldt Univ, Theoret Biophys, Invalidenstr 42, D-10115 Berlin, Germany. [Herwald, Sanna E.; Hogan, Jennifer A.; Pierce, Jessica V.; Kumamoto, Carol A.] Tufts Univ, Sackler Sch Biomed Sci, Grad Program Mol Microbiol, Boston, MA 02111 USA. [Herwald, Sanna E.; Hogan, Jennifer A.; Pierce, Jessica V.; Kumamoto, Carol A.] Tufts Univ, Dept Mol Biol & Microbiol, 136 Harrison Ave, Boston, MA 02111 USA. [Tyc, Katarzyna M.] Univ Utah, Dept Biochem, Salt Lake City, UT 84112 USA. [Pierce, Jessica V.] NIDDK, NIH, Genet Biochem Branch, Bethesda, MD 20892 USA. RP Klipp, E (reprint author), Humboldt Univ, Theoret Biophys, Invalidenstr 42, D-10115 Berlin, Germany.; Kumamoto, CA (reprint author), Tufts Univ, Sackler Sch Biomed Sci, Grad Program Mol Microbiol, Boston, MA 02111 USA.; Kumamoto, CA (reprint author), Tufts Univ, Dept Mol Biol & Microbiol, 136 Harrison Ave, Boston, MA 02111 USA. EM edda.klipp@rz.hu-berlin.de; carol.kumamoto@tufts.edu FU National Institutes of Health [R01AI081794, R01AI081794-02S1]; European Commission through European Marie Curie Initial Training Network, FINSysB [PITN-GA-2008-214004]; NIH [T32AI07422, T32GM008448] FX We thank Drs. Tim van Opijnen, Bree Aldridge, Kearney Gunsalus and Talya Davis for helpful discussion and Dr. Al Brown for catalyzing our collaboration. This research was supported by grants R01AI081794 and R01AI081794-02S1 from the National Institutes of Health to C.A.K. and by the European Commission through the European Marie Curie Initial Training Network, FINSysB (PITN-GA-2008-214004) to E.K. J.V.P. was partially supported by T32AI07422 and S.E.H. by T32GM008448 from the NIH. K.M.T. was supported by the European Commission through the European Marie Curie Initial Training Network, FINSysB (PITN-GA-2008-214004). NR 70 TC 1 Z9 1 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD MAR 1 PY 2016 VL 10 AR 20 DI 10.1186/s12918-016-0268-1 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DE9IR UT WOS:000370950700001 PM 26927448 ER PT J AU Sinder, BP Lloyd, WR Salemi, JD Marini, JC Caird, MS Morris, MD Kozloff, KM AF Sinder, Benjamin P. Lloyd, William R. Salemi, Joseph D. Marini, Joan C. Caird, Michelle S. Morris, Michael D. Kozloff, Kenneth M. TI Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age SO BONE LA English DT Article DE Sclerostin antibody; Osteogenesis imperfecta; Raman spectroscopy; Nanoindentation; Anabolic therapy; Bone quality ID BONE-MINERAL DENSITY; BRTL/+ MOUSE MODEL; POSTMENOPAUSAL WOMEN; STRENGTH; MATRIX; MASS; BLOSOZUMAB; FRACTURE; QUALITY AB Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (01). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical 01 Gly -> Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5 weeks with Sd-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4 wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages > 3 wks) and rapidly growing Brtl/+ (at tissue ages > 4 wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and animal age on bone quality. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sinder, Benjamin P.; Salemi, Joseph D.; Caird, Michelle S.; Kozloff, Kenneth M.] Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Ann Arbor, MI 48109 USA. [Sinder, Benjamin P.; Salemi, Joseph D.; Kozloff, Kenneth M.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Lloyd, William R.; Morris, Michael D.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Marini, Joan C.] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. RP Kozloff, KM (reprint author), 2015 Biomed Sci Res Bldg,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM kenkoz@umich.edu FU NIH [R01 AR062522, R01 AR052010] FX Mike Ominsky provided feedback on the data and reviewed the manuscript. Bonnie Nolan, Kathy Sweet, Logan White, and Mary Eddy assisted with animal work. John Baker assisted with histology of paraffin sections. David Barton helped develop the custom hydrated nanoindentation testing device. Scl-Ab was graciously provided by Amgen and UCB. Funding support from NIH to KMK (R01 AR062522) and MDM (R01 AR052010) is gratefully acknowledged. NR 36 TC 8 Z9 8 U1 2 U2 6 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 MAR PY 2016 VL 84 BP 222 EP 229 DI 10.1016/j.bone.2016.01.001 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DE8VK UT WOS:000370914600026 PM 26769006 ER PT J AU Tully, CM Apolo, AB Zabor, EC Regazzi, AM Ostrovnaya, I Furberg, HF Rosenberg, JE Bajorin, DF AF Tully, Christopher M. Apolo, Andrea B. Zabor, Emily C. Regazzi, Ashley M. Ostrovnaya, Irina Furberg, Helena F. Rosenberg, Jonathan E. Bajorin, Dean F. TI The high incidence of vascular thromboembolic events in patients with metastatic or unresectable urothelial cancer treated with platinum chemotherapy agents SO CANCER LA English DT Article DE bladder cancer; carboplatin; cisplatin; thrombosis; urothelial carcinoma ID TRANSITIONAL-CELL CARCINOMA; CISPLATIN-BASED CHEMOTHERAPY; GEMCITABINE PLUS CISPLATIN; PHASE-II; VENOUS THROMBOEMBOLISM; BLADDER-CANCER; RISK-FACTORS; RETROSPECTIVE ANALYSIS; ONCOLOGY-GROUP; LUNG-CANCER AB BACKGROUNDThe current study compared the incidence of vascular thromboembolic events (VTEs) in patients with metastatic or unresectable urothelial carcinoma (UC) who were treated with gemcitabine and carboplatin (GCb); gemcitabine, carboplatin, and bevacizumab (GCbBev); or gemcitabine and cisplatin (GCis). METHODSPatients with UC who were treated with GCbBev on protocol were analyzed prospectively and 2 contemporary control cohorts receiving GCb or GCis were evaluated retrospectively. VTE was defined as either venous or arterial (myocardial infarctions or cerebral vascular accidents) thrombosis. VTEs were considered to be related to treatment if they occurred during treatment or within 4 weeks of the completion of treatment. Associations with chemotherapy regimen were tested using either the Fisher exact test or Kruskal-Wallis test. Clinical factors associated with VTEs were analyzed using conditional logistic regression stratified by treatment regimen. RESULTSAmong 198 patients, VTEs occurred in 13 of 51 patients treated with GCbBev (26%), 22 of 92 patients treated with GCb (24%), and 8 of 55 patients treated with GCis (15%). Patient characteristics were significantly different between the treatment cohorts in terms of age, prior cystectomy, tumor location near pelvic vessels, Khorana risk group, and receipt of antiplatelet therapy. The incidence of VTE and type of VTE (arterial vs venous) did not differ by type of chemotherapy. Prior cystectomy was associated with an increased risk of VTE (odds ratio, 2.2; 95% confidence interval, 1.0-4.9 [P=.047]). CONCLUSIONSThe incidence of VTE in Cis-treated patients was similar to prior reports. However, the VTE rate in Cb-treated patients was>20%, a figure not previously defined in patients with UC and higher than expected. This high incidence of both Cis-related and Cb-related VTEs warrants greater awareness by treating physicians and deserves further study. (c) 2015 American Cancer Society. C1 [Tully, Christopher M.; Regazzi, Ashley M.; Rosenberg, Jonathan E.; Bajorin, Dean F.] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10065 USA. [Tully, Christopher M.; Rosenberg, Jonathan E.; Bajorin, Dean F.] Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA. [Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Zabor, Emily C.; Ostrovnaya, Irina; Furberg, Helena F.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Bajorin, DF (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10065 USA. EM bajorind@mskcc.org OI Regazzi, Ashley/0000-0002-6019-1852 FU Zena and Michael A. Wiener Research and Therapeutic Program in Bladder Cancer; National Cancer Institute Cancer Center Core Grant [P30 CA008748] FX Supported by The Zena and Michael A. Wiener Research and Therapeutic Program in Bladder Cancer and a National Cancer Institute Cancer Center Core Grant (P30 CA008748). NR 44 TC 2 Z9 2 U1 2 U2 4 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 MAR 1 PY 2016 VL 122 IS 5 BP 712 EP 721 DI 10.1002/cncr.29801 PG 10 WC Oncology SC Oncology GA DF2IP UT WOS:000371166300011 PM 26618338 ER PT J AU Burnside, ES Drukker, K Li, H Bonaccio, E Zuley, M Ganott, M Net, JM Sutton, EJ Brandt, KR Whitman, GJ Conzen, SD Lan, L Ji, Y Zhu, YT Jaffe, CC Huang, EP Freymann, JB Kirby, JS Morris, EA Giger, ML AF Burnside, Elizabeth S. Drukker, Karen Li, Hui Bonaccio, Ermelinda Zuley, Margarita Ganott, Marie Net, Jose M. Sutton, Elizabeth J. Brandt, Kathleen R. Whitman, Gary J. Conzen, Suzanne D. Lan, Li Ji, Yuan Zhu, Yitan Jaffe, Carl C. Huang, Erich P. Freymann, John B. Kirby, Justin S. Morris, Elizabeth A. Giger, Maryellen L. TI Using computer-extracted image phenotypes from tumors on breast magnetic resonance imaging to predict breast cancer pathologic stage SO CANCER LA English DT Article DE breast cancer stage; magnetic resonance imaging (MRI); prognosis; quantitative image analysis ID ENHANCED MR-IMAGES; MAXIMUM-LIKELIHOOD-ESTIMATION; LYMPH-NODE METASTASES; BINORMAL ROC CURVES; PROGNOSTIC MARKERS; MOLECULAR SUBTYPES; DCE-MRI; LESIONS; CLASSIFICATION; IDENTIFICATION AB BACKGROUNDThe objective of this study was to demonstrate that computer-extracted image phenotypes (CEIPs) of biopsy-proven breast cancer on magnetic resonance imaging (MRI) can accurately predict pathologic stage. METHODSThe authors used a data set of deidentified breast MRIs organized by the National Cancer Institute in The Cancer Imaging Archive. In total, 91 biopsy-proven breast cancers were analyzed from patients who had information available on pathologic stage (stage I, n=22; stage II, n=58; stage III, n=11) and surgically verified lymph node status (negative lymph nodes, n=46;1 positive lymph node, n=44; no lymph nodes examined, n=1). Tumors were characterized according to 1) radiologist-measured size and 2) CEIP. Then, models were built that combined 2 CEIPs to predict tumor pathologic stage and lymph node involvement, and the models were evaluated in a leave-1-out, cross-validation analysis with the area under the receiver operating characteristic curve (AUC) as the value of interest. RESULTSTumor size was the most powerful predictor of pathologic stage, but CEIPs that captured biologic behavior also emerged as predictive (eg, stage I and II vs stage III demonstrated an AUC of 0.83). No size measure was successful in the prediction of positive lymph nodes, but adding a CEIP that described tumor homogeneity significantly improved discrimination (AUC=0.62; P=.003) compared with chance. CONCLUSIONSThe current results indicate that MRI phenotypes have promise for predicting breast cancer pathologic stage and lymph node status. (c) 2015 American Cancer Society. C1 [Burnside, Elizabeth S.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Drukker, Karen; Li, Hui; Conzen, Suzanne D.; Lan, Li; Giger, Maryellen L.] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Bonaccio, Ermelinda] Roswell Pk Canc Inst, Dept Radiol, Buffalo, NY 14263 USA. [Zuley, Margarita; Ganott, Marie] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Net, Jose M.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Sutton, Elizabeth J.] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA. [Brandt, Kathleen R.] Mayo Clin, Dept Diagnost Radiol, Rochester, MN USA. [Whitman, Gary J.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Imaging, Houston, TX 77030 USA. [Ji, Yuan] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ji, Yuan; Zhu, Yitan] NorthShore Univ HealthSyst, Program Computat Genom & Med, Evanston, IL USA. [Jaffe, Carl C.; Huang, Erich P.; Freymann, John B.; Kirby, Justin S.] NCI, NIH, Rockville, MD USA. RP Giger, ML (reprint author), Univ Chicago, Radiol MC 2026,5841 S Maryland Ave, Chicago, IL 60637 USA.; Morris, EA (reprint author), Mem Sloan Kettering Canc Ctr, Breast Imaging Serv, 1275 York Ave, New York, NY 10065 USA. EM m-giger@uchicago.edu; m-giger@uchicago.edu FU University of Chicago Dean Bridge Fund; National Institutes of Health [R01CA165229, R01LM010921, K24CA194251, T32 EB002103] FX This work was supported by the University of Chicago Dean Bridge Fund and by grants from the National Institutes of Health (R01CA165229, R01LM010921, K24CA194251, and T32 EB002103). NR 35 TC 0 Z9 0 U1 8 U2 17 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 MAR 1 PY 2016 VL 122 IS 5 BP 748 EP 757 DI 10.1002/cncr.29791 PG 10 WC Oncology SC Oncology GA DF2IP UT WOS:000371166300015 PM 26619259 ER PT J AU Friedman, DN Chou, JF Oeffinger, KC Kleinerman, RA Ford, JS Sklar, CA Li, YL McCabe, MS Robison, LL Marr, BP Abramson, DH Dunkel, IJ AF Friedman, Danielle Novetsky Chou, Joanne F. Oeffinger, Kevin C. Kleinerman, Ruth A. Ford, Jennifer S. Sklar, Charles A. Li, Yuelin McCabe, Mary S. Robison, Leslie L. Marr, Brian P. Abramson, David H. Dunkel, Ira J. TI Chronic medical conditions in adult survivors of retinoblastoma: Results of the Retinoblastoma Survivor Study SO CANCER LA English DT Article DE follow-up studies; questionnaires; retinoblastoma; risk; survivors ID CHILDHOOD-CANCER SURVIVOR; LONG-TERM SURVIVORS; HEREDITARY RETINOBLASTOMA; 5-YEAR SURVIVORS; LATE MORTALITY; FOLLOW-UP; RISK; RADIOTHERAPY; CHILDREN; LIFE AB BACKGROUNDLimited data are available regarding long-term morbidity in adult survivors of retinoblastoma (Rb). METHODSThe Retinoblastoma Survivor Study is a retrospective cohort of adult survivors of Rb diagnosed between 1932 and 1994. Participants completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study surveys. Chronic conditions were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03). Multivariate Poisson regression was used to compare survivors of Rb with 2377 non-Rb controls, consisting of the Childhood Cancer Survivor Study sibling cohort and survivors with bilateral versus unilateral disease. RESULTSSurvivors of Rb (53.6% with bilateral disease) and non-Rb controls had a mean age of 43.3 years (standard deviation, 11 years) and 37.6 years (SD, 8.6 years), respectively, at the time of study enrollment. At a median follow-up of 42 years (range, 15-75 years), 86.6% of survivors of Rb had at least 1 condition and 71.1% had a severe/life-threatening (grade 3-4) condition. The adjusted relative risk (RR) of a chronic condition in survivors compared with non-Rb controls was 1.4 (95% confidence interval [95% CI], 1.3-1.4; P<.01); for a grade 3 to 4 condition, the RR was 7.6 (95% CI, 6.4-8.9; P<.01). Survivors were at an excess risk regardless of laterality. After stratifying by laterality and excluding ocular conditions and second malignant neoplasms (SMNs), only those with bilateral disease were found to be at an increased risk of any nonocular, non-SMN condition (RR, 1.2; 95% CI, 1.1-1.2) and for grade 3 to 4 nonocular, non-SMN conditions (RR, 1.7; 95% CI, 1.2-2.5). CONCLUSIONSSurvivors of Rb have an increased risk of chronic conditions compared with non-Rb controls. After excluding ocular conditions and SMNs, this excess risk was found to persist only for those with bilateral disease. (c) 2016 American Cancer Society. C1 [Friedman, Danielle Novetsky; Oeffinger, Kevin C.; Sklar, Charles A.; Dunkel, Ira J.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10065 USA. [Chou, Joanne F.; Li, Yuelin] Mem Sloan Kettering Canc Ctr, Dept Epidemiol Biostat, New York, NY 10065 USA. [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Kleinerman, Ruth A.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Ford, Jennifer S.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10065 USA. [McCabe, Mary S.] Mem Sloan Kettering Canc Ctr, Survivorship Ctr, Dept Med, New York, NY 10065 USA. [Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA. [Marr, Brian P.; Abramson, David H.] Mem Sloan Kettering Canc Ctr, Ophthalm Oncol Serv, New York, NY 10065 USA. RP Friedman, DN (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10065 USA. EM friedmad@mskcc.org OI Friedman, Danielle Novetsky/0000-0003-4668-9176 FU New York Community Trust; Charles A. Frueauff Foundation; Perry's Promise Fund; National Cancer Institute [U24 CA55727]; Clinical and Translational Science Center at Weill Cornell Medical College [KL2TR000458]; Intramural Research Program of the National Institutes of Health; NIH/NCI Cancer Center Support Grant [P30CA008748] FX Supported by the New York Community Trust, the Charles A. Frueauff Foundation, the Perry's Promise Fund, National Cancer Institute grant U24 CA55727 (Childhood Cancer Survivor Study; Dr. Armstrong, Principal Investigator), grant KL2TR000458 of the Clinical and Translational Science Center at Weill Cornell Medical College, the Intramural Research Program of the National Institutes of Health, and the NIH/NCI Cancer Center Support Grant P30CA008748. NR 30 TC 4 Z9 4 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 MAR 1 PY 2016 VL 122 IS 5 BP 773 EP 781 DI 10.1002/cncr.29704 PG 9 WC Oncology SC Oncology GA DF2IP UT WOS:000371166300018 PM 26755259 ER PT J AU Seol, HS Lee, SE Song, JS Rhee, JK Singh, SR Chang, S Jang, SJ AF Seol, Hyang Sook Lee, Sang Eun Song, Joon Seon Rhee, Je-Keun Singh, Shree Ram Chang, Suhwan Jang, Se Jin TI Complement proteins C7 and CFH control the stemness of liver cancer cells via LSF-1 SO CANCER LETTERS LA English DT Article DE Liver tumor-initiating cell; Complement protein C7; CFH; Stemness factor; LSF-1; HCC ID HEPATOCELLULAR-CARCINOMA; INFLAMMATION; TUMOR; IMMUNITY; ACTIVATION; RESPONSES; ONCOGENE; C5A AB Tumor-initiating, cells are important for the formation and maintenance of tumor bulks in various tumors. To identify surface markers of liver tumor-initiating cells, we performed primary tumorsphere culture and analyzed the expression of cluster of differentiation (CD) antigen genes using NanoString. Interestingly, we found significant upregulation of the complement proteins (p = 1.60 x 10(-18)), including C7 and CFH. Further studies revealed that C7 and CFH are required to maintain sternness in liver cancer cells. Knockdown of C7 and CFH expression abrogated tumorsphere formation and induced differentiation, whereas overexpression stimulated sternness factor expression as well as in vivo cell growth. Mechanistically, by studying C7 and CFH-dependent LSF-1 expression and its direct role on sternness factor transcription, we found that LSF-1 is involved in this regulation. Taken together, our data demonstrate the unprecedented role of complement proteins on the maintenance of sternness in liver tumor initiating cells. Published by Elsevier Ireland Ltd. C1 [Seol, Hyang Sook; Lee, Sang Eun; Jang, Se Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea. [Song, Joon Seon; Jang, Se Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. [Rhee, Je-Keun; Chang, Suhwan] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Biomed Sci, Seoul, South Korea. [Singh, Shree Ram] NCI, Basic Res Lab, Stem Cell Regulat & Anim Aging Sect, Ctr Canc Res, Frederick, MD 21701 USA. RP Jang, SJ (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea.; Jang, SJ (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea.; Chang, S (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Biomed Sci, Seoul, South Korea. EM suhwan.chang@amc.seoul.kr; jangsejin@amc.seoul.kr RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2015R1A1A3A04001354]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) [HI06C0868]; National R&D Program for Cancer Control - Ministry of Health &Welfare, Republic of Korea [1320140] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2015R1A1A3A04001354), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) (grant number: HI06C0868), and the National R&D Program for Cancer Control (grant number: 1320140) funded by the Ministry of Health &Welfare, Republic of Korea. NR 28 TC 1 Z9 1 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD MAR 1 PY 2016 VL 372 IS 1 BP 24 EP 35 DI 10.1016/j.canlet.2015.12.005 PG 12 WC Oncology SC Oncology GA DE7QU UT WOS:000370832600003 PM 26723877 ER PT J AU Pasqua, T Mahata, S Bandyopadhyay, GK Biswas, A Perkins, GA Sinha-Hikim, AP Goldstein, DS Eiden, LE Mahata, SK AF Pasqua, Teresa Mahata, Sumana Bandyopadhyay, Gautam K. Biswas, Angshuman Perkins, Guy A. Sinha-Hikim, Amiya P. Goldstein, David S. Eiden, Lee E. Mahata, Sushil K. TI Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo SO CELL AND TISSUE RESEARCH LA English DT Article DE Norepinephrine; Epinephrine; Dense core vesicle; Synaptic vesicle; Mitochondria ID TYROSINE-HYDROXYLASE ACTIVITY; INDUCED INSULIN-RESISTANCE; TARGETED ABLATION; NEUROTRANSMITTER RELEASE; SYNAPTIC-TRANSMISSION; SECRETORY VESICLES; SECRETOGRANIN-III; OSMOTIC-PRESSURE; AXONAL-TRANSPORT; ADRENAL-MEDULLA AB Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30-40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100-200 nm) than in WT mice (200-350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an similar to 47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell. C1 [Pasqua, Teresa; Bandyopadhyay, Gautam K.; Biswas, Angshuman; Mahata, Sushil K.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Mahata, Sumana] CALTECH, Pasadena, CA 91125 USA. [Perkins, Guy A.] Natl Ctr Microscopy & Imaging Res, San Diego, CA USA. [Sinha-Hikim, Amiya P.] Charles R Drew Univ Med & Sci, 1621 E 120th St, Los Angeles, CA 90059 USA. [Sinha-Hikim, Amiya P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Goldstein, David S.] NINDS, IRP, Clin Neurocardiol Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Eiden, Lee E.] NIMH, IRP, Sect Mol Neurosci, Bethesda, MD 20892 USA. [Mahata, Sushil K.] VA San Diego Healthcare Syst, San Diego, CA USA. [Mahata, Sushil K.] Univ Calif San Diego, Dept Med, Metab Physiol & Ultrastruct Biol Lab, 9500 Gilman Dr, La Jolla, CA 92093 USA. RP Mahata, SK (reprint author), Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA.; Mahata, SK (reprint author), VA San Diego Healthcare Syst, San Diego, CA USA.; Mahata, SK (reprint author), Univ Calif San Diego, Dept Med, Metab Physiol & Ultrastruct Biol Lab, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM smahata@ucsd.edu FU Department of Veterans Affairs; UCSD [RO091B] FX Transmission Electron Microscopy was conducted at the Cellular & Molecular Medicine Electron Microscopy Core Facility at UCSD. A Research Career Scientist Award from the Department of Veterans Affairs supports S.K.M. Mahata's personal fund and UCSD Academic Senate Grant (RO091B) supported this work. NR 84 TC 5 Z9 5 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X EI 1432-0878 J9 CELL TISSUE RES JI Cell Tissue Res. PD MAR PY 2016 VL 363 IS 3 BP 693 EP 712 DI 10.1007/s00441-015-2316-3 PG 20 WC Cell Biology SC Cell Biology GA DE9JZ UT WOS:000370954400008 PM 26572539 ER PT J AU Pasqua, T Mahata, S Bandyopadhyay, GK Biswas, A Perkins, GA Sinha-Hikim, AP Goldstein, DS Eiden, LE Mahata, SK AF Pasqua, Teresa Mahata, Sumana Bandyopadhyay, Gautam K. Biswas, Angshuman Perkins, Guy A. Sinha-Hikim, Amiya P. Goldstein, David S. Eiden, Lee E. Mahata, Sushil K. TI Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo (vol 363, pg 693, 2016) SO CELL AND TISSUE RESEARCH LA English DT Correction C1 [Pasqua, Teresa; Bandyopadhyay, Gautam K.; Biswas, Angshuman; Mahata, Sushil K.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Mahata, Sumana] CALTECH, Pasadena, CA 91125 USA. [Perkins, Guy A.] Natl Ctr Microscopy & Imaging Res, San Diego, CA USA. [Sinha-Hikim, Amiya P.] Charles R Drew Univ Med & Sci, 1621 E 120th St, Los Angeles, CA 90059 USA. [Sinha-Hikim, Amiya P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Goldstein, David S.] NINDS, IRP, Clin Neurocardiol Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Eiden, Lee E.] NIMH, IRP, Sect Mol Neurosci, Bethesda, MD 20892 USA. [Mahata, Sushil K.] VA San Diego Healthcare Syst, San Diego, CA USA. [Mahata, Sushil K.] Univ Calif San Diego, Metab Physiol & Ultrastruct Biol Lab, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. RP Mahata, SK (reprint author), Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA.; Mahata, SK (reprint author), VA San Diego Healthcare Syst, San Diego, CA USA.; Mahata, SK (reprint author), Univ Calif San Diego, Metab Physiol & Ultrastruct Biol Lab, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM smahata@caltech.edu; smahata@ucsd.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X EI 1432-0878 J9 CELL TISSUE RES JI Cell Tissue Res. PD MAR PY 2016 VL 363 IS 3 BP 823 EP 823 DI 10.1007/s00441-016-2362-5 PG 1 WC Cell Biology SC Cell Biology GA DE9JZ UT WOS:000370954400017 PM 26809511 ER PT J AU Wickner, RB Kelly, AC AF Wickner, Reed B. Kelly, Amy C. TI Prions are affected by evolution at two levels SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Amyloid; Ure2p; Sup35p; HET-s; Rnq1; Parallel in-register beta sheet ID CHRONIC WASTING DISEASE; WHITE-TAILED DEER; HET-S PRION; BOVINE SPONGIFORM ENCEPHALOPATHY; BETA-SHEET STRUCTURE; CREUTZFELDT-JAKOB-DISEASE; 2-MU-M CIRCLE PLASMID; CHAIN RELEASE FACTOR; MESSENGER-RNA DECAY; SACCHAROMYCES-CEREVISIAE AB Prions, infectious proteins, can transmit diseases or be the basis of heritable traits (or both), mostly based on amyloid forms of the prion protein. A single protein sequence can be the basis for many prion strains/variants, with different biological properties based on different amyloid conformations, each rather stably propagating. Prions are unique in that evolution and selection work at both the level of the chromosomal gene encoding the protein, and on the prion itself selecting prion variants. Here, we summarize what is known about the evolution of prion proteins, both the genes and the prions themselves. We contrast the one known functional prion, [Het-s] of Podospora anserina, with the known disease prions, the yeast prions [PSI+] and [URE3] and the transmissible spongiform encephalopathies of mammals. C1 [Wickner, Reed B.; Kelly, Amy C.] NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. [Kelly, Amy C.] ARS, NCAUR, USDA, 1815 N Univ St, Peoria, IL 61604 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov; amy.kelly@ars.usda.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported in part by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health NR 165 TC 2 Z9 2 U1 12 U2 27 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAR PY 2016 VL 73 IS 6 BP 1131 EP 1144 DI 10.1007/s00018-015-2109-6 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DF1DQ UT WOS:000371079200002 PM 26713322 ER PT J AU Le Couteur, DG Solon-Biet, S Cogger, VC Mitchell, SJ Senior, A de Cabo, R Raubenheimer, D Simpson, SJ AF Le Couteur, David G. Solon-Biet, Samantha Cogger, Victoria C. Mitchell, Sarah J. Senior, Alistair de Cabo, Rafael Raubenheimer, David Simpson, Stephen J. TI The impact of low-protein high-carbohydrate diets on aging and lifespan SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Aging; Ageing; Caloric restriction; Geometric Framework; CPC diet; Dietary protein; Dietary carbohydrate ID SHORT-TERM CALORIE; MITOCHONDRIAL OXIDATIVE STRESS; SKELETAL-MUSCLE MITOCHONDRIA; ESSENTIAL AMINO-ACIDS; TEPHRITID FRUIT-FLY; AGE-RELATED DISEASE; DROSOPHILA-MELANOGASTER; GEOMETRIC ANALYSIS; GRADED-LEVELS; ANASTREPHA-LUDENS AB Most research on nutritional effects on aging has focussed on the impact of manipulating single dietary factors such as total calorie intake or each of the macronutrients individually. More recent studies using a nutritional geometric approach called the Geometric Framework have facilitated an understanding of how aging is influenced across a landscape of diets that vary orthogonally in macronutrient and total energy content. Such studies have been performed using ad libitum feeding regimes, thus taking into account compensatory feeding responses that are inevitable in a non-constrained environment. Geometric Framework studies on insects and mice have revealed that diets low in protein and high in carbohydrates generate longest lifespans in ad libitum-fed animals while low total energy intake (caloric restriction by dietary dilution) has minimal effect. These conclusions are supported indirectly by observational studies in humans and a heterogeneous group of other types of interventional studies in insects and rodents. Due to compensatory feeding for protein dilution, low-protein, high-carbohydrate diets are often associated with increased food intake and body fat, a phenomenon called protein leverage. This could potentially be mitigated by supplementing these diets with interventions that influence body weight through physical activity and ambient temperature. C1 [Le Couteur, David G.; Solon-Biet, Samantha; Cogger, Victoria C.; Senior, Alistair; Raubenheimer, David; Simpson, Stephen J.] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Le Couteur, David G.; Solon-Biet, Samantha; Cogger, Victoria C.] Concord Hosp, Ageing & Alzheimers Inst, Concord 2139, Australia. [Le Couteur, David G.; Solon-Biet, Samantha; Cogger, Victoria C.] Concord Hosp, ANZAC Res Inst, Concord 2139, Australia. [Mitchell, Sarah J.] Natl Inst ON Aging, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Senior, Alistair; de Cabo, Rafael] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. [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 Simpson, SJ (reprint author), Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia.; Simpson, SJ (reprint author), Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. EM david.lecouteur@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 Aging and Alzheimers Research Institute; NHMRC [571328, 1084267]; Intramural Program of the National Institute on Aging, NIH FX We acknowledge funding from the Aging and Alzheimers Research Institute, NHMRC grants #571328 and #1084267 and our co-authors in studies cited in this review. RdC and SJM are funded by the Intramural Program of the National Institute on Aging, NIH. NR 128 TC 14 Z9 15 U1 39 U2 73 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAR PY 2016 VL 73 IS 6 BP 1237 EP 1252 DI 10.1007/s00018-015-2120-y PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DF1DQ UT WOS:000371079200009 PM 26718486 ER PT J AU Mason, JM Randall, TA Frydrychova, RC AF Mason, James M. Randall, Thomas A. Frydrychova, Radmila Capkova TI Telomerase lost? SO CHROMOSOMA LA English DT Review ID END-PROTECTION PROBLEM; SHORT TANDEM REPEATS; BOMBYX-MORI; ORTHOPTERA TETTIGONIIDAE; REVERSE-TRANSCRIPTASE; RETROTRANSPOSON FAMILIES; TERMINAL HETEROCHROMATIN; RHYNCHOSCIARA DIPTERA; DROSOPHILA TELOMERES; CHROMOSOME ENDS AB Telomerase and telomerase-generated telomeric DNA sequences are widespread throughout eukaryotes, yet they are not universal. Neither telomerase nor the simple DNA repeats associated with telomerase have been found in some plant and animal species. Telomerase was likely lost from Diptera before the divergence of Diptera and Siphonaptera, some 260 million years ago. Even so, Diptera is one of the most successful animal orders, making up 11 % of known animal species. In addition, many species of Coleoptera and Hemiptera seem to lack canonical telomeric repeats at their chromosome ends. These and other insects that appear to lack canonical terminal repeat sequences account for another 10-15 % of animal species. Conversely, the silk moth Bombyx mori maintains canonical telomeric sequences at its chromosome ends but seems to lack a functional telomerase. We speculate that a telomere-specific capping complex that recognizes the telomeric repeats and protects chromosome ends is the determining factor in maintaining canonical telomeric sequences and that telomerase is an early and efficacious mechanism for satisfying the needs of capping complex. There are alternate mechanisms for maintaining chromosome ends that do not depend on telomerase, such as recombination found in some human cancer cells and yeast mutants. These mechanisms may maintain the canonical telomeric repeats or allow the terminal sequence to evolve when specificity of the capping complex for terminal repeat sequences is weak. C1 [Mason, James M.] NIEHS, Lab Genome Integr & Struct Biol, POB 12233, Res Triangle Pk, NC 27709 USA. [Randall, Thomas A.] NIEHS, Integrat Bioinformat, POB 12233, Res Triangle Pk, NC 27709 USA. [Frydrychova, Radmila Capkova] Biol Ctr AS CR, Inst Entomol, Ceske Budejovice, Czech Republic. RP Frydrychova, RC (reprint author), Biol Ctr AS CR, Inst Entomol, Ceske Budejovice, Czech Republic. EM Radmila.Frydrychova@hotmail.com FU Grant Agency of the Czech Republic [14-07172S]; European Union [316304]; Grant Agency of the University of South Bohemia [052/2013/P, 038/2014/P]; NIH, National Institute of Environmental Health Sciences FX This work was supported by Grant No. 14-07172S from the Grant Agency of the Czech Republic (to RCF). We acknowledge the use of research infrastructure that has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 316304 (to RCF). Additional support was provided from Grant no. 052/2013/P and no. 038/2014/P of the Grant Agency of the University of South Bohemia (to RCF) and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (to JMM and TAR). NR 80 TC 7 Z9 7 U1 8 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 EI 1432-0886 J9 CHROMOSOMA JI Chromosoma PD MAR PY 2016 VL 125 IS 1 BP 65 EP 73 DI 10.1007/s00412-015-0528-7 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DE9KB UT WOS:000370954600006 PM 26162505 ER PT J AU Novelle, MG Ali, A Dieguez, C Bernier, M de Cabo, R AF Novelle, Marta G. Ali, Ahmed Dieguez, Carlos Bernier, Michel de Cabo, Rafael TI Metformin: A Hopeful Promise in Aging Research SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID ACTIVATED PROTEIN-KINASE; HER-2/NEU TRANSGENIC MICE; EXTENDS LIFE-SPAN; INHIBITS HEPATIC GLUCONEOGENESIS; FEMALE SHR MICE; CAENORHABDITIS-ELEGANS; DIETARY RESTRICTION; CALORIC RESTRICTION; RESPIRATORY-CHAIN; C.-ELEGANS AB Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector. C1 [Novelle, Marta G.; Ali, Ahmed; Bernier, Michel; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Novelle, Marta G.] Univ Santiago de Compostela, Inst Invest Sanitaria, Res Ctr Mol Med & Chron Dis CIMUS, Santiago De Compostela 15782, Spain. [Novelle, Marta G.; Dieguez, Carlos] CIBER Fisiopatol Obesidad & Nutr CIBERobn, Santiago De Compostela 15706, Spain. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; NOVELLE, MARTA G/0000-0003-0285-7182; , rafael/0000-0003-2830-5693 FU National Institute on Aging, National Institutes of Health FX This work is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. CIBER de Fisiopatologia de la Obesidad y Nutricion is an initiative of ISCIII. The funding agency had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 110 TC 3 Z9 3 U1 1 U2 15 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD MAR PY 2016 VL 6 IS 3 AR a025932 DI 10.1101/cshperspect.a025932 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DF2LX UT WOS:000371175800005 PM 26931809 ER PT J AU Teumer, A Tin, A Sorice, R Gorski, M Yeo, NC Chu, AY Li, M Li, Y Mijatovic, V Ko, YA Taliun, D Luciani, A Chen, MH Yang, Q Foster, MC Olden, M Hiraki, LT Tayo, BO Fuchsberger, C Dieffenbach, AK Shuldiner, AR Smith, AV Zappa, AM Lupo, A Kollerits, B Ponte, B Stengel, B Kramer, BK Paulweber, B Mitchell, BD Hayward, C Helmer, C Meisinger, C Gieger, C Shaffer, CM Muller, C Langenberg, C Ackermann, D Siscovick, D Boerwinkle, E Kronenberg, F Ehret, GB Homuth, G Waeber, G Navis, G Gambaro, G Malerba, G Eiriksdottir, G Li, G Wichmann, HE Grallert, H Wallaschofski, H Volzke, H Brenner, H Kramer, H Leach, IM Rudan, I Hillege, HL Beckmann, JS Lambert, JC Luan, JA Zhao, JH Chalmers, J Coresh, J Denny, JC Butterbach, K Launer, LJ Ferrucci, L Kedenko, L Haun, M Metzger, M Woodward, M Hoffman, MJ Nauck, M Waldenberger, M Pruijm, M Bochud, M Rheinberger, M Verweij, N Wareham, NJ Endlich, N Soranzo, N Polasek, O van der Harst, P Pramstaller, PP Vollenweider, P Wild, PS Gansevoort, RT Rettig, R Biffar, R Carroll, RJ Katz, R Loos, RJF Hwang, SJ Coassin, S Bergmann, S Rosas, SE Stracke, S Harris, TB Corre, T Zeller, T Illig, T Aspelund, T Tanaka, T Lendeckel, U Volker, U Gudnason, V Chouraki, V Koenig, W Kutalik, Z O'Connell, JR Parsa, A Heid, IM Paterson, AD de Boer, IH Devuyst, O Lazar, J Endlich, K Susztak, K Tremblay, J Hamet, P Jacob, HJ Boger, CA Fox, CS Pattaro, C Kottgen, A AF Teumer, Alexander Tin, Adrienne Sorice, Rossella Gorski, Mathias Yeo, Nan Cher Chu, Audrey Y. Li, Man Li, Yong Mijatovic, Vladan Ko, Yi-An Taliun, Daniel Luciani, Alessandro Chen, Ming-Huei Yang, Qiong Foster, Meredith C. Olden, Matthias Hiraki, Linda T. Tayo, Bamidele O. Fuchsberger, Christian Dieffenbach, Aida Karina Shuldiner, Alan R. Smith, Albert V. Zappa, Allison M. Lupo, Antonio Kollerits, Barbara Ponte, Belen Stengel, Benedicte Kraemer, Bernhard K. Paulweber, Bernhard Mitchell, Braxton D. Hayward, Caroline Helmer, Catherine Meisinger, Christa Gieger, Christian Shaffer, Christian M. Mueller, Christian Langenberg, Claudia Ackermann, Daniel Siscovick, David Boerwinkle, Eric Kronenberg, Florian Ehret, Georg B. Homuth, Georg Waeber, Gerard Navis, Gerjan Gambaro, Giovanni Malerba, Giovanni Eiriksdottir, Gudny Li, Guo Wichmann, H. Erich Grallert, Harald Wallaschofski, Henri Voelzke, Henry Brenner, Herrmann Kramer, Holly Leach, I. Mateo Rudan, Igor Hillege, Hans L. Beckmann, Jacques S. Lambert, Jean Charles Luan, Jian'an Zhao, Jing Hua Chalmers, John Coresh, Josef Denny, Joshua C. Butterbach, Katja Launer, Lenore J. Ferrucci, Luigi Kedenko, Lyudmyla Haun, Margot Metzger, Marie Woodward, Mark Hoffman, Matthew J. Nauck, Matthias Waldenberger, Melanie Pruijm, Menno Bochud, Murielle Rheinberger, Myriam Verweij, Niek Wareham, Nicholas J. Endlich, Nicole Soranzo, Nicole Polasek, Ozren van der Harst, Pim Pramstaller, Peter Paul Vollenweider, Peter Wild, Philipp S. Gansevoort, Ron T. Rettig, Rainer Biffar, Reiner Carroll, Robert J. Katz, Ronit Loos, Ruth J. F. Hwang, Shih-Jen Coassin, Stefan Bergmann, Sven Rosas, Sylvia E. Stracke, Sylvia Harris, Tamara B. Corre, Tanguy Zeller, Tanja Illig, Thomas Aspelund, Thor Tanaka, Toshiko Lendeckel, Uwe Volker, Uwe Gudnason, Vilmundur Chouraki, Vincent Koenig, Wolfgang Kutalik, Zoltan O'Connell, Jeffrey R. Parsa, Afshin Heid, Iris M. Paterson, Andrew D. de Boer, Ian H. Devuyst, Olivier Lazar, Jozef Endlich, Karlhans Susztak, Katalin Tremblay, Johanne Hamet, Pavel Jacob, Howard J. Boeger, Carsten A. Fox, Caroline S. Pattaro, Cristian Koettgen, Anna CA DCCT EDIC TI Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes SO DIABETES LA English DT Article ID GLOMERULAR-FILTRATION-RATE; RISK POPULATION COHORTS; KIDNEY-DISEASE; COLLABORATIVE METAANALYSIS; MODULATES PROTEINURIA; EXPRESSION; HERITABILITY; MORTALITY; INSIGHTS; RAB38 AB Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 x 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 x 10(-7)) and 13% for RAB38/CTSC (P = 5.8 x 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria. C1 [Teumer, Alexander; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Teumer, Alexander; Voelzke, Henry; Nauck, Matthias; Volker, Uwe] German Ctr Cardiovascular Res DZHK, Partner Site Greifswald, Greifswald, Germany. [Tin, Adrienne; Li, Man; Coresh, Josef; Woodward, Mark; Koettgen, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Sorice, Rossella] CNR, Inst Genet & Biophys, Adriano Buzzati Traverso, Naples, Italy. [Gorski, Mathias; Olden, Matthias; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Gorski, Mathias; Boeger, Carsten A.] Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany. [Yeo, Nan Cher; Hoffman, Matthew J.; Jacob, Howard J.] Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Chu, Audrey Y.] Brigham & Womens Hosp, Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chu, Audrey Y.; Hwang, Shih-Jen; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Chu, Audrey Y.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Li, Yong; Koettgen, Anna] Univ Freiburg, Med Ctr, Renal Div, Hugstetter Str 55, D-79106 Freiburg, Germany. [Mijatovic, Vladan; Malerba, Giovanni] Univ Verona, Dept Life & Reprod Sci, I-37100 Verona, Italy. [Ko, Yi-An; Susztak, Katalin] Univ Penn, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Taliun, Daniel; Fuchsberger, Christian; Pramstaller, Peter Paul; Pattaro, Cristian] Univ Lubeck, Ctr Biomed, European Acad Bozen Bolzano EURAC, Bolzano, Italy. [Luciani, Alessandro; Devuyst, Olivier] Univ Zurich, Inst Physiol, Mech Inherited Kidney Disorders Grp, Zurich, Switzerland. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Foster, Meredith C.] Tufts Med Ctr, Boston, MA USA. [Olden, Matthias] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Hiraki, Linda T.; Paterson, Andrew D.] Hosp Sick Children, Res Inst, Genet & Genome Biol Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Tayo, Bamidele O.; Kramer, Holly] Loyola Univ Chicago, Maywood, IL USA. [Dieffenbach, Aida Karina; Brenner, Herrmann; Butterbach, Katja] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Dieffenbach, Aida Karina] German Canc Consortium DKTK, Heidelberg, Germany. [Shuldiner, Alan R.; Mitchell, Braxton D.; O'Connell, Jeffrey R.; Parsa, Afshin] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Smith, Albert V.; Eiriksdottir, Gudny; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Zappa, Allison M.] Med Coll Wisconsin, Human & Mol Genet Ctr, Milwaukee, WI 53226 USA. [Lupo, Antonio] Univ Verona, Renal Unit, Dept Med, I-37100 Verona, Italy. [Kollerits, Barbara; Kronenberg, Florian; Haun, Margot; Coassin, Stefan] Med Univ Innsbruck, Div Genet Epidemiol, A-6020 Innsbruck, Austria. [Ponte, Belen] Univ Hosp Geneva, Nephrol Div, Dept Specialties Internal Med, Geneva, Switzerland. [Stengel, Benedicte; Metzger, Marie] Ctr Rech Epidemiol & Sante Populat CESP Team 5, INSERM U 1018, Villejuif, France. [Stengel, Benedicte; Metzger, Marie] Univ Versailles, Univ Paris Sud, Ctr Rech Epidemiol & Sante Populat CESP Team 5, UMRS 1018, St Quentin en Yvelines, France. [Kraemer, Bernhard K.] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Med 5, Mannheim, Germany. [Paulweber, Bernhard; Kedenko, Lyudmyla] Paracelsus Med Univ, Salzburger Landesklin, Dept Internal Med 1, Salzburg, Austria. [Hayward, Caroline] Univ Edinburgh, Human Genet Unit, Inst Genet & Mol Med, Med Res Council, Edinburgh EH8 9YL, Midlothian, Scotland. [Helmer, Catherine] Bordeaux Univ, ISPED, INSERM U897, Bordeaux, France. [Meisinger, Christa; Grallert, Harald; Waldenberger, Melanie; Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Gieger, Christian; Heid, Iris M.] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Shaffer, Christian M.; Denny, Joshua C.; Carroll, Robert J.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Mueller, Christian; Zeller, Tanja] Univ Heart Ctr Hamburg, Hamburg, Germany. [Mueller, Christian; Zeller, Tanja] German Ctr Cardiovasc Res DZHK eV, Partner Site Hamburg, Kiel, Germany. [Langenberg, Claudia; Luan, Jian'an; Zhao, Jing Hua; Wareham, Nicholas J.; Loos, Ruth J. F.] Univ Cambridge, Sch Clin Med, Epidemiol Unit, Med Res Council, Cambridge, England. [Ackermann, Daniel] Univ Hosp Bern, Univ Clin Nephrol Hypertens & Clin Pharmacol, Inselspital, CH-3010 Bern, Switzerland. [Ackermann, Daniel] Univ Bern, Bern, Switzerland. [Siscovick, David; Li, Guo] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David; Li, Guo] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [DCCT EDIC] Epidemiol Diabet Intervent & Complicat Res Grp, Diabet Control & Complicat Trial, Madras, Tamil Nadu, India. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, Cardiol, Geneva, Switzerland. [Homuth, Georg; Volker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany. [Waeber, Gerard; Vollenweider, Peter] Univ Lausanne Hosp, Dept Internal Med, Lausanne, Switzerland. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Gambaro, Giovanni] Univ Cattolica Sacro Cuore, Div Nephrol, Dept Internal Med & Med Specialties, Columbus Gemelli Univ, Rome, Italy. [Wichmann, H. Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Wichmann, H. Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. Erich] Tech Univ Munich, Inst Med Stat & Epidemiol, D-80290 Munich, Germany. [Grallert, Harald] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Grallert, Harald] German Ctr Diabet Res DZD, Neuherberg, Germany. [Wallaschofski, Henri; Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Leach, I. Mateo; Verweij, Niek] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Hillege, Hans L.; van der Harst, Pim; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Nephrol, Groningen, Netherlands. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, Lausanne, Switzerland. [Beckmann, Jacques S.] Univ Lausanne, Lausanne, Switzerland. [Beckmann, Jacques S.; Kutalik, Zoltan] Swiss Inst Bioinformat, Lausanne, Switzerland. [Lambert, Jean Charles; Chouraki, Vincent] Inst Pasteur, INSERM UMR 1167 Risk Factors & Mol Determinants A, F-59019 Lille, France. [Chalmers, John; Woodward, Mark] Univ Sydney, George Inst Global Hlth, Camperdown, NSW, Australia. [Coresh, Josef] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. RP Teumer, A (reprint author), Univ Med Greifswald, Inst Community Med, Greifswald, Germany.; Teumer, A (reprint author), German Ctr Cardiovascular Res DZHK, Partner Site Greifswald, Greifswald, Germany. RI Brenner, Hermann/B-4627-2017; Beckmann, Jacques S /A-9772-2008; Woodward, Mark/D-8492-2015; Kronenberg, Florian/B-1736-2008; Stengel, Benedicte/G-5730-2015; Cossette, Suzanne/I-8008-2016; Lambert, jean-charles/A-9553-2014; Li, Yong/A-6283-2011; Bochud, Murielle/A-3981-2010; Waldenberger, Melanie/B-5355-2014; Colaus, PsyColaus/K-6607-2013; Verweij, Niek/A-4499-2017; HELMER, Catherine/I-6581-2015; Grallert, Harald/B-3424-2013; Polasek, Ozren/B-6002-2011; Paterson, Andrew/A-4088-2011; Smith, Albert Vernon/K-5150-2015; OI Brenner, Hermann/0000-0002-6129-1572; Beckmann, Jacques S /0000-0002-9741-1900; Kronenberg, Florian/0000-0003-2229-1120; Lambert, jean-charles/0000-0003-0829-7817; Bochud, Murielle/0000-0002-5727-0218; Waldenberger, Melanie/0000-0003-0583-5093; HELMER, Catherine/0000-0002-5169-7421; Polasek, Ozren/0000-0002-5765-1862; Paterson, Andrew/0000-0002-9169-118X; Verweij, Niek/0000-0002-4303-7685; Smith, Albert Vernon/0000-0003-1942-5845; Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Mitchell, Braxton/0000-0003-4920-4744; Li, Yong/0000-0003-2651-8791 FU National Foundation for Alzheimer's disease and related disorders; Institut Pasteur de Lille; Centre National de Genotypage; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; MGEN; Institut de la Longevite; Agence Francaise de Securite Sanitaire des Produits de Sante; Aquitaine and Bourgogne Regional Councils; Fondation de France; French Ministry of Research/INSERM "Cohortes et collections de donnees biologiques" programme; Eisai; Prognomix, Inc.; Genome Quebec; Canadian Institutes of Health Research (CIHR); Les Laboratoires Servier, France; National Health and Medical Research Council of Australia; National Institutes of Health (NIH) [N01-AG-1-2100, HHSN271201200022C]; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NIH [R01-AG-18728, R01-HL-088119, U01-GM-074518-04, U01-HL0-72515-06, U01-HL0-84756, K12-RR0-23250, HHSN268200625226C, UL1-RR0-25005, 2R01LM0- 10098, R01-DK0-76077, DK0-87635]; Baltimore Veterans Administration Medical Center Geriatric Research Education and Clinical Center; Paul Beeson Physician Faculty Scholars in Aging Research Program; Mid-Atlantic Nutrition Obesity Research Center [P30-DK0-72488]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01-HG0-04402]; NIH Roadmap for Medical Research; Emmy Noether Programme of the German Research Foundation [KO 3598/2-1]; Intramural Research Program of the NIH, National Institute on Aging; National Center for Research Resources [M01-RR-00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK-063491]; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 33CM30-124087, 310030_146490]; Medical Research Council U.K.; Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]; Medical Research Council; Cancer Research U.K.; Baden-Wurttemberg State Ministry of Science, Research and Arts; German Federal Ministry of Education and Research [01ET0717]; CHANCES (Consortium on Health and Ageing: Network of Cohorts in Europe and the United States) project [242244]; Medical Research Council [MC_U106179471]; Wellcome Trust; National Heart, Lung and Blood Institute Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Boston University School of Medicine Department of Medicine and Boston Medical Center; Dr. Robert Pfleger-Stiftung; MSD Stipend Diabetes; University Hospital of Regensburg; KfH Stiftung Praventivmedizin e.V.; Else Kroner-Fresenius-Stiftung [2012_A147]; University Hospital Regensburg; Else Kroner-Fresenius Stiftung [2012_A147, P48/08//A11/08]; Wellcome Trust [WT098051, WT091310]; European Union [257082, HEALTH-F5-2011-282510, LSHG-CT-2006-018947]; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; Regensburg University Medical Center, Germany; F4 by the University of Ulm, Germany; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; German Federal Ministry of Education and Research; State of Bavaria; University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center; Netherlands Organization of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces; Province of Groningen; University Medical Center Groningen; University of Groningen; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Ministry of Health and Department of Educational Assistance; University and Research of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; Dutch Kidney Foundation [E033]; EU [FP-6 LSHM CT 2006 037697]; Netherlands Organisation for Health Research and Development NWO-Groot grant [175.010.2007.006]; NWO VENI [916.761.70]; ZonMw grant [90.700.441]; Dutch Inter University Cardiology Institute Netherlands (ICIN); Kamillo Eisner Stiftung; Genomics of Lipidassociated Disorders (GOLD) of the "Austrian Genome Research Programme GEN-AU"; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network "Greifswald Approach to Individualized Medicine (GANI_MED)" - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Lausanne University Hospital; Geneva University Hospital; Bern University Hospital, Switzerland; Swiss School of Public Health Plus (SSPH+); National Institute of General Medical Sciences (NIGMS) [RC2-GM092318]; Electronic Medical Records and Genomics (eMERGE) Network; National Human Genome Research Institute; NIGMS [U01-HG04603]; European Community [305608]; [R01-HL0-87641]; [R01-HL-9367]; [R01-HL0-86694]; [2R01-069321]; [N01-HC-85079]; [N01-HC-85080]; [N01-HC-85081]; [N01-HC-85082]; [N01-HC-85083]; [N01-HC-85084]; [N01-HC-85085]; [N01-HC-85086]; [N01-HC-35129]; [N01-HC-15103]; [N01-HC-55222]; [N01-HC-75150]; [N01-HC-45133]; [U01-HL0-80295]; [R01-HL0-87652] FX 3C Study: The work was made possible by the generous participation of the control subjects, the patients, and their families. The authors thank Dr. Anne Boland, Centre National de Genotypage, for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille, and the Centre National de Genotypage. The Three-City (3C) Study was performed as part of a collaboration between INSERM, the Victor Segalen Bordeaux II University, and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Fondation de France, and the joint French Ministry of Research/INSERM "Cohortes et collections de donnees biologiques" programme. Lille Genopole received an unconditional grant from Eisai.; ADVANCE Study: The genetic epidemiological work was funded by Prognomix, Inc., and by grants from Genome Quebec and Canadian Institutes of Health Research (CIHR). The clinical study was managed by The George Institute for Global Health (University of Sydney, Sydney, New South Wales, Australia) with grants received from Les Laboratoires Servier, France, and from the National Health and Medical Research Council of Australia. The genotyping was performed at the genomic platform of Centre de Recherche du Centre hospitalier de l'Universite de Montreal (CRCHUM). The authors acknowledge the technical help of Carole Long and Mounsif Haloui and the bioinformatic analyses performed by Gilles Godefroid, Francois-Christophe Blanchet-Marois, and Francois Harvey (CRCHUM, Universite de Montreal, Montreal, Quebec, Canada). Also acknowledged are the members of the genetic substudy of ADVANCE, Stephen Harrap (Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia) and Michel Marre (Diabetologie, Endocrinologie, Nutrition at Hopital Bichat, Paris, France). M.W. did not participate in animal experiments.; AGES Study: The study has been funded by National Institutes of Health (NIH) contracts N01-AG-1-2100 and HHSN271201200022C, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.; Amish Study: The authors thank the Amish research volunteers for their long-standing partnership in research and the research staff at the Amish Research Clinic for their hard work and dedication. The study is supported by grants and contracts from the NIH, including R01-AG-18728 (Amish Longevity Study), R01-HL-088119 (Amish Calcification Study), U01-GM-074518-04 (Pharmacogenomics of Anti-Platelet Intervention [PAPI] Study), U01-HL0-72515-06 (Heredity and Phenotype Intervention [HAPI] Study), U01-HL0-84756, and K12-RR0-23250 (University of Maryland Multidisciplinary Clinical Research Career Development Program), the University of Maryland General Clinical Research Center, grant M01-RR-16500, the Baltimore Veterans Administration Medical Center Geriatric Research Education and Clinical Center, and the Paul Beeson Physician Faculty Scholars in Aging Research Program. Partial funding was also provided by the Mid-Atlantic Nutrition Obesity Research Center (P30-DK0-72488).; ARIC Study: The ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01-HL0-87641, R01-HL-9367 and R01-HL0-86694, National Human Genome Research Institute contract U01-HG0-04402, and NIH contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1-RR0-25005, a component of the NIH and NIH Roadmap for Medical Research. This work as well as Y.L. and A.K. were supported by the Emmy Noether Programme of the German Research Foundation (KO 3598/2-1 to A.K.).; Baltimore Longitudinal Study of Aging (BLSA): BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; CHS: The CHS research reported in this article was supported by National Heart, Lung, and Blood Institute contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, and grant numbers U01-HL0-80295 and R01-HL0-87652, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR-00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK-063491 to the Southern California Diabetes Endocrinology Research Center.; CoLaus Study: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661).; CROATIA-Split Study: The CROATIA-Split study was supported through grants from the Medical Research Council U.K., and Ministry of Science, Education and Sport of the Republic of Croatia (No. 108-1080315-0302). The authors acknowledge the invaluable contributions of the recruitment team from the Croatian Centre for Global Health, University of Split, the administrative teams in Croatia and Edinburgh, and the people of Split. The SNP genotyping for the Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark.; EPIC-Norfolk Study: The EPIC-Norfolk Study is supported by program grants from the Medical Research Council, and Cancer Research U.K. The authors acknowledge the contribution of the staff and participants of the EPIC-Norfolk Study.; ESTHER Study: The authors thank all the individuals who took part in the ESTHER (Epidemiological investigations of the chances of preventing, recognizing early and optimally treating chronic diseases in an elderly population) study and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. This work was supported in part by the Baden-Wurttemberg State Ministry of Science, Research and Arts, by the German Federal Ministry of Education and Research (grant number 01ET0717), and by the CHANCES (Consortium on Health and Ageing: Network of Cohorts in Europe and the United States) project funded in the Seventh Framework Programme of the Directorate-General for Research and Innovation in the European Commission (grant number 242244).; Fenland Study: The Fenland study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust. The authors are grateful to all the volunteers for their time and help and to the general practitioners and practice staff for assistance with recruitment. The authors thank the Fenland Study Investigators, Fenland Study Co-ordination team, and the Epidemiology Field, Data and Laboratory teams.; Framingham Heart Study: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the NIH and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Boston University School of Medicine Department of Medicine and Boston Medical Center.; GENDIAN Study: The support of the physicians, the patients, and the staff of the Diabetes Zentrum Mergentheim (Head: Prof. Dr. Thomas Haak), the diabetes outpatient clinic Dr. Nusser - Dr. Kreisel, the dialysis centers KfH Amberg, KfH Bayreuth, KfH Deggendorf, KfH Donauworth, KfH Freising, KfH Freyung, KfH Furth, KfH Hof, KfH Ingolstadt, KfH Kelheim, KfH Munchen Elsenheimerstrasse, KfH Munchen-Schwabing, KfH Neumarkt, KfH Neusass, KfH Oberschleissheim, KfH Passau, KfH Plauen, KfH Regensburg Gunzstrasse, KfH Regensburg Caritas-Krankenhaus, KfH Straubing, KfH Sulzbach-Rosenberg, KfH Weiden, Dialysezentrum Augsburg Dr. Kirschner, Dialysezentrum Bad Alexandersbad, KfH Bamberg, Dialysezentrum Emmering, Dialysezentrum Klinikum Landshut, Dialysezentrum Landshut, Dialysezentrum Pfarrkirchen, Dialysezentrum Schwandorf, Dr. Angela Gotz, the medical doctoral student Johanna Christ, and the study nurse Ingrid Lugauer. The expert technical assistance of Claudia Strohmeier is gratefully acknowledged. Phenotyping was funded by the Dr. Robert Pfleger-Stiftung (C.A.B.), the MSD Stipend Diabetes (C.A.B.), and the University Hospital of Regensburg (intramural grant ReForM A to Dr. Angela Gotz, ReForM C to C.A.B.). Genome-wide genotyping was funded by the KfH Stiftung Praventivmedizin e.V. (C.A.B., Dr. Jens Bruning), the Else Kroner-Fresenius-Stiftung (2012_A147 to C. A. B. and I. M. H.), and the University Hospital Regensburg (C. A. B.). Data analysis was funded by the Else Kroner-Fresenius Stiftung (2012_A147 to I. M. H. and C. A. B. and P48/08//A11/08 to C. A. B. and B. K. K.). GENDIAN Study Group: M. G., I. M. H., B. K. K., M. R., Michael Broll, Alexander Lammert, Jens Bruning, M. O., Klaus Stark, Claudia Strohmeier, Simone Neumeier, Sarah Hufnagel, Petra Jackermeier, Emilia Ruff, Johanna Christ, Peter Nurnberg, Thomas Haak, and C. A. B.; INCIPE Study: The INCIPE (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points) study was cosponsored by Fondazione Cassa di Risparmio di Verona, Azienda Ospedaliera di Verona, and University of Verona, Italy. N.S.'s research is supported by the Wellcome Trust (grant codes WT098051 and WT091310), the European Union Framework Program 7 (EPIGENESYS grant code 257082 and BLUEPRINT grant code HEALTH-F5-2011-282510).; KORA-F3/KORA-F4 Study: The genetic epidemiological work was funded by the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else Kroner-Fresenius-Stiftung (P48/08//A11/08 to C. A. B., B. K. K. and 2012_A147 to C. A. B. and I. M. H.). The kidney parameter measurements in F3 were funded by the Else Kroner-Fresenius-Stiftung (C. A. B., B. K. K.) and the Regensburg University Medical Center, Germany, and in F4 by the University of Ulm, Germany (W.K.). De novo genotyping as well as partly genome-wide genotyping costs in F3 and F4 were funded by the Else Kroner-Fresenius-Stiftung (C. A. B., B. K. K.). The KORA research platform and the MONICA (Multinational MONItoring of Trends and Determinants in CArdiovascular Disease) Augsburg studies were initiated and financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum Munchen. The LINUX platform for computation were funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center.; LifeLines Study: The LifeLines Cohort Study and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO grant 175.010.2007.006, the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation, and Dutch Diabetes Research Foundation. LifeLines is a multidisciplinary prospective population-based cohort study examining in a unique three-generation design the health and health-related behaviors of 165,000 individuals living in the Northeast region of the Netherlands. It uses a broad range of investigative procedures in assessing the biomedical, sociodemographic, behavioral, physical, and psychological factors that contribute to the health and disease of the general population, with a special focus on multimorbidity and complex genetics.; MICROS (Microisolates in South Tyrol) Study: The authors are grateful to all participants. The authors thank the primary care practitioners Raffaela Stocker, Stefan Waldner, Toni Pizzecco, Josef Plangger, Ugo Marcadent, and the personnel of the Hospital of Silandro Department of Laboratory Medicine for their participation and collaboration in the research project. The authors thank Dr. Peter Riegler (Hemodialysis Unit, Hospital of Merano) for the important discussions. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union Framework Program 6 EUROSPAN project (contract No. LSHG-CT-2006-018947).; PREVEND Study: PREVEND (Prevention of Renal and Vascular End-stage Disease) genetics is supported by the Dutch Kidney Foundation grant E033; the EU project grant GENECURE (FP-6 LSHM CT 2006 037697); the NIH grant 2R01LM0-10098; The Netherlands Organisation for Health Research and Development NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441; and the Dutch Inter University Cardiology Institute Netherlands (ICIN).; SAPHIR Study: The SAPHIR (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk) study was partially supported by a grant from the Kamillo Eisner Stiftung to B. P. and by grants from the Genomics of Lipidassociated Disorders (GOLD) of the "Austrian Genome Research Programme GEN-AU" to F. K.; SHIP/SHIP-Trend/GANI_MED Study: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research grants 01ZZ9603, 01ZZ0103, and 01ZZ0403; the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network "Greifswald Approach to Individualized Medicine (GANI_MED)" funded by the Federal Ministry of Education and Research grant 03IS2061A. Genome-wide data have been supported by the Federal Ministry of Education and Research grant 03ZIK012 and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the "Center of Knowledge Interchange" program of the Siemens AG, the German Centre for Diabetes Research (DZD), and the Cache Campus program of the InterSystems GmbH. The SHIP authors are grateful to Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation as well as to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum Munchen) for the genotyping of the SHIP-Trend cohort.; SKIPOGH (Swiss Kidney Project on Genes in Hypertension) Study: This research was funded by grant 33CM30-124087 from the Swiss National Science Foundation. The study also received support from Lausanne University Hospital, Geneva University Hospital, and Bern University Hospital, Switzerland. M. B. received support from the Swiss School of Public Health Plus (SSPH).; Vanderbilt Study: Genotyping was supported by National Institute of General Medical Sciences (NIGMS) RC2-GM092318 (Omni1 and Omni5 array). This work was supported by the Electronic Medical Records and Genomics (eMERGE) Network, initiated and funded by the National Human Genome Research Institute, with additional funding from the NIGMS, through U01-HG04603 (660 array).; Susztak Laboratory: Work in the laboratory of K.S. was supported by NIH R01-DK0-76077 and DK0-87635.; Jacobs Laboratory: Work in the H.J.J. and J.L. laboratories was supported by 2R01-069321 to H.J.J.; Devuyst Laboratory: This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 305608 (EURenOmics) and the Swiss National Science Foundation project grant 310030_1464904 NR 41 TC 5 Z9 5 U1 3 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAR PY 2016 VL 65 IS 3 BP 803 EP 817 DI 10.2337/db15-1313 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DE9MF UT WOS:000370961000032 PM 26631737 ER PT J AU Tamborlane, WV Haymond, MW Dunger, D Shankar, R Gubitosi-Klug, R Bethin, K Karres, J Tomasi, P Libman, I Hale, PH Portman, R Klingensmith, G Reed, M Blumer, J Giacoia, G AF Tamborlane, William V. Haymond, Morey W. Dunger, David Shankar, Ravi Gubitosi-Klug, Rose Bethin, Kathleen Karres, Janina Tomasi, Paolo Libman, Ingrid Hale, Paula H. Portman, Ronald Klingensmith, Georgeanna Reed, Michael Blumer, Jeffrey Giacoia, George CA NICHD Diabet Working Grp TI Expanding Treatment Options for Youth With Type 2 Diabetes: Current Problems and Proposed Solutions: A White Paper From the NICHD Diabetes Working Group SO DIABETES CARE LA English DT Editorial Material ID PEDIATRIC-PATIENTS; GLYCEMIC CONTROL; ADOLESCENTS; METFORMIN; CHILDREN; ONSET; MONOTHERAPY; TRIAL C1 [Tamborlane, William V.] Yale Univ, Sch Med, New Haven, CT USA. [Haymond, Morey W.] Baylor Coll Med, Houston, TX 77030 USA. [Dunger, David] Univ Cambridge, Cambridge, England. [Shankar, Ravi] Merck & Co Inc, Whitehouse Stn, NJ USA. [Gubitosi-Klug, Rose] Univ Hosp Rainbow Babies & Childrens Hosp, Cleveland, OH USA. [Bethin, Kathleen] Womens & Childrens Hosp, Buffalo, NY USA. [Karres, Janina; Tomasi, Paolo] European Med Agcy, London, England. [Libman, Ingrid] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Hale, Paula H.] Novo Nordisk Inc, Bagsvaerd, Denmark. [Portman, Ronald] Novartis Pharmaceut, E Hartford, CT USA. [Klingensmith, Georgeanna] Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Reed, Michael] Akron Childrens Hosp, Akron, OH USA. [Blumer, Jeffrey] Univ Toledo, 2801 W Bancroft St, Toledo, OH 43606 USA. [Giacoia, George] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Tamborlane, WV (reprint author), Yale Univ, Sch Med, New Haven, CT USA. EM william.tamborlane@yale.edu OI Zeitler, Philip/0000-0001-5756-7858 FU Medical Research Council [G0800661] NR 20 TC 3 Z9 3 U1 0 U2 4 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 MAR PY 2016 VL 39 IS 3 BP 323 EP 329 DI 10.2337/dc15-1649 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DF1HW UT WOS:000371091500013 PM 26908928 ER PT J AU Greco, G Ferket, BS D'Alessandro, DA Shi, W Horvath, KA Rosen, A Welsh, S Bagiella, E Neill, AE Williams, DL Greenberg, A Browndyke, JN Gillinov, AM Mayer, ML Keim-Malpass, J Gupta, LS Hohmann, SF Gelijns, AC O'Gara, PT Moskowitz, AJ AF Greco, Giampaolo Ferket, Bart S. D'Alessandro, David A. Shi, Wei Horvath, Keith A. Rosen, Alexander Welsh, Stacey Bagiella, Emilia Neill, Alexis E. Williams, Deborah L. Greenberg, Ann Browndyke, Jeffrey N. Gillinov, A. Marc Mayer, Mary Lou Keim-Malpass, Jessica Gupta, Lopa S. Hohmann, Samuel F. Gelijns, Annetine C. O'Gara, Patrick T. Moskowitz, Alan J. TI Diabetes and the Association of Postoperative Hyperglycemia With Clinical and Economic Outcomes in Cardiac Surgery SO DIABETES CARE LA English DT Article ID CRITICALLY-ILL PATIENTS; INTENSIVE INSULIN THERAPY; INPATIENT GLYCEMIC CONTROL; GLUCOSE CONTROL; STRESS HYPERGLYCEMIA; CRITICAL ILLNESS; 3 DOMAINS; MORTALITY; MANAGEMENT; HEALTH AB OBJECTIVEThe management of postoperative hyperglycemia is controversial and generally does not take into account pre-existing diabetes. We analyzed clinical and economic outcomes associated with postoperative hyperglycemia in cardiac surgery patients, stratifying by diabetes status.RESEARCH DESIGN AND METHODSMulticenter cohort study in 4,316 cardiac surgery patients operated on in 2010. Glucose was measured at 6-h intervals for 48 h postoperatively. Outcomes included cost, hospital length of stay (LOS), cardiac and respiratory complications, major infections, and death. Associations between maximum glucose levels and outcomes were assessed with multivariable regression and recycled prediction analyses.RESULTSIn patients without diabetes, increasing glucose levels were associated with a gradual worsening of outcomes. In these patients, hyperglycemia (180 mg/dL) was associated with an additional cost of $3,192 (95% CI 1,972 to 4,456), an additional hospital LOS of 0.8 days (0.4 to 1.3), an increase in infections of 1.6% (0.5 to 2.8), and an increase in respiratory complications of 2.6% (0.0 to 5.3). However, among patients with insulin-treated diabetes, optimal outcomes were associated with glucose levels considered to be hyperglycemic (180 to 240 mg/dL). This level of hyperglycemia was associated with cost reductions of $6,225 (-12,886 to -222), hospital LOS reductions of 1.6 days (-3.7 to 0.4), infection reductions of 4.1% (-9.1 to 0.0), and reductions in respiratory complication of 12.5% (-22.4 to -3.0). In patients with non-insulin-treated diabetes, outcomes did not differ significantly when hyperglycemia was present.CONCLUSIONSGlucose levels <180 mg/dL are associated with better outcomes in most patients, but worse outcomes in patients with diabetes with a history of prior insulin use. These findings support further investigation of a stratified approach to the management of patients with stress-induced postoperative hyperglycemia based on prior diabetes status. C1 [Greco, Giampaolo; Ferket, Bart S.; Shi, Wei; Bagiella, Emilia; Williams, Deborah L.; Gupta, Lopa S.; Gelijns, Annetine C.; Moskowitz, Alan J.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Int Ctr Hlth Outcomes & Innovat Res InCHOIR, New York, NY 10029 USA. [D'Alessandro, David A.] Albert Einstein Coll Med, Montefiore Med Center, Dept Cardiothorac Surg, New York, NY USA. [Horvath, Keith A.; Greenberg, Ann] NIH, Dept Cardiothorac Surg, Heart Ctr, Suburban Hosp, Bldg 10, Bethesda, MD 20892 USA. [Rosen, Alexander] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Welsh, Stacey] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. [Neill, Alexis E.] Emory Univ, Hosp Midtown, Dept Cardiothorac Surg, Atlanta, GA 30322 USA. [Browndyke, Jeffrey N.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Gillinov, A. Marc] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Mayer, Mary Lou] Univ Penn, Sch Med, Dept Surg, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Keim-Malpass, Jessica] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Hohmann, Samuel F.] Univ HealthSyst Consortium, Chicago, IL USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. RP Greco, G (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Int Ctr Hlth Outcomes & Innovat Res InCHOIR, New York, NY 10029 USA. EM giampaolo.greco@mountsinai.org OI Moskowitz, Alan/0000-0002-4412-9450; Browndyke, Jeffrey/0000-0002-8573-7073 FU National Heart, Lung, and Blood Institute [7U01-HL-088942]; Canadian Institutes of Health Research; Institute for Health Technology Studies (InHealth); InHealth; National Institutes of Health; National Heart, Lung, and Blood Institute FX This study was funded by National Heart, Lung, and Blood Institute grant 7U01-HL-088942, the Canadian Institutes of Health Research, and the Institute for Health Technology Studies (InHealth).; G.G. reports grants from InHealth during the conduct of the study. A.E.N. reports receiving grants and nonfinancial support from the National Institutes of Health during the conduct of the study. A.M.G. reports receiving personal fees from Edwards Lifesciences, Medtronic, St. Jude Medical, On-X, Tendyne, AtriCure, and Abbott outside of the submitted work. A.C.G. and A.J.M. report receiving grants from the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research during the conduct of the study. No other potential conflicts of interest relevant to this article were reported. NR 39 TC 3 Z9 3 U1 1 U2 3 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 MAR PY 2016 VL 39 IS 3 BP 408 EP 417 DI 10.2337/dc15-1817 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DF1HW UT WOS:000371091500025 PM 26786574 ER PT J AU Chen, LW Li, SS He, CY Zhu, YY Louis, GMB Yeung, E Hu, FB Zhang, CL AF Chen, Liwei Li, Shanshan He, Chunyan Zhu, Yeyi Louis, Germaine M. Buck Yeung, Edwina Hu, Frank B. Zhang, Cuilin TI Age at Menarche and Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study Among 27,482 Women SO DIABETES CARE LA English DT Article ID ASSOCIATION; ADULTHOOD AB OBJECTIVETo examine the association between age at menarche and risk of gestational diabetes mellitus (GDM).RESEARCH DESIGN AND METHODSA prospective cohort study of 42,109 eligible pregnancies from 27,482 women in the Nurses' Health Study II.RESULTSThe adjusted risk ratios for GDM across the age at menarche categories (11, 12, 13, and 14 years) were 1.34 (95% CI 1.14-1.58), 1.13 (0.97-1.31), 1.11 (0.95-1.29), and 1.00 (referent; P for trend = 0.0005), respectively. Analysis of the mediating effect indicated that 42.1% (P = 0.0007) of the association was mediated through prepregnancy BMI.CONCLUSIONSThese findings suggested that earlier menarche was significantly associated with an increased risk of GDM. This association was largely mediated through prepregnancy excessive body adiposity. C1 [Chen, Liwei] Clemson Univ, Dept Publ Hlth Sci, Clemson, SC USA. [Li, Shanshan; Zhu, Yeyi; Louis, Germaine M. Buck; Yeung, Edwina; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [He, Chunyan] Indiana Univ Sch Med, Dept Publ Hlth & Melvin, Indianapolis, IN 46202 USA. [He, Chunyan] Indiana Univ Sch Med, Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, 75 Francis St, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Chen, LW (reprint author), Clemson Univ, Dept Publ Hlth Sci, Clemson, SC USA. EM liweic@clemson.edu OI Yeung, Edwina/0000-0002-3851-2613; Buck Louis, Germaine/0000-0002-1774-4490 FU National Institutes of Health [CA-50385, DK-58845]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX The Nurses' Health Study II was funded by research grants CA-50385 and DK-58845 from the National Institutes of Health. When this study was conducted, L.C., S.L., Y.Z., G.M.B.L., E.Y., and C.Z. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 15 TC 1 Z9 1 U1 3 U2 7 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 MAR PY 2016 VL 39 IS 3 BP 469 EP 471 DI 10.2337/dc15-2011 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DF1HW UT WOS:000371091500033 PM 26813668 ER PT J AU Olson, SW Yoon, S Baker, T Prince, LK Oliver, D Abbott, KC AF Olson, S. W. Yoon, S. Baker, T. Prince, L. K. Oliver, D. Abbott, K. C. TI Longitudinal plasma metanephrines preceding pheochromocytoma diagnosis: a retrospective case-control serum repository study SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID VON-HIPPEL-LINDAU; BIOCHEMICAL-DIAGNOSIS; REFRACTORY HYPERTENSION; SECONDARY HYPERTENSION; FREE NORMETANEPHRINE; ADRENAL MASS; MANAGEMENT; PARAGANGLIOMAS; INCIDENTALOMA; LOCALIZATION AB Objective: Plasma metanephrines (PMN) are highly sensitive for diagnosis of pheochromocytoma, but the natural history of PMN before pheochromocytoma diagnosis has not been previously described. The aim of the study was to compare the progression of PMN before pheochromocytoma diagnosis to matched healthy and essential hypertension disease controls. Design: A retrospective case-control Department of Defense Serum Repository (DoDSR) study. Methods: We performed a DoDSR study that compared three longitudinal pre-diagnostic PMN for 30 biopsy-proven pheochromocytoma cases to three longitudinal PMN for age, sex, race, and age of serum sample matched healthy and essential hypertension disease controls. Predominant metanephrine (MN) or normetanephrine (NMN) production was identified for each case and converted to a percentage of the upper limit of normal to allow analysis of all cases together. PMN were measured by Quest Diagnostics. Results: The predominant plasma metanephrine (PPM) was > 100 and 300% of the upper limit of normal a median of 6.6 and 4.1 years before diagnosis respectively. A greater percentage of pheochromocytoma patients had a PPM > 100 and > 300% of the upper limit of normal compared with combined healthy and essential hypertension disease controls < 2, 2-8, and >8 years prior to diagnosis. For patients with a baseline PPM 90-300% of the upper limit of normal, a 25% rate of rise per year was 100% specific for pheochromocytoma. Conclusions: PPMs elevate years before diagnosis which suggests that delayed diagnoses are common. For mild PMN elevations, follow-up longitudinal PMN trends may provide a highly specific and economical diagnostic tool. C1 [Olson, S. W.; Yoon, S.; Prince, L. K.; Oliver, D.] Walter Reed Natl Mil Med Ctr, Dept Nephrol, 8901 Rockville Pike, Bethesda, MD 20889 USA. [Baker, T.] Joint Pathol Ctr, Dept Chief, 606 Stephen Sitter Ave, Silver Spring, MD 20910 USA. [Abbott, K. C.] NIDDK, Bethesda, MD 20892 USA. RP Olson, SW (reprint author), Walter Reed Natl Mil Med Ctr, Dept Nephrol, 8901 Rockville Pike, Bethesda, MD 20889 USA. EM Stephen.w.olson.mil@mail.mil NR 48 TC 1 Z9 1 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD MAR PY 2016 VL 174 IS 3 BP 289 EP 295 DI 10.1530/EJE-15-0651 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DE8HM UT WOS:000370876800009 PM 26671972 ER PT J AU Ngwa, W Ngoma, T Zietman, A Mayr, N Elzawawy, A Winningham, TA Balogun, O Enwerem-Bromson, N Ntizimira, C Olopade, OI Oluwole, D Odedina, F Williams, M Flanigan, J Asana, L Ngwa, K Avery, S Pollard, JM Roland, T Funwi-gabga, N Mbarika, V Hardenbergh, P Winkfield, K Pipman, Y Stefan, C Ngoma, M Mohammed, S Katz, M Erno, S Moni, J Fitzgerald, T Tonlaar, N Efstathiou, J Gierga, D Ayo, C Knaul, F Gospodarowicz, M Makrigiorgos, GM Nguyen, PL AF Ngwa, Wilfred Ngoma, Twalib Zietman, Anthony Mayr, Nina Elzawawy, Ahmed Winningham, Thomas A. Balogun, Onyinye Enwerem-Bromson, Nelly Ntizimira, Christian Olopade, Olufunmilayo I. Oluwole, Doyin Odedina, Folakemi Williams, Makeda Flanigan, John Asana, Lydia Ngwa, Kenneth Avery, Stephen Pollard, Julianne M. Roland, Teboh Funwi-gabga, Neba Mbarika, Victor Hardenbergh, Patricia Winkfield, Karen Pipman, Yakov Stefan, Christina Ngoma, Mamsau Mohammed, Sulma Katz, Matthew Erno, Sajo Moni, Janaki Fitzgerald, Thomas Tonlaar, Nathan Efstathiou, Jason Gierga, David Ayo, Charles Knaul, Felicia Gospodarowicz, Mary Makrigiorgos, G. Mike Nguyen, Paul L. TI Closing the Cancer Divide Through Ubuntu: Information and Communication Technology-Powered Models for Global Radiation Oncology SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RADIOTHERAPY; RESPONSIBILITY; COUNTRIES; THERAPY; AFRICA; ACCESS; CARE C1 [Ngwa, Wilfred; Makrigiorgos, G. Mike; Nguyen, Paul L.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Ngwa, Wilfred; Mayr, Nina; Makrigiorgos, G. Mike; Nguyen, Paul L.] Harvard Univ, Sch Med, 75 Francis St, Boston, MA 02115 USA. [Ngwa, Wilfred; Erno, Sajo] Univ Massachusetts Lowell, Dept Phys & Appl Phys, Lowell, MA USA. [Ngoma, Twalib] Muhimbili Univ Hlth & Allied Sci, Dept Clin Oncol, Dar Es Salaam, Tanzania. [Zietman, Anthony; Winkfield, Karen; Efstathiou, Jason; Gierga, David] Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA USA. [Mayr, Nina] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Elzawawy, Ahmed; Stefan, Christina] African Org Res & Training Canc, Rondebosch, South Africa. [Winningham, Thomas A.] Hlth First Canc Inst, Titusville, FL USA. [Balogun, Onyinye] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY USA. [Enwerem-Bromson, Nelly] IAEA, Program Act Canc Therapy, A-1400 Vienna, Austria. [Ntizimira, Christian] Kibagabaga Hosp, Kigali City, Rwanda. [Olopade, Olufunmilayo I.] Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA. [Oluwole, Doyin] Pink Ribbon Red Ribbon, Dallas, TX USA. [Odedina, Folakemi] Univ Florida, Coll Pharm, Gainesville, FL USA. [Williams, Makeda; Flanigan, John] NCI, Ctr Global Hlth, Rockville, MD USA. [Asana, Lydia; Ngwa, Kenneth] African Renaissance Ambassador Corp, Orlando, FL USA. [Avery, Stephen] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Pollard, Julianne M.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Roland, Teboh] Johns Hopkins Univ, Dept Radiat Oncol, Baltimore, MD USA. [Funwi-gabga, Neba] Southern Alberta Inst Technol, Calgary, AB, Canada. [Mbarika, Victor] Informat & Commun Technol Univ, Baton Rouge, LA USA. [Hardenbergh, Patricia] Shaw Reg Canc Ctr, Edwards, CO USA. [Pipman, Yakov] Amer Assoc Physicists Med, Int Educ Activ Comm, College Pk, MD USA. [Stefan, Christina] South African Med Res Council, Cape Town, South Africa. [Ngoma, Mamsau] Ocean Rd Canc Inst, Dar Es Salaam, Tanzania. [Mohammed, Sulma] Purdue Univ, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. [Mohammed, Sulma] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. [Katz, Matthew] Lowell Gen Hosp, Lowell, MA USA. [Moni, Janaki; Fitzgerald, Thomas] Univ Massachusetts, Sch Med, Dept Radiat Oncol, Worcester, MA USA. [Tonlaar, Nathan] Radiating Hope, Salt Lake City, UT USA. [Ayo, Charles] Covenant Univ, Ota, Nigeria. [Knaul, Felicia] Harvard Univ, Sch Med, Harvard Global Equ Initiat, Boston, MA USA. [Gospodarowicz, Mary] Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. [Gospodarowicz, Mary] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. RP Ngwa, W (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; Ngwa, W (reprint author), Harvard Univ, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM wngwa@lroc.harvard.edu FU Harvard Radcliffe Institute; Varian Medical Systems; Brigham and Women's Hospital Center for Community Health and Health Equity FX This work was supported by Harvard Radcliffe Institute, Varian Medical Systems, and Brigham and Women's Hospital Center for Community Health and Health Equity. NR 26 TC 2 Z9 2 U1 3 U2 7 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 MAR 1 PY 2016 VL 94 IS 3 BP 440 EP 449 DI 10.1016/j.ijrobp.2015.10.063 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DE7KX UT WOS:000370816500005 PM 26867873 ER PT J AU Zhang, T Lv, CF Wang, J Zheng, WB Lu, LZ Liu, SJ Bao, J AF Zhang, T. Lv, C-F. Wang, J. Zheng, W-B Lu, L-Z. Liu, S-J. Bao, J. TI Direct tuberculosis drug susceptibility testing: time-saving and cost-effective in detecting MDR-TB SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE tuberculosis; multidrug-resistant TB; DR-TB; DST; rifampicin; isoniazid ID MULTIDRUG-RESISTANT TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; RAPID DETECTION; GLOBAL BURDEN; METAANALYSIS; DIAGNOSTICS; ASSAY; GENEXPERT; COUNTRIES; CHINA AB BACKGROUND: Recent advances have made molecular diagnosis of tuberculosis (TB) and drug susceptibility testing (DST) possible, but the high costs involved present a huge challenge. The refinement and improvement of affordable methods therefore remain a priority. Conventional indirect DST is inexpensive and reliable, but time-consuming. A direct DST method for the direct testing of sputum samples without culture has been developed to reduce the time required for DST, but there have been conflicting results. METHODS AND RESULTS: Direct and indirect DST against isoniazid and rifampicin were performed on 208 sputum smear-positive specimens, 186 from newly diagnosed patients and 22 from previously treated patients; respectively 169 and 180 of the direct and indirect DST results were reportable. In comparison with indirect DST, direct DST resulted in a saving of on average 10.5 days. The time to direct DST results was inversely correlated with the number of acid-fast bacilli in the sputum samples. CONCLUSION: Direct DST is highly sensitive, reliable, cost-effective and time-saving in comparison with indirect DST. C1 [Zhang, T.; Lv, C-F.; Wang, J.; Zheng, W-B; Lu, L-Z.; Liu, S-J.] Shenzhen Nanshan Ctr Chron Dis Control, Shenzhen 518054, Guangdong, Peoples R China. [Bao, J.] NIAID, HJF DAIDS, Div Henry M Jackson Fdn Adv Mil Med, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Zhang, T (reprint author), Shenzhen Nanshan Ctr Chron Dis Control, Shenzhen 518054, Guangdong, Peoples R China.; Bao, J (reprint author), Henry M Jackson Fdn Adv Mil Med, 5601 Fishers Lane, Bethesda, MD 20892 USA. EM taozhang315@126.com; Baoj@mail.nih.gov FU Research Grants of Shenzhen Science and Technology Project, Shenzhen, China [JCYJ20130329100436295]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA [HH-SN272200800014C] FX The study was supported by the Research Grants of Shenzhen Science and Technology Project, Shenzhen, China (contract no. JCYJ20130329100436295). JB was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA (contract no HH-SN272200800014C). NR 31 TC 1 Z9 1 U1 3 U2 5 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD MAR PY 2016 VL 20 IS 3 BP 323 EP 328 DI 10.5588/ijtld.15.0637 PG 6 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA DF2RU UT WOS:000371192300010 PM 27046712 ER PT J AU Resnik, DB Tyler, AM Black, JR Kissling, G AF Resnik, David B. Tyler, Ana M. Black, Jennifer R. Kissling, Grace TI Authorship policies of scientific journals SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID EQUAL CONTRIBUTIONS; CREDIT AB We analysed the authorship policies of a random sample of 600 journals from the Journal Citation Reports database. 62.5% of the journals we sampled had an authorship policy. Having an authorship policy was positively associated with impact factor. Journals from the biomedical sciences and social sciences/humanities were more likely to have an authorship policy than journals from the physical sciences, engineering or mathematical sciences. Among journals with a policy, the most frequent type of policy was guidance on criteria for authorship (99.7%); followed by guidance on acknowledgments (97.3%); requiring that authors make substantial contributions to the research (94.7%); requiring that authors be accountable for the research as a whole (84.8%); guidance on changes in authorship (77.9%); requiring that authors give final approval to the manuscript (77.6%); requiring that authors draft or critically revise the manuscript (71.7%); providing guidance on corporate authorship (58.9%); prohibiting gift, guest or ghost authorship (31.7%); requiring authors to describe their contributions (5.3%); limiting the number of authors for some types of articles (4.0%) and requiring authors to be accountable for their part in the research (1.1%). None of the policies addressed equal contribution statements. Journals that do not have authorship policies should consider adopting or developing ones. C1 [Resnik, David B.; Kissling, Grace] NIEHS, NIH, Box 12233,Mail Drop CU 108, Res Triangle Pk, NC 27709 USA. [Tyler, Ana M.] Case Western Reserve Univ, NIEHS, Cleveland, OH 44106 USA. [Black, Jennifer R.] Emory Univ, NIEHS, Atlanta, GA 30322 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 108, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported by the Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). NR 23 TC 3 Z9 3 U1 0 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD MAR PY 2016 VL 42 IS 3 BP 199 EP 202 DI 10.1136/medethics-2015-103171 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DE7QB UT WOS:000370830700015 PM 26714812 ER PT J AU Margolin, G Petrykowska, HM Jameel, N Bell, DW Young, AC Elnitski, L AF Margolin, Gennady Petrykowska, Hanna M. Jameel, Nader Bell, Daphne W. Young, Alice C. Elnitski, Laura TI Robust Detection of DNA Hypermethylation of ZNF154 as a Pan-Cancer Locus with in Silico Modeling for Blood-Based Diagnostic Development SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CIRCULATING TUMOR DNA; NUCLEIC-ACIDS; METHYLATION BIOMARKERS; LUNG-CANCER; QUALITY; GENOME; QUANTIFICATION; ASSOCIATION; PLASMA; BREAST AB Sites that display recurrent, aberrant DNA methylation in cancer represent potential biomarkers for screening and diagnostics. Previously, we identified hypermethylation at the ZNF154 CpG island in 15 solid epithelial tumor types from 13 different organs. In this study, we measure the magnitude and pattern of differential methylation of this region across colon, lung, breast, stomach, and endometrial tumor samples using next generation bisulfite amplicon sequencing. We found that all tumor types and subtypes are hypermethylated at this locus compared with normal tissue. To evaluate this site as a possible pan-cancer marker, we compare the ability of several sequence analysis methods to distinguish the five tumor types (184 tumor samples) from normal tissue samples (n = 34). The classification performance for the strongest method, measured by the area under (the receiver operating characteristic) curve (AUC), is 0.96, close to a perfect value of 1. Furthermore, in a computational simulation of circulating tumor DNA, we were able to detect limited amounts of tumor DNA diluted with normal DNA: 1% tumor DNA in 99% normal DNA yields AUCs of up to 0.79. Our findings suggest that hypermethylation of the ZNF154 CpG island is a relevant biomarker for identifying solid tumor DNA and may have utility as a generalizable biomarker for circulating tumor DNA. C1 [Margolin, Gennady; Petrykowska, Hanna M.; Jameel, Nader; Elnitski, Laura] NHGRI, Translat & Funct Genom Branch, 5625 Fishers Ln, Rockville, MD 20852 USA. [Young, Alice C.] NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, Rockville, MD 20852 USA. [Bell, Daphne W.] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA. RP Elnitski, L (reprint author), NHGRI, Translat & Funct Genom Branch, 5625 Fishers Ln, Rockville, MD 20852 USA. EM elnitski@mail.nih.gov FU Intramural Program of the National Human Genome Research Institute, NIH; NIH [HG200323] FX Supported by the Intramural Program of the National Human Genome Research Institute, NIH, and NIH grant HG200323 (L.E.). NR 41 TC 5 Z9 5 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAR PY 2016 VL 18 IS 2 BP 283 EP 298 DI 10.1016/j.jmoldx.2015.11.004 PG 16 WC Pathology SC Pathology GA DE9ZA UT WOS:000370997200014 PM 26857064 ER PT J AU Pomeraniec, IJ Ksendzovsky, A Awad, AJ Fezeu, F Jane, JA AF Pomeraniec, I. Jonathan Ksendzovsky, Alexander Awad, Ahmed J. Fezeu, Francis Jane, John A., Jr. TI Natural and surgical history of Chiari malformation Type I in the pediatric population SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Article DE Chiari malformation; syringomyelia; pediatric neurosurgery; natural history ID POSTERIOR-FOSSA DECOMPRESSION; OF-NEUROLOGICAL-SURGEONS; SPONTANEOUS RESOLUTION; CRANIOCERVICAL JUNCTION; CEREBELLAR TONSILS; CLINICAL ARTICLE; SYRINGOMYELIA; DURAPLASTY; CHILDREN; OUTCOMES AB OBJECTIVE The natural and surgical history of Chiari malformation Type I (CM-I) in pediatric patients is currently not well described. In this study the authors discuss the clinical and radiological presentation and outcomes in a large cohort of pediatric CM-I patients treated with either conservative or surgical management. METHODS The authors retrospectively reviewed 95 cases involving pediatric patients with CM-I who presented between 2004 and 2013. The patients ranged in age from 9 months to 18 years (mean 8 years) at presentation. The cohort was evenly split between the sexes. Twenty-five patients underwent posterior fossa decompression (PFD) with either dural splitting or duraplasty. Seventy patients were managed without surgery. Patients were followed radiologically (mean 44.8 months, range 1.2-196.6 months) and clinically (mean 66.3 months, range 1.2-106.5 months). RESULTS Seventy patients were treated conservatively and followed with serial outpatient neurological and radiological examinations, whereas 25 patients were treated with PFD. Of these 25 surgical patients, 11 were treated with duraplasty (complete dural opening) and 14 were treated with a dura-splitting technique (incomplete dural opening). Surgical intervention was associated with better clinical resolution of symptoms and radiological resolution of tonsillar ectopia and syringomyelia (p = 0.0392). Over the course of follow-up, 20 (41.7%) of 48 nonsurgical patients who were symptomatic at presentation experienced improvement in symptoms and 18 (75%) of 24 symptomatic surgical patients showed clinical improvement (p = 0.0117). There was no statistically significant difference in resolution of symptoms between duraplasty and dura-splitting techniques (p = 0.3572) or between patients who underwent tonsillectomy and tonsillopexy (p = 0.1667). Neither of the 2 patients in the conservative group with syrinx at presentation showed radiological evidence of resolution of the syrinx, whereas 14 (87.5%) of 16 patients treated with surgery showed improvement or complete resolution of syringomyelia (p = 0.0392). In the nonsurgical cohort, 3 patients (4.3%) developed new or increased syrinx. CONCLUSIONS The overwhelming majority of CM-I patients (92.9%) managed conservatively do not experience clinical or radiological progression, and a sizeable minority (41.7%) of those who present with symptoms improve. However, appropriately selected symptomatic patients (sleep apnea and dysphagia) and those presenting with syringomyelia should be considered surgical candidates because of the high rates of clinical (75%) and radiological improvement (87.5%). C1 [Pomeraniec, I. Jonathan; Ksendzovsky, Alexander; Awad, Ahmed J.; Fezeu, Francis; Jane, John A., Jr.] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22908 USA. [Ksendzovsky, Alexander] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Pomeraniec, IJ (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Neurosurg, Box 800212, Charlottesville, VA 22908 USA. EM ijp3by@virginia.edu NR 39 TC 2 Z9 2 U1 1 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD MAR PY 2016 VL 17 IS 3 BP 343 EP 352 DI 10.3171/2015.7.PEDS1594 PG 10 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA DE8VR UT WOS:000370915300016 PM 26588459 ER PT J AU Arora, A Agarwal, D Abdel-Fatah, TMA Lu, HM Croteau, DL Moseley, P Aleskandarany, MA Green, AR Ball, G Rakha, EA Chan, SYT Ellis, IO Wang, LL Zhao, YL Balajee, AS Bohr, VA Madhusudan, S AF Arora, Arvind Agarwal, Devika Abdel-Fatah, Tarek M. A. Lu, Huiming Croteau, Deborah L. Moseley, Paul Aleskandarany, Mohammed A. Green, Andrew R. Ball, Graham Rakha, Emad A. Chan, Stephen Y. T. Ellis, Ian O. Wang, Lisa L. Zhao, Yongliang Balajee, Adayabalam S. Bohr, Vilhelm A. Madhusudan, Srinivasan TI RECQL4 helicase has oncogenic potential in sporadic breast cancers SO JOURNAL OF PATHOLOGY LA English DT Article DE RECQL4 helicase; breast cancer; tumour suppressor; oncogene ID ROTHMUND-THOMSON-SYNDROME; GENE; EXPRESSION AB RECQL4 helicase is a molecular motor that unwinds DNA, a process essential during DNA replication and DNA repair. Germ-line mutations in RECQL4 cause type II Rothmund-Thomson syndrome (RTS), characterized by a premature ageing phenotype and cancer predisposition. RECQL4 is widely considered to be a tumour suppressor, although its role in human breast cancer is largely unknown. As the RECQL4 gene is localized to chromosome 8q24, a site frequently amplified in sporadic breast cancers, we hypothesized that it may play an oncogenic role in breast tumourigenesis. To address this, we analysed large cohorts for gene copy number changes (n = 1977), mRNA expression (n = 1977) and protein level (n = 1902). Breast cancer incidence was also explored in 58 patients with type II RTS. DNA replication dynamics and chemosensitivity was evaluated in RECQL4-depleted breast cancer cells in vitro. Amplification or gain in gene copy number (30.6%), high-level mRNA expression (51%) and high levels of protein (23%) significantly associated with aggressive tumour behaviour, including lymph node positivity, larger tumour size, HER2 overexpression, ER-negativity, triple-negative phenotypes and poor survival. RECQL4 depletion impaired the DNA replication rate and increased chemosensitivity in cultured breast cancer cells. Thus, although recognized as a 'safe guardian of the genome', our data provide compelling evidence that RECQL4 is tumour promoting in established breast cancers. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Arora, Arvind; Madhusudan, Srinivasan] Univ Nottingham, Sch Med, Acad Unit Oncol, Div Canc & Stem Cells, Nottingham NG5 1PB, England. [Arora, Arvind; Abdel-Fatah, Tarek M. A.; Moseley, Paul; Chan, Stephen Y. T.; Madhusudan, Srinivasan] Univ Nottingham Hosp, Dept Oncol, Nottingham, England. [Agarwal, Devika; Ball, Graham] Nottingham Trent Univ, Sch Sci & Technol, Clifton Campus, Nottingham, England. [Lu, Huiming; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Aleskandarany, Mohammed A.; Green, Andrew R.; Rakha, Emad A.; Ellis, Ian O.] Univ Nottingham, Sch Med, Dept Pathol, Nottingham NG5 1PB, England. [Wang, Lisa L.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Zhao, Yongliang] Chinese Acad Sci, Lab Dis Genom & Individualized Med, Beijing Inst Gen, Beijing, Peoples R China. [Balajee, Adayabalam S.] Oak Ridge Associated Univ, REAC TS, Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37831 USA. RP Madhusudan, S (reprint author), Univ Nottingham, Acad Unit Oncol, Div Canc & Stem Cells, Sch Med,Nottingham Univ Hosp, Nottingham NG5 1PB, England. EM srinivasan.madhusudan@nottingham.ac.uk OI Madhusudan, Srinivasan/0000-0002-5354-5480 FU Cancer Research UK; NIA NIH HHS [AG000726-24] NR 13 TC 4 Z9 4 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD MAR PY 2016 VL 238 IS 4 BP 495 EP 501 DI 10.1002/path.4681 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA DE7TQ UT WOS:000370840000003 PM 26690729 ER PT J AU Zhu, RX Baker, SS Moylan, CA Abdelmalek, MF Guy, CD Zamboni, F Wu, DF Lin, WL Liu, WS Baker, RD Govindarajan, S Cao, ZW Farci, P Diehl, AM Zhu, LX AF Zhu, Ruixin Baker, Susan S. Moylan, Cynthia A. Abdelmalek, Manal F. Guy, Cynthia D. Zamboni, Fausto Wu, Dingfeng Lin, Weili Liu, Wensheng Baker, Robert D. Govindarajan, Sugantha Cao, Zhiwei Farci, Patrizia Diehl, Anna Mae Zhu, Lixin TI Systematic transcriptome analysis reveals elevated expression of alcohol-metabolizing genes in NAFLD livers SO JOURNAL OF PATHOLOGY LA English DT Article DE non-alcoholic; ADH; ALDH; CYP2E1 ID PEDIATRIC NONALCOHOLIC STEATOHEPATITIS; MITOCHONDRIAL DYSFUNCTION; ALDEHYDE DEHYDROGENASE; INSULIN-RESISTANCE; DISEASE; HEPATITIS; APOPTOSIS; ETHANOL; PATHOGENESIS; RECEPTORS AB Obese animals and non-alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy-proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD-associated genes and NAFLD pathophysiology. Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up-regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley (c) Sons, Ltd. C1 [Zhu, Ruixin; Wu, Dingfeng; Lin, Weili; Cao, Zhiwei] Tongji Univ, Dept Bioinformat, Shanghai 200092, Peoples R China. [Baker, Susan S.; Liu, Wensheng; Baker, Robert D.; Zhu, Lixin] SUNY Buffalo, Dept Pediat, Digest Dis & Nutr Ctr, 3435 Main St,422BRB, Buffalo, NY 14214 USA. [Moylan, Cynthia A.; Abdelmalek, Manal F.; Diehl, Anna Mae] Duke Univ, Div Gastroenterol & Hepatol, Dept Med, Durham, NC USA. [Guy, Cynthia D.] Durham Vet Affairs Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Durham, NC USA. [Guy, Cynthia D.] Duke Univ, Dept Pathol, Durham, NC 27706 USA. [Zamboni, Fausto] Brotzu Hosp, Liver Transplantat Ctr, I-09134 Cagliari, Italy. [Govindarajan, Sugantha] Univ So Calif, Dept Pathol, Los Angeles, CA 90089 USA. [Farci, Patrizia] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, LX (reprint author), SUNY Buffalo, Dept Pediat, Digest Dis & Nutr Ctr, 3435 Main St,422BRB, Buffalo, NY 14214 USA.; Diehl, AM (reprint author), Duke Univ, Dept Med, Durham, NC USA. EM annamae.diehl@duke.edu; lixinzhu@buffalo.edu FU Intramural NIH HHS NR 48 TC 2 Z9 2 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD MAR PY 2016 VL 238 IS 4 BP 531 EP 542 DI 10.1002/path.4650 PG 12 WC Oncology; Pathology SC Oncology; Pathology GA DE7TQ UT WOS:000370840000007 PM 26415102 ER PT J AU Eze, N Smith, LM LaGasse, LL Derauf, C Newman, E Arria, A Huestis, MA Della Grotta, SA Dansereau, LM Neal, C Lester, BM AF Eze, Nwando Smith, Lynne M. LaGasse, Linda L. Derauf, Chris Newman, Elana Arria, Amelia Huestis, Marilyn A. Della Grotta, Sheri A. Dansereau, Lynne M. Neal, Charles Lester, Barry M. TI School-Aged Outcomes following Prenatal Methamphetamine Exposure: 7.5-Year Follow-Up from the Infant Development, Environment, and Lifestyle Study SO JOURNAL OF PEDIATRICS LA English DT Article ID NEUROBEHAVIORAL DISINHIBITION; BEHAVIOR PROBLEMS; EARLY ADVERSITY; CHILDREN; AMPHETAMINE; CHILDHOOD; PREGNANCY; MOTHERS; HEALTH; WOMEN AB Objective To assess the relationship between prenatal methamphetamine exposure (PME) and behavior problems at age 7.5 years and the extent to which early adversity mediated this relationship. Study design The multicenter, longitudinal Infant Development, Environment, and Lifestyle study enrolled 412 mother-infant pairs at 4 sites. Methamphetamine-exposed participants (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched participants (n = 208) denied methamphetamine use and had a negative meconium screen. At the 7.5-year follow-up, 290 children with complete Child Behavior Checklist data and an early adversity index score were available for analysis (n = 146 exposed). Results PME was significantly associated with an increased early adversity index score (P<.001) and with increased externalizing, rule-breaking behavior, and aggressive behavior (P<.05). Early adversity was also associated with higher externalizing behavior scores. Early adversity significantly mediated the relationship between PME and behavioral problems. After adjusting the mediation model for sex, prenatal tobacco, alcohol, and marijuana exposures, and study site, the association of PME with early adversity remained significant. Conclusions Though PME is associated with behavioral problems, early adversity may be a strong determinant of behavioral outcome for children exposed to methamphetamine in utero. Early adversity significantly mediated the relationship between PME and behavioral problems. C1 [Eze, Nwando; Smith, Lynne M.] Univ Calif Los Angeles, Dept Pediat, David Geffen Sch Med, Torrance, CA 90502 USA. [Eze, Nwando; Smith, Lynne M.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA USA. [LaGasse, Linda L.; Della Grotta, Sheri A.; Dansereau, Lynne M.; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Women & Infants Hosp, Pediat Div,Brown Ctr Study Children Risk, Providence, RI 02912 USA. [Derauf, Chris; Neal, Charles] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Newman, Elana] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Arria, Amelia] Univ Maryland, Ctr Substance Abuse Res, College Pk, MD 20742 USA. [Huestis, Marilyn A.] Natl Inst Drug Abuse, Sect Chem & Drug Metab, Bethesda, MD USA. [Derauf, Chris] Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN USA. RP Smith, LM (reprint author), UCLA, Dept Pediat, David Geffen Sch Med, Los Angeles Biomed Res Inst,Harbor UCLA Med Ctr, 1124 W Carson St,RB-1 Box 446, Torrance, CA 90502 USA. EM smith@labiomed.org OI Arria, Amelia/0000-0002-6360-9265 FU National Institute on Drug Abuse [R01DA014918]; National Institutes of Health/National Center for Advancing Translational Science at the University of California, Los Angeles [CTSI UL1TR000124]; National Center for Research Resources [U54RR026136] FX Supported by the National Institute on Drug Abuse (R01DA014918), the National Institutes of Health/National Center for Advancing Translational Science at the University of California, Los Angeles (CTSI UL1TR000124), and the National Center for Research Resources (U54RR026136). The authors declare no conflicts of interest. NR 29 TC 0 Z9 0 U1 11 U2 19 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2016 VL 170 BP 34 EP + DI 10.1016/j.jpeds.2015.11.070 PG 6 WC Pediatrics SC Pediatrics GA DE7MH UT WOS:000370820500011 PM 26781836 ER PT J AU Chugani, DC Chugani, HT Wiznitzer, M Parikh, S Evans, PA Hansen, RL Nass, R Janisse, JJ Dixon-Thomas, P Behen, M Rothermel, R Parker, JS Kumar, A Muzik, O Edwards, DJ Hirtz, D AF Chugani, Diane C. Chugani, Harry T. Wiznitzer, Max Parikh, Sumit Evans, Patricia A. Hansen, Robin L. Nass, Ruth Janisse, James J. Dixon-Thomas, Pamela Behen, Michael Rothermel, Robert Parker, Jacqueline S. Kumar, Ajay Muzik, Otto Edwards, David J. Hirtz, Deborah CA Autism Ctr Excellence Network TI Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial SO JOURNAL OF PEDIATRICS LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; BRAIN-SEROTONIN SYNTHESIS; BLOOD SEROTONIN; 5-HT1A RECEPTOR; MICROGLIAL ACTIVATION; LOCOMOTOR-ACTIVITY; DORSAL RAPHE; MOUSE; ANXIETY; RAT AB Objectives To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). Study design Children 2-6 years of age with ASD (N=166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. Results There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P=.400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P=.006); the 2.5-mg buspirone group showed significant improvement (P=.003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P=.018) or if they showed normal levels of blood serotonin (P=.044). Adverse events did not differ significantly among treatment groups. Conclusions Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. C1 [Chugani, Diane C.; Chugani, Harry T.; Dixon-Thomas, Pamela; Behen, Michael; Parker, Jacqueline S.; Kumar, Ajay; Muzik, Otto] Wayne State Univ, Sch Med, Carman & Ann Adams Dept Pediat, Detroit, MI USA. [Chugani, Diane C.; Chugani, Harry T.; Behen, Michael; Parker, Jacqueline S.; Kumar, Ajay; Muzik, Otto] Childrens Hosp Michigan, Detroit, MI USA. [Chugani, Harry T.; Kumar, Ajay; Muzik, Otto] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI USA. [Wiznitzer, Max] Rainbow Babies & Childrens Hosp, Univ Hosp Case Med Ctr, Neurosci Inst, 2101 Adelbert Rd, Cleveland, OH 44106 USA. [Parikh, Sumit] Case Western Reserve Univ, Cleveland Clin Neurogenet & Metab, Neurosci Inst, Lerner Coll Med, Cleveland, OH 44106 USA. [Evans, Patricia A.] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Evans, Patricia A.] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Hansen, Robin L.] Univ Calif Davis, Med Invest Neurodeve Disorders MIND Inst, Dept Pediat, Davis, CA 95616 USA. [Nass, Ruth] NYU, Langone Med Ctr, Dept Neurol, New York, NY USA. [Nass, Ruth] NYU, Langone Med Ctr, Dept Child & Adolescent Psychiat, New York, NY USA. [Janisse, James J.] Wayne State Univ, Sch Med, Dept Med & Publ Hlth Sci, Detroit, MI USA. [Rothermel, Robert] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Kumar, Ajay; Muzik, Otto] Wayne State Univ, Sch Med, Dept Radiol, Detroit, MI USA. [Edwards, David J.] Univ Waterloo, Sch Pharm, Waterloo, ON N2L 3G1, Canada. [Hirtz, Deborah] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Chugani, DC (reprint author), Nemours Al DuPont Hosp Children, 1600 Rockland Rd,ARB 291, Wilmington, DE 19803 USA. EM Diane.Chugani@nemours.org FU National Institute of Neurological Disorders and Stroke [5U01 NS61264] FX Supported by the National Institute of Neurological Disorders and Stroke (cooperative agreement 5U01 NS61264). The authors declare no conflicts of interest. NR 63 TC 2 Z9 2 U1 2 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2016 VL 170 BP 45 EP + DI 10.1016/j.jpeds.2015.11.033 PG 13 WC Pediatrics SC Pediatrics GA DE7MH UT WOS:000370820500013 PM 26746121 ER PT J AU Uzark, K Zak, V Shrader, P McCrindle, BW Radojewski, E Varni, JW Daniels, K Handisides, J Hill, KD Lambert, LM Margossian, R Pemberton, VL Lai, WW Atz, AM AF Uzark, Karen Zak, Victor Shrader, Peter McCrindle, Brian W. Radojewski, Elizabeth Varni, James W. Daniels, Kaitlyn Handisides, Jill Hill, Kevin D. Lambert, Linda M. Margossian, Renee Pemberton, Victoria L. Lai, Wyman W. Atz, Andrew M. CA Pediat Heart Network Investigators TI Assessment of Quality of Life in Young Patients with Single Ventricle after the Fontan Operation SO JOURNAL OF PEDIATRICS LA English DT Article ID CONGENITAL HEART-DISEASE; GENERIC CORE SCALES; FUNCTIONAL HEALTH-STATUS; ADULT SURVIVORS; CHILDREN; ADOLESCENTS; VALIDITY; RELIABILITY; FEASIBILITY; EXERCISE AB Objectives To assess self-reported quality of life (QOL) in a large multicenter cohort of adolescent and young adults surviving Fontan. Study design Cross-sectional. The Pediatric Quality of Life Inventory (PedsQL) was administered to 408 survivors of Fontan ages 13-25 years enrolled in the Pediatric Heart Network Fontan Follow-up Study. Subjects also completed either the Child Health Questionnaire (age <19 years) or Short Form Health Survey (age >= 19 years). PedsQL data were compared with matched controls without a chronic health condition. Correlations between the measures were examined. Results Mean PedsQL scores for subjects receiving Fontan were significantly lower than those for the control group for physical and psychosocial QOL (P<.001). Overall, 45% of subjects receiving Fontan had scores in the clinically significant impaired range for physical QOL with 30% in the impaired range for psychosocial QOL. For each 1 year increase in age, the physical functioning score decreased by an average of 0.76 points (P=.004) and the emotional functioning score decreased by an average of 0.64 points (P=.03). Among subjects >= 19 years of age, the physical functioning score decreased by an average of 2 points for each year increase in age (P=.02). PedsQL scale scores were significantly correlated with conceptually related Child Health Questionnaire (P<.001) and Short Form Health Survey scores (P<.001). Conclusions Survivors of Fontan are at risk for significantly impaired QOL which may decline with advancing age. Routine assessment of QOL is essential to inform interventions to improve health outcomes. The PedsQL allowed QOL assessment from pediatrics to young adulthood. C1 [Uzark, Karen] Univ Michigan, Mott Childrens Hosp, L2110 Womens,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. [Zak, Victor; Shrader, Peter] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [McCrindle, Brian W.; Radojewski, Elizabeth] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Varni, James W.] Texas A&M Univ, College Stn, TX USA. [Daniels, Kaitlyn] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Handisides, Jill; Margossian, Renee] Boston Childrens Hosp, Boston, MA USA. [Hill, Kevin D.] Duke Univ, Med Ctr, Durham, NC USA. [Lambert, Linda M.] Primary Childrens Med Ctr, Salt Lake City, UT USA. [Pemberton, Victoria L.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Lai, Wyman W.] Columbia Univ, Med Ctr, New York, NY USA. [Atz, Andrew M.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Uzark, K (reprint author), Univ Michigan, Mott Childrens Hosp, L2110 Womens,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM karenu@med.umich.edu OI Lambert, Linda/0000-0002-4334-700X FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288]; Mapi Research Trust FX Supported by the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288). This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health/National Heart, Lung, and Blood Institute. J.V. holds the copyright and the trademark for the PedsQL and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality of Life Inventory. He